Single locus polymorphism of classical HLA genes

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D. Meyer R. M. Single S. J. Mack A. Lancaster M. P. Nelson H. A. Erlich M. Fernandez-Vin˜a G. Thomson

Authors’ addresses

Diogo Meyer1*, Richard M. Single2*, Steven J. Mack3,4, Alex Lancaster1, Mark P. Nelson1, Henry A. Erlich3,4, Marcelo Fernandez-Vin˜a5,6, Glenys Thomson1 1 Dept. of Integrative Biology, University of California, Berkeley, CA, USA, 2Dept. of Medical Biostatistics, University of Vermont, Burlington, VT, USA, 3Roche Molecular Systems, Alameda, California, USA, 4 Children’s Hospital Oakland Research Institute, Oakland, California, USA, 5Department of Oncology, Georgetown University, Washington DC, USA, 6C.W. Bill Young/DoD Marrow Donor Program, Naval Medical Research Center, Bethesda, MD, USA, *These authors contributed equally to the manuscript.

MS.269

13th IHWS Anthropology/Human Genetic Diversity Joint Report Chapter 4: Single locus polymorphism of classical HLA genes

Introduction to Chapter 4

In the introduction we describe the overall goals and, in Table 1, report on the steps taken to ensure that information in all datasets was analyzed at a common level of resolution. Table 2 summarizes the number of populations with data for each locus. We describe the contents of Tables 3–5 in the methods section. In the results section we provide an overview of the population and regional summaries (Tables 3 and 4, respectively) along with highlights from Tables 4 and 5 of specific high frequency alleles in certain regions. We give an example of the rules used to filter the data in Table 6. In Tables 7 and 8 we summarize any deviations from Hardy-Weinberg Proportions (HWP) and neutrality, respectively. The tables listed below are included as a part of this joint report:

Acknowledgements

We thank Anajane Smith, Leslie Louie, John Hansen, and Steve Marsh for their comments. We are grateful to Peg Boyle for her help with the tables included in this chapter, at the IHWG website under the Anthropology component (www.ihwg.org/ components/diversr.htm), and in the eBook version of HLA 2004. Funding provided by GM35326 and NIH grant AI49213.

HLA 2004: Immunobiology of the Human MHC. Proceedings of the 13th International Histocompatibility Workshop and Congress

Table 1. Allele binning rules. Table 2. Summary of the data available for 10 different geographic regions for HLA-A, C, B, DRB1, DQA1, DQB1, and DPB1. Table 3. Overall summary description of the HLA data generated according to population. Table 3.1. HLA-A Table 3.2. HLA-B Table 3.3. HLA-C Table 3.4. HLA-DRB1 Table 3.5. HLA-DQA1 Table 3.6. HLA-DQB1 Table 3.7. HLA-DPA1 Table 3.8. HLA-DPB1 Table 4. Regional tables Table 4.1. HLA-A Alleles Table 4.2. HLA-B Alleles Table 4.3. HLA-C Alleles

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Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 4.4. HLA-DRB1 Alleles Table 4.5. HLA-DQA1 Alleles Table 4.6. HLA-DQB1 Alleles Table 4.7. HLA-DPB1 Alleles Table 4.8. HLA-DPA1 Alleles Table 5. Summary tables describing HLA alleles found among specific populations from different regions Table 5.1. HLA-A Table 5.2. HLA-B Table 5.3. HLA-C Table 5.4. HLA-DRB1 Table 5.5. HLA-DQA1 Table 5.6. HLA-DQB1 Table 5.7. HLA-DPA1 Table 5.8. HLA-DPB1 Table 6. Example of ‘‘binning rules’’ Table 7. Deviation from HWP Table 8. Deviation from neutrality (F-test) Additional tables are posted at the IHWG website under the Anthropology component (www.ihwg.org/components/diversr.htm), and in the eBook edition of HLA 2004 to be published by PubMed (http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?dbΩBooks).

Introduction

This chapter has five goals. First, we provide a description of the levels of polymorphism of the classical HLA loci surveyed in the Anthropology Component of the 13th International Workshop (13th IHWS). Second, we analyze how polymorphism varies both among loci and populations. Third, we test for deviation of genotype frequencies from Hardy-Weinberg proportions. Fourth, we test the fit of allele frequencies to neutral expectations. Finally, we characterize the extent of interpopulation genetic differentiation at HLA loci. The analytical methods employed are described elsewhere in this volume (10). In order to compare allelic distributions and population genetic results among populations and regions, we analyzed all datasets at a common level of resolution. This required two steps. First, we made a best estimate for allele and genotype calls in the cases where there was ambiguity. Second, we assigned alleles that were not distinguishable from each other (due to heterogeneity in typing methodology) to a single category, a process we call ‘‘binning’’. Two forms of ambiguity were present in the data prior to our analyses: genotypic (cases in which multiple genotype

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HLA 2004: Immunobiology of the Human MHC

calls are compatible with a probe hit pattern), and allelic (cases in which the methodology employed was unable to distinguish variants). The method employed to reduce ambiguity is described in detail in this volume (5). This process results in four or five digit allele calls for each individual. In a subsequent step, implemented via the filter in the PyPop software (4), additional rules were applied to ensure that the sets of alleles for all datasets were directly comparable. Five digit allele names were reduced to common four digit allele names, and any four digit typings ending in ‘‘00’’ were assigned a four digit allele name that exists in the IMGT/HLA database (as described in reference 5). Finally, we binned alleles that were only detectable in a subset of samples (due to the use of a higher resolution typing method) with the variants that were detected using the lower resolution methodology. Table 1 identifies the alleles that were chosen to be binned (‘‘original allele’’), and the name they were assigned for the analyses (‘‘binned allele’’).

Methods

Population samples with fewer than 10 individuals typed at a locus were not included in any of the analyses or tables for that locus. Population genetic analyses were only performed for samples of at least 20 individuals. Three tables are reported for each locus: a summary table, a regional table, and a population table (located in the appendix). The content of these tables is described below. In order to facilitate the discussion of the degree of sharing of alleles among regions, we used a threshold frequency of 0.05 to identify higher frequency alleles in a population sample. We defined an allele that is observed in samples from a particular region, but only with a frequency below the threshold, as being present in that region. We use the term regionally frequent to refer to an allele that was observed with a frequency at or above the threshold of 0.05 in a particular region. When the context is clear, we abbreviate this term as frequent. Thus, for the purpose of this exposition, an allele is classified as being either absent, present, or frequent in a particular region. Summary Table

Tables 3.1 to 3.8 show the statistics that describe the distribution of alleles by region and across all populations. The last column corresponds to all regions combined and is preceded by a separate column for each region. In this table we report sample-size weighted averages over all population samples in each region for the statistics indicated with an asterisk below. Due to the presence of a few very large samples for certain

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 1. Allele binning rules Locus A

Original allele name *2409

Binned allele name *2402

C

*0706

*0701

B

*0706

*0705

DRB1

*1443 *1506

*1405 *1501

DQA1

*0104 *0302 *0303 *0502

*0101 *0301 *0301 *0501

Locus DQB1

Original allele name *0202 *0309 *0609 *0611

Binned allele name *0201 *0301 *0605 *0602

DPB1

*2301 *3901 *4801 *4901 *5101 *6201 *7601

*0401 *0401 *0201 *0402 *0402 *4001 *1401

Table 2. Summary of the data available for 10 different geographic regions for HLA-A, C, B, DRB1, DQA1, DQB1, and DPB1. Region Subsaharan Africa (SSA) North Africa (NAF) Europe (EUR) Southwest Asia (SWA) Southeast Asia (SEA) Oceania (OCE) Australia (AUS) Northeast Asia (NEA) North America (NAM) South America (SAM)

Total no. of Populations 11 5 8 8 24 9 4 5 8 5

No. of Populations with data for each HLA Locus A C B DRB1 10 9 10 4 2 0 2 5 7 5 7 4 7 5 7 2 22 19 22 18 8 4 5 6 4 4 4 2 5 3 3 2 5 3 5 6 3 3 3 4

loci, the following procedure was used to modify the weights. If the maximum sample size in a region was more than 1.5 times the next largest in that region, the weight used for the largest population was 1.5 times that of the next largest. In this way, the large samples maintain a proportionally larger contribution to the weighted mean without overwhelming the contribution of the smaller samples. For example, in European populations typed at the DRB1 locus, the Irish population has a sample size of 1,000. The next largest population in this region has a sample size of 103. So, the adjusted weight assigned to the Irish population sample is 1.5*103Ω154.5. The statistics reported in Tables 3.1–3.8 are the following: O Number of population samples typed O Expected heterozygosity (gene diversity)* O Locus-level Fst* (defined in the chapter ‘‘Statistical Methods for Analysis of Population Genetic Data’’) O Number of different alleles (k) per region O Range of values for all populations in that region: The minimum and maximum values of k for population samples in the region are reported.

DQA1 3 2 2 1 0 4 2 0 6 4

DQB1 4 3 3 1 3 6 2 0 6 4

DPB1 3 0 3 0 1 5 2 0 4 2

O Number of different alleles needed to reach a frequency of 0.5*: The minimum number of different alleles necessary to account for 50% of the allele frequency. Small values correspond to samples where a few alleles are observed at high frequencies; high values correspond to cases where allele frequencies are more even, with several alleles at similar frequencies. O Number of regionally frequent alleles: Alleles with a frequency of 0.05 or more in at least one population sample. O Regionally frequent alleles that are frequent in only one region: For each region, this specifies how many of the frequent alleles have a frequency at or above the threshold exclusively in that region. O Regionally frequent alleles observed in only one region: For each region, this specifies how many of the frequent alleles are exclusive to that region, regardless of their frequency. For the number of population samples typed and frequent alleles present and/or frequent in only one region, the value for the ‘‘All Regions’’ category is the sum of the values across all regions. This is not the case for the number of different alleles HLA 2004: Immunobiology of the Human MHC

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Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 3. Overall summary description of the HLA data. i) A frequent allele is defined as one that exists with a frequency of at least 0.05 in at least one population. ii) For a complete description of the statistics reported in the table, see the ‘‘Summary Table’’ subsection of the ‘‘Methods’’ section. Table 3.1. HLA-A Region SSA No. of populations typed 10 Expected heterozygosity 0.93 Locus-level Fst 0.02 No. of different alleles (k) per 63 region Range of values for k per (20–39) population No. needed to reach a 5.69 frequency of 0.5 No. of frequent alleles 15 Frequent alleles frequent in 4 only one region Frequent alleles present in 0 only one region

NAF 2 0.92 0.01 28

EUR 7 0.86 0.01 43

SWA 7 0.91 0.03 57

SEA 22 0.77 0.08 43

OCE 8 0.71 0.11 27

AUS 4 0.72 0.04 12

NEA 5 0.87 0.02 67

NAM 5 0.72 0.11 32

SAM 3 0.69 0.21 16

Total 73 0.82 0.1 108

(21–27)

(15–28)

(16–41)

(5–34)

(4–18)

(6–10)

(11–42)

(4–29)

(5–12)

(4–42)

3.04

4.52

2.44

2.31

1.9

3.24

1.96

1.75

5

3.33

9 1

10 0

16 3

11 1

13 1

5 0

11 1

7 0

8 3

36 14

0

0

0

0

0

0

1

0

0

1

Table 3.2. HLA-B Region SSA No. of populations typed 10 Expected heterozygosity 0.94 Locus-level Fst 0.01 No. of different alleles (k) per 107 region Range of values for k per (30–50) population No. needed to reach a 7.2 frequency of 0.5 No. of frequent alleles 18 Frequent alleles frequent in 8 only one region Frequent alleles present in 0 only one region

NAF 2 0.95 0.01 48

EUR 7 0.93 0.02 81

SWA 7 0.94 0.03 83

SEA 22 0.89 0.05 94

OCE 5 0.9 0.07 59

AUS 4 0.83 0.04 27

NEA 3 0.94 0.02 63

NAM 5 0.88 0.05 66

SAM 3 0.87 0.1 42

Total 68 0.91 0.06 196

(34–40)

(25–49)

(23–51)

(7–66)

(14–35)

(7–21)

(20–52)

(10–55)

(10–32)

(7–66)

4.76

4.35

2.9

7.31

4.17

4.25

8.5

5.49

6.9

5.59

8 1

15 2

21 5

21 1

19 3

7 0

14 1

13 3

12 7

67 31

0

0

0

0

1

0

0

0

3

4

Table 3.3. HLA-C Region SSA No. of populations typed 9 Expected heterozygosity 0.9 Locus-level Fst 0.02 No. of different alleles (k) per 35 region Range of values for k per (12–25) population No. needed to reach a 4.06 frequency of 0.5 No. of frequent alleles 12 Frequent alleles frequent in 1 only one region Frequent alleles present in 0 only one region

NAF 0

EUR 5 0.9 0.01 28

SWA 5 0.92 0.03 46

SEA 19 0.84 0.05 32

OCE 4 0.85 0.05 27

AUS 4 0.81 0.02 16

NEA 3 0.9 0.02 28

NAM 3 0.85 0.08 24

SAM 3 0.76 0.06 10

Total 55 0.87 0.07 56

(17–24)

(18–37)

(7–24)

(10–19)

(5–15)

(12–25)

(7–22)

(6–8)

(5–37)

4.28

4.75

3.06

3.22

2.28

4.56

3.62

2.32

3.69

12 1

17 4

12 1

11 0

7 0

10 0

10 1

6 1

29 9

0

0

0

0

0

0

1

0

1

Table 3.4. HLA-DRB1 Region SSA No. of populations typed 4 Expected heterozygosity 0.91 Locus-level Fst 0.03 No. of different alleles (k) per 57 region Range of values for k per (19–48) population No. needed to reach a 4.76 frequency of 0.5 No. of frequent alleles 14 Frequent alleles frequent in 4 only one region Frequent alleles present in 0 only one region

4

NAF 5 0.91 0.01 39

EUR 4 0.9 0.02 39

SWA 2 0.93 0.03 37

SEA 18 0.85 0.07 34

OCE 6 0.74 0.14 28

AUS 2 0.84 0.05 24

NEA 2 0.94 0.01 45

NAM 6 0.78 0.16 33

SAM 4 0.8 0.07 26

Total 53 0.86 0.11 96

(21–32)

(18–33)

(22–35)

(8–25)

(5–21)

(12–22)

(27–41)

(6–24)

(9–18)

(5–48)

4.78

4.11

3.26

2.02

6.49

2.44

2.23

3.84

5.8

3

11 1

10 1

12 2

15 1

12 1

7 2

12 1

12 1

9 1

43 15

0

0

0

0

0

1

0

0

1

2

HLA 2004: Immunobiology of the Human MHC

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 3.5. HLA-DQA1 Region SSA No. of populations typed 3 Expected heterozygosity 0.79 Locus-level Fst 0.01 No. of different alleles (k) per 7 region Range of values for k per pop- (7–7) ulation No. needed to reach a fre- 2 quency of 0.5 No. of frequent alleles 7 Frequent alleles frequent in 0 only one region Frequent alleles present in 0 only one region

NAF 2 0.81 0.01 8

EUR 2 0.81 0.01 8

SWA 1 0.8 NA 8

(7–8)

(8–8)

2.49

SEA 0

OCE 4 0.69 0.04 7

AUS 2 0.77 0.03 7

(8–8)

(6–7)

2.51

3

6 0

6 0

0

NEA 0

NAM 6 0.53 0.18 7

SAM 4 0.59 0.09 6

Total 24 0.7 0.14 8

(5–7)

(4–7)

(3–5)

(3–8)

1.65

2

1.31

1.43

1.96

6 0

7 1

5 0

4 0

4 0

8 1

0

0

0

0

0

0

0

NAF 3 0.82 0.01 19

EUR 3 0.87 0.02 16

SWA 1 0.87 NA 17

SEA 3 0.78 0.1 15

OCE 6 0.76 0.12 14

AUS 2 0.76 0.07 12

NAM 6 0.54 0.26 12

SAM 4 0.6 0.09 6

Total 32 0.75 0.15 23

(13–17)

(10–14)

(17–17)

(12–14)

(9–13)

(6–12)

(4–10)

(3–6)

(3–17)

Table 3.6. HLA-DQB1 Region SSA No. of populations typed 4 Expected heterozygosity 0.84 Locus-level Fst 0.01 No. of different alleles (k) per 17 region Range of values for k per pop- (9–15) ulation No. needed to reach a fre- 3 quency of 0.5 No. of frequent alleles 8 Frequent alleles frequent in 1 only one region Frequent alleles present in 0 only one region

NEA 0

2.33

3

3

2.23

2.2

2

1.27

1.2

2.25

7 0

9 0

7 0

8 0

9 0

5 0

6 0

5 0

14 1

0

0

0

0

0

0

0

0

0

NAF 0

EUR 1 0.23 NA 4

SEA 0

OCE 5 0.5 0.22 5

AUS 0

Table 3.7. HLA-DPA1 Region SSA No. of populations typed 1 Expected heterozygosity 0.75 Locus-level Fst NA No. of different alleles (k) per 7 region Range of values for k per pop- (7–7) ulation No. needed to reach a fre- 2 quency of 0.5 No. of frequent alleles 4 Frequent alleles frequent in 1 only one region Frequent alleles present in 1 only one region

SWA 0

NEA 0

NAM 2 0.15 0.05 4

SAM 1 0.44 NA 3

Total 10 0.47 0.28 8

(4–4)

(4–5)

(3–3)

(3–3)

(3–7)

1

1

1

1

1.19

2 0

3 0

2 0

3 0

4 1

0

0

0

0

1

NAM 4 0.74

SAM 2

Total 20

Table 3.8. HLA-DPB1 Region SSA No. of populations typed 3 Expected heterozygosity 0.83 Locus-level Fst 0.01 NA 0.13 No. of different alleles (k) per 37 region Range of values for k per pop- (14–29) ulation No. needed to reach a fre- 2.31 quency of 0.5 No. of frequent alleles 8 Frequent alleles frequent in 2 only one region Frequent alleles present in 1 only one region

NAF 0

EUR 3 0.75 0.01

SWA 0

SEA 1 0.74

OCE 5 0.63

AUS 2 0.66

0.05 20

0.07 19

0.15 19

10

11

10

47

(9–17)

(19–19)

(6–13)

(5–10)

(4–9)

(7–8)

(4–29) 1.96

0.05

0

NEA 0 0.61

2

3

2

1.6

1.46

1.47

6 0

5 1

8 1

4 1

4 0

6 2

0

0

0

1

0

0

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14 7

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Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 4. Regional tables 1) A frequent allele is defined as one that exists with a frequency of at least .05 in at least one population. 2) An asterisk (*) next to a frequency indicates that the allele was found in only one population in that region. 3) A blank indicates that the allele was not found in any population in the region. Table 4.1. HLA-A Alleles Maximum Frequency in each region for frequent Alleles

Allele *0101 *0201 *0202 *0203 *0204 *0205 *0206 *0207 *0211 *0217 *0222 *0301 *0302 *1101 *1102 *2301 *2402 *2403 *2407 *2410 *2601 *2603 *2901 *2902 *3001 *3002 *3101 *3201 *3301 *3303 *3401 *3601 *6601 *6801 *6802 *7401

Number of population samples per region 10 2 7 7 SSA NAF EUR SWA 0.118 0.146 0.202 0.171 0.184 0.179 0.344 0.206 0.091 *0.007 0.01 0.02 *0.002 *0.010 *0.007 0.087 *0.015 0.024 0.05 0.012 0.005 0.03 *0.007 *0.007 0.13 0.004 0.007 *0.009 0.013 0.098 0.045 0.25 0.098 *0.003 *0.042 0.014 0.083 0.043 0.042 0.08 0.235 *0.004 0.228 0.083 0.08 0.067 0.043 0.062 0.171 0.16 *0.006 0.007 0.06 0.011 0.043 0.021 0.108 0.141 0.233 0.035 0.026 0.027 0.094 0.007 0.07 0.068 0.07 0.116 0.094

0.03

0.053

0.117

0.067 0.075 0.09 0.022 0.037 0.056 *0.015

0.011 0.065 0.014 0.043 0.05 0.057 0.036 0.013

0.067 0.02 0.03 0.042 0.131 0.105 0.013 0.07

0.021 0.042 0.052 0.014

0.024 0.048 0.029

0.004 0.009 0.08 0.017 *0.004

22 SEA 0.032 0.191 *0.002 0.133

8 OCE 0.07 0.3 0.09

*0.001 0.12 0.131 0.012

0.13 0.016 *0.020

*0.005 0.016

0.02

0.044

0.437 0.05

0.24

0.783 *0.011 0.22 0.05 0.06

0.298

0.4 0.128 0.006 0.863 0.006 0.157 0.041 0.218 0.027 *0.004 0.031 0.003 0.028 0.009 0.006 0.133 0.219 0.001 0.006 *0.004 0.005

0.082 0.02

0.029 0.019

0.09 0.167 *0.009 *0.010 *0.020

*0.005 0.681

Regional Table

5 NEA 0.114 0.165 0.008 0.014 0.032 0.183 0.048 *0.005 0.004 *0.007 0.069 0.007 0.105 0.029 0.343 *0.005 *0.004 0.124 0.086 0.004 *0.004 0.05

*0.005

or number of frequent alleles, due to the sharing of alleles across regions. The averages reported in the ‘‘All Regions’’ category for the previously mentioned statistics were computed as sample size weighted averages across all samples that met the inclusion criteria, not by region. Similarly, the locuslevel Fst for the ‘‘All Regions’’ category was computed over all samples and is not an average of the regional values.

*0.005

0.105 0.021 0.046 0.132 0.004 0.018

5 NAM 0.086 0.546 *0.006

3 SAM *0.011 0.308 0.171

*0.006 0.165 0.058 *0.080 *0.091 0.072 0.002 0.025

*0.010

*0.018 0.581 0.02 *0.002

0.602 0.038

0.023 0.021 0.019 *0.014 0.268 *0.016 *0.002 *0.006

0.212 0.03 *0.002

0.468 *0.010

0.105

No. Regions Frequent 8 10 1 2 1 2 4 1 2 1 1 5 1 6 2 4 9 1 2 1 5 1 1 3 3 2 6 2 1 5 3 1 1 4 2 1

No. Regions Present 10 10 6 5 3 7 7 4 6 5 4 9 7 9 3 7 10 8 4 3 8 1 5 8 7 6 10 10 7 9 4 3 7 10 6 5

Alleles that were observed in only one population sample in that region are marked with an asterisk, in order to highlight regionally frequent alleles that were not shared within the region. This table facilitates the identification of specific alleles responsible for the patterns seen in the summary table. The number of alleles listed is equal to the total number of regionally frequent alleles indicated in the summary table. Population Table

Regional detail is provided in Tables 4.1–4.8. These tables allow an assessment of the degree of sharing of specific alleles found at or above the threshold frequency of 0.05 in at least one population sample (regionally frequent alleles). The statistic reported in the tables is the maximum frequency for that allele in samples from the region. While other statistics could have been used for these tables (mean, median, etc.), we chose the maximum to highlight the sharing (and absence from some regions) of specific high frequency alleles.

