Haplotype frequencies and linkage disequilibrium among classical HLA genes

87604$2481 P248 17-11-05 10:40:24 PDF GL 87604 C5 JR248

Richard M. Single 13th International HistocompatibilityDiogo Meyer Workshop Anthropology/HumanSteven J. Mack

Genetic Diversity Joint ReportAlex Lancaster

Mark P. Nelson Chapter 5: Haplotype frequencies and linkageHenry A. Erlich disequilibrium among classicalMarcelo Fernandez-Vina HLA genesGlenys Thomson

Authors’ address

Richard M. Single2*, Diogo Meyer1*, Steven J. Mack3,4,Alex Lancaster1, Mark P. Nelson1, Henry A. Erlich3,4,Marcelo Fernandez Vina5,6, Glenys Thomson1

1Dept. of Integrative Biology, University ofCalifornia, Berkeley, CA, USA, 2Dept. of MedicalBiostatistics, University of Vermont,Burlington, VT, USA, 3Roche MolecularSystems, Alameda, California, USA,4Children’s Hospital Oakland Research InstituteOakland, California, USA, 5Department ofOncology, Georgetown University, WashingtonDC, USA, 6C.W. Bill Young/DoD MarrowDonor Program, Naval Medical ResearchCenter, Bethesda, MD, USA, *These authorscontributed equally to the manuscript

HLA 2004:

Immunobiology of the Human MHC.

Proceedings of the 13th International

Histocompatibility Workshop and Congress

1

Introduction to Chapter 5

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. We

describe the contents of Tables 3–5 in the methods section.

In the results section we provide an overview of the popula-

tion and regional summaries (Tables 3 and 4, respectively)

along with highlights from Tables 4 and 5 of specific high

frequency haplotypes in certain regions.

The following tables are included as a part of this joint

report:

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. Summary tables describing the characteristics of

frequent haplotypes observed in ten different

geographic regions.

Table 3.1. HLA-A:B

Table 3.2. HLA-A:DPB1

Table 3.3. HLA-B:DRB1

Table 3.4. HLA-B:DPB1

Table 3.5. HLA-C:B

Table 3.6. HLA-DRB1:DPB1

Table 3.7. HLA-DRB1:DQB1

Table 3.8. HLA-A:C:B

Table 3.9. HLA-A:B:DRB1

Table 3.10. HLA-DRB1:DQA1:DQB1

Table 4. Maximum frequency of ‘‘regionally frequent’’

haplotypes according to geographic region.

Table 4.1. HLA-A:B




Single et al ¡ 13th IHWS Anthropology/Human Genetic Diversity Joint Report – Chapter 5. Haplotype frequencies and linkage disequilibrium among classical HLA genes

Table 4.5. HLA-C:B




Table 4.9. HLA-A:B: DRB1


Table 5. Description of the 3 most frequent haplotypes

identified among specific populations according

to geographic region.

Table 5.1. HLA-A:B

Table 5.2. HLA-A:B:DRB1





Table 5.7. HLA-C:B




Additional tables are posted at the IHWG website under the

Anthropology component (http://www.ihwg.org/compo-

nents/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).

Table 1. Allele binning rules

HLA Locus Original allele name Binned allele name HLA Locus Original allele name Binned allele nameA *2409 *2402 DQB1 *0202 *0201

*0309 *0301C *0706 *0701 *0609 *0605

*0611 *0602B *0706 *0705

DPB1 *2301 *0401DRB1 *1443 *1405 *3901 *0401

*1506 *1501 *4801 *0201*4901 *0402

DQA1 *0104 *0101 *5101 *0402*0302 *0301 *6201 *4001*0303 *0301 *7601 *1401*0502 *0501

Table 2. Summary of the data available for 10 different geographic regions for HLA-A, C, B, DRB1, DQA1, DQB1, and DPB1