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4 AUS 0.053 0.175

HLA 2004: Immunobiology of the Human MHC

Population level information is provided in Tables 5.1–5.8. These tables describe the distribution of all alleles at the individual population level for each locus. For each population sample in a given region, every allele found in at least one population sample from that region is listed along with its frequency. The tables also contain the sample size and expected heterozygosity for each population.

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 4.2. HLA-B Alleles Maximum Frequency in each region for frequent Alleles

Allele *0702 *0705 *0801 *1301 *1302 *1402 *1404 *1501 *1502 *1503 *1504 *1506 *1510 *1513 *1521 *1522 *1525 *1535 *1801 *2703 *2704 *2705 *3501 *3503 *3505 *3508 *3511 *3701 *3801 *3802 *3901 *3905 *3906 *3909 *4001 *4002 *4004 *4005 *4006 *4101 *4102 *4201 *4402 *4403 *4410 *4501 *4601 *4801 *4803 *4901 *5001 *5101 *5102 *5104 *5201 *5301 *5401 *5502 *5601 *5602 *5701 *5703 *5801 *5802 *5901 *7801 *8101

Number of population samples per region 10 2 7 7 SSA NAF EUR SWA 0.082 0.037 0.172 0.065 0.027 0.015 0.005 0.069 0.067 0.088 0.162 0.112 0.011 0.061 0.028 *0.022 0.066 0.034 0.043 0.037 0.057 0.028 *0.002 *0.050 0.025 0.122 *0.008 *0.002 *0.031 0.1 0.015 0.014 0.046 0.087

*0.015

22 SEA 0.024 0.061 0.011 0.28 0.02 *0.006

5 OCE 0.02 0.031

4 AUS *0.045

0.06 *0.010 *0.005

0.06 0.18 0.009

0.031 0.22 *0.010

*0.008 *0.007

*0.003

0.147

*0.015

0.069 0.04

0.133 0.059

0.014

0.4

0.073 0.069 0.07

0.035 0.27

3 NEA 0.072 0.003 *0.008 0.01 0.045

5 NAM 0.068 *0.002 0.045

0.13 *0.005 *0.003

0.083 *0.002 *0.004

0.005

*0.009 *0.021 *0.011 0.114 *0.003 0.198

*0.006 *0.004

0.135

*0.006

0.159

0.064 0.025

0.051 *0.007

0.113

0.085

0.099

0.012 0.127 *0.006

*0.022 0.044 *0.015

0.018 0.071 0.091

*0.006

*0.022

0.007 0.061 0.117 0.111 0.007 0.019

0.109 *0.015 0.035 0.01 0.069 0.002

0.011 0.006

*0.007 0.015

0.016 *0.003 *0.004

0.058 0.087 0.069

*0.022 *0.007 *0.007

0.024 0.067 *0.002 0.028 *0.014 0.014

0.023 0.016

*0.015 0.015

0.094 0.027

0.018 0.05

*0.004 *0.003 0.031 0.023 0.148 0.034 0.085 0.074 0.093

*0.007 *0.022 0.066 *0.029 0.088 0.125

0.017 0.021 *0.003 0.13 0.064

0.143 0.055 0.009 0.012 0.086 0.106

0.046 0.016 0.057 0.005 *0.004 0.083 0.159

3 SAM *0.028

0.066

0.01

0.012

0.051 0.088 0.044

0.05 0.028 0.162 *0.007

0.034 0.085 0.175

0.015 0.015

0.014 0.021 *0.010 0.017

0.031 0.057 0.1 0.124

0.022 0.015 0.037 *0.007

0.069 0.062

*0.015

0.042 0.003 0.029

*0.003

*0.002

*0.010

*0.011

0.019 *0.109

*0.005 *0.005 *0.005

*0.003 0.052 0.159 0.011

0.033 0.016 0.031 0.085 0.02 0.021 0.128 0.04

*0.020

0.014 0.354 0.23

0.29 0.14

*0.001 0.04

*0.082

0.017

0.005 0.12 0.034 0.017 0.102 0.028 0.072 *0.008

*0.003 0.008 0.064 *0.001 0.004 0.172 0.26 0.016 0.002 0.084 0.04 0.006 0.03

0.006 0.037

0.035

0.039 *0.008 *0.012 0.077

0.184 0.276

0.058 0.097

0.039 0.296

0.058

0.146 *0.004 *0.006 *0.006

0.02

0.025 *0.007

0.047 0.068

0.041 0.034

*0.005

0.062 0.047

*0.007 *0.007

*0.017 0.125 *0.008

0.158 0.045 0.073

0.027 *0.005

0.052 0.146 0.204 0.006 0.02

0.355 0.189 0.015

0.109

0.069

*0.010

0.168 *0.006 0.011 0.004 0.121 0.135

0.031 *0.022 0.106 0.025 0.008

0.006 0.085 *0.009

0.033

*0.017

0.067

*0.011 *0.002

0.062 *0.012

0.027

0.019 *0.009 0.142 0.011 0.059

0.049 0.111 0.239 0.083 *0.009 *0.398 0.104 *0.003

*0.015 0.021 0.1 *0.060

0.02 *0.020 0.01 0.12 0.213 0.233 0.02

0.005 *0.008 *0.012

0.115 0.485 *0.006 *0.002

0.033

0.021 *0.007 *0.001

*0.002 0.027

0.008 0.012 0.11 0.549 0.003

0.08

*0.009

0.057 0.066 0.034

No. Regions Frequent 5 2 4 4 1 1 1 5 2 1 1 1 1 2 2 1 3 1 6 1 1 3 5 2 3 1 1 1 2 2 3 1 2 1 5 7 1 1 3 1 1 1 3 6 1 2 2 3 1 2 2 7 1 1 2 2 2 2 3 2 1 1 5 1 1 1 1

HLA 2004: Immunobiology of the Human MHC

No. Regions Present 10 8 8 7 8 7 2 9 7 9 1 3 4 3 3 2 6 1 9 3 4 8 10 10 4 7 1 8 9 4 10 6 6 2 10 10 1 4 7 5 5 5 8 9 2 6 4 8 3 5 8 10 6 4 9 7 3 5 8 3 9 4 9 4 2 4 3

7

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 4.3. HLA-C Alleles Maximum Frequency in each region for frequent Alleles Number of population samples per region 9 5 5 19 Allele *0102 *0202 *0302 *0303 *0304 *0401 *0403 *0407 *0501 *0602 *0701 *0702 *0703 *0704 *0801 *0802 *0806 *1202 *1203 *1402 *1403 *1502 *1503 *1505 *1507 *1601 *1604 *1701 *1801

SSA 0.025 0.158 0.046 0.037 0.089 0.213 0.061 0.04 0.217 0.179 0.089

EUR 0.072 0.056 0.005 0.122 0.111 0.22 *0.002 *0.011 0.127 0.162 0.187 0.186

0.065 0.036 0.067

0.048 0.005 0.057

SWA 0.069 0.09 0.045 0.042 0.016 0.225 0.031 0.054 0.032 0.177 0.135 0.094 *0.018 0.031 0.042 0.074

SEA 0.219 *0.004 0.109 0.157 0.52 0.209 0.4 *0.005 0.007 0.032 0.075 0.667 *0.112 0.084 0.3 0.002

0.009 0.037 0.02 0.005 0.012 *0.003 0.014

0.012 0.089 0.047 0.014 0.028

0.104 0.075 0.08 0.052 0.155

0.109 0.019 0.047 0.027 0.05

0.005

0.283 *0.004 0.184 0.1

0.05 0.005 0.029

0.05 0.098 0.032 0.065 0.055 *0.005

0.027 *0.027 *0.010

4

4

3

3

3

OCE 0.24

AUS 0.375 *0.006 *0.006 0.151 0.022 0.275 0.157

NAM 0.089 0.238 *0.002 0.044 0.389 0.317

SAM *0.212

*0.008 0.244 *0.016 *0.101 *0.004 0.026 *0.018

0.05 0.04 0.33

0.034 0.028 0.034 0.096

NEA 0.205 0.011 0.055 0.219 0.119 0.115 *0.009 *0.003 0.029 0.115 0.025 0.138

0.08 0.31 0.01

0.007 *0.006 *0.007

0.02 0.1 *0.008

0.04 0.02 0.016

*0.051

0.064 0.05 0.21 0.13 0.08 *0.020

0.09 *0.010 *0.010 *0.040 *0.005 *0.020

0.286

0.04 0.023 0.105 0.042 0.069 0.003 *0.002

0.036 0.065 0.079 0.232

0.069

0.192 0.409 0.185

*0.010 0.364 *0.010

0.045 0.173

*0.002 *0.015 0.024

*0.006

*0.002 *0.001

*0.016

No. Regions Frequent 8 4 3 6 7 9 3 2 1 6 5 9 1 3 4 3 1 2 3 2 1 5 1 1 1 2 1 2 1

No. Regions Present 9 7 8 9 9 9 6 6 7 9 8 9 2 8 9 8 1 7 8 7 5 9 3 7 5 6 5 5 3

Table 4.4. HLA-DRB1 Alleles Maximum Frequency in each region for frequent Alleles Allele *0101 *0102 *0301 *0302 *0401 *0402 *0403 *0404 *0405 *0406 *0407 *0411 *0412 *0701 *0801 *0802 *0803 *0804 *0806 *0807 *0901 *1001 *1101 *1102 *1104 *1201 *1202 *1301 *1302 *1303 *1401 *1402 *1404 *1405 *1406 *1407 *1408 *1409 *1501 *1502 *1503 *1601 *1602

8

Number of population 4 5 SSA NAF 0.023 0.022 0.079 0.066 0.083 0.202 0.193 0.011 0.023 *0.010 *0.002 0.081 *0.002 0.035 0.006 0.016 0.022 0.061 0.04

samples per region 4 2 EUR SWA 0.128 0.047 *0.008 *0.010 0.16 0.151 *0.005 0.161 *0.020 0.015 *0.024 0.005 0.06 0.047 0.02 0.005 0.032 *0.000 0.018 *0.010

18 SEA 0.009

6 OCE *0.011

2 AUS *0.010

2 NEA 0.078

0.126

0.048

*0.045

0.053

6 NAM 0.02 *0.005 0.031

*0.005

0.053

0.232

*0.010 *0.015 0.086

0.025 0.01 0.08 *0.058 *0.008

0.167 0.125

0.091 0.02 *0.027

*0.012 0.47 0.574

0.227 0.316

0.047 0.016 0.438

0.055 *0.010 0.108

*0.002

0.038

0.079

0.224 0.097

*0.005

0.121 0.034 0.04

0.107

*0.009

0.031 *0.004

0.028

0.037 *0.005 0.015

*0.005 0.069 0.03 0.058 0.075

*0.036

*0.045 0.255

0.029

0.005 *0.010 *0.005 0.067

0.134 0.388 0.168 0.027

0.04 0.132 0.018 *0.012

0.08

0.214 0.027

0.011 *0.006 0.236 *0.076

0.005 0.016 0.01

0.017 0.037 0.216 0.076 0.007 0.052 0.007 0.087 0.145 0.076 0.017 *0.006

0.02 0.045 0.092 0.051 0.035 0.01 0.038 0.111 0.051 0.02 *0.015

0.17 0.078 0.005 0.005 0.005 *0.001

0.088 0.012 *0.012 0.018

0.007 0.017 0.07 0.005 0.06 0.044 *0.005 0.194 0.045 0.034 0.04

0.018 0.147 0.102 *0.014 *0.065 0.018 0.014 0.138 0.049 *0.020 0.051 0.071 0.05

0.01 *0.002 0.062 0.17 0.022

0.126 0.066 0.015 0.025 *0.010

*0.002 0.005 *0.005 0.182 0.019 0.11 *0.005

0.069 0.087 *0.006 *0.059

0.083

0.075 *0.005

0.017 0.284

0.063

0.176 0.044 0.27

0.043

0.009 0.059 0.324 0.02 0.036 *0.015 0.34 *0.013 0.037 0.127

*0.006 0.052 0.29 0.006 *0.027 *0.005 0.08 0.338 0.03 0.011

*0.005

*0.138 0.092

0.12 0.21

0.276 0.476

0.3

0.015 *0.110 *0.040 0.354

0.556

0.269

HLA 2004: Immunobiology of the Human MHC

0.103 *0.016 0.04 0.068 *0.013 *0.003

4 SAM *0.019 *0.009 0.009 *0.009

*0.009

*0.005

0.101 *0.220 *0.045 0.134 0.012

0.035 *0.005 0.003 *0.003

0.09

0.122 0.033

0.031

*0.011 0.013

*0.005 *0.005 0.19

*0.009

0.351

No. Regions Frequent 2 2 6 1 3 1 4 2 5 1 2 2 1 8 1 2 4 1 1 1 4 1 7 2 2 4 2 4 3 2 4 3 1 1 1 1 2 1 7 5 1 2 4

No. Regions Present 10 6 10 4 7 4 10 9 9 6 5 4 1 10 7 7 8 6 4 1 9 7 9 4 9 9 7 10 8 8 9 6 4 3 5 4 4 2 9 7 4 5 9

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 4.5. HLA-DQA1 Alleles Maximum Frequency in each region for frequent Alleles

Allele *0101 *0102 *0103 *0201 *0301 *0401 *0501 *0601

Number of population samples per region 3 2 2 1 SSA NAF EUR SWA 0.196 0.117 0.165 *0.147 0.343 0.208 0.265 *0.165 0.084 0.057 0.11 *0.090 0.084 0.214 0.176 *0.088 0.09 0.177 0.115 *0.149 0.202 0.042 0.048 *0.024 0.282 0.301 0.28 *0.329 *0.005 0.005 *0.008

4 OCE 0.326 0.554 0.065 0.065 0.174

2 AUS 0.167 0.146 0.359 *0.040 0.202

6 NAM 0.129 *0.047 0.009 0.047 0.79 0.425 0.58

4 SAM *0.028

0.146 0.109

0.305 *0.005

3 SEA 0.11 0.37 0.045 0.17 0.05

6 OCE 0.076 0.582 0.037 0.053 0.115 0.044 0.221 0.413 0.352 0.26 0.242 0.005 *0.005 *0.021

2 AUS *0.071 0.091 *0.045 *0.015 *0.020 0.439 *0.030 0.024 0.217 0.313 *0.040 0.02

6 NAM 0.074 0.62 0.778 0.078 *0.012 0.425 0.026

4 NAM 0.018 0.171 0.134 0.36 0.62 0.038

2 SAM 0.018 *0.071 0.1 0.163 0.691

0.021

0.184

*0.036 0.055 0.459 0.265 0.66

No. Regions Frequent 7 6 6 6 8 3 8 1

No. Regions Present 8 7 8 8 8 6 8 5

Table 4.6. HLA-DQB1 Alleles Maximum Frequency in each region for frequent Alleles

Allele *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 *0605

Number of population 4 3 SSA NAF 0.172 0.398 0.221 0.187 0.029 0.112 0.009 0.015 *0.005 0.005 0.207 0.068 0.227 0.12 0.011 0.04 0.009 0.03 0.04 0.247 0.115 0.052 0.035 0.107 0.068 0.057 0.031

samples per region 3 1 EUR SWA 0.203 *0.163 0.208 *0.257 0.257 *0.126 0.057 *0.018 *0.014 0.071 *0.016 0.125 *0.084 0.135 *0.061 0.038 *0.055 *0.024 *0.041 0.186 *0.067 0.094 *0.039 0.024 *0.037 *0.030 *0.014

0.115 0.482 0.045 0.1 0.055 0.01 *0.012 0.025

4 SAM 0.064 0.651 0.409 0.097 0.286 *0.028

0.068 0.032 *0.004 *0.005

No. Regions Frequent 9 9 5 5 2 6 6 4 4 3 6 2 2 1

No. Regions Present 9 9 9 9 7 8 9 7 8 6 8 8 6 7

Table 4.7. HLA-DPB1 Alleles Maximum Frequency in each region for frequent Alleles

Allele *0101 *0201 *0301 *0401 *0402 *0501 *1301 *1401 *1701 *1801 *2201 *2801 *3101 *3501

Number of population 3 3 SSA EUR 0.358 0.083 0.126 0.172 0.069 0.15 0.104 0.49 0.24 0.172 *0.011 0.05 0.075 0.02 0.02 0.02 0.061 0.034 0.099 *0.004

samples per region 1 5 SEA OCE *0.029 0.436 *0.029 0.347 *0.077 0.059 *0.173 0.375 *0.038 0.076 *0.240 0.436 *0.135 0.215 *0.038 0.045 *0.010 *0.106

*0.004 *0.012

*0.005 0.011 0.087

2 AUS *0.010 0.156 *0.031 0.105 0.684 *0.010

0.198 *0.051

No. Regions Frequent 3 6 6 7 5 4 3 1 1 1 1 1 1 1

No. Regions Present 7 7 7 7 6 6 5 6 3 1 3 2 2 2

Table 4.8. HLA-DPA1 Alleles Maximum Frequency in each region for frequent Alleles

Allele *0103 *0201 *0202 *0301

Number of population samples per region 1 1 5 2 SSA EUR OCE NAM *0.349 *0.870 0.776 0.954 *0.198 *0.115 0.209 0.12 *0.209 *0.010 0.708 *0.015 *0.217

1 SAM *0.717 *0.206 *0.076

No. Regions Frequent 5 5 3 1

Results Effects of ambiguity reduction and filtering

The binning/filtering steps were applied to the data prior to the analyses (see Introduction). Table 6 provides an example of the

No. Regions Present 5 5 5 1

transformations that were carried out at DRB1 in the four SSA population samples. In the Doggon sample two 5 digit alleles (*11011 and *11012) were reported; these were collapsed to *1101 since for many population samples these alleles could not be distinguished. In the Rwandan sample *1100 alleles are HLA 2004: Immunobiology of the Human MHC

9

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5. Summary tables describing HLA alleles found among specific populations from different regions i) These tables list the set of all alleles found among populations from the region. ii) A blank indicates that the allele was not found in that population. Table 5.1. HLA-A Table 5.1a. HLA-A alleles found in Sub-Saharan Africa (SSA) Population

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0202 *0204 *0205 *0206 *0210 *0214 *0217 *0224 *0225 *0226 *0234 *0236 *0301 *0302 *1101 *2301 *2303 *2305 *2402 *2403 *2406 *2413 *2423 *2501 *2601 *2605 *2608 *2609 *2612 *2901 *2902 *2903 *3001 *3002 *3004 *3008 *3101 *3103 *3104 *3201 *3202 *3203 *3301 *3303 *3401 *3402 *3601 *4301 *6601 *6602 *6603 *6801 *6802 *6804 *6901 *7401 *7403 *8001

10

Doggon 276 21 0.893 0.007 0.011 0.083 0.076 0.022

Kenyan 142 286 39

Kenyan Highlander 482 28

Kenyan Lowlander 530 30

Mandenka 186 25

North America (Af) 510 28

0.941 0.031

0.927 0.118 0.027 0.017 0.118 0.066

0.94 0.074 0.004

0.916 0.027 0.016

0.115 0.03

0.087

0.028

0.007 0.087 0.049 0.007 0.014

Shona 450 30

Ugandan 326 34

Zambian 86 20

Zulu 372 28

0.938 0.055 0.006

0.918 0.004

0.888 0.035

0.936 0.035

0.081 0.091

0.124 0.033

0.091 0.036

0.932 0.083 0.003 *0106 0.184 0.034

0.128 0.023

0.004 0.04 0.032

0.011 0.005

0.029

0.031

0.021 0.003

0.012

0.046

0.006

0.012

0.055 0.003 0.043 0.067

0.058

0.051

0.081 0.003

0.097

0.005 0.004

0.008

0.013

0.004

0.002 0.004 0.004

0.043

0.004 0.007 0.004 0.052

0.031

0.036

0.038

0.098

0.04

0.228

0.045

0.071

0.089

0.177

0.024 0.11

0.127

0.007 0.021

0.01

0.006

0.005

0.027

0.004

0.008

0.006

0.043

0.002 0.024

0.016

0.043 0.006

0.024

0.004 0.004 0.017 0.012 0.018

0.012

0.016

0.011 0.108

0.004 0.006

0.033 0.141 0.04

0.004 0.004 0.021 0.049 0.007 0.084 0.073 0.004

0.01 0.05

0.002 0.011 0.053

0.048 0.037 0.004

0.064 0.058 0.013

0.004 0.006

0.013 0.008

0.019

0.026

0.011

0.016

0.007 0.004 0.007 0.028 0.07

0.002 0.002

0.013 0.009

0.027 0.081

0.02 0.039

0.05 0.012

0.026 0.03

0.022

0.041 0.031

0.017

0.05 0.004

0.068 0.009

0.005

0.02 0.012

0.004 0.007 0.018 0.094 0.036

0.024 0.01

0.038

0.039

0.004 0.096

0.006 0.031

0.058

0.038 0.124

0.051 0.049 0.002

0.091 0.147 0.011

0.031 0.04

0.14 0.233

0.025

0.035

0.005 0.005

0.008 0.007 0.009 0.002 0.004 0.015 0.024 0.002 0.033 0.029 0.004 0.038 0.002 0.002 0.013 0.098

0.036 0.062

0.014 0.105

0.006 0.116

0.015 0.075

0.07 0.016 0.005

0.025 0.063 0.002

0.036

0.094 0.004

0.017

0.077 0.023

0.022

0.041

0.029

0.038

0.01

0.002

0.014

0.108 0.091 0.019 0.008

HLA 2004: Immunobiology of the Human MHC

0.003 0.021

0.019

0.012 0.031

0.003

0.028 0.012 0.028

0.012 0.035 0.012 0.012

0.04 0.005 0.024 0.03 0.008

0.028 0.052

0.032 0.047

0.086

0.023

0.032

0.023

0.016

0.003 0.052 0.003 0.003

0.011

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1b. HLA-A alleles found in North Africa (NAF) Population Chaouya 134 27

2n k Expected Heterozygosity *0101 *0102 *0201 *0202 *0205 *0301 *0302 *1101 *2301 *2402 *2501 *2601 *2902 *3001 *3002 *3004 *3010 *3101 *3201 *3301 *3303 *3402 *6601 *6801 *6802 *6901 *7401 *8001

0.922 0.127 0.007 0.179 0.007 0.015 0.045 0.03 0.067 0.045 0.015 0.03 0.067 0.075 0.045 0.007 0.007 0.022 0.037 0.007 0.015 0.015 0.015 0.037 0.052 0.015 0.007 0.007

Metalsa 144 21 0.913 0.146 0.174 0.035 0.042 0.042 0.083 0.062 0.007 0.007 0.042 0.014 0.09 0.007 0.021 0.035 0.056 0.014 0.021 0.042 0.049 0.014

reported; this allele was filtered to *1101 since among the *11xx alleles this is the one at highest frequency. We quantified the effect of the binning and filtering on polymorphism and population genetic analyses. Out of the 335 datasets (i.e., combinations of populations and loci), 113 had some alleles binned/filtered. The decrease in number of alleles due to binning/filtering was in general low, and only exceeded 3 in 9 out of 335 datasets: Algerian (DRB1), Cape York (C), Czech (A), Czech (DRB1), Filipino (C), Georgian (A), Han-Chinese (A), Kenyan Lowlander (A), Kinh (DQB1). The reduction in expected heterozygosity (He) due to binning/filtering was lower than 2% in 327 out of 335 datasets; the 8 cases in which the decrease in He was greater than 2% were: Seri (A), Bari (C), Puyuma (C), Finn (DRB1, DQB1), Slovenian (DQA1), Yupik (DQA1), and PNG Highlander (DQB1). Overall, the binning/filtering process had a small impact upon the measures of polymorphism.

Population genetic analyses Test of Hardy-Weinberg proportions

Table 7 shows the number and proportion of populations that deviate from HWP, for each locus. At the 0.05 level of significance 14% and 11% of the 13th IHWS population samples

deviate significantly from HWP at HLA-A and HLA-C, and approximately 5% for HLA-B. HWP is rejected for a higher proportion of populations at class II loci; roughly 10% deviate significantly for DRB1 and DPA1, 22% for DQB1, 25% for DQA1, and 30% for DPB1. Notice, however, that the higher proportions correspond to loci with fewer population samples (e.g., DPB1 is represented by only 20 population samples). Number of alleles

The number of alleles varied greatly among population samples for a given locus, and among loci (see the ranges in Table 3). For all loci the SSA African population samples were among those with the highest number of alleles, while SAM were among the lowest. Samples from EUR also had high values of k, often approaching those of SSA. Population samples from NAM and AUS were frequently among those with the lowest values of k. Heterozygosity

For all HLA loci, He was high within individual populations. Global averages were 0.82, 0.87, and 0.91 for A, C, and B, respectively. For class II beta loci, the global averages were 0.75, 0.86, and 0.74 for DQB1, DRB1 and DPB1. The values for class II alpha loci (DQA1 and DPA1) were 0.7 and 0.47 respectively (Table 3). The He values were within 86–94% of the maximum possible heterozygosity attainable for the number of alleles at that locus (with the exception of DPA1, with an He that was 68% of the theoretical maximum). For all loci, SSA and NAF population samples were consistently among those with the highest He. EUR and SWA population samples also displayed He values that were usually very close to those of Africans. The NAM, SAM, and AUS populations were usually the least polymorphic among all populations, with the lowest He at individual loci. The OCE and SEA populations displayed a wide range of He, possibly due to the distribution of complexity levels among populations from these regions, as described in the following paragraph. Higher complexity levels correspond to more admixed populations (see reference 5, for a description of the three complexity levels). The largest variation in He values for different loci in the same population was seen in the OCE region. Figure 1 is a scatterplot of the He values for all populations at HLA-B (grouped by region), exemplifying some of the trends described above; scatterplots for all loci are presented at the IHWG website under the Anthropology component (www.ihwg.org/components/diversr.htm) and also in the eBook version of HLA 2004 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dbΩBooks). HLA 2004: Immunobiology of the Human MHC

11

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Figure 1. Scatterplot of expected heterozygosity at HLA-B. The solid lines indicate the mean value for that region; the numbers on the x-axis are sample sizes.

12

HLA 2004: Immunobiology of the Human MHC

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1c. HLA-A alleles found in Europe (EUR) Population

2n k Expected Heterozygosity *0101 *0201 *0202 *0203 *0205 *0206 *0207 *0211 *0217 *0220 *0224 *0226 *0234 *0301 *0302 *1101 *2301 *2402 *2403 *2405 *2416 *2501 *2502 *2601 *2608 *2901 *2902 *3001 *3002 *3004 *3101 *3201 *3202 *3301 *3303 *3402 *6601 *6602 *6801 *6802 *6803 *6806 *6901

Bulgarian 24 7

Croatian 300 27

Cuban (Eu) 138 25

Czech 210 22

Finn 90 180 15

Georgian 210 23

Irish 2000 25

North America (Eu) 594 28

0.785 0.333 0.208

0.871 0.097 0.263

0.917 0.08 0.181

0.854 0.129 0.276 0.005

0.794 0.089 0.344

0.841 0.057 0.31 0.01

0.848 0.202 0.274

0.875 0.157 0.258

0.007 0.003

0.022

0.024 0.005

0.014

0.012

0.002 0.008 0.002

0.005 0.005

∞0.001

0.083 0.003

0.007 0.007 0.007

0.003 0.003

0.005

0.11

0.087

0.186

0.25

0.083

0.04 0.023 0.16

0.058 0.08 0.116 0.007

0.033 0.019 0.105

0.05 0.006 0.094

0.042

0.003 0.03 0.003 0.053

0.208

0.005 0.138 0.014 0.062 0.019 0.171

0.143 0.002 0.08 0.014 0.061

0.123 0.007 0.077 0.017 0.064 0.003

0.02 ∞0.001 0.018 ∞0.001

0.035

0.005

0.042

0.007

0.043

0.011

0.036

0.029

0.011

0.007 0.003 0.013 0.003

0.007 0.065

0.005 0.014 0.014

0.011 0.006 0.006

0.005 0.005 0.01

0.03 0.057 0.01 0.01 0.013

0.014 0.029

0.029 0.024

0.05 0.022

0.01 0.048

0.036

0.01

0.005 0.01

0.024

0.014

0.003 0.043 0.003

0.043

0.007 0.022 0.007 0.029 0.029 0.014

0.01 0.01

0.044

0.033

0.048

0.048 0.011 0.012 ∞0.001 0.026 0.032

0.039 0.003 0.003 0.044 0.013 0.007 0.002 0.03 0.04

0.006 0.002 ∞0.001 0.001

0.01 0.005 0.002 0.007

0.026 0.009

0.03 0.008

0.006 0.005

Test of neutrality

We used the homozygosity statistic (F, the expected proportion of homozygotes under HWP) to test the null hypothesis of neutrality. We employed a one-tailed test, defining as significantly departing from neutrality the population samples with F values among the 5% lowest expected under the null hypothesis. By testing for significantly low F values we are testing for deviation from neutrality due to balancing selection. The proportion of rejections was greatest for HLA-C and DQA1 (45% and 50%) (Table 8). At the B and DRB1 loci, neutrality was rejected in 25% and 21% of the population samples, and was rejected for A and DQB1 in approximately 11% of the samples. No samples deviated from neutrality at DPA1 and DPB1. The lack of evidence for deviation from neu-

0.003

trality at DPB1 is consistent with an analysis of the 12th IHWS data (12). The homozygosity statistic was also analyzed by standardizing it with respect to the mean and variance expected at equilibrium (yielding the normalized deviate, FND). Under the null hypothesis of neutrality the mean of FND values taken over populations is asymptotically normal with a mean of zero. A t-test rejected this hypothesis for all loci (p∞0.01) except for DPA1 and DPB1 (p±0.05). The mean FND over all populations was negative for all loci, indicating a trend in the direction of lower FND values relative to neutral expectations. Figure 2 is a scatterplot of the values of FND for all populations at the HLA-B locus (grouped by region); notice that most of the points lie below the value of zero, indicating that homozygosHLA 2004: Immunobiology of the Human MHC

13

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1d. HLA-A alleles found in Southwest Asia (SWA)

2n k

Population Arab Druze

Israeli Jews

Kurdish

New Delhi

Omani

South Indian

200 26

234 41

60 16

132 18

238 25

176 21

Tamil 100 16

0.928 0.171 0.021 0.004 0.128 0.009

0.921 0.067

0.895 0.038

0.903 0.071

0.906 0.125

0.877 0.17

0.083

0.061

0.206 0.004

0.057

0.01

0.043 0.004

0.05

0.03 0.03

0.021

Expected Heterozygosity 0.931 *0101 0.04 *0103 *0106 *0201 0.155 *0202 0.02 *0203 *0205 0.04 *0206 *0208 *0210 *0211 0.005 *0213 *0214 *0216 *0217 *0219 *0220 *0222 *0224 *0226 *0236 *0301 0.06 *0302 0.025 *1101 0.11 *1102 *1104 0.004 *2301 0.055 *2402 0.08 *2403 0.06 *2404 0.01 *2405 0.015 *2406 *2407 *2413 *2416 0.005 *2501 *2601 0.055 *2609 *2901 0.045 *2902 0.02 *3001 0.03 *3002 *3004 0.045 *3101 0.005 *3201 0.04 *3202 0.005 *3203 *3301 *3303 0.01 *3402 0.005 *3601 *6601 *6801 0.03 *6802 *6806 *6901 0.03 *7401

0.01

0.004 0.004

0.068

0.097

0.02 0.13

0.004 0.006 0.009 0.004 0.006 0.013 0.013 0.004 0.004 0.034 0.017 0.064 0.004 0.026 0.077

0.008

0.05 0.083 0.1

0.098 0.023 0.235

0.05 0.013 0.113

0.08 0.017 0.119

0.04 0.01 0.18

0.067 0.117

0.015 0.114 0.008

0.017 0.071

0.142

0.16

0.006 0.006 0.009 0.013 0.004 0.017 0.06 0.004 0.026 0.013 0.021 0.009 0.017 0.013

0.117

0.076

0.101

0.067

0.015

0.004 0.008

0.017 0.017 0.017 0.067

0.004 0.013 0.064 0.004 0.009 0.03 0.009

0.067

0.03 0.03

0.042 0.017 0.025 0.105

0.061

0.013 0.021 0.004 0.008 0.055 0.017

0.061

0.011 0.006

0.01

0.04

0.02

0.011

0.01

0.131 0.011 0.006

0.07 0.01

0.062

0.07

0.034

0.08

0.017 0.004

ity values are lower than neutral expectations. Scatterplots for FND at all loci are presented at the IHWG web site and in the eBook version of HLA 2004.

Description of polymorphism

In the subsections below we provide a brief overview of the tables containing population summaries (Table 3 family) and

14

0.028 0.004

HLA 2004: Immunobiology of the Human MHC

the regional details (Table 4 family). This overview highlights a few specific high frequency alleles for each locus that are either present and/or frequent in most regions or unique to a certain region. HLA-A

A total of 73 population samples were typed at the A locus, with each region represented by at least two population sam-

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Figure 2. Scatterplot of FND at HLA-B. The solid lines indicate the mean value for that region; the numbers on the x-axis are sample sizes. The dashed line at FNDΩ0 is the expected value under neutrality and equilibrium conditions.

HLA 2004: Immunobiology of the Human MHC

15

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1e. HLA-A alleles found in Southeast Asia (SEA) Population

2n k Expected Heterozygosity *0101 *0201 *0202 *0203 *0205 *0206 *0207 *0210 *0211 *0212 *0222 *0224 *0236 *0301 *1101 *1102 *1104 *2301 *2402 *2403 *2406 *2407 *2408 *2410 *2501 *2601 *2602 *2901 *2902 *3001 *3002 *3004 *3101 *3201 *3301 *3303 *3401 *6601 *6602 *6801 *6802 *6901 *7401

Han Chinese 149 298 22

Han Chinese 572 1138 20

Malay 248 24

Minnan 204 15

0.055

0.86 0.003 0.104

0.851 0.011 0.062

0.887 0.032 0.065

0.834 0.005 0.088

0.108

0.036

0.067

0.078

0.052

0.064

0.035 0.094 0.002

0.027 0.082

0.04 0.131 0.003

0.047 0.131

0.02 0.02

0.029 0.113

Ami 97 196 6

Atayal 212 8

Bunun 202 6

Chinese 564 20

Hakka 110 13

0.549

0.589

0.604

0.793

0.026

0.066

0.04

0.854 0.005 0.053

0.005 0.015

0.094 0.005

0.074

0.874 0.015 0.092 0.002 0.044 0.001 0.046 0.069

0.012 0.002 0.004 0.004 0.026 0.087

0.08 0.052

0.099 0.01

0.016 0.277 0.018

0.4 0.045

0.628

0.618

0.584

0.005 0.172

0.145

0.014 0.002 0.08

0.219

0.193

0.007 0.265 0.03

0.008 0.287 0.04

0.154 0.003

0.177 0.012 0.012

0.309 0.039

0.154 0.002

0.173

0.186

0.01 0.003 0.003

0.005

0.004 0.157 0.004 0.04

0.005

0.02

0.034

0.016

0.064

0.02

0.017

0.012

0.027

0.01

0.011

0.016

0.018

0.013 0.003

0.018

0.004

0.01 0.001

0.028

0.009

0.017 0.007

0.018 0.004

0.004 0.004

0.025 0.005

0.115 0.005

0.082 0.009

0.101 0.003

0.1 0.003 0.001

0.109 0.06

0.083

0.012 0.241 0.002 0.006 0.184 0.006 0.002 0.022 0.002 0.028 0.004 0.011 0.004 0.016 0.001 0.028 0.009 0.002 0.118 0.016 0.001 0.001

0.006 0.004 0.005 0.005

ples. There were 108 different alleles observed worldwide. The number of different alleles per population ranged from 4 to 42. Of the 36 different regionally frequent alleles, 11 were frequent in at least four regions (*0101, *0201, *0206, *0301, *1101, *2301, *2402, *2601, *3101, *3303, and *6801). The *0201 allele had a frequency above the threshold in every region and the *2402 allele was frequent in all regions except SSA, where it was just below the threshold. Four additional frequent alleles were present in each of the regions (*0101, *3101, *3201, and *6801). One frequent allele was present in only one region (*2603: frequent in NEA).

16

North America (As) 822 34

HLA 2004: Immunobiology of the Human MHC

0.003

0.004

0.001 0.002

HLA-C

A total of 55 population samples were typed at the C locus, including at least two populations from each region, except for NAF that was not sampled. There were 56 different alleles observed worldwide. The number of different alleles per population ranged from five to 37. Of the 29 different regionally frequent alleles, 10 were frequent in at least four regions (*0102, *0202, *0303, *0304, *0401, *0602, *0701, *0702, *0801, and *1502). Alleles *0401 and *0702 had frequencies above the threshold in each of the regions where there were populations

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1e. HLA-A alleles found in Southeast Asia (SEA), continued Population

2n k Expected Heterozygosity *0101 *0201 *0202 *0203 *0205 *0206 *0207 *0210 *0211 *0212 *0222 *0224 *0236 *0301 *1101 *1102 *1104 *2301 *2402 *2403 *2406 *2407 *2408 *2410 *2501 *2601 *2602 *2901 *2902 *3001 *3002 *3004 *3101 *3201 *3301 *3303 *3401 *6601 *6602 *6801 *6802 *6901 *7401

Paiwan 51 Pazeh 102 110 6 10

Puyuma 49 100 8

Rukai 100 5

Saisiat 102 7

0.251

0.783

0.564

0.399

0.632

0.039

0.055

0.02

0.03

0.045

0.06

0.036 0.064

0.12

0.029

0.03

Singapore (Chinese) 172 16

Siraya 102 11

Thai 196 21

Thao 60 7

Toroko 110 6

Tsou 102 5

Yami 100 5

0.729

0.709

0.369

0.575

0.039

0.868 0.005 0.031

0.584

0.108

0.864 0.012 0.076

0.067

0.191

0.029

0.02

0.01

0.099

0.059

0.133

0.02 0.116

0.052 0.069

0.02 0.122

0.02 0.017

0.033

0.055

0.005 0.005

0.02

0.282 0.109

0.02 0.07

0.04

0.118 0.127

0.006 0.215 0.047

0.176 0.069

0.005 0.26 0.031

0.217

0.073 0.018

0.108 0.029

0.36 0.03

0.863

0.336

0.64

0.76

0.569

0.215

0.471

0.082 0.005

0.6

0.445

0.784

0.54

0.006

0.041

0.05

0.041 0.039

0.027

0.03

0.14

0.049

0.023

0.02

0.005

0.017

0.218

0.049

0.015

0.01

0.012

0.01

0.031

0.009

0.017

0.02

0.015

0.036

0.006 0.093

0.049

0.133 0.01

0.04

typed for this locus. In addition to these two alleles, six other frequent alleles were present in each of the regions (*0102, *0303, *0304, *0602, *0801, and *1502). Two frequent alleles were present in two or fewer regions (*0703: frequent in SEA and present in SWA; *0806: frequent in NAM). HLA-B

A total of 68 populations were typed at the B locus with each region represented by at least 2 population samples. There were 196 different alleles observed worldwide. The number of different alleles per population ranged from 7 to 66. Of

0.006

0.05

0.005

the 67 regionally frequent alleles, 11 were frequent in at least four regions (*0702, *0801, *1301, *1501, *1801, *3501, *4001, *4002, *4403, *5101, and *5801). No allele was frequent in every region. The *4002 allele was frequent in all regions except SSA, NAF, and EUR. The *5101 allele was frequent in all regions except NAF, OCE, and AUS. Seven regionally frequent alleles were present in each of the regions (*0702, *3501, *3503, *3901, *4001, *4002, and *5101). Nine frequent alleles were present in two or fewer regions (*1404: frequent in SWA and present in SSA; *1522: frequent in SAM and present in SSA; *3909: frequent in SAM and present in SEA; *4410: freHLA 2004: Immunobiology of the Human MHC

17

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1f. HLA-A alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0101 *0201 *0203 *0206 *0207 *0211 *0301 *1101 *1102 *1104 *2402 *2403 *2404 *2405 *2407 *2408 *2410 *2601 *2902 *3101 *3201 *3303 *3401 *3601 *6601 *6801 *6803

Population American Samoa 100 13

East Timorese 114 13

Filipino 188 16

Indonesian 100 18

Ivatan 100 7

Moluccan 50 7

PNG Highlander 184 5

PNG Lowlander 95 158 4

0.838 0.005 0.069 0.005 0.016 0.016

0.79

0.366

0.641

0.04

0.06 0.06

0.005

0.02 0.16

0.14

0.261 0.005

0.9 0.07 0.04 0.09 0.02 0.01 0.02 0.02 0.14 0.02

0.774

0.13

0.767 0.018 0.009 0.044 0.018

0.07 0.05

0.32

0.005 0.103

0.437

0.01 0.33

0.009 0.404

0.213 0.011

0.16

0.32

0.16

0.783

0.392

0.14

0.005 0.138

0.16

0.09

0.22

0.06

0.009 0.018

0.016 0.027 0.005

0.05 0.03

0.01

0.018

0.817 0.13

0.3

0.01 0.02

0.1

0.167 0.009

0.074 0.133

0.02 0.01 0.09 0.03

0.082 0.02 0.13

0.16

0.103

0.089

0.01 0.02 0.01

Table 5.1g. HLA-A alleles found in Australia (AUS)

2n k Expected Heterozygosity *0101 *0201 *0301 *1101 *2402 *2406 *2413 *3101 *3201 *3303 *3401 *6801

Population Cape York 206 10 0.797 0.053 0.175 0.044 0.18 0.223

Groote Eylandt 150 7 0.742 0.027 0.107 0.24 0.293

0.111 0.014 0.097 0.083 0.014

0.005 0.019 0.005 0.291 0.005

0.007 0.007 0.32

quent in SSA and present in SEA; *5901: frequent in NEA and present in SEA; *1504, *3511, and *4004: frequent in SAM; *1535: frequent in OCE). HLA-DRB1

A total of 53 population samples were typed at the DRB1 locus with each region represented by at least 2 population samples. There were 96 different alleles observed worldwide. The number of different alleles per population ranged from five to 48. Of the 43 regionally frequent alleles, 13 were frequent in at least four regions (*0301, *0403, *0405, *0701, *0803,

18

Kimberley 72 6 0.508

HLA 2004: Immunobiology of the Human MHC

0.681

Yuendumu 382 10 0.698 0.008 0.113 0.003 0.076 0.298 0.013 0.018 0.029 0.003 0.44

*0901, *1101, *1201, *1301, *1401, *1501, *1502, and *1602). No allele was frequent in every region. The *0701 allele was frequent in every region except AUS and NAM, where the maximum frequency was just under the threshold. Five frequent alleles were present in each of the regions (*0101, *0301, *0403, *0701, and *1301). Nine frequent alleles were present in all but one region (*0404, *0405, *0901, *1101, *1104, *1201, *1401, *1501, and *1602). Three frequent alleles were present in two or fewer regions (*0412 frequent in AUS; *0807 frequent in SAM; *1409: frequent in AUS and present in SSA).