Total no. of No. of Populations with data for each HLA Locus*Region Populations A C B DRB1 DQA1 DQB1 DPB1Subsaharan Africa (SSA) 11 10 9 10 4 3 4 3North Africa (NAF) 5 2 0 2 5 2 3 0Europe (EUR) 8 7 5 7 4 2 3 3Southwest Asia (SWA) 8 7 5 7 2 1 1 0Southeast Asia (SEA) 24 22 19 22 18 0 3 1Oceania (OCE) 9 8 4 5 6 4 6 5Australia (AUS) 4 4 4 4 2 2 2 2Northeast Asia (NEA) 5 5 3 3 2 0 0 0North America (NAM) 8 5 3 5 6 6 6 4South America (SAM) 5 3 3 3 4 4 4 2Note: The numbers of populations for combinations of loci are listed in thefirst row of Tables 3.1–3.10.

2 HLA 2004: Immunobiology of the Human MHC

Introduction

The frequency of haplotypes and the degree of linkage dis-

equilibrium (LD) among loci provide information about the

evolutionary forces acting on genes, and the history of human

populations. These population associations are also useful in

the mapping of disease loci (13). An understanding of LD

patterns is necessary for detecting evidence of selection.

In this paper we describe the degree of LD and the distribu-

tion of haplotypes in the 13th Workshop data. We highlight

haplotypes observed at high frequency in at least one popula-

tion, the degree of sharing of the frequent haplotypes among

populations and regions, and the degree to which frequent

haplotypes in one region may be infrequent or absent in other

regions. The analytical methods employed are described else-

where in this volume (27).

The results are presented separately for the following groups

of two and three locus haplotypes: A:B, C:B, B:DRB1, A:DPB1,

B:DPB1, DRB1:DQB1, DRB1:DPB1, A:C:B, A:B:DRB1, and

DRB1:DQA1:DQB1 (see table index above).

The goals for these analyses include placing the classical

class I and class II loci of the MHC region in the context of

genomic and geographic variation. This includes a descrip-

tion of patterns that exist across regions and across popula-

tions within regions, an assessment of the effects of demogra-


Table 3. Summary tables describing the characteristics of frequent haplotypes observed in ten different geographic regions.The following notes apply to all of the ‘‘Table 3’’ set of haplotype summaries:i) A frequent haplotype is defined as one that exists with a frequency of at least .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:B Haplotypes

RegionSSA NAF EUR SWA SEA OCE AUS NEA NAM SAM Total

No. of populations 10 2 7 6 21 5 3 3 4 2 63sampled per region

Expected heterozygosity 0.99 0.98 0.98 0.98 0.94 0.94 0.94 0.98 0.95 0.95 0.96

No. of different 746 153 479 389 501 178 64 226 224 99 1798haplotypes (k) per region

Range of values for k per (57–221) (76–93) (63–240) (55–121) (13–232) (24–75) (31–44) (61–130) (27–165) (54–69) (13–240)population

No. needed to reach a 30.7 25.48 19.15 21.9 12.89 9.67 6.69 16.77 13.06 7.8 18.25frequency of 0.5

No. of frequent 4 0 7 6 27 13 11 6 15 7 79haplotypes

Frequent haplotypes 4 0 6 3 19 8 6 4 11 7 68frequent in only oneregion

Frequent haplotypes 2 0 0 0 0 1 0 2 2 5 12present in only one region

Percentage of haplos 0.51 0.62 0.49 0.59 0.43 0.47 0.3 0.46 0.46 0.56 0.47estimated with countΩ1

Total freq. of haplos 0.22 0.41 0.18 0.32 0.13 0.19 0.05 0.15 0.12 0.22 0.17estimated with countΩ1

Wn 0.48 0.62 0.5 0.58 0.61 0.68 0.58 0.61 0.56 0.54 0.56

Dø 0.7 0.81 0.6 0.76 0.62 0.67 0.45 0.68 0.51 0.7 0.64

Fraction not found (FNF) 0.39 0.31 0.29 0.36 0.4 0.36 0.44 0.45 0.32 0.22 0.37

Complementary fraction 0.06 0.22 0.06 0.12 0.1 0.13 0.11 0.07 0.11 0.11 0.09(CF)

phy, and a characterization of the decay of LD with distance.