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1h. HLA-A alleles found in Northeast Asia (NEA)

2n k Expected Heterozygosity *0101 *0102 *0201 *0203 *0204 *0205 *0206 *0207 *0210 *0211 *0212 *0214 *0217 *0219 *0220 *0222 *0228 *0233 *0236 *0240 *0244 *0245 *0246 *0301 *0302 *1101 *1106 *2301 *2303 *2304 *2402 *2403 *2404 *2406 *2408 *2410 *2413 *2414 *2415 *2417 *2418 *2421 *2501 *2601 *2602 *2603 *2606 *2608 *2611 *2612 *2618 *2901 *2902 *3001 *3004 *3008 *3101 *3102 *3105 *3201 *3301 *3303 *6601 *6801 *6803 *6812 *8001

Population Buriat 280 42 0.905 0.114 0.15 0.004 0.032 0.043 0.021

Korean 200 400 17 0.872 0.012

Okinawan 210 11 0.815 0.005

Ryukuan 284 24 0.822 0.004

0.165 0.008

0.09

0.116

Tuva 378 31 0.894 0.066 0.003 0.143 0.003

0.014 0.095 0.048

0.143 0.014 0.005

0.183 0.007

0.004 0.007 0.004

0.008 0.069 0.016 0.003 0.005 0.003

0.007 0.007 0.007 0.004 0.004 0.005 0.003 0.007 0.021 0.029 0.007 0.075 0.014 0.004 0.007 0.2

0.004 0.007 0.007

0.012 0.105

0.067

0.056 0.007

0.069 0.003 0.087 0.029

0.23

0.343

0.004 0.011 0.011

0.335 0.004

0.214 0.005 0.003

0.004 0.007

0.004 0.004

0.004 0.004 0.004 0.004 0.014

0.055 0.022 0.01

0.124 0.086

0.088 0.011 0.028 0.004 0.004

0.003 0.045

0.003 0.003 0.003 0.004 0.004 0.011

0.002

0.075 0.004 0.004

0.04

0.05 0.008

0.003 0.105

0.081

0.005

0.003 0.098 0.021

0.046

0.018 0.132

0.019

0.004 0.018 0.004 0.007 0.004

HLA 2004: Immunobiology of the Human MHC

0.071 0.003 0.011

19

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1i. HLA-A alleles found in North America (NAM)

2n k Expected Heterozygosity *0101 *0201 *0202 *0205 *0206 *0210 *0301 *0302 *1101 *2301 *2402 *2403 *2407 *2423 *2501 *2601 *2608 *2902 *3001 *3002 *3007 *3101 *3201 *3301 *3303 *3402 *6602 *6801 *6802 *6803 *6805 *7401

Population Amerindian 514 29 0.87 0.086 0.212 0.006 0.006 0.068 0.072 0.002 0.025 0.018 0.235 0.004 0.002 0.016 0.023 0.002 0.021 0.019 0.014 0.002 0.078 0.016 0.002 0.006 0.002 0.002 0.053 0.006

Canoncito 82 4 0.69

Pima 99 172 10 0.668 0.006 0.436

0.378 0.049

Seri 66 6 0.631

Yupik 504 16 0.61 0.004 0.024

0.545

0.076 0.006

0.165 0.006 0.002 0.008

0.012 0.305

0.36

0.045

0.581 0.02 0.002 0.002 0.004

0.006

0.268

0.006

0.015

0.004 0.002

0.076

0.152

0.012

0.017

0.212 0.03

0.155 0.01

0.002 0.002

Table 5.1j. HLA-A alleles found in South America (SAM)

2n k Expected Heterozygosity *0101 *0201 *0204 *0211 *0217 *0222 *0302 *1104 *2402 *2403 *3101 *3201 *3202 *6801 *6803 *6901

Population Bari 88 5 0.576 0.011 0.216

Guarani Nandeva 104 12 0.76

0.192 0.171 0.028

0.308 0.058 0.058

0.007 0.007 0.469

0.01 0.01 0.048 0.038 0.356 0.01 0.01 0.087

0.08 0.091 0.602

0.105 0.021

0.01

HLA-DQA1

A total of 24 populations were typed at the DQA1 locus, with population samples representing eight of the ten regions. Only one SWA population was sampled at this locus; all other

20

Guarani Kaiowa 286 8 0.702

HLA 2004: Immunobiology of the Human MHC

sampled regions had at least two populations. There were 8 different alleles observed worldwide. The number of different alleles per population ranged from three to eight. Each of these eight alleles was regionally frequent. Six were frequent in at

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.1k. HLA-A alleles found in other regions (OTH)

2n k Expected Heterozygosity *0101 *0102 *0201 *0202 *0204 *0205 *0206 *0211 *0212 *0213 *0216 *0217 *0220 *0224 *0301 *0302 *1101 *2301 *2402 *2403 *2404 *2422 *2501 *2601 *2608 *2611 *2901 *2902 *3001 *3002 *3004 *3008 *3101 *3201 *3301 *3303 *3401 *3402 *3601 *6601 *6602 *6801 *6802 *6803 *6805 *6815 *6901 *7401 *8001

Population Brazilian 194 26 0.901 0.077 0.232 0.026

Brazilian (Af Eu) 198 34 0.928 0.091

Cuban (Af Eu) 78 22 0.917 0.077

0.192 0.04 0.005 0.015

0.192 0.013

Mexican 120 23 0.871 0.083 0.008 0.292

0.026 0.05

0.015

North America (Hi) 494 36 0.906 0.059 0.006 0.231 0.006 0.014 0.032 0.006 0.004 0.002

0.008

0.098 0.005 0.026 0.052 0.119

0.005 0.005 0.04 0.051 0.061 0.02 0.086 0.01 0.005

0.09 0.103 0.051 0.013

0.017 0.042 0.025 0.133

0.075 0.006 0.055 0.018 0.126 0.002

0.005 0.036 0.005

0.005 0.025

0.038

0.058

0.03 0.025 0.025

0.038 0.013 0.064

0.025 0.008 0.008

0.026 0.021 0.026 0.015

0.005 0.04 0.02 0.01 0.03

0.013 0.038 0.038 0.064

0.05 0.017 0.017 0.008

0.021 0.015 0.01

0.025 0.01 0.01

0.072 0.01

0.025 0.035

0.036 0.004

0.01 0.026 0.021 0.036 0.005

0.026 0.008 0.013 0.013 0.038 0.026

0.002 0.051 0.024 0.032 0.002 0.047 0.028 0.026 0.01 0.002 0.006 0.004 0.004

0.067 0.008 0.042 0.017

0.026 0.022 0.012 0.008

0.008

0.006 0.004

0.005 0.013 0.01 0.005

0.015 0.005

least six regions (*0101, *0102, *0103, *0201, *0301, and *0501). Two alleles were frequent in each of the typed regions (*0301 and *0501). Three additional frequent alleles were present in each of the eight typed regions (*0101, *0103, and *0201). No allele was present in fewer than five regions. HLA-DQB1

A total of 32 populations were typed at the DQB1 locus, with population samples representing nine of the ten regions. Only one SWA population was sampled at this locus; all other sampled regions had at least two populations. There were 23 different alleles observed worldwide. The number of different

alleles per population ranged from three to 17. Of the 14 regionally frequent alleles, nine were frequent in at least four regions (*0201, *0301, *0402, *0501, *0602, *0302, *0303, *0502, and *0503). Two alleles were frequent in each of the typed regions (*0201 and *0301). Three additional frequent alleles were present in each of the nine regions (*0302, *0303, and *0501). All frequent alleles were present in at least six regions. HLA-DPA1

A total of 11 populations were typed at the DPA1 locus, with population samples from five of the ten regions. Only OCE and NAM had more than one population sampled at this loHLA 2004: Immunobiology of the Human MHC

21

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2. HLA-B Table 5.2a. HLA-B alleles found in Sub-Saharan Africa (SSA) Population

2n k Expected Heterozygosity *0702 *0704 0.002 *0705 *0707 *0712 *0717 *0801 *0804 *0805 *1301 *1302 *1303 *1304 *1401 *1402 *1403 *1404 *1406 *1501 *1502 *1503 *1509 *1510 *1515 *1516 *1517 *1518 *1522 *1531 *1537 *1555 *1564 *1567 *1801 *1803 *1807 *1812 *2703 *2705 *3501 *3502 *3503 *3508 *3517 *3520 *3528 *3534 *3701 *3801 *3901 *3902 *3903 *3905 *3906 *3910 *4001 *4002 *4005 *4006 *4012 *4016 *4101 *4102 *4103 *4201 *4202 *4402 *4403 *4405 *4410

22

Doggon 276 31

Kenyan Kenyan 142 Highlander 286 480 46 39

Kenyan Lowlander 530 47

Mandenka 188 37

North America (Af) 502 49

Shona 452 39

Ugandan 322 50

Zambian 88 30

Zulu 402 33

0.912 0.058

0.951 0.035

0.946 0.01

0.943 0.025

0.949 0.053

0.952 0.082

0.941 0.046

0.964 0.062

0.941 0.045

0.932 0.05

0.002

0.004

0.027

0.014

0.011

0.01

0.062

0.034

0.067

0.007 0.002 0.007

0.004 0.031

0.004

0.004 0.021

0.046

0.03

0.048 0.005

0.046

0.031 0.013

0.011 0.011

0.007

0.023 0.008

0.011

0.012

0.022

0.028

0.011 0.011

0.025

0.002 0.006

0.011 0.043 0.002

0.008 0.018

0.002 0.013 0.024

0.016 0.037

0.045 0.034

0.022 0.02

0.025

0.023

0.005

0.077

0.062

0.057

0.1

0.084

0.025

0.045

0.087

0.013 0.002 0.002

0.006 0.003

0.027

0.002 0.007 0.069 0.007 0.022

0.063

0.087

0.069

0.052

0.079 0.002 0.017

0.036

0.032

0.011 0.004 0.004

0.007 0.004

0.01 0.01

0.004 0.013 0.002

0.011

0.01 0.002 0.074 0.024 0.002 0.01 0.004 0.008

0.01 0.011

0.006 0.006

0.004 0.002

0.002

0.004

0.004

0.003 0.002

0.007

0.004 0.059

0.048

0.043 0.006

0.027

0.025

0.002 0.008 0.002 0.034

0.016

0.032

0.064

0.05 0.003

0.013 0.002

0.006 0.012 0.037 0.016 0.006 0.006

0.034 0.011

0.04

0.004 0.004 0.127

0.014 0.024

0.035 0.006

0.122

0.012 0.064

0.002 0.023

0.03 0.002

0.004 0.004 0.005 0.004 0.008

0.011 0.006 0.005

0.006 0.004 0.016 0.004

0.003 0.006 0.016

0.002

0.006 0.003 0.004 0.007

0.007

0.01

0.011

0.021 0.01 0.002 0.004

0.002 0.002

0.012 0.016 0.016

0.023

0.003 0.012 0.007 0.138 0.014

0.011 0.004 0.011 0.006

0.011

0.002

0.002 0.004

0.014 0.004 0.004 0.073 0.004

0.031 0.006 0.069

0.079 0.004

0.005 0.016

0.056

0.069 0.011

0.017

0.008

0.015

0.005

0.02 0.034

0.071

0.074

0.002

HLA 2004: Immunobiology of the Human MHC

0.009 0.003

0.011 0.023

0.005 0.002

0.012 0.009 0.034 0.047

0.148

0.129 0.017

0.023 0.011

0.085

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2a. Continued *4415 *4426 *4501 *4502 *4701 *4702 *4703 *4901 *5001 *5002 *5101 *5102 *5104 *5106 *5107 *5108 *5112 *5201 *5301 *5302 *5305 *5501 *5502 *5601 *5701 *5702 *5703 *5704 *5801 *5802 *6701 *7021 *7301 *7801 *8101 *8201 *8202

0.062

0.025 0.011 0.025

0.004 0.052 0.004 0.004

0.006

0.002

0.056

0.066

0.012

0.031 0.038

0.002 0.046

0.002 0.013 0.004 0.002

0.017

0.042

0.023

0.027

0.054

0.016

0.004

0.037 0.016

0.034 0.006

0.016 0.005

0.012 0.002

0.093

0.028

0.045

0.037

0.011 0.009 0.007 0.002 0.004

0.003 0.003 0.037

0.011

0.007

0.05

0.057

0.002

0.102

0.015

0.002 0.007 0.04

0.004 0.005 0.016 0.003 0.004 0.083 0.159

0.087 0.004 0.014

0.085

0.068

0.037 0.053

0.016 0.106

0.093

0.008 0.002 0.007 0.011 0.007 0.022

0.004 0.004 0.014 0.056

0.002 0.008 0.004 0.029

0.008 0.006 0.009

0.08 0.07

0.1 0.085

0.068 0.125

0.002

0.002

0.012

0.027 0.016 0.005 0.005 0.069

0.016 0.05

0.003 0.031

0.024 0.014 0.004

0.004 0.007 0.044

0.012

0.011 0.023 0.057

0.064 0.034

0.044 0.064

0.04 0.043

0.023

0.032 0.097 0.002

0.009 0.003

0.023

0.03 0.002

0.005 0.069

0.002 0.053

0.028 0.004 0.007

0.04 0.002

0.062 0.019

cus. There were 8 different alleles observed worldwide. The number of different alleles per population ranged from three to seven. Of the four regionally frequent alleles, three were frequent in at least three regions (*0103, *0201, and *0202). The *0103 and *0201 alleles were frequent in each of the typed regions. In addition to these frequent alleles, the *0202 allele was present in each of the five regions. The *0301 allele was frequent in one population from SSA and not found in other regions. HLA-DPB1

A total of 20 population samples were typed at the DPB1 locus, with population samples representing seven of the ten regions. Only one SEA population was sampled at this locus. All other sampled regions had at least two populations. There were 47 different alleles were observed worldwide. The number of different alleles per population samples ranged from four to 29. Of the 14 regionally frequent alleles, five were frequent in at least four regions (*0201, *0301, *0401, *0402, and *0501). The *0401 allele was frequent in each of the typed regions. Three additional frequent alleles were present in each of the seven regions (*0101, *0201, and *0301). There were four frequent alleles that were present in two or fewer regions (*1801: frequent in SSA;

0.008 0.022

0.04

*2801: frequent in SEA and present in OCE; *3101: frequent in OCE and present in SSA; *3501: frequent in SAM and present in SSA).

Discussion

In this section we compare the results for levels of polymorphism among HLA genes and populations. We also compare results for HLA and non-HLA loci; to carry out this last contrast we used a survey by Stephens et al., 2001 (11; hereafter referred to as the ‘‘Stephens dataset’’), which examined variation within 313 genes in 82 unrelated individuals of diverse ancestry. Number of alleles per locus

The number of known alleles at HLA loci, considering all those detected to date (7), follows the relationship B±A±C for class I (with 499, 258, and 125 known alleles), and DRB1±DPB1±DQB1 for class II beta genes (with 321, 100, and 53 known alleles). The class II alpha genes have the lowest number of alleles, with approximately 20 each at DPA1 and DQA1. In order to assess whether the relative degree of polymorphism within individual populations reflects the worldwide HLA 2004: Immunobiology of the Human MHC

23

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2b. HLA-B alleles found in North Africa (NAF)

2n k Expected Heterozygosity *0702 *0705 *0801 *1302 *1401 *1402 *1403 *1503 *1510 *1517 *1801 *2702 *2703 *2705 *2708 *3501 *3502 *3503 *3508 *3701 *3801 *3901 *3905 *3906 *3910 *4001 *4002 *4006 *4101 *4102 *4201 *4202 *4402 *4403 *4501 *4701 *4901 *5001 *5002 *5101 *5201 *5301 *5501 *5701 *5703 *5801 *5802 *7801

Population Chaouya 136 40 0.959 0.037 0.015 0.066 0.022 0.007 0.029 0.007 0.007 0.015 0.029 0.044 0.007 0.007 0.037 0.015

Metalsa 136 34 0.941 0.022 0.007 0.088 0.015 0.037 0.015 0.051 0.007 0.007 0.022 0.044 0.007 0.015

0.022 0.007 0.022 0.007 0.007 0.015 0.015 0.015 0.007 0.022 0.015 0.029 0.037 0.074 0.066 0.037 0.088 0.015 0.044 0.015 0.015 0.007 0.022 0.015 0.037

0.007 0.015

0.007 0.007 0.066 0.007 0.088 0.125 0.044 0.007 0.051 0.074 0.044 0.044 0.007 0.015 0.007 0.007 0.015 0.007 0.015

variation in numbers of alleles among loci, we selected specific pairs of loci and determined the fraction of populations that had more alleles at one locus versus the other. For each pair of loci compared we restricted attention to populations where the number of sampled individuals at one locus was within 10% of the number at the other locus. All populations had more alleles at the B locus than at the A locus. Fifty-six percent had more B alleles than DRB1 alleles. Of the 14 populations where this was not true, 11 were from SEA, two were from AUS, and one was from NAM. All populations had more alleles at the DRB1 locus than at the DQB1 locus. Ninety one percent of populations had more DQB1 alleles than DQA1 alleles. Of the two populations

24

HLA 2004: Immunobiology of the Human MHC

where this was not true, one was from NAM and one was from SAM. Heterozygosity

We found that He values observed at HLA loci are substantially higher than the values observed for non-HLA data. We compared He for HLA to the results of the Stephens dataset by identifying the He values that bound the middle 50% of the observations (i.e., the first and third quartiles). Given that He is positively correlated with sample size, we restricted this analysis to the datasets for which sample sizes were similar to those of the Stephens data; we analyzed all HLA datasets with sample sizes between 50 and 120 (the Stephens dataset is comprised of 82 individuals). In the Stephens dataset the middle 50% of heterozygosity values were between 0.4 to 0.7. For the least variable HLA class I locus (HLA-A) the first and third quartiles for He were 0.68 and 0.88, and for the least polymorphic class II beta genes these values were 0.71 and 0.76. The least polymorphic of the class II alpha genes, DPA1, had the middle 50% of He values bounded by 0.23 and 0.46, similar to the non-HLA loci. For all but the B and DRB1 loci the mean number of alleles for the HLA and non-HLA data were similar, demonstrating that the number of alleles alone was not responsible for the observed differences in expected heterozygosity. In fact, we found that even after removing samples with more than 30 alleles from the HLA data and creating a dataset with a distribution of allele numbers similar to that of the Stephens dataset, the HLA heterozygosities remained substantially higher (not shown). This highlights the fact that the striking feature of HLA polymorphism is not just the number of alleles observed at a locus, but the fact that they occur at intermediate frequencies, resulting in high expected heterozygosities. The HLA loci differed from non-HLA genes by showing higher He. However, we found that these values were ordered in a similar manner for both sets of markers, with the following order of He: (SSA, NAF, EUR)±SWA±(NAM, SAM, AUS). This pattern mirrors the results for non-HLA loci (3), which have been interpreted as the result of the differences in the demographic processes these regions experienced. Our results show that while HLA loci have a distinctively high He, probably resulting from the effect of natural selection, the demographic effects detected at other loci are also evident in these genes. Expected heterozygosity and population complexity

Levels of He at HLA loci are a result of natural selection acting on a specific locus, as well as the demographic history that a

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2c. HLA-B alleles found in Europe (EUR)

2n k Expected Heterozygosity *0702 *0705 *0720 *0726 *0801 *0804 *0805 *1302 *1303 *1401 *1402 *1501 *1503 *1507 *1508 *1509 *1510 *1517 *1518 *1524 *1534 *1801 *1802 *1803 *2702 *2704 *2705 *2709 *3501 *3502 *3503 *3504 *3505 *3508 *3510 *3514 *3520 *3521 *3701 *3801 *3802 *3901 *3902 *3903 *3905 *3906 *4001 *4002 *4006 *4101 *4102 *4201 *4402 *4403 *4405 *4407 *4408 *4501 *4601 *4701 *4801 *4901 *5001 *5101 *5102 *5105 *5107 *5108 *5109 *5118 *5127 *5201 *5202 *5301 *5501 *5502 *5601 *5701 *5702 *5703 *5801 *7301

Population Bulgarian 22 13 0.864

Croatian 300 44 0.942 0.097

Cuban (Eu) 140 37 0.958 0.079

Czech 212 33 0.944 0.127

Finn 90 180 25 0.916 0.144

Georgian 216 42 0.935 0.032 0.005

Irish 2000 49 0.909 0.172 ∞0.001

North America (Eu) 574 48 0.94 0.11 0.003

0.007 0.045

0.045

0.017 0.013 0.007 0.02

0.057

0.052

0.089

0.005 0.019

0.162

0.108

0.029

0.066

0.017

0.056 0.005

0.017

0.014

0.003 0.02 0.057 0.003

0.029 0.057 0.021 0.014

0.014 0.047

0.122

0.014 0.06

0.022 0.036 0.038 0.001 0.001 ∞0.001

0.003 0.037 0.057

0.009 0.003

0.005 0.014

∞0.001 ∞0.001 0.002 ∞0.001

0.005 0.007 0.003

0.078

0.046

0.028

0.017 0.006 0.061

0.005

∞0.001 0.001

0.031 0.002

0.003

0.007

0.005 0.014

0.045

0.003 0.113

0.064

0.075

0.045 0.045

0.017 0.007 0.037

0.007

0.019

0.014

0.028

0.043 0.027 0.03

0.029 0.007 0.014

0.061 0.009 0.009

0.117

0.003

0.007 0.007

0.005

0.011

0.013 0.003 0.02 0.067

0.021 0.043

0.024 0.047 0.014

0.045 0.045

0.017

0.005 0.083 0.009 0.111

0.273 0.091 0.045

0.003 0.01 0.027

0.023

0.004 0.002

0.019 0.003 0.003 0.002

0.066

0.002

0.011

0.009 0.046

0.016 0.009

0.011

0.028

0.009

0.019 0.023 0.002 0.005

∞0.001

0.003

0.006 0.045

0.002

0.029 ∞0.001 0.054

0.019 0.005 0.005 0.005

0.007 0.014 0.014 0.021

0.002

0.024 0.014

0.011 0.094 0.017

0.019

0.008 0.054 0.003

0.007 0.068 0.016 0.007 0.007 0.003 0.113 0.033

0.007 0.01

0.014 0.019

0.017 0.006

0.009

0.021

0.003 ∞0.001

0.06 0.02

0.05 0.064

0.08 0.042 0.005

0.044 0.017

0.037 0.014 0.005

0.13 0.064 ∞0.001

0.003

0.017 0.013 0.12 0.007

0.021 0.007 0.021

0.006 0.009

0.05 0.021 0.064

0.019 0.024 0.066

0.006

0.056

0.023 0.028 0.162

0.002 0.001 0.01 0.01 0.027

0.002 0.003 0.002 0.007 0.01 0.052

0.005 0.023 0.005 0.001 0.182

0.045

0.005 0.005 0.005

0.003

0.003

0.014

0.003 0.007

0.021 0.007

0.009

0.011

0.028

0.002 0.023

0.013 0.017

0.036

0.005 0.033

0.017 0.017

0.005 0.009

0.002 0.038 ∞0.001

0.003 0.013

0.029

0.014

0.014 0.009

0.003

HLA 2004: Immunobiology of the Human MHC

0.014 0.002 0.003 0.021 0.01 0.007 0.042 0.002 0.014

25

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2d. HLA-B alleles found in Southwest Asia (SWA)

2n k Expected Heterozygosity *0702 *0705 *0801 *0805 *1301 *1302 *1401 *1402 *1404 *1501 *1502 *1503 *1505 *1508 *1513 *1516 *1517 *1518 *1525 *1528 *1529 *1540 *1801 *2702 *2705 *2707 *2714 *3501 *3502 *3503 *3508 *3512 *3513 *3520 *3521 *3701 *3702 *3801 *3901 *3902 *3906 *3910 *4001 *4002 *4006 *4011 *4101 *4102 *4201 *4202 *4402 *4403 *4405 *4406 *4407 *4415 *4501 *4701 *4801 *4804 *4901 *5001 *5101 *5104 *5106 *5107 *5108 *5114 *5201 *5301 *5302 *5501 *5601 *5701 *5702 *5703 *5801 *5802 *7301 *7801 *7802 *7803 *8101

26

Population Arab Druze 200 39 0.955 0.065 0.015 0.005 0.03 0.02

Israeli Jews 218 51 0.964 0.009 0.028 0.005 0.014 0.028

Kurdish 58 24 0.938 0.069 0.034 0.017 0.017 0.034

New Delhi 132 31 0.933 0.008 0.015 0.083

Omani 240 38 0.925 0.017 0.004 0.112

0.008

South Indian 208 33 0.925 0.024 0.01 0.067

Tamil 98 23 0.929

0.014 0.014

0.061

0.041 0.071

0.004 0.021

0.028 0.05 0.008

0.031 0.009

0.046 0.014 0.017

0.009

0.02

0.008 0.008

0.004 0.004 0.004 0.024 0.014 0.005

0.031 0.041 0.01

0.008 0.085 0.025 0.005 0.045 0.03 0.05 0.03

0.046 0.004

0.005 0.01

0.05

0.034

0.038

0.031

0.018

0.017 0.017

0.015 0.015

0.05 0.028 0.028 0.009 0.005 0.005

0.052 0.017 0.086 0.034

0.068

0.071

0.01

0.02

0.091

0.004 0.058

0.082

0.071

0.01

0.01

0.035

0.025

0.01 0.005 0.05 0.01 0.055

0.018 0.005 0.009 0.069 0.005 0.005

0.008 0.008 0.017

0.005

0.025 0.085 0.06 0.005 0.005 0.02

0.087

0.02

0.004 0.01 0.033 0.004

0.005 0.018 0.005

0.008 0.008 0.106

0.018 0.009

0.008 0.008

0.005 0.05 0.02

0.004

0.088

0.005 0.01 0.005 0.13

0.143

0.019

0.051

0.008 0.012

0.005 0.028 0.05 0.009 0.005 0.009

0.086 0.052

0.008 0.106

0.012

0.01 0.004 0.012 0.004

0.005 0.005

0.017

0.032 0.055 0.009 0.005 0.009

0.034 0.034 0.121

0.015 0.098

0.004 0.029 0.175

0.023

0.01 0.025 0.005 0.03

0.009 0.018 0.078 0.018 0.005 0.018

0.015

0.01 0.005 0.01 0.12

0.01 0.092

0.024 0.005

0.02

0.103 0.034

0.061

0.042 0.029

0.12 0.01

0.082

0.034 0.017

0.017

0.009

0.038 0.015 0.038

0.014 0.014 0.029

0.01 0.102

0.005 0.015

0.028 0.032

0.068

0.072

0.02

0.005

0.023

0.012 0.004 0.004 0.067 0.008 0.008

0.008 0.005 0.01 0.012

HLA 2004: Immunobiology of the Human MHC

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2e. HLA-B alleles found in Southeast Asia (SEA) Population

2n k Expected Heterozygosity *0702 *0705 *0801 *1301 *1302 *1401 *1402 *1501 *1502 *1503 *1505 *1506 *1507 *1508 *1511 *1512 *1513 *1515 *1516 *1517 *1518 *1521 *1524 *1525 *1527 *1529 *1531 *1532 *1534 *1542 *1558 *1801 *1802 *1803 *2704 *2705 *2706 *2707 *3501 *3502 *3503 *3505 *3508 *3517 *3520 *3701 *3801 *3802 *3901 *3902 *3905 *3907 *3909 *3915 *4001 *4002 *4003 *4005 *4006 *4007 *4010 *4012 *4201 *4202 *4402 *4403 *4410 *4501 *4601 *4801 *4803

Ami 97 196 8

Atayal 212 10

Bunun 202 10

Chinese 562 49

Hakka 110 31

0.77

0.788

0.828

0.931 0.009 0.016

0.907

0.267

0.08 0.018 0.002

0.005

0.044 0.071

0.027 0.009 0.064 0.018 0.027 0.027 0.009

HanChinese 149 298 35

HanChinese 572 1144 55

0.915 0.01 0.017

Malay 202 38

Minnan 204 32

0.949 0.01 0.02

0.907

0.084 0.017

0.919 0.002 0.014 0.003 0.078 0.019

0.054 0.005

0.074 0.01

0.04 0.057

0.022 0.102

0.015 0.084

0.034 0.059

0.005

North America (As) 792 66

Paiwan 51 102 11

Pazeh 110 22

0.956 0.024 0.013 0.011 0.039 0.02 0.001

0.79

0.897

0.255

0.118

0.047 0.051 0.001

0.039

0.027 0.036

0.01

0.109

0.002 0.003 0.001 0.002

0.018 0.009

0.01

0.005 0.012

0.003

0.005 0.069

0.001

0.026

0.028

0.064

0.007 0.002

0.018 0.009

0.011 0.002

0.009

0.001 0.004 0.002 0.003

0.019 0.004

0.005 0.04 0.01

0.005 0.005

0.004 0.001 0.003 0.001 0.003 0.003 0.001 0.001 0.013 0.013 0.001 0.008 0.001 0.001

0.001 0.001 0.009 0.009 0.01

0.002 0.012

0.08

0.018

0.009

0.009

0.004 0.007 0.002

0.007 0.003

0.001 0.001

0.099

0.01

0.019

0.015 0.01

0.025

0.003

0.001

0.01

0.01

0.02

0.016

0.01

0.003 0.007

0.01 0.01

0.035 0.01 0.005 0.069

0.005

0.005

0.01 0.005 0.003 0.015 0.006 0.035 0.001 0.009 0.003 0.001

0.109

0.01

0.018 0.009

0.005 0.002 0.003 0.102

0.198

0.149

0.012 0.071 0.002 0.002

0.036 0.036

0.047 0.023

0.004 0.009 0.054 0.014

0.003

0.003

0.174 0.017

0.001 0.001 0.152 0.005

0.005 0.059 0.005

0.201 0.039

0.01

0.04

0.01

0.002 0.014 0.327 0.051

0.349 0.019

0.213 0.025

0.014

0.149 0.018

0.218 0.018

0.012

0.009

0.002

0.005 0.005 0.045

0.064 0.02

0.008 0.004 0.061 0.02 0.001

0.101 0.03 0.001 0.001 0.018

0.049

0.018 0.018

0.333 0.137

0.218 0.027 0.009

0.01 0.001 0.003 0.005

0.26

0.005 0.17

0.089

0.016

0.009

0.003

0.004 0.116 0.016 0.016

0.136

0.134 0.017

0.009

0.002 0.008 0.001 0.163 0.013 0.014

0.064

0.005

0.008 0.042 0.001

0.015

0.152 0.02

0.068 0.021

HLA 2004: Immunobiology of the Human MHC

0.088

0.082 0.055

27

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2e. Continued Population Ami 97 *5001 *5101 *5102 *5104 *5106 *5107 *5201 *5401 *5501 *5502 *5503 *5504 *5507 *5601 *5602 *5603 *5604 *5701 *5801 *5901 *6701 *7802 *8101

Atayal

Hakka

HanChinese 149

0.027 0.009

0.084 0.013

HanChinese 572 0.001 0.043 0.01

0.005

0.009 0.025

0.027

0.003 0.01 0.017

0.001 0.006 0.03

0.134

0.018

0.036

0.03

0.022

Bunun

Chinese 0.002 0.05 0.014

Minnan

0.015 0.04

0.039 0.01

Paiwan 51

Pazeh 0.009 0.009

0.005

0.02

0.118

0.03 0.005 0.01

0.005 0.01 0.039 0.029

0.019 0.035 0.004 0.028

0.009 0.059

0.036

0.001 0.005 0.204

0.019

0.05

0.009

0.018

0.002 0.004

0.009

0.089 0.002 0.004 0.002

0.109

0.013 0.003

0.104

0.018

population has experienced. The demographic history of a population affects all loci equally, and is expected to result in a correlation among levels of diversity at different genes. Differing selection among loci, on the over hand, may result in discordant levels of polymorphism. We investigated the importance of demographic history upon polymorphism at different genes by contrasting a simple demographic classification of populations to the levels of He. Populations were assigned to three classes of complexity (see reference 5, this volume, for the full definition of this variable). An analysis of variance showed that, after accounting for regional differences, complexity was an important predictor of quartile rank of He for all loci except DQB1, DPB1, and DPA1. For all class I loci, DRB1, and DQA1, populations with complexity equal to one had significantly lower quartile ranks (i.e., lower He) than either of the two higher complexity levels. Across all loci, population samples with higher complexity levels tend to be among the highest quartile ranks for their region. This pattern was evident but not as strong for populations from AUS, NEA, NAM, and SAM where all populations had a complexity level of one or two. In African populations, the He for all loci was among the highest regardless of the complexity level. Test of neutrality and distribution of allele frequencies

Our analyses detected a large proportion of populations with homozygosity (F) values that were significantly lower than

28

Malay

North America (As) 0.001 0.064 0.006 0.001

HLA 2004: Immunobiology of the Human MHC

0.006

0.006 0.003

0.005 0.001 0.001 0.003 0.073

0.01

0.005 0.005 0.02 0.05

0.009

0.001

0.009 0.073 0.005 0.005

0.002

0.001

0.088

0.01

0.036 0.009 0.027

neutral expectations (Table 8). We found that, even for populations for which neutrality was not rejected, most of the F values were lower than neutral expectations (yielding FND values which were negative). The mean FND at each locus deviated significantly from neutral expectations for all loci except DPA1 and DPB1. Thus, even for loci at which only 10% of the populations deviated from neutrality (e.g., HLA-A), the entire set of populations provided evidence of deviation from neutrality (9). Several processes are consistent with these findings: bottlenecks, the binning/filtering process, and balancing selection. Population bottlenecks are an unlikely explanation, since it is unlikely that they would have occurred in such a wide range of populations. In addition, there is growing evidence that human populations are characterized by a genetic signature of population expansion, rather than reduction (11). We investigated the effect of the binning/filtering process, since it could result in an excess of intermediate frequency alleles, leading to deviation from neutrality. We found that of the 77 samples for which neutrality was rejected at the 0.05 level, only two were nonsignificant when the data was analyzed without binning/filtering [Finn (DRB1, DQB1)]. Eight population samples [Slovenian (DQA1), Chaouya (B), Metalsa (A), Malay (C), Doggon (DRB1), Rwandan (DQB1), Ugandan (C), Zulu (B)] were significant after binning/filtering, but not before. This shift towards significance is an expected consequence of binning/ filtering, which reduces the number of alleles but has a small

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2e, Continued

2n k Expected Heterozygosity *0702 *0705 *0801 *1301 *1302 *1401 *1402 *1501 *1502 *1503 *1505 *1506 *1507 *1508 *1511 *1512 *1513 *1515 *1516 *1517 *1518 *1521 *1524 *1525 *1527 *1529 *1531 *1532 *1534 *1542 *1558 *1801 *1802 *1803 *2704 *2705 *2706 *2707 *3501 *3502 *3503 *3505 *3508 *3517 *3520 *3701 *3801 *3802 *3901 *3902 *3905 *3907 *3909 *3915 *4001 *4002 *4003 *4005 *4006 *4007 *4010 *4012 *4201 *4202 *4402 *4403 *4410 *4501 *4601 *4801 *4803 *5001 *5101

Population Puyuma 49 100 11

Rukai 100 9

Saisiat 102 9

Singapore (Chinese) 172 42

Siraya 102 25

Thai 198 32

Thao 60 10

Toroko 110 7

Tsou 102 10

Yami 100 8

0.873

0.835

0.597

0.93 0.012 0.017

0.908

0.839

0.764

0.844

0.756

0.17

0.28

0.029

0.047 0.012

0.01 0.127 0.01

0.933 0.01 0.061 0.005 0.091 0.015

0.217

0.009

0.176

0.04

0.006 0.029 0.116

0.029 0.01

0.01 0.061

0.017 0.01

0.12

0.006

0.01

0.049

0.4

0.009

0.029

0.03

0.133

0.218

0.245

0.25

0.355 0.073

0.176 0.088

0.03 0.23

0.191

0.088

0.04

0.06 0.18

0.015 0.005 0.006 0.07

0.07

0.006

0.049 0.02

0.015

0.117

0.006 0.02 0.012 0.006 0.006 0.017

0.09

0.056 0.069

0.035 0.025 0.04

0.006 0.017

0.029

0.006 0.006

0.01 0.05

0.13

0.01 0.549

0.012 0.006 0.006 0.064 0.012

0.01 0.01 0.01

0.029 0.01

0.035 0.015

0.11

0.005 0.005 0.17 0.06

0.12

0.19 0.13

0.07

0.314 0.01

0.128

0.127 0.196

0.04 0.015

0.017 0.012

0.02

0.01

0.006

0.01

0.03

0.145 0.017 0.012

0.039 0.049

0.172

0.039 0.02

0.023

0.01

0.035

0.017 0.083

HLA 2004: Immunobiology of the Human MHC

29

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2e, Continued Population Puyuma 49 *5102 *5104 *5106 *5107 *5201 *5401 *5501 *5502 *5503 *5504 *5507 *5601 *5602 *5603 *5604 *5701 *5801 *5901 *6701 *7802 *8101

Rukai

Saisiat

Singapore (Chinese)

Thai 0.015

Thao

Toroko

Tsou

0.145

0.118

Yami

0.006 0.023 0.006 0.052 0.035 0.04

0.06

0.02

0.015 0.029

0.017 0.025

0.029

0.1

0.006 0.04

0.01

0.006 0.006 0.01

0.02 0.01 0.01

0.006 0.058

0.059

0.086

0.05

0.01

effect on the expected heterozygosity, increasing the proportion of alleles at intermediate frequencies. This pattern is also seen for FND values, which were more negative after binning for 324/335 datasets (indicating a shift to intermediate frequencies). The 11 datasets for which binning/filtering increased the FND included five with large decreases in expected heterozygosity (2% ∞) due to binning [Bari(C), Puyuma (C), Finn (DRB1, DQB1), PNG Highlander (DQB1)], in addition to six samples with smaller changes in expected heterozygosity [Kenyan (A), American Samoa (C), Czech (B), Kenyan (B), Shona (B), Algerian (DRB1)]. Overall, we found that while the binning/filtering did result in datasets with more alleles at intermediate frequencies, there was only a minor change to the proportion of datasets with significant deviation from neutral expectations. In addition, the overall trend of the data in the direction of an excess of intermediate frequency alleles is clearly present in the unbinned/unfiltered data. A form of balancing selection remains a likely explanation for the overall excess in intermediate frequency alleles seen in the data, since it is consistent with other features of HLA polymorphism. The frequency of singleton alleles describes how much of the total frequency spectrum exists in the form of alleles that are observed as a single copy. The number of different alleles needed to reach a frequency of 0.5 focuses on the other extreme of the frequency spectrum. It provides information on the number and frequency of higher frequency alleles that

30

Siraya

HLA 2004: Immunobiology of the Human MHC

are observed in the dataset. Low values for this statistic imply a few high frequency alleles. Moderate values are a result of more even allele frequencies. For all loci but HLA-B, the average frequency of singleton alleles was less than 3% of the total allele frequency. For HLAB, the most polymorphic in our dataset, the mean contribution of singletons to the allele frequency was 5%. The minimum number of alleles needed to attain a frequency of 0.5 highlights the extent of polymorphism in the HLA data. For the HLA class I genes, on average, 2.7, 3.1, and 4.7 high frequency alleles are required to account for a frequency of 0.5 (at HLA-A, C and B). This illustrates the fact that, on average, no single allele dominates the allele frequency spectrum, and that several intermediate frequency alleles are observed. For class II beta genes, the values are 1.8, 2.1, and 3.3, at DPB1, DQB1, and DRB1. For the less polymorphic alpha genes, the values are 1.1 and 1.7 for DPA1 and DQA1. For all loci, the minimum number of alleles needed to attain a frequency of 0.5 is a measure that is positively correlated with heterozygosity. Deviation from Hardy-Weinberg Proportions

Deviation from Hardy-Weinberg proportions may indicate processes of biological interest (selection, inbreeding), or provide information about methodological shortcomings of the survey (heterogeneous populations, typing error). Among the population samples with significant deviation from HWP,

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2f. HLA-B alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0702 *0705 *0803 *1301 *1302 *1402 *1501 *1502 *1503 *1506 *1513 *1518 *1521 *1523 *1525 *1531 *1535 *1801 *1802 *1803 *2704 *2706 *2708 *3501 *3503 *3505 *3520 *3701 *3801 *3802 *3901 *4001 *4002 *4006 *4008 *4010 *4011 *4012 *4014 *4403 *4601 *4701 *4801 *4803 *5101 *5102 *5106 *5201 *5301 *5401 *5501 *5502 *5504 *5601 *5602 *5604 *5701 *5801 *6701

Population American Samoa 100 25 0.87 0.01

Filipino 188 35 0.94

Indonesian 98 30 0.937 0.02 0.031

Ivatan 100 16 0.878

0.053

0.01 0.01

0.06

0.04

0.005 0.005 0.053

0.031 0.082

0.22

0.007

0.021 0.01 0.01

0.01 0.01 0.01 0.03

0.005 0.032 0.005 0.059

PNG Highlander 150 14 0.846 0.007

0.02

0.147 0.133 0.01 0.02 0.01

0.01

0.027

0.03

0.073

0.04 0.069 0.027 0.005

0.051

0.02 0.07

0.02 0.01 0.016

0.01

0.016 0.005 0.085 0.005 0.005 0.021 0.128 0.016 0.064 0.085

0.01 0.031 0.051

0.033 0.013

0.01 0.04 0.29 0.03 0.01 0.01 0.01 0.01 0.01

0.06

0.02 0.071 0.112 0.01 0.082

0.06 0.03 0.17 0.14

0.147 0.047

0.011

0.011 0.021

0.02 0.02 0.007

0.1 0.06

0.037 0.027 0.005 0.005 0.005 0.005

0.08 0.02 0.02 0.02 0.01

0.01 0.007

0.12 0.03 0.02 0.1 0.01

0.011

0.01 0.01

0.005 0.069

0.213 0.233

0.02 0.031

0.01

32/45 have more homozygotes than expected under HWP, and only 13/45 show an excess of heterozygotes. Among population samples where deviation from HWP is not significant, a smaller proportion (143/290) show more homozygotes than expected under HWP. Although selection favoring heterozygotes has been invoked to explain HLA diversity (2)

we found that most datasets with significant deviation from HWP had more homozygotes than expected under HWP, a finding that is consistent with the presence of blank alleles in the data. However, a small excess of homozygotes over HWP expectations is not incompatible with a few genotypes showing heterozygote excess and contributing to overall deviation HLA 2004: Immunobiology of the Human MHC

31

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Figure 3. Barplots of the degree of sharing of alleles among world regions for HLA-BFor each region there are two columns. The first depicts the fraction of alleles in a region which are either exclusively found in that region (black), shared by two (dark gray), three (light gray), or more than three regions (white) regions. The second column shows the contribution of the alleles in each category to the overall alleles frequency in that region (i.e., a frequency weighted version of the first column). The total number of alleles is indicated at the top of each set of columns.

from HWP. We are currently investigating the contribution of individual genotypes to overall deviation from HWP. The binning/filtering process had little impact on the results; only nine out of 335 datasets differed with respect to rejection of HWP before and after binning/filtering. Of these, six [Czech (DQB1), Finn (DQB1, DRB1), Yupik (A), Yupik (C), Kenyan (DQB1)] show significant deviation for the unbinned/unfiltered data, whereas three [Algerian (DQB1), Seri (A), Kenyan (DPB1)] are only significant after binning/filtering. These population samples are among those with the highest change in number of alleles and heterozygosity due to binning/filtering (6/9 of these population samples show changes in the number of alleles of three or greater).

32

HLA 2004: Immunobiology of the Human MHC

Deviations from HWP may arise due to the merging of diverged populations, creating an excess of homozygotes. We investigated whether this effect was present using the categorization of populations into three classes of complexity. There is not trend of increasing rejection with complexity (results not shown). Population structure is therefore unlikely to offer an explanation for the observed deviations from HWP. Our study of deviation from HWP at HLA loci provides some methodological insights into the analysis of very polymorphic datasets. We found that the Markov-Chain Monte Carlo (MCMC) implementation of the exact test needs long chains to obtain reliable results. The default values for many software packages (on the order of 100,000) proved to be

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2g. HLA-B alleles found in Australia (AUS)

2n k Expected Heterozygosity *0702 *0801 *1301 *1401 *1501 *1502 *1506 *1521 *1525 *1801 *2705 *3501 *3503 *3801 *3901 *4001 *4002 *4402 *4403 *4801 *5001 *5101 *5501 *5601 *5602 *5701 *5801

Population Cape York 200 21 0.862 0.045 0.035 0.27 0.005

Groote Eylandt 150 15 0.839

Kimberley 76 7 0.745

Yuendumu 386 11 0.835

0.02 0.233 0.007

0.132

0.244 0.008

0.007 0.015 0.135 0.01 0.005 0.005 0.005 0.02 0.035 0.08 0.08 0.025

0.06 0.08

0.173 0.18 0.007 0.007

0.026

0.124 0.057

0.013 0.184 0.276

0.021 0.049 0.189 0.003

0.005 0.007 0.007 0.005 0.165 0.03 0.015 0.01

0.18 0.027 0.007

too low for the most polymorphic HLA loci, and resulted in unreliable p-values. We compared results between analyses using shorter and longer (100,000 and 1 million, respectively) chain lengths, and found the greatest differences in the datasets with very high levels of polymorphism; this is probably a consequence of the fact that when there are large numbers of possible genotypes, the MCMC method requires greater chain length to provide adequate sampling of the space of possible configurations. We also investigated the differences between the exact and chi-squared methods by comparing populations where the latter could be performed after combining cells with fewer than 5 expected genotypes. Across all loci, 31 of the 112 instances where the chi-square test was applicable had discrepant results at the 0.05 level of significance. The chisquare test was significant in 19 cases when the exact test was not, and the opposite was true in 12 cases. These results indicate only fair agreement overall between the two tests, with a kappa statistic for inter-rater agreement of 0.26. Agreement between the two tests was better for class II loci than class I loci (kappaΩ0.41 vs. 0.14) and was better for populations with complexity level one than levels two or three (kappaΩ 0.52 vs. 0.15). Lower heterozygosity was also associated with

0.355 0.013

0.003 0.114 0.189

better agreement between the two tests, which partly explains the worse agreement for the more polymorphic class I loci. Future work will include a more thorough investigation of the behavior of tests of HWP for highly polymorphic loci. Differentiation among populations

We quantified inter-population differentiation within each region using Fst, and these values are reported in Table 3. The samples from SSA, NAF and EUR showed the lowest interpopulation differentiation (Fst values 0.01–0.03). Differentiation among populations within NAM, SAM, and OCE was high, and AUS, and Asian (NEA, SEA and SWA) populations were intermediate. A recent survey of 377 autosomal microsatellite loci showed similar trends, with greatest differentiation among populations in the Americas and Oceania, and lowest in Europe (8). Differentiation among regions of the world for HLA loci is discussed in detail by Sanchez-Mazas (2004, this volume). The author found that differentiation within and among continents for HLA loci was similar to that for non-HLA genes. Thus, similar to the results reported above for differentiation among populations within regions, we find that although balancing selection may be shaping the allele frequency distribution within HLA 2004: Immunobiology of the Human MHC