To compare distributions of haplotypes and population ge-

netic results among populations and regions, we ensured that

the information in all datasets was reported at a common

level of resolution. This required two steps: making a best

estimate for allele and genotypes calls in the cases where there

was ambiguity, and assigning into a common category those

alleles that differed among population samples due to hetero-

geneity in typing methodology. We refer to this second step

as ‘‘binning’’.

The method used to reduce genotypic and allelic ambiguity

(19), its implementation in the PyPop software framework

(17), and some of the implications (21) are described in

detail elsewhere in this volume. For the purpose of across

population analyses, we binned alleles that were only detect-

able in a subset of samples (due to the use of a higher resolu-

tion typing method) with the variants that are detected using

the lower resolution methodology. Table 1 identifies the allel-

es that were binned (‘‘original allele name’’), and the allelic

category into which they were binned (‘‘binned allele

name’’).

3HLA 2004: Immunobiology of the Human MHC

Methods

For two-locus haplotypes, populations with fewer than 40

individuals typed at both loci were not included in the anal-

yses. For three-locus haplotypes this cutoff was set at 50 indi-

viduals. For each population, we report results for haplotypes

that were estimated to have occurred at least once. For the

purpose of documenting the number of different haplotypes

and the extent to which they were shared among regions,

haplotypes that were estimated with a frequency corre-

sponding to less than one occurrence (a consequence of the

EM estimation) were not considered to be present in the

population. A description of the details for how the haplotype

frequency estimation was carried out can be found in the

statistical methods section of this volume (27).

Although we report some details on tests of the significance

of LD, we have chosen not to focus the discussion on signifi-

cance tests. Several authors have found significant LD across

large distances in the MHC region (1, 8, 29). Correction for

multiple tests is warranted for various sets of comparisons.

However, the appropriate correction will depend on the ques-


Table 3.2. HLA-A:DPB1 Haplotypes


No. of populations 2 1 1 3 1 2 10sampled per regionExpected 0.98 0.94 0.97 0.89 0.93 0.87 0.93heterozygosityNo. of different 203 70 57 65 34 29 335haplotypes (k) perregionRange of values for k (119–126) (70–70) (57–57) (14–45) (34–34) (14–27) (14–126)per populationNo. needed to reach a 21.8 8 13 4.5 5 3 11.8frequency of 0.5No. of frequent 2 4 5 15 7 7 30haplotypesFrequent haplotypes 2 3 2 7 4 3 21frequent in only oneregionFrequent haplotypes 2 0 0 3 2 0 7present in only oneregionPercentage of haplos 0.46 0.56 0.7 0.32 0.4 0.35 0.42estimated withcountΩ1Total freq. of haplos 0.19 0.21 0.41 0.07 0.08 0.06 0.14estimated with countΩ1Wn 0.34 0.4 0.54 0.38 0.37 0.42 0.38Dø 0.48 0.49 0.65 0.44 0.37 0.26 0.44Fraction not found 0.18 0.05 0.08 0.25 0.17 0.02 0.17(FNF)Complementary 0.03 0 0.06 0.13 0.11 0.08 0.07fraction (CF)