33

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2h. HLA-B alleles found in Northeast Asia (NEA)

2n k Expected Heterozygosity *0702 *0705 *0801 *0803 *1301 *1302 *1401 *1501 *1502 *1503 *1507 *1511 *1517 *1518 *1524 *1525 *1527 *1534 *1801 *2702 *2704 *2705 *2711 *3501 *3502 *3503 *3506 *3701 *3801 *3802 *3901 *3902 *4001 *4002 *4003 *4006 *4011 *4019 *4402 *4403 *4601 *4701 *4801 *4804 *5001 *5101 *5102 *5106 *5110 *5201 *5301 *5302 *5303 *5401 *5501 *5502 *5601 *5605 *5701 *5801 *5901 *6701 *7301

Population Korean 200 400 37 0.944

Okinawan 208 20 0.91

Tuva 360 52 0.956

0.038 0.002

0.014

0.01 0.045 0.008 0.088 0.005

0.01

0.072 0.003 0.008 0.003 0.006 0.033

0.13

0.042 0.003

0.005 0.015

0.005

0.022

0.029

0.017 0.008 0.006 0.011 0.003

0.159

0.006 0.011 0.003 0.003 0.008 0.003 0.056 0.017 0.011 0.003 0.039 0.008

0.002

0.052 0.062 0.002 0.008 0.012 0.018 0.04 0.05 0.005 0.035 0.01 0.068 0.062 0.002 0.025 0.125 0.008

0.077 0.058 0.096 0.058

0.024 0.01 0.014 0.087

0.025

0.024

0.048

0.106

0.025 0.002 0.002 0.005 0.055 0.01 0.002

0.019 0.005

0.008 0.003 0.05 0.097 0.006 0.003 0.006 0.047 0.025 0.014 0.047 0.003 0.017 0.061 0.003 0.003 0.031 0.022 0.003 0.003 0.022 0.028 0.008 0.033 0.067

0.062 0.014

We quantified regional differentiation by investigating the degree of allele sharing among regions. Figure 3 shows the results for HLA-B. For each region there are two columns; the first depicts the fraction of alleles in a region which are either exclusively found in that region, shared by two, three, or more than three regions. The second column shows the contribution of the alleles in each category to the overall allele frequency in that region. Notice that although there may be a relatively large number of alleles that are exclusive to a region (e.g., more than 10% in SSA), their frequencies are small (see height of black area in second column for each region). This pattern is observed among regions and loci, and reflects the fact that exclusive alleles, or those shared by few regions, are in general the rare ones. Specific exclusive alleles that are present with a frequency above 0.05 can be identified in Table 4. Graphs of allele sharing for all loci are present at the IHWG website. We compared the distribution of region specific alleles to the findings of Zhivotovsky et al., 2003 (13), who analyzed 377 autosomal microsatellite loci in 52 populations. The authors found that 7.4% of the non-singleton alleles were region specific (referred to as ‘‘private’’), and that these were found in greatest number in SSA, followed by OCE, lowest in Amerindian populations, and intermediate for the remaining world regions. Among the HLA loci that we surveyed 17% and 22% of the class I and II non-singleton alleles, respectively, were region specific. The higher proportion of region specific alleles results from the greater polymorphism that is observed at the HLA genes. We found that SSA had the highest number of private alleles for A, B, DPB1 and DRB1 (DPA1, DQA1 and DQB1 had two or fewer private alleles in the entire dataset, and are not considered further in this discussion). HLA-C differed from the other genes, with only one private allele in SSA, and five in SWA. Populations from SAM were among those with the lowest number of private alleles for A, C, DQB1 and DRB1. Interestingly, for HLA-B, SAM had five region specific alleles (the second highest value), in agreement with previous results that HLA-B shows a high degree of allelic turnover for HLA-B (6). In contrast to results obtained with microsatellites, we did not find a high frequency of alleles exclusive to OCE.

0.003 0.008

Conclusions

individual populations, it does not appear to be slowing down the rate of inter-population differentiation, as has been seen for other loci under balancing selection (e.g. CCR5, (1)).

34

HLA 2004: Immunobiology of the Human MHC

In this chapter we provided a description of the polymorphism at classical HLA genes, and carried out population genetic analyses of the 13th IHWS dataset. We found features that indicate the HLA genes have experienced selection, including an excess of intermediate frequency alleles, and high

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2i. HLA-B alleles found in North America (NAM)

2n k Expected Heterozygosity *0702 *0705 *0801 *1302 *1401 *1402 *1501 *1502 *1503 *1507 *1509 *1510 *1515 *1516 *1517 *1524 *1525 *1801 *2702 *2703 *2705 *2706 *2707 *3501 *3502 *3503 *3508 *3510 *3512 *3701 *3801 *3901 *3903 *3905 *3906 *3911 *4001 *4002 *4003 *4005 *4006 *4015 *4019 *4101 *4102 *4402 *4403 *4404 *4501 *4801 *4803 *4901 *5001 *5101 *5102 *5108 *5201 *5301 *5303 *5501 *5601 *5701 *5801 *5802 *7301 *7801

Population Amerindian 468 55 0.944 0.068 0.002 0.045 0.021 0.004 0.011 0.083 0.004 0.006 0.002 0.006 0.002 0.006 0.002 0.002 0.002 0.019

Canoncito 82 15 0.885

Pima 99 178 21 0.891 0.017

Seri 66 10 0.714

0.006

Yupik 504 21 0.84 0.016 0.004

0.006 0.012

0.011

0.045

0.058 0.002

0.037

0.09 0.002

0.037

0.079

0.015

0.006 0.004 0.109 0.115

0.107 0.002 0.006 0.002

0.207

0.124

0.485

0.002 0.107

0.002 0.006 0.009 0.041 0.004 0.004 0.015 0.038 0.056 0.002 0.004 0.004 0.002

0.006

0.002 0.002 0.006 0.037 0.159 0.037 0.049

0.045 0.073 0.006 0.039 0.101

0.152

0.146

0.091

0.006 0.006

0.03

0.008 0.002

0.03

0.147

0.01 0.296

0.024 0.006 0.006 0.041 0.034 0.004 0.015 0.017 0.011 0.004 0.105 0.006 0.004 0.004 0.009

0.098

0.049 0.134

0.169 0.006 0.011 0.135

0.121 0.015

0.002 0.004 0.103

0.006 0.085 0.024

0.002

0.009 0.009 0.017 0.011 0.002 0.015 0.012

levels of polymorphism. We also found that the demographic history of human populations accounts for several features of HLA variation, such as the variation in levels of polymorphism among world regions, and the distribution of region

specific alleles. Thus, although HLA alleles bear signatures of loci under natural selection, they also record features of the demographic history of human populations.

HLA 2004: Immunobiology of the Human MHC

35

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2j. HLA-B alleles found in South America (SAM)

2n k Expected Heterozygosity *0702 *1301 *1401 *1501 *1503 *1504 *1507 *1508 *1520 *1522 *3501 *3503 *3504 *3505 *3506 *3508 *3509 *3510 *3511 *3512

Population Bari 88 10 0.745

Guarani-Kaiowa 288 32 0.915

0.028 0.009 0.009 0.009

0.114

0.159 0.011

0.011

Guarani-Nandeva 106 30 0.919

0.003 0.125 0.01 0.007 0.01 0.021 0.01 0.007 0.142 0.014 0.003 0.003 0.003 0.059 0.003

0.198 0.009 0.028 0.009 0.009 0.019 0.009 0.047 0.066 0.047

0.019

Table 5.2j. HLA-B alleles found in South America (SAM) Population Bari *3516 *3901 *3902 *3903 *3905 *3906 *3907 *3909 *3911 *3913 *4001 *4002 *4004 *4005 *4801 *4802 *5101 *5104 *5105 *5106 *5110 *5201

0.239

Guarani-Kaiowa 0.003 0.049 0.014 0.003 0.111 0.09

Guarani-Nandeva 0.028 0.019 0.019 0.094 0.009 0.009 0.028

0.083 0.01 0.003

0.009 0.009

0.398 0.101 0.003

0.104 0.009

0.011 0.011

0.007 0.007 0.062 0.003

0.057 0.066 0.009

0.003 0.021

0.009

0.011 0.034

Table 5.2k. HLA-B alleles found in other regions (OTH)

2n k Expected Heterozygosity *0702 *0705 *0707 *0801 *0803 *0805 *1302 *1401 *1402 *1405 *1501 *1503 *1505 *1508 *1509 *1510 *1515 *1516 *1517 *1523 *1524 *1528 *1530 *1537 *1538 *1539 *1801 *2702 *2703 *2705 *3501 *3502 *3503 *3504 *3505 *3508 *3509 *3512 *3516 *3517 *3520 *3701

36

Population Brazilian 178 43 0.961 0.056 0.067 0.006 0.006 0.056 0.011 0.034

Brazilian (Af Eu) 138 54 0.967 0.101 0.007 0.043 0.022 0.036 0.022 0.007 0.022 0.014

0.017 0.006 0.011

Cuban (Af Eu) 84 33 0.95 0.06 0.024

Mexican 80 37 0.962 0.05

North America (Hi) 480 62 0.965 0.067 0.004

0.048

0.025

0.038

0.012

0.012 0.012 0.05

0.015 0.012 0.044

0.038 0.012

0.029 0.019 0.002 0.006

0.024 0.024

0.012 0.012 0.014 0.007 0.014

0.025 0.025 0.025 0.025

0.012

0.006 0.004 0.002 0.004

0.012 0.002 0.002 0.014 0.007 0.067 0.028

0.012 0.062 0.012

0.051

0.048

0.007 0.017 0.045

0.051 0.022

0.051 0.011

0.012 0.095 0.024 0.024

0.012 0.075

0.022 0.011

0.012 0.014

0.006

0.014 0.007 0.007

HLA 2004: Immunobiology of the Human MHC

0.012

0.062 0.012 0.025 0.025

0.025 0.071 0.004 0.01 0.006 0.008 0.004 0.002 0.023 0.006 0.004

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.2k. Continued

*3801 *3802 *3901 *3902 *3903 *3905 *3906 *3908 *4001 *4002 *4003 *4004 *4005 *4012 *4101 *4102 *4201 *4202 *4402 *4403 *4404 *4405 *4406 *4407 *4501 *4701 *4801 *4802 *4901 *5001 *5101 *5102 *5104 *5107 *5108 *5201 *5301 *5302 *5501 *5601 *5701 *5702 *5703 *5801 *5802 *6701 *7301 *7801 *8101 *8201

Population Brazilian 0.022

Brazilian (Af Eu) 0.022 0.007 0.029

Cuban (Af Eu)

Mexican 0.012

North America (Hi) 0.017

0.012

0.019 0.004

0.012

0.007 0.05 0.017 0.028 0.017

0.007 0.007 0.014

0.012 0.06 0.012

0.038 0.012

0.007 0.012 0.011 0.039 0.045 0.045 0.006

0.012 0.007 0.022 0.029 0.036 0.007 0.007 0.007 0.014

0.028 0.006 0.022 0.034 0.067

0.024 0.048 0.012 0.048

0.025

0.004 0.004 0.002 0.01 0.004 0.002 0.033 0.054 0.002 0.002

0.036 0.007 0.014 0.014 0.051 0.007 0.007

0.021 0.019 0.006 0.015 0.05

0.06 0.012 0.048

0.015 0.038

0.012

0.012

0.019 0.023 0.062 0.004

0.05 0.012

0.006 0.011 0.017

0.029 0.022 0.007

0.012 0.107

0.011 0.006 0.006 0.011 0.022 0.006 0.006

0.05

0.044 0.029

0.025

0.008 0.002 0.019

0.007 0.014 0.022 0.007

0.012 0.048 0.024

0.022

0.012 0.012

0.006

0.006 0.01

0.012

0.002 0.004 0.002

0.007

HLA 2004: Immunobiology of the Human MHC

37

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.3. HLA-C Table 5.3a. HLA-C alleles found in Sub-Saharan Africa (SSA) Population

2n k Expected Heterozygosity *0102 *0202 *0302 *0303 *0304 *0305 *0308 *0310 *0401 *0404 *0407 *0501 *0602 *0701 *0702 *0704 *0705 *0708 *0714 *0801 *0802 *0804 *1202 *1203 *1204 *1402 *1403 *1502 *1503 *1505 *1601 *1602 *1604 *1701 *1801

Doggon 258 19 0.84 0.008 0.054 0.012 0.016

0.213 0.004 0.008 0.054 0.062 0.047

Kenyan 142 224 25 0.892 0.004 0.058 0.027

Kenyan Highlander 480 21 0.887 0.002 0.088 0.046

0.04 0.004 0.004 0.129 0.004 0.022 0.174 0.179 0.045 0.027 0.004

Kenyan Lowlander 530 22 0.902

North America (Af) Shona 504 452 23 21 0.909 0.909

0.042

0.1 0.032 0.002 0.047

0.097 0.028 0.018 0.044

0.111 0.011 0.009 0.084

0.115 0.012

0.132 0.008

0.157

0.017 0.217 0.152 0.008 0.065

0.011 0.187 0.117 0.038 0.051 0.008

0.02 0.115 0.135 0.089 0.01 0.002 0.002 0.032 0.008 0.002 0.024

0.004

Ugandan 326 24 0.913 0.025 0.092 0.018 0.037 0.052 0.003

Zambian 90 12 0.894

Zulu 196 18 0.89

0.1

0.158

0.022 0.089

0.005 0.051

0.148

0.141

0.144

0.031

0.015 0.007 0.128 0.106 0.046 0.042

0.04 0.117 0.16 0.061 0.018

0.033 0.122 0.044 0.022

0.138 0.128 0.051 0.015

0.006 0.061

0.067

0.005 0.036 0.026

0.002 0.029 0.038

0.023 0.008 0.008 0.019

0.018 0.004

0.006 0.015

0.051 0.008

0.009

0.01

0.011

0.019

0.004 0.004

0.01

0.004

0.006

0.002

0.004 0.085 0.004

0.008 0.044 0.012

0.006 0.045 0.006

0.014 0.083

0.002 0.08

0.012 0.003 0.003 0.049 0.003

0.103 0.036

0.102 0.023

0.087 0.049

0.06 0.038

0.082 0.049

0.028 0.009

0.283 0.004 0.143 0.016

0.061

0.009 0.037

0.002 0.004 0.004

0.02 0.002 0.002

0.01 0.01

0.015

0.005

0.1

0.056

0.156 0.1

0.184 0.031

Table 5.3b. HLA-C alleles found in North Africa (NAF) No Data Table 5.3c. HLA-C alleles found in Europe (EUR)

2n k Expected Heterozygosity *0102 *0202 *0302 *0303 *0304 *0401 *0403 *0407 *0501 *0602 *0701 *0702 *0704 *0707 *0801 *0802 *1202 *1203 *1204 *1301 *1402 *1403 *1502 *1504 *1505 *1507 *1601 *1602 *1604 *1701

38

Population Bulgarian 22 11 0.864 0.091

0.091

Czech 210 22 0.908 0.019 0.048 0.005 0.038 0.052 0.11

Finn 90 180 17 0.894 0.072 0.056 0.122 0.111 0.133

Georgian 214 24 0.903 0.033 0.019 0.005 0.047 0.023 0.22

Irish 2000 23 0.886 0.024 0.02 0.002 0.05 0.064 0.082

0.011 0.061 0.039 0.144 0.156 0.006

North America (Eu) 584 22 0.912 0.029 0.033 0.003 0.07 0.08 0.108 0.002

0.028 0.117 0.103 0.065 0.009

0.127 0.088 0.187 0.186 0.013

0.096 0.086 0.161 0.12 0.019

0.005 0.014 0.009 0.089 0.023

∞0.001 0.057 0.003 0.025

0.039 0.012 0.053

0.047 0.014 0.028 0.028

0.004 ∞0.001 0.011

0.019 0.042 0.005 0.009

0.05 ∞0.001 ∞0.001 0.004

0.045 0.091 0.045

0.057 0.162 0.129 0.124 0.048 0.005

0.045 0.091 0.045

0.024 0.005 0.086

0.006 0.028

0.029

0.006

0.01 0.005 0.005

0.022

0.01 0.005

0.006

0.029

0.022

0.045 0.273 0.136

HLA 2004: Immunobiology of the Human MHC

∞0.001

0.019 0.017 0.003 0.005 0.026 0.003 0.015

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.3d. HLA-C alleles found in Southwest Asia (SWA)

2n k Expected Heterozygosity *0102 *0103 *0104 *0202 *0203 *0302 *0303 *0304 *0305 *0306 *0307 *0312 *0401 *0403 *0404 *0407 *0501 *0602 *0604 *0701 *0702 *0703 *0704 *0705 *0707 *0713 *0801 *0802 *0805 *1202 *1203 *1204 *1205 *1207 *1402 *1403 *1502 *1504 *1505 *1507 *1508 *1601 *1602 *1604 *1701 *1801

Population Arab Druze 200 23 0.896 0.01 0.065

Israeli Jews 188 37 0.943 0.016 0.016 0.016 0.09 0.021 0.027

Kurdish 58 18 0.891 0.069

New Delhi 112 23 0.925 0.036

Tamil 96 20 0.908 0.021

0.018

0.01

0.045

0.021 0.042

0.017 0.005

0.016 0.009 0.005 0.005

0.225 0.005 0.015 0.13 0.005 0.09 0.04

0.101 0.005 0.027 0.027 0.032 0.122 0.011 0.037 0.032

0.018 0.116 0.009

0.042 0.031

0.017 0.017 0.052

0.054

0.042

0.062

0.177

0.069 0.034

0.125 0.089 0.018

0.135 0.094

0.224

0.017

0.031

0.005 0.009 0.015 0.015 0.075 0.015 0.005 0.005 0.07 0.05 0.02 0.015 0.065 0.055

0.005 0.027 0.074 0.005 0.08 0.032 0.011 0.011 0.011 0.005 0.005 0.027 0.016 0.005 0.032 0.011 0.011 0.021 0.005

0.017

0.042

0.103 0.052

0.071 0.062

0.104 0.01

0.017 0.052 0.155

0.08 0.009 0.027 0.009 0.009 0.098

0.021 0.021 0.104

0.009

0.01 0.031

0.017 0.017 0.052

0.01

0.018

HLA 2004: Immunobiology of the Human MHC

39

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.3e. HLA-C alleles found in Southeast Asia (SEA) Population

2n k Expected Heterozygosity *0102 *0103 *0202 *0302 *0303 *0304 *0401 *0403 *0404 *0406 *0407 *0501 *0504 *0602 *0701 *0702 *0703 *0704 *0801 *0802 *0805 *1202 *1203 *1402 *1403 *1502 *1505 *1507 *1601 *1602 *1701 *1801

2n k Expected Heterozygosity *0102 *0103 *0202 *0302 *0303 *0304 *0401 *0403 *0404 *0406 *0407 *0501 *0504 *0602 *0701 *0702 *0703 *0704 *0801 *0802 *0805 *1202 *1203 *1402 *1403 *1502 *1505 *1507 *1601 *1602 *1701 *1801

40

Ami 97 196 9

Atayal 212 8

Bunun 202 8

Chinese 562 19

Hakka 110 15

Malay 214 20

Minnan 204 16

North America (As) Paiwan 51 802 102 24 9

Pazeh 110 11

0.811 0.219

0.821 0.061

0.811 0.114

0.88 0.169

0.855 0.209

0.903 0.042

0.868 0.201 0.005

0.901 0.146

0.688 0.049

0.873 0.127

0.054 0.337 0.114 0.064

0.087 0.041 0.128 0.044 0.021

0.109 0.036 0.164 0.027 0.018

0.051 0.014 0.047 0.122 0.098

0.093 0.054 0.142 0.034 0.01

0.004 0.076 0.042 0.098 0.055 0.025 0.002

0.01 0.098 0.52 0.088 0.01

0.036 0.082 0.191 0.009 0.118

0.118

0.145

0.088

0.136

0.041 0.122 0.209 0.026

0.085 0.198 0.071 0.033

0.002

0.107

0.288

0.26

0.184

0.01

0.178 0.089

0.08

0.005

0.05

0.027 0.016 0.208 0.009 0.126 0.002 0.016 0.016 0.036 0.002 0.037 0.012

0.009

0.018 0.009 0.227

0.005 0.005 0.019 0.075

0.007 0.015 0.206

0.032 0.019 0.192

0.073

0.112 0.084 0.187

0.01 0.108

0.021 0.112 0.001

0.027 0.009 0.036

0.005 0.047 0.005 0.047

0.029 0.01 0.029

0.009 0.027

0.023 0.005

0.049

0.029 0.019 0.046 0.027 0.029 0.009

0.005

0.004 0.002 0.001

0.109 0.018 0.02

Population Puyuma 49 100 8

Rukai 100 8

Saisiat 102 9

Siraya 102 14

Thai 184 19

Thao 60 7

Toroko 110 7

Tsou 102 9

Yami 100 7

0.805 0.05

0.721 0.07

0.519 0.02

0.88 0.098 0.01

0.894 0.168

0.781 0.15

0.782 0.136

0.795 0.118

0.751

0.13 0.47 0.02 0.07

0.01 0.176 0.039

0.049 0.157 0.206 0.069 0.049

0.098 0.005 0.103 0.016 0.054

0.05

0.06 0.26 0.03 0.12

0.1 0.227 0.018

0.098 0.304 0.01 0.049

0.08 0.21 0.01 0.4

0.383 0.067 0.117

0.011 0.005

0.09

0.16

0.667

0.108

0.01

0.016 0.071 0.19

0.15

0.318

0.275

0.11

0.3

0.07

0.049

0.108

0.06 0.076

0.083

0.191

0.098

0.16

0.01

0.098

0.009

0.029

0.03

0.02

0.02

0.01

0.01

0.09

0.01

0.033 0.016 0.027 0.016 0.005 0.027

0.01

HLA 2004: Immunobiology of the Human MHC

0.02

0.027

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.3f. HLA-C alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0102 *0103 *0302 *0303 *0304 *0307 *0401 *0403 *0406 *0407 *0602 *0701 *0702 *0704 *0801 *0802 *1202 *1203 *1204 *1402 *1502 *1503 *1505 *1507 *1508 *1601 *1604

Population American Samoa 100 18 0.859 0.24 0.02 0.02 0.21 0.03 0.04 0.06

Table 5.3h. HLA-C alleles found in Northeast Asia (NEA)

Filipino 188 19 0.841

Indonesian 100 15 0.889

Ivatan 100 10 0.834

0.037

0.06

0.01

0.064 0.016 0.064

0.03 0.05 0.03

0.05 0.09

0.122 0.08 0.016

0.1 0.07

0.13 0.05

0.011 0.011 0.33 0.021 0.106 0.005 0.005 0.005 0.005 0.016 0.08

0.05 0.04 0.17 0.08 0.21

0.02 0.01 0.08 0.15 0.01 0.02

0.04 0.01 0.01 0.05

0.16 0.07 0.31 0.04

0.09

0.01 0.01 0.04 0.01 0.005 0.02

Table 5.3g. HLA-C alleles found in Australia (AUS)

2n k Expected Heterozygosity *0102 *0202 *0302 *0303 *0304 *0401 *0403 *0501 *0602 *0701 *0702 *0704 *0801 *0802 *1203 *1502

Population Cape York 178 15 0.844 0.185 0.006 0.006 0.028 0.022 0.275 0.157 0.034 0.028 0.034 0.096 0.006 0.006

Kimberley 56 5

Yuendumu 384 8

0.807 0.267

0.729 0.375

0.795 0.247

0.151 0.007 0.253 0.123 0.014 0.014 0.021

0.125

0.055 0.005 0.268 0.151 0.003 0.068

0.007 0.007

0.051 0.067

0.137

0.286

Okinawan 210 12

Tuva 348 25

0.908 0.185 0.012 0.01 0.055 0.1 0.085

0.858 0.205

0.065

0.033

0.01 0.06 0.025 0.07 0.008

0.019 0.138 0.019

0.923 0.078 0.006 0.011 0.055 0.095 0.112 0.032 0.115 0.009 0.003 0.029 0.115 0.02 0.086 0.02 0.006 0.052

0.219 0.119

0.098 0.008 0.025 0.002

0.1

0.105 0.042 0.03

0.071 0.024 0.029

0.024

0.002 0.002

0.04 0.023 0.003 0.009 0.069 0.006 0.003 0.006

Table 5.3i. HLA-C alleles found in North America (NAM)

Groote Eylandt 146 11

0.179 0.036

2n k Expected Heterozygosity *0102 *0103 *0202 *0302 *0303 *0304 *0305 *0401 *0403 *0407 *0501 *0602 *0701 *0702 *0704 *0705 *0801 *0802 *1202 *1203 *1204 *1402 *1403 *1502 *1504 *1505 *1507 *1604

Population Korean 200 400 21

0.203

2n k Expected Heterozygosity *0102 *0202 *0302 *0303 *0304 *0401 *0404 *0501 *0602 *0701 *0702 *0704 *0801 *0802 *0803 *0806 *1202 *1203 *1205 *1402 *1502 *1505 *1601 *1701

Population Amerindian 496 22 0.913 0.089 0.075 0.002 0.036 0.115 0.151 0.014 0.036 0.065 0.079 0.129 0.008 0.022 0.016 0.004

Canoncito 82 7

Yupik 298 17

0.775 0.037 0.037

0.767 0.017 0.238

0.232

0.044 0.389 0.101 0.007 0.003 0.003 0.007 0.02

0.244

0.007

0.073 0.317

0.03 0.101

0.004 0.026 0.018 0.069 0.002 0.024 0.016

0.003 0.003 0.061

HLA 2004: Immunobiology of the Human MHC

0.023 0.003

41

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.3j. HLA-C alleles found in South America (SAM)

2n k Expected Heterozygosity *0102 *0303 *0304 *0401 *0602 *0702 *0801 *1502 *1503 *1507

Population Bari Guarani-Kaiowa 66 286 6 6 0.693 0.212

Guarani-Nandeva 104 8

0.767

0.808

0.409 0.015

0.094 0.217 0.185

0.303

0.364

0.045

0.045 0.094

0.192 0.192 0.173 0.01 0.24 0.01 0.01 0.173

0.015

Table 5.3k. HLA-C alleles found in other regions (OTH)

2n k Expected Heterozygosity *0102 *0103 *0202 *0302 *0303 *0304 *0305 *0401 *0404 *0407 *0501 *0602 *0604 *0701 *0702 *0704 *0708 *0714 *0801 *0802 *0804 *1202 *1203 *1402 *1403 *1502 *1504 *1505 *1507 *1509 *1601 *1602 *1604 *1701 *1801

42

Population Brazilian (Af Eu) 212 30

Mexican 58 15

North America (Hi) 492 26

0.927 0.024 0.005 0.042

0.863 0.086

0.921 0.049

0.017

0.047 0.047

0.103 0.086

0.137 0.005 0.024 0.061 0.024 0.005 0.156 0.08 0.009 0.019 0.014 0.005 0.075

0.138

0.035 0.01 0.026 0.075 0.002 0.148

0.017 0.034

0.059 0.067

0.014 0.038 0.024 0.024 0.033 0.009

0.017 0.017 0.017

0.276

0.106 0.13 0.012

0.052

0.016 0.053 0.002 0.022 0.045 0.016 0.002 0.035

0.017

0.006

0.103

0.005 0.024 0.005 0.009 0.033 0.005

0.002 0.063 0.006 0.017

0.01 0.002

HLA 2004: Immunobiology of the Human MHC

Table 5.4. HLA-DRB1 Table 5.4a. HLA-DRB1 alleles found in Sub-Saharan Africa (SSA)

2n k Expected Heterozygosity *0101 *0102 *0301 *0302 *0303 *0305 *0401 *0402 *0403 *0404 *0405 *0410 *0701 *0802 *0803 *0804 *0806 *0808 *0811 *0901 *1001 *1101 *1102 *1103 *1104 *1108 *1109 *1114 *1119 *1201 *1202 *1203 *1204 *1205 *1301 *1302 *1303 *1304 *1306 *1307 *1309 *1310 *1317 *1323 *1325 *1331 *1401 *1402 *1403 *1409 *1415 *1417 *1419 *1421 *1501 *1503 *1602

Population Doggon 276 19 0.9 0.004 0.043 0.083 0.076

0.011 0.04 0.236 0.076 0.011 0.036 0.043 0.076

0.025

0.014 0.069 0.076 0.022

Rwandan 560 48

Shona 458 26

Zulu 176 24

0.917 0.011 0.079 0.055 0.041 0.004 0.002 0.005 0.002 0.002 0.002 0.011 0.004 0.057 0.002

0.919 0.02 0.061 0.072 0.066

0.884 0.023

0.034

0.046

0.004 0.002 0.005 0.036 0.093 0.048

0.015 0.037 0.144 0.046

0.005 0.004 0.002 0.004 0.002 0.021 0.002 0.002 0.009 0.043 0.145 0.057 0.002 0.002 0.002 0.002 0.007 0.002 0.002 0.002 0.007 0.002 0.004 0.002 0.004

0.036 0.022

0.17 0.002

0.009

0.051 0.193 0.023

0.002 0.022

0.006 0.011

0.046

0.08 0.011 0.006 0.011

0.007

0.017 0.023 0.216 0.028 0.006 0.006

0.052 0.007 0.004 0.002

0.045

0.087 0.066 0.009

0.034 0.114 0.006

0.015

0.017 0.006 0.006

0.002

0.002 0.153 0.009

0.062

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.4b. HLA-DRB1 alleles found in North Africa (NAF)

2n k Expected Heterozygosity *0101 *0102 *0103 *0301 *0302 *0308 *0401 *0402 *0403 *0404 *0405 *0406 *0701 *0801 *0803 *0804 *0806 *0901 *1001 *1101 *1102 *1103 *1104 *1109 *1201 *1301 *1302 *1303 *1304 *1310 *1401 *1402 *1406 *1501 *1502 *1503 *1504 *1601 *1602

Population Algerian 99 198 32 0.928 0.015 0.015 0.02 0.152 0.01 0.081 0.02 0.005 0.03 0.015 0.136 0.01 0.005 0.015 0.035 0.086 0.025 0.005 0.035 0.01 0.035 0.045 0.02 0.005 0.005 0.01 0.015 0.03 0.066 0.005 0.025 0.01

Table 5.4c. Continued

Moroccan 98 196 21

Moroccan 99 182 27

0.891 0.005 0.066

0.929 0.022 0.055

Chaouya 198 28

Metalsa 198 27

0.921 0.01 0.025

0.906

0.116 0.01

0.202

0.179 0.01 0.005

0.154 0.011

0.01 0.071 0.035 0.01 0.04 0.025 0.162 0.005 0.005

0.066 0.02 0.01 0.061 0.04 0.121 0.005

0.036 0.031

0.049 0.022 0.016 0.055 0.022 0.121 0.027

0.01 0.005 0.045 0.025 0.051 0.01 0.01

0.04

0.005 0.005 0.02 0.025 0.045 0.015

0.046 0.036 0.214 0.026 0.005

0.016 0.005 0.011 0.033 0.022 0.027

0.031 0.092

0.015

0.022

0.03 0.061 0.051

0.005 0.035 0.111 0.02 0.005

0.01 0.01 0.066 0.02

0.005 0.038 0.093 0.044

0.015

0.01

0.02

0.016

0.01 0.126

0.071

0.015

0.005 0.096 0.005 0.005

0.071 0.016 0.011

0.01

0.005

0.02

0.011

Table 5.4c. HLA-DRB1 alleles found in Europe (EUR)

2n k Expected Heterozygosity *0101 *0102 *0103 *0301 *0302 *0401 *0402 *0403 *0404 *0405 *0406 *0407 *0408 *0416 *0701 *0801 *0802 *0803 *0804 *0806 *0901

Population Czech 206 30

Finn 90 180 18

Irish 2000 33

Slovenian 200 25

0.922 0.073

0.879 0.128

0.922 0.11

0.073 0.005 0.049 0.01 0.005 0.019 0.005

0.089

0.889 0.079 0.008 0.033 0.16

0.06 0.015

0.005

0.011

0.17 0.034

0.044 0.078

0.11 0.003 0.004 0.047 0.004 ∞0.001 0.018 0.002 ∞0.001 0.16 0.017 0.001 0.002 ∞0.001 0.001 0.007

0.161 0.039

0.005 0.005 0.005

0.006

0.12

0.03

*1001 *1101 *1102 *1103 *1104 *1201 *1202 *1301 *1302 *1303 *1305 *1327 *1401 *1501 *1502 *1601 *1602 *1603

Population Czech 0.01 0.068 0.005 0.005 0.049 0.044 0.087 0.024 0.034 0.005 0.005 0.039 0.116 0.019 0.024

Finn 90 0.017 0.033 0.006 0.017

Irish 0.007 0.024 0.001 0.004 0.013 0.012

Slovenian 0.005 0.07 0.005 0.005 0.06

0.194 0.006 0.006

0.036 0.033 0.012

0.005 0.055 0.045 0.015

0.011 0.144

0.014 0.182 0.004 0.002

0.04 0.095 0.005 0.11 0.005

0.011

0.005

Table 5.4d. HLA-DRB1 alleles found in Southwest Asia (SWA)

2n k Expected Heterozygosity *0101 *0102 *0301 *0401 *0402 *0403 *0404 *0405 *0407 *0408 *0410 *0701 *0801 *0802 *0803 *0805 *0901 *1001 *1101 *1102 *1103 *1104 *1201 *1202 *1301 *1302 *1303 *1305 *1401 *1404 *1406 *1407 *1408 *1501 *1502 *1503 *1601

Population South Indian 218 22 0.908 0.028 0.151 0.06 0.018 0.032 0.005 0.069 0.005 0.018 0.018 0.147 0.041

0.009 0.014 0.138 0.014 0.018 0.05 0.005 0.005 0.069 0.087

Turk 490 35 0.946 0.047 0.01 0.09 0.02 0.024 0.041 0.02 0.018 0.01 0.004 0.088 0.012 0.012 0.006 0.006 0.01 0.02 0.102 0.014 0.014 0.065 0.018 0.002 0.043 0.049 0.02 0.002 0.051 0.006 0.002 0.002 0.063 0.039 0.006 0.059

0.005 0.015 0.1 0.015 0.005 0.005

HLA 2004: Immunobiology of the Human MHC

43

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.4e. HLA-DRB1 alleles found in Southeast Asia (SEA) Population

2n k Expected Heterozygosity *0101 *0301 *0403 *0404 *0405 *0406 *0408 *0410 *0436 *0701 *0802 *0803 *0818 *0901 *1001 *1101 *1104 *1201 *1202 *1301 *1302 *1303 *1312 *1401 *1403 *1404 *1405 *1407 *1418 *1501 *1502 *1505 *1602 *1605

Ami 97 Atayal

Bunun

Hakka

Kinh

Malay

Minnan

Muong

Paiwan 51

Pazeh

Puyuma 49 Rukai

Saisiat

Siraya

Thao

Toroko

Tsou

Yami

196 9

212 11

202 11

110 21

204 24

108 20

204 25

166 17

102 12

110 16

100 13

100 9

102 11

102 16

60 13

110 10

102 10

100 8

0.766

0.855

0.842

0.927

0.865

0.823

0.893

0.87

0.783

0.808

0.9

0.863

0.841

0.82

0.759

0.134

0.082 0.036

0.127 0.018

0.01 0.088

0.036 0.009

0.02

0.039 0.098

0.05 0.017

0.027

0.01

0.064 0.027

0.024

0.01

0.036 0.009

0.02 0.01 0.04

0.04

0.014

0.044 0.025 0.01 0.044

0.914 0.005 0.054 0.049 0.015 0.064 0.015

0.882

0.08

0.848 0.009 0.046 0.009

0.02

0.127 0.01

0.017

0.036

0.069 0.01 0.029

0.02

0.167

0.064

0.04

0.24

0.167

0.049

0.017 0.15

0.127

0.284

0.02

0.118

0.02

0.03

0.059

0.098

0.05

0.045

0.02

0.225

0.145 0.009 0.045 0.082

0.19

0.27

0.098

0.118

0.2

0.191

0.108

0.05

0.03 0.05

0.05 0.28

0.01 0.255

0.02 0.098

0.2

0.018 0.045

0.186

0.13

0.388 0.168

0.005

0.009 0.027

0.049

0.01

0.193

0.173

0.1

0.054

0.036

0.118

0.059

0.066

0.132

0.084

0.155 0.027 0.073

0.142 0.044 0.005

0.287

0.036 0.055 0.009 0.036

0.241

0.084

0.018 0.064

0.025 0.304 0.02 0.02 0.015 0.005 0.029

0.042

0.035

0.018

0.01 0.005

0.005 0.194

0.042

0.064

0.009 0.073 0.045

0.026

0.038

0.064

0.036

0.039 0.078 0.005 0.01 0.015

0.019 0.08

0.107

0.009

0.005

0.01 0.083 0.009 0.028 0.046 0.009 0.046 0.009 0.028 0.324 0.009 0.019

0.01 0.118 0.176 0.02 0.059 0.025 0.103 0.005 0.034

0.006 0.006 0.03 0.078 0.03 0.012 0.102 0.006 0.006 0.012 0.151

0.037

0.005 0.034 0.005 0.005 0.015 0.005

0.12 0.12

0.078 0.01

0.066 0.127

0.028

0.083

0.199

0.009

0.02

0.059 0.265

0.02 0.127

0.164

0.15

0.036

0.06

0.01 0.01

0.009 0.064 0.018

0.1 0.21

0.01

0.155

0.08

0.284

0.176

0.017 0.117

0.264

0.206

0.34

0.01

0.02

0.033

0.127

0.049

0.03

0.03

0.069

0.039 0.02

0.017

0.118

0.05

0.01

0.049

0.117

0.01

Population

44

East Timorese Filipino 166 188 18 21

Ivatan 100 12

Moluccan 80 11

PNG Highlander 174 15

0.736

0.762

0.748

0.854

0.04 0.02

0.025

0.132

0.024 0.018 0.018 0.012 0.012 0.012 0.09 0.006 0.03 0.151 0.006 0.018 0.03 0.006 0.012 0.036 0.476 0.042

0.765 0.011 0.048 0.032 0.064 0.005 0.027 0.005 0.048 0.005 0.043 0.059 0.011 0.117 0.005 0.005 0.027 0.005 0.011 0.011 0.011

0.452

0.029 0.075

0.006

0.038

0.063

0.01 0.06

0.075

0.006 0.006

0.29

0.038 0.125

0.052 0.006

0.04

0.08 0.02 0.01

0.012

0.01 0.37 0.05

0.038 0.062 0.462 0.05

0.039

Table 5.4g. HLA-DRB1 alleles found in Australia (AUS)

Table 5.4f. HLA-DRB1 alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0101 *0301 *0403 *0405 *0406 *0410 *0411 *0701 *0801 *0803 *0809 *0901 *1101 *1104 *1201 *1202 *1203 *1301 *1302 *1303 *1401 *1404 *1405 *1407 *1408 *1501 *1502 *1602

0.01 0.12

PNG Lowlander 95 160 5 0.592

0.006

0.556

0.04

0.006

0.006 0.138 0.092 0.276 0.121 0.029

0.162 0.269

HLA 2004: Immunobiology of the Human MHC

2n k Expected Heterozygosity *0101 *0103 *0301 *0401 *0403 *0404 *0405 *0410 *0411 *0412 *0701 *0803 *1001 *1201 *1202 *1301 *1401 *1402 *1408 *1409 *1410 *1501 *1502 *1602

Population Cape York 198 22 0.839 0.01 0.005 0.045 0.005 0.01 0.015 0.086 0.025 0.015 0.04 0.354 0.005 0.005 0.005 0.015 0.045 0.071 0.101 0.035 0.045 0.051 0.01

Kimberley 82 12 0.842

0.049 0.012 0.11 0.256 0.037 0.012 0.049 0.085 0.22 0.024 0.134 0.012

0.3

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.4h. HLA-DRB1 alleles found in Northeast Asia (NEA)

2n k Expected Heterozygosity *0101 *0301 *0308 *0317 *0401 *0403 *0404 *0405 *0406 *0407 *0408 *0410 *0415 *0701 *0801 *0802 *0803 *0804 *0806 *0901 *1001 *1101 *1104 *1113 *1130 *1201 *1202 *1203 *1301 *1302 *1312 *1320 *1401 *1402 *1403 *1405 *1406 *1407 *1408 *1412 *1413 *1501 *1502 *1601 *1602

Population Korean 200 398 27 0.937 0.078 0.02

Table 5.4j. HLA-DRB1 alleles found in South America (SAM)

Tuva 378 41 0.944 0.034 0.053 0.003 0.003 0.053 0.019 0.008 0.04

0.005 0.025 0.01 0.08 0.058

2n k Expected Heterozygosity *0101 *0102 *0301 *0302 *0403 *0404 *0405 *0407 *0410 *0411 *0701 *0801 *0802 *0804 *0807 *0901 *1101 *1104 *1111 *1301 *1303 *1305 *1402 *1406 *1413 *1602

0.008 0.003 0.005 0.003 0.103 0.016 0.011 0.008 0.013 0.003 0.061 0.034 0.04 0.005 0.003 0.008 0.069 0.011 0.019 0.058 0.05 0.003 0.008 0.029 0.013 0.029 0.011

0.068 0.04 0.068 0.121 0.008 0.03

0.055 0.03 0.018 0.075 0.028 0.01 0.035 0.005 0.003

Population GuaraniKaiowa 288 10

GuaraniNandeva 106 18

0.795

0.808 0.019 0.009 0.009 0.009

Ticuna 98 9

Yanomamo 110 15

0.779

0.83 0.009

0.041 0.02

0.003 0.087

0.019

0.042

0.047 0.009

0.108 0.003 0.101 0.097

0.075 0.038 0.066 0.047 0.009 0.028 0.009

0.316 0.01 0.031 0.224 0.082

0.091 0.027 0.227 0.009 0.009 0.055 0.027 0.009 0.009 0.027 0.036

0.009 0.031 0.205

0.255

0.003 0.351

0.009 0.33

0.236 0.009 0.245

0.218

0.003 0.003

0.003 0.003 0.122 0.029 0.011 0.003

0.078 0.033 0.013

Table 5.4i. HLA-DRB1 alleles found in North America (NAM) Population Canoncito 80 8

2n k Expected Heterozygosity 0.679 *0101 *0102 *0301 *0401 *0403 *0404 *0406 0.012 *0407 0.038 *0408 *0410 *0411 *0413 *0701 *0801 *0802 0.438 *0804 *0811 *0901 0.012 *1101 *1103 *1104 *1201 *1301 *1302 *1303 *1401 0.038 *1402 0.338 *1404 *1406 0.012 *1501 *1503 *1601 *1602 0.112

Lacandon 324 11

Maya 30 9

Pima 17 34 5

Seri 66 6

Sioux 192 24

Yupik 504 21

Zuni 100 9

0.644 0.003

0.68

0.353

0.658

0.852 0.004

0.8 0.02

0.003

0.067

0.046 0.068

0.067

0.903 0.016 0.005 0.031 0.01 0.167 0.125

0.006 0.232 0.03 0.002

0.07

0.096

0.533

0.47

0.141 0.036

0.002 0.002 0.036

0.574

0.133 0.03

0.047 0.016 0.073

0.015 0.029

0.03 0.05

0.008 0.012 0.033

0.029

0.033

0.303

0.015

0.031

0.031 0.016 0.005 0.01 0.005 0.01 0.005

0.074

0.033

0.794

0.046

0.067 0.033

0.029

0.046

0.118

0.167

0.089 0.005

0.133 0.002 0.004 0.079 0.107

0.21 0.02

0.002 0.004 0.004 0.067 0.222

0.32 0.09

0.031 0.005 0.005 0.115

0.008 0.046

HLA 2004: Immunobiology of the Human MHC

0.19

45

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.4k. HLA-DRB1 alleles found in other regions (OTH) Population Brazilian (Af Eu) 198 34 0.95 0.051 0.035 0.005 0.121 0.025 0.035 0.015 0.01 0.01 0.02 0.02

2n k Expected Heterozygosity *0101 *0102 *0103 *0301 *0302 *0401 *0402 *0403 *0404 *0405 *0407 *0410 *0411 *0701 *0801 *0802 *0804 *0807 *0901 *1001 *1101 *1102 *1103 *1104 *1201 *1301 *1302 *1303 *1304 *1305 *1401 *1402 *1406 *1501 *1502 *1503 *1601 *1602

0.02 0.076 0.025 0.005 0.03 0.01 0.025 0.01 0.061 0.025 0.01 0.035 0.015 0.071 0.045 0.005

Table 5.5c. HLA-DQA1 alleles found in Europe (EUR) Mexican 408 36 0.937 0.029 0.042 0.005 0.044 0.007 0.002 0.017 0.017 0.042 0.029 0.147 0.005 0.029 0.066 0.015 0.125 0.005 0.007 0.029 0.01 0.002 0.022 0.01 0.022 0.025 0.01 0.002 0.002 0.012 0.034 0.059 0.044 0.015 0.005 0.01 0.051

0.035 0.005 0.051 0.01 0.045 0.025 0.01

Table 5.5. Table 5.5a. HLA-DQA1 alleles found in Sub-Saharan Africa (SSA)

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501

Population Kenyan_142 238 7

Shona 458 7

Zulu 178 7

0.782 0.164 0.303 0.025 0.084 0.034 0.109 0.282

0.787 0.197 0.343 0.066 0.037 0.059 0.111 0.188

0.808 0.062 0.281 0.084 0.056 0.09 0.202 0.225

Table 5.5b. HLA-DQA1 alleles found in North Africa (NAF)

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501 *0601

46

Population Moroccan 98 196 8 0.801 0.117 0.158 0.015 0.214 0.148 0.041 0.301 0.005

Moroccan 99 192 7 0.814 0.115 0.208 0.057 0.12 0.177 0.042 0.281

HLA 2004: Immunobiology of the Human MHC

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501 *0601

Population Czech 210 8 0.83 0.124 0.162 0.11 0.176 0.11 0.048 0.267 0.005

Slovenian 200 8 0.798 0.165 0.265 0.055 0.1 0.115 0.015 0.28 0.005

Table 5.5d. HLA-DQA1 alleles found in Southwest Asia (SWA) Population Turk 490 8 0.804 0.147 0.165 0.09 0.088 0.149 0.024 0.329 0.008

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501 *0601

Table 5.5e. HLA-DQA1 alleles found in Southeast Asia (SEA) No data. Table 5.5f. HLA-DQA1 alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0501 *0601

Population East Timorese 172 6 0.696 0.262 0.459 0.017 0.064 0.122 0.076

Moluccan 92 7 0.652 0.13 0.554 0.033 0.065 0.033 0.076 0.109

PNG Highlander 184 6

PNG Lowlander 48 96 7

0.726 0.326 0.359 0.065 0.011 0.174 0.065

0.648 0.104 0.552 0.031 0.01 0.104 0.146 0.052

Table 5.5g. HLA-DQA1 alleles found in Australia (AUS)

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0501 *0601

Population Cape York 198 7 0.775 0.167 0.096 0.359 0.04 0.202 0.131 0.005

Kimberley 82 5 0.766 0.085 0.146 0.28 0.183 0.305

Table 5.5h. HLA-DQA1 alleles found in Northeast Asia (NEA) No data.