Table 3.3. HLA-B:DRB1 Haplotypes


No. of populations 2 2 3 1 14 3 1 2 2 2 32sampled per regionExpected 0.98 0.98 0.97 0.97 0.92 0.95 0.95 0.98 0.94 0.95 0.95heterozygosityNo. of different haplo- 244 143 337 88 208 135 61 265 90 99 1164types (k) per regionRange of values for k (107–167) (75–90) (68–272) (88–88) (13–93) (34–81) (61–61) (148–153) (28–71) (53–67) (13–272)per populationNo. needed to reach a 26.8 20.53 15.93 16 7.34 10.38 9 21.95 6.2 8.6 14.17frequency of 0.5No. of frequent 1 3 7 4 33 10 3 1 11 8 73haplotypesFrequent haplotypes 1 2 5 3 28 6 3 0 10 8 66frequent in only oneregionFrequent haplotypes 1 1 0 0 2 2 0 0 3 7 16present in only oneregionPercentage of haplos 0.5 0.69 0.48 0.54 0.39 0.5 0.52 0.58 0.49 0.53 0.48estimated withcountΩ1Total freq. of haplos 0.2 0.42 0.18 0.24 0.13 0.2 0.17 0.24 0.11 0.2 0.19estimated with countΩ1Wn 0.46 0.65 0.47 0.59 0.62 0.59 0.58 0.54 0.54 0.6 0.56Dø 0.63 0.83 0.71 0.77 0.73 0.66 0.64 0.78 0.69 0.79 0.72Fraction not found 0.33 0.34 0.36 0.42 0.48 0.34 0.43 0.48 0.38 0.42 0.42(FNF)Complementary 0.02 0.22 0.06 0.19 0.2 0.11 0.2 0.13 0.14 0.19 0.14fraction (CF)



Table 3.4. HLA-B:DPB1 Haplotypes


No. of populations 2 1 2 1 2 8sampled per regionExpected 0.98 0.98 0.96 0.93 0.94 0.97heterozygosityNo. of different 225 89 102 45 62 423haplotypes (k) perregionRange of values for k (132–134) (89–89) (33–74) (45–45) (32–42) (32–134)per populationNo. needed to reach a 24.6 18 10.42 7 7 16.64frequency of 0.5No. of frequent 0 2 11 4 10 26haplotypesFrequent haplotypes 0 2 10 3 10 25frequent in only oneregionFrequent haplotypes 0 0 5 0 3 8present in only oneregionPercentage of haplos 0.51 0.53 0.42 0.41 0.47 0.47estimated with countΩ1Total freq. of haplos 0.22 0.23 0.15 0.1 0.15 0.18estimated with countΩ1Wn 0.42 0.51 0.51 0.62 0.59 0.49Dø 0.53 0.61 0.53 0.53 0.53 0.53Fraction not found 0.21 0.18 0.24 0.36 0.18 0.22(FNF)Complementary 0.04 0.1 0.05 0.21 0.05 0.06fraction (CF)

Table 3.5. HLA-C:B Haplotypes


No. of populations 9 5 4 18 4 3 3 3 2 51sampled per regionExpected 0.96 0.94 0.97 0.91 0.94 0.87 0.96 0.92 0.93 0.93heterozygosityNo. of different 295 209 184 255 121 54 141 110 60 828haplotypes (k) perregionRange of values for k (37–108) (41–108) (44–89) (10–145) (22–56) (24–31) (44–88) (15–95) (35–44) (10–145)per populationNo. needed to reach a 10.15 6.6 13.81 6.54 6.88 3 10.05 6.78 5.4 7.88frequency of 0.5No. of frequent 13 8 12 25 16 8 13 11 8 76haplotypesFrequent haplotypes 9 2 8 8 1 3 5 4 7 47frequent in only oneregionFrequent haplotypes 4 0 0 0 1 0 0 2 4 11present in only oneregionPercentage of haplos 0.43 0.44 0.58 0.4 0.51 0.4 0.44 0.38 0.45 0.43estimated withcountΩ1Total freq. of haplos 0.1 0.07 0.27 0.08 0.19 0.06 0.1 0.07 0.1 0.1estimated with countΩ1Wn 0.75 0.75 0.72 0.8 0.8 0.86 0.78 0.79 0.83 0.78Dø 0.89 0.93 0.91 0.89 0.9 0.9 0.89 0.89 0.94 0.9Fraction not found 0.75 0.76 0.61 0.77 0.68 0.72 0.76 0.77 0.79 0.75(FNF)Complementary 0.3 0.32 0.39 0.44 0.49 0.27 0.41 0.44 0.54 0.38fraction (CF)



Table 3.6. HLA-DRB1:DPB1 Haplotypes


No. of populations 2 2 1 3 1 3 2 14sampled per regionExpected 0.97 0.97 0.96 0.92 0.94 0.91 0.88 0.94heterozygosityNo. of different 147 111 53 97 48 65 43 360haplotypes (k) perregionRange of values for k (65–111) (70–73) (53–53) (37–52) (48–48) (16–51) (17–29) (16–111)per populationNo. needed to reach a 14.6 13.49 11 5.6 6 6.18 3 9.07frequency of 0.5No. of frequent 6 5 3 11 4 12 9 45haplotypesFrequent haplotypes 6 4 2 8 3 10 7 40frequent in only oneregionFrequent haplotypes 4 0 0 2 1 3 3 13present in only oneregionPercentage of haplos 0.43 0.45 0.7 0.41 0.39 0.34 0.41 0.42estimated withcountΩ1Total freq. of haplos 0.14 0.16 0.4 0.12 0.11 0.09 0.11 0.14estimated with countΩ1Wn 0.44 0.42 0.54 0.48 0.51 0.57 0.55 0.49Dø 0.49 0.54 0.61 0.45 0.51 0.52 0.7 0.52Fraction not found 0.26 0.22 0.07 0.21 0.36 0.3 0.36 0.25(FNF)Complementary 0.03 0.08 0.07 0.1 0.11 0.17 0.29 0.11fraction (CF)

Table 3.7. HLA-DRB1:DQB1 Haplotypes


No. of populations 3 3 2 1 3 4 2 5 4 27sampled per regionExpected 0.94 0.93 0.94 0.95 0.89 0.82 0.88 0.8 0.81 0.88heterozygosityNo. of different 121 98 66 62 68 53 33 52 32 307haplotypes (k) perregionRange of values for k (36–94) (35–72) (43–47) (62–62) (34–38) (9–30) (14–29) (11–33) (11–19) (9–94)per populationNo. needed to reach a 6.71 6.35 6 8 4.35 2.77 3.6 2.54 2.23 4.71frequency of 0.5No. of frequent 11 6 8 6 8 11 8 13 9 43haplotypesFrequent haplotypes 5 0 2 0 1 2 5 5 1 21frequent in only oneregionFrequent haplotypes 1 0 0 0 0 1 2 2 1 7present in only oneregionPercentage of haplos 0.45 0.44 0.54 0.37 0.44 0.41 0.28 0.33 0.33 0.4estimated with countΩ1Total freq. of haplos 0.07 0.12 0.12 0.05 0.11 0.05 0.04 0.03 0.04 0.07estimated with countΩ1Wn 0.7 0.75 0.81 0.77 0.77 0.83 0.89 0.91 0.94 0.81Dø 0.86 0.92 0.92 0.95 0.85 0.92 0.9 0.95 0.99 0.91Fraction not found 0.66 0.68 0.78 0.84 0.65 0.72 0.88 0.84 0.94 0.76(FNF)Complementary 0.3 0.51 0.29 0.34 0.33 0.4 0.68 0.68 0.87 0.48fraction (CF)



tion being addressed. A global correction for multiple tests is

not feasible here, since the number of loci typed varies from

population to population and even from region to region.

When significance results are presented, we give the uncor-

rected results and results corrected for the number of compar-

Table 3.8. HLA-A:C:B Haplotypes


No. of populations 8 5 3 18 3 3 3 2 2 47sampled per regionExpected 0.99 0.98 0.99 0.94 0.96 0.94 0.98 0.96 0.96 0.97heterozygosityNo. of different 1013 614 287 681 162 99 320 244 119 2790haplotypes (k) perregionRange of values for k (103-279) (76-323) (71-119) (15-323) (37-88) (39-49) (83-155) (55-206) (55-80) (15-323)per populationNo. needed to reach a 37.81 21.60 30.61 16.71 12.29 7.09 21.37 24.00 9.20 23.39frequency of 0.5No. of frequent 3 6 1 29 10 14 4 6 7 73haplotypesFrequent haplotypes 3 6 1 23 6 13 3 5 7 67frequent in only oneregionFrequent haplotypes 2 0 0 2 0 3 2 1 4 14present in only oneregionPercentage of haplos 0.61 0.57 0.75 0.50 0.62 0.41 0.58 0.53 0.63 0.56estimated withcountΩ1Total freq. of haplos 0.31 0.22 0.52 0.19 0.31 0.10 0.25 0.20 0.25 0.24estimated with countΩ1

Table 3.9. HLA-A:B:DRB1 Haplotypes


No. of populations 2 2 3 1 14 3 1 2 1 2 31sampled per regionExpected 0.99 0.99 0.98 0.99 0.94 0.97 0.98 0.99 0.97 0.97 0.97heterozygosityNo. of different 450 211 747 109 415 189 83 414 105 146 2601haplotypes (k) perregionRange of values for k (169–294) (101–112) (95–584) (109–109) (18–125) (44–110) (83–83) (207–227) (105–105) (68–97) (18–584)per populationNo. needed to reach 60.40 40.50 36.81 30.00 10.67 16.22 15.00 45.53 11.00 12.80 28.15a frequency of 0.5No. of frequent 1 0 4 0 34 8 2 0 4 6 57haplotypesFrequent haplotypes 1 0 4 0 32 7 2 0 3 6 55frequent in only oneregionFrequent haplotypes 1 0 2 0 16 5 1 0 1 6 32present in only oneregionPercentage of haplos 0.73 0.83 0.66 0.69 0.50 0.61 0.60 0.72 0.49 0.64 0.62estimated withcountΩ1Total freq. of haplos 0.47 0.67 0.34 0.45 0.21 0.31 0.26 0.42 0.11 0.31 0.33estimated withcountΩ1


isons made for a given pair of loci. These tests only indicate

whether the association between the alleles at a pair of loci is

significantly non-random. They do not indicate the strength

of the association.

The choice of statistic to use for the comparison of the


Table 3.10. HLA-DRB1:DQA1:DQB1 Haplotypes


No. of populations 2 2 2 1 2 1 4 3 17sampled per regionExpected heterozygosity 0.94 0.92 0.94 0.95 0.89 0.89 0.79 0.81 0.89No. of different 88 60 80 68 49 30 51 31 275haplotypes (k) per regionRange of values for k per (47–63) (40–43) (46–54) (68–68) (30–31) (30–30) (12–35) (12–19) (12–68)populationNo. needed to reach a 6.60 4.94 6.50 8.00 4.00 4.00 2.45 2.29 4.84frequency of 0.5No. of frequent 7 6 8 6 10 5 14 8 38haplotypesFrequent haplotypes 3 1 2 0 7 3 7 1 24frequent in only oneregionFrequent haplotypes 1 0 0 0 3 0 2 1 7present in only one regionPercentage of haplos 0.43 0.42 0.60 0.43 0.39 0.30 0.32 0.40 0.41estimated with countΩ1Total freq. of haplos 0.09 0.09 0.15 0.06 0.07 0.05 0.04 0.05 0.07estimated with countΩ1

strength of LD among populations continues to be a topic of

interest (5, 9, 13, 23, 25, 26, 35). The effects of sample size

and marker characteristics (e.g., allele frequencies, heterozy-

gosity) should inform the choice of LD statistic when samples

with different properties are compared (28, 33). For highly

polymorphic data, multiallelic extensions of measures for bi-

allelic loci summarize the overall disequilibrium between

each pair of alleles at the two loci (14, 32, 34).

For each population, the overall measures Wn, Dø, and FNF

were computed for locus pairs as described in the statistical

methods section of this volume (27). FNF is the number of

haplotypes observed relative to the number expected under

linkage equilibrium (LE), given the sample size and the

number of alleles at the constituent loci for the haplotype. In

addition to these measures