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.5i. HLA-DQA1 alleles found in North America (NAM)

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501

Population Canoncito 80 4 0.577 0.025

Lacandon 324 4 0.338 0.003

Maya 30 4 0.453

2n k Expected Heterozygosity *0101 *0103 *0201 *0301 *0401 *0501

0.59

0.226 0.215 0.559

0.062 0.425 0.488

0.79 0.012 0.194

0.7 0.033 0.233

GuaraniNandeva 106 5 0.515 0.028 0.009 0.113 0.189 0.66

Ticuna 98 3

Yanomamo 110 5

0.643

0.601

0.459 0.265 0.276

0.036 0.055 0.391 0.027 0.491

Table 5.5k. HLA-DQA1 alleles found in other regions (OTH) Population Mexican 408 7 0.794 0.096 0.081 0.042 0.064 0.289 0.147 0.282

2n k Expected Heterozygosity *0101 *0102 *0103 *0201 *0301 *0401 *0501

2n k Expected Heterozygosity *0201 *0203 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0602 *0603 *0604 *0605 *0608 *0613 *0615

0.851 0.164 0.004 0.221 0.022 0.009 0.111 0.177 0.009 0.15 0.009 0.062 0.053 0.009

0.029 0.029 0.941

0.03 0.485 0.303 0.182

Rwandan 560 13

Shona 458 15

Sioux 192 7 0.637 0.026 0.047 0.005 0.047 0.521 0.068 0.286

Yupik 116 5 0.684 0.129

Zuni 100 4 0.583 0.02

0.009 0.44 0.121 0.302

0.21 0.19 0.58

Table 5.6b. HLA-DQB1 alleles found in North Africa (NAF)

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0304 *0305 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 *0605 *0606 *0607 *0608

Population Algerian 99 198 17

Moroccan 98 196 13

Moroccan 99 192 16

0.833 0.328 0.187 0.066 0.015 0.005

0.785 0.398 0.148 0.112 0.005

0.846 0.297 0.141 0.089 0.01

0.005 0.02 0.071 0.04 0.03 0.04 0.076 0.035 0.056 0.015

0.005 0.031 0.117 0.02 0.026

0.01

0.066 0.015 0.026 0.031

0.005 0.005

0.068 0.12 0.016 0.016 0.016 0.115 0.01 0.068 0.005 0.005 0.016

Table 5.6c. HLA-DQB1 alleles found in Europe (EUR)

Table 5.6. HLA-DQB1 Table 5.6a. HLA-DQB1 alleles found in Sub-Saharan Africa (SSA) Population Kenyan 142 226 13

Seri 66 4 0.639

0.033

Table 5.5j. HLA-DQA1 alleles found in South America (SAM) Population GuaraniKaiowa 288 3

Pima 17 34 3 0.112

Zulu 174 9

0.84 0.157

0.837 0.133

0.837 0.172

0.186 0.005 0.009 0.005 0.034 0.195 0.005 0.005 0.216 0.018 0.107 0.057

0.14 0.022 0.009

0.167 0.029

0.094 0.227 0.011 0.007 0.247 0.052 0.024 0.022 0.002 0.009 0.002

0.207 0.098

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0304 *0401 *0402 *0501 *0502 *0503 *0504 *0601 *0602 *0603 *0604 *0605

Population Czech 212 13 0.872 0.203 0.208 0.09 0.047 0.005 0.042 0.09 0.028 0.038 0.024 0.108 0.094 0.024

Finn 90 70 10

Slovenian 200 14

0.841 0.171 0.043 0.257 0.057

0.874 0.2 0.175 0.085 0.03 0.005

0.014 0.071 0.114

0.186 0.071 0.014

0.01 0.125 0.135 0.035 0.005 0.08 0.07 0.015 0.03

0.218 0.017 0.034 0.057

HLA 2004: Immunobiology of the Human MHC

47

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.6d. HLA-DQB1 alleles found in Southwest Asia (SWA) Population Turk 490 17 0.867 0.163 0.257 0.127 0.018 0.012 0.004 0.016 0.084 0.061 0.055 0.002 0.041 0.067 0.039 0.037 0.014 0.002

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0304 *0305 *0402 *0501 *0502 *0503 *0504 *0601 *0602 *0603 *0604 *0605 *0608

Population

Table 5.6e. HLA-DQB1 alleles found in Southeast Asia (SEA)

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0401 *0501 *0502 *0503 *0504 *0601 *0602 *0603 *0604 *0605 *0606

48

Population Kinh 200 12

Malay 110 12

0.803 0.065 0.37 0.045 0.17 0.05 0.115 0.08 0.015

0.819 0.109 0.355 0.018 0.055 0.018 0.1 0.118 0.045

0.035 0.02 0.01

0.1 0.055 0.009

0.025

0.018

Table 5.6f. HLA-DQB1 alleles found in Oceania (OCE)

Muong 164 14 0.724 0.11 0.104 0.024 0.085 0.024 0.11 0.482 0.006 0.006 0.018 0.006 0.012 0.006 0.006

HLA 2004: Immunobiology of the Human MHC

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 *0605

East Timorese 172 10 0.816 0.029 0.174 0.023 0.012 0.023 0.221 0.25 0.058 0.192 0.017

Filipino 188 13 0.842 0.064 0.176 0.037 0.053 0.016 0.027 0.16 0.282 0.069 0.085

Moluccan 92 9 0.765 0.076 0.174 0.011

PNG Highlander 182 9 0.779 0.011 0.06

PNG Lowlander 48 96 10

PNG Lowlander 95 182 9 0.581

0.022

0.005 0.115 0.044

0.785 0.01 0.198 0.031 0.042 0.01 0.021

0.098 0.413 0.043 0.12 0.043

0.033 0.352 0.137 0.242

0.312 0.062 0.26 0.052

0.005 0.005 0.021

Table 5.6g. HLA-DQB1 alleles found in Australia (AUS)

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0502 *0503 *0601 *0602 *0603

Population Cape York 198 12 0.82 0.071 0.091 0.045 0.015 0.02 0.126 0.03 0.01 0.217 0.313 0.04 0.02

Kimberley 82 6 0.682 0.049

0.439 0.024 0.171 0.305 0.012

Table 5.6h. HLA-DQB1 alleles found in Northeast Asia (NEA) No data.

0.582 0.005 0.005 0.005 0.247 0.005 0.137 0.005 0.005

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.6i. HLA-DQB1 alleles found in North America (NAM)

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0401 *0402 *0501 *0503 *0504 *0602 *0603 *0605

Population Canoncito 80 6 0.579 0.488 0.038 0.012 0.012 0.425 0.025

Lacandon 324 5 0.357 0.003 0.194 0.778

Maya 30 5 0.589 0.067 0.133 0.6

0.022 0.003

0.167

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0402 *0501

0.619 0.559 0.17 0.097 0.174

GuaraniNandeva 106 6

Ticuna 98 5

Yanomamo 110 3

0.535 0.019 0.651 0.075 0.047 0.179 0.028

0.697 0.01 0.276 0.378 0.051 0.286

0.551 0.064 0.527 0.409

Population Mexican 408 13 0.821 0.105 0.245 0.272 0.012 0.147 0.088 0.012 0.012 0.012 0.054 0.017 0.017 0.005

Table 5.7. HLA-DPA1 Table 5.7a. HLA-DPA1 alleles found in Sub-Saharan Africa (SSA)HLAC alleles found in other regions (OTH)

2n k Expected Heterozygosity *0103 *0201 *0202 *0203 *0301 *0302 *0401

0.059

Sioux 190 9 0.706 0.074 0.268 0.453 0.047

Yupik 502 10 0.574 0.008 0.62 0.038 0.078

Zuni 100 6 0.616 0.03 0.55 0.11 0.03

0.303

0.089 0.026 0.005

0.173 0.002 0.068 0.002 0.008 0.004

0.26 0.02

0.032 0.005

Table 5.6k. HLA-DQB1 alleles found in other regions (OTH)

2n k Expected Heterozygosity *0201 *0301 *0302 *0303 *0402 *0501 *0502 *0503 *0601 *0602 *0603 *0604 *0605

0.941

Seri 66 4 0.639 0.03 0.182 0.485

0.033

Table 5.6j. HLA-DQB1 alleles found in South America (SAM) Population GuaraniKaiowa 288 4

Pima 17 34 2 0.111

Population Kenyan 142 258 7 0.748 0.349 0.198 0.209 0.004 0.217 0.008 0.016

Table 5.7b. HLA-DPA1 alleles found in North Africa (NAF) No data. Table 5.7c. HLA-DPA1 alleles found in Europe (EUR) Population Slovenian 200 4 0.23 0.87 0.005 0.115 0.01

2n k Expected Heterozygosity *0103 *0104 *0201 *0202

Table 5.7d. HLA-DPA1 alleles found in Southwest Asia (SWA) No data. Table 5.7e. HLA-DPA1 alleles found in Southeast Asia (SEA) No data. Table 5.7f. HLA-DPA1 alleles found in Oceania (OCE) Population

2n k Expected Heterozygosity *0103 *0104 *0201 *0202 *0401

East Timorese 172 4 0.633 0.233 0.209 0.517 0.041

PNG Lowlander 48 96 4

Filipino 188 5

Moluccan 92 4

PNG Highlander 156 4

0.464 0.16 0.005 0.096 0.707 0.032

0.502 0.228

0.37 0.776

0.554 0.562

0.065 0.663 0.043

0.019 0.16 0.045

0.062 0.354 0.021

Table 5.7g. HLA-DPA1 alleles found in Australia (AUS) No data. Table 5.7h. HLA-DPA1 alleles found in Northeast Asia (NEA) No data. Table 5.7i. HLA-DPA1 alleles found in North America (NAM)

2n k Expected Heterozygosity *0103 *0201 *0202 *0401

Population Pima 17 30 1 0 1

Pima 99 194 3

Seri 50 3

0.089 0.954 0.031 0.015

0.246 0.86 0.12

HLA 2004: Immunobiology of the Human MHC

0.02

49

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.7j. HLA-DPA1 alleles found in South America (SAM) Population Ticuna 92 3 0.437 0.717 0.207 0.076

2n k ExpectedHeterozygosity *0103 *0201 *0202

Table 5.7k. HLA-DPA1 alleles found in other regions (OTH) No data. Table 5.8. HLA-DPB1 Table 5.8a. HLA-DPB1 alleles found in Sub-Saharan Africa (SSA)

2n k Expected Heterozygosity *0101 *0201 *0202 *0301 *0401 *0402 *0501 *0601 *0901 *1001 *1101 *1301 *1401 *1501 *1701 *1801 *1901 *2001 *2201 *2501 *2701 *2901 *3001 *3101 *3401 *3501 *4001 *4601 *5001 *5501 *6001 *6501 *6801 *7501 *8001 *8701 *8801

Population Kenyan 142 246 29 0.87 0.207 0.098 0.069 0.081 0.24

Shona 456 19

Zulu 174 14

0.81 0.357 0.107 0.002 0.064 0.044 0.178

0.824 0.322 0.126 0.052 0.103 0.184 0.011 0.006

0.004 0.033 0.024 0.02 0.004 0.061 0.037 0.004 0.004 0.004 0.008 0.004 0.012 0.004 0.016 0.012

0.018 0.044 0.011 0.007 0.031 0.099 0.013

0.011 0.029 0.075 0.011 0.011 0.052 0.006

0.004 0.002

0.004 0.004 0.012 0.008 0.008 0.008

0.011 0.002 0.004 0.002

0.004 0.004

Table 5.8b. HLA-DPB1 alleles found in North Africa (NAF). No data.

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HLA 2004: Immunobiology of the Human MHC

Table 5.8c. HLA-DPB1 alleles found in Europe (EUR)

2n k Expected Heterozygosity *0101 *0201 *0202 *0301 *0401 *0402 *0501 *0601 *0901 *1001 *1101 *1301 *1401 *1501 *1601 *1701 *1901 *2001 *2601 *4101

Population Czech 204 17 0.769 0.029 0.172 0.01 0.083 0.402 0.172 0.02 0.01

Finn 90 60 9

Slovenian 200 15

0.772 0.083 0.133 0.017 0.15 0.4 0.133 0.05

0.716 0.055 0.125

0.02 0.02 0.005 0.017 0.005 0.005 0.034 0.005 0.005 0.005

0.085 0.49 0.13 0.005 0.01 0.01 0.01 0.01 0.02 0.02 0.01 0.015

0.017 0.005

Table 5.8d. HLA-DPB1 alleles found in Southwest Asia (SWA) No data. Table 5.8e. HLA-DPB1 alleles found in Southeast Asia (SEA)

2n k Expected Heterozygosity *0101 *0201 *0202 *0301 *0401 *0402 *0501 *0901 *1301 *1401 *1501 *1701 *1901 *2101 *2401 *2601 *2801 *3301 *3601

Population Malay 104 19 0.87 0.029 0.029 0.029 0.077 0.173 0.038 0.24 0.019 0.135 0.038 0.01 0.01 0.01 0.019 0.01 0.01 0.106 0.01 0.01

Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 5.8f. HLA-DPB1 alleles found in Oceania (OCE)

2n k Expected Heterozygosity *0101 *0201 *0202 *0301 *0401 *0402 *0501 *0601 *0901 *1301 *1401 *1501 *2101 *2201 *2701 *2801 *2901 *3101 *3201

Population East Timorese 172 9 0.74 0.029 0.029 0.041 0.11 0.076 0.436 0.215 0.041

Table 5.8i. HLA-DPB1 alleles found in North America (NAM)

Filipino 188 13

Moluccan 92 11

PNG Highlander 176 16

0.718 0.436 0.048 0.005 0.059 0.059

0.807 0.337 0.076

0.708 0.028 0.347

0.75 0.073 0.135

0.033 0.109 0.033 0.217

0.04 0.375

0.042 0.344

0.165

0.323 0.01

0.282 0.021 0.043 0.021 0.005 0.011 0.005

0.065 0.022

0.045

PNG Lowlander 48 96 10

0.021

2n k Expected Heterozygosity *0101 *0201 *0301 *0401 *0402 *0501 *1001 *1101 *1401 *1501 *1701 *1901 *2001

Population Canoncito Maya 80 30 6 5

Pima 17 34 3

Pima 99 190 9

Sioux 164 9

Zuni 100 4

0.656

0.547

0.645 0.011 0.089 0.053 0.305 0.5 0.011

0.759 0.018 0.171 0.134 0.36 0.25 0.018 0.012 0.03

0.511

0.138 0.025 0.312 0.475 0.038

0.023

0.733 0.033

0.412 0.529

0.005 0.021

0.03 0.32 0.62 0.03

0.033 0.033 0.005 0.006

Table 5.8j. HLA-DPB1 alleles found in South America (SAM) 0.011 0.011 0.087

0.031 0.01

Table 5.8g. HLA-DPB1 alleles found in Australia (AUS)

2n k Expected Heterozygosity *0101 *0201 *0301 *0401 *0501 *1101 *1301 *1501 *1601 *2201

0.059 0.167

0.012

0.01 0.005

0.431

Population Cape York 192 10 0.719 0.01 0.156 0.031 0.104 0.453 0.01 0.01 0.016 0.01 0.198

Kimberley 76 5 0.503 0.092 0.105 0.684

2n k Expected Heterozygosity *0101 *0201 *0301 *0401 *0402 *1401 *1901 *2701 *3501 *4501

Population Ticuna 98 8 0.743 0.01 0.071 0.071 0.163 0.429 0.184

Yanomamo 110 7 0.496 0.018 0.1 0.064 0.691 0.109 0.009

0.02 0.051 0.009

Table 5.8k. HLA-DPB1 alleles found in other regions (OTH) No data.

0.026 0.092

Table 5.8h. HLA-DPB1 alleles found in Northeast Asia (NEA) No data.

HLA 2004: Immunobiology of the Human MHC

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Meyer et al ¡ C4. Single locus polymorphism of classical HLA genes

Table 6. Example of ‘‘binning rules’’

unfiltered

filtered

Allele *1100 *1101 *11011 *11012 *1101

Population Doggon 0.018 0.025 0.043

Rwandan 0.011 0.082

Shona

Zulu

0.144

0.216

0.093

0.144

0.216

Table 7. Deviation from HWP Locus A C B DRB1 DQA1 DQB1 DPA1 DPB1

AlphaΩ0.05 No. Signif. 10 6 4 5 6 7 1 6

No. NS 63 49 64 48 18 25 9 14

Pct. Signif. 13.7 10.9 5.88 9.43 25 21.9 10 30

AlphaΩ0.01 No. Signif. 2 2 1 2 2 3 1 1

No. NS 71 53 67 51 22 29 9 19

Pct. Signif. 2.74 3.64 1.47 3.77 8.33 9.38 10 5

No. NS 65 30 51 42 12 28 10 20

Pct. Signif. 11 45.5 25 20.8 50 12.5 0 0

AlphaΩ0.01 No. Signif. 5 6 3 3 6 1 0 0

No. NS 68 49 65 50 18 31 10 20

Pct. Signif. 6.85 10.9 4.41 5.66 25 3.13 0 0

Table 8. Deviation from neutrality (F-test) Locus A C B DRB1 DQA1 DQB1 DPA1 DPB1

AlphaΩ0.05 No. Signif. 8 25 17 11 12 4 0 0

References 1. Bamshad MJ, Mummidi S, Gonzalez E, Ahuja SS, Dunn DM, Watkins WS, Wooding S, Stone AC, Jorde LB, Weiss RB, Ahuja SK. A strong signature of balancing selection in the 5ø cis-regulatory region of CCR5. Proc Natl Acad Sci USA 99, 10539–10544, 2002. 2. Black FL, Salzano FM. Evidence for heterosis in the HLA system. American Journal of Human Genetics 33, 894–899, 1981. 3. Kidd KK, Morar B, Castiglione CM, Zhao HY, Pakstis AJ, Speed WC, Bonne-Tamir B, Lu RB, Goldman D, Lee CY, Nam YS, Grandy DK, Jenkins T, Kidd JR. A global survey of haplotype frequencies and linkage disequilibrium at the DRD2 locus. Human Genetics 103, 211–227, 1998. 4. Lancaster A, Nelson MP, Single RM, Meyer D, Thomson G. Software framework for the Biostatistics Core. In: HLA 2004 Immunobiology of the Human MHC. Eds: Hansen JA, Dupont B. IHWG Press, 2005. 5. Mack SJ, Sanchez-Mazas A, Erlich HA. Methods used for the generation and analysis of data in the 13th International Histocompatibility Workshop. In HLA 2004: Immunobiology of the human MHC. Eds: Hansen JA, Dupont B. IHWG Press, 2005.

52

6. Parham P, Arnett KL, Adams EJ, Little AM, Tees K, Barber LD, Marsh SG, Ohta T, Markow T, Petzl-Erler ML. Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 50, 219–232, 1997. 7. Robinson J, Malik A, Parham P, Bodmer JG, Marsh SGE. IMGT/HLA Database-a sequence database for the human major histocompatibility complex. Tissue Antigens 55, 280–287, 2000. 8. Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, Feldman MW. Genetic structure of human populations. Science 298, 2381–2385, 2002. 9. Salamon H, Klitz W, Easteal S, Gao X, Erlich HA, Fernandez-Vina M, Trachtenberg EA, McWeeney SK, Nelson MP, Thomson G. Evolution of HLA class II molecules: Allelic and amino acid site variability across populations. Genetics 152, 393–400, 1999. 10. Single RM, Meyer D, Thomson G. Statistical Methods for Analysis of Population Genetic Data. In: HLA 2004 Immunobiology of the Human MHC. Eds: Hansen JA, Dupont B. IHWG Press, 2005.

HLA 2004: Immunobiology of the Human MHC

11. Stephens JC, Schneider JA, Tanguay DA, Choi J, Acharya T, Stanley SE, Jiang R, Messer CJ, Chew A, Han JH, Duan J, Carr JL, Lee MS, Koshy B, Kumar AM, Zhang G, Newell WR, Windemuth A, Xu C, Kalbfleisch TS, Shaner SL, Arnold K, Schulz V, Drysdale CM, Nandabalan K, Judson RS, Ruano G, Vovis GF. Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489– 493, 2001. 12. Valdes AM, McWeeney SK, Meyer D, Nelson MP, Thomson G. Locus and population specific evolution in HLA class II genes. Annals of Human Genetics 63, 27–43, 1999. 13. Zhivotovsky LA, Rosenberg NA, Feldman MW. Features of evolution and expansion of modern humans, inferred from genomewide microsatellite markers. American Journal of Human Genetics 72, 1171–1186, 2003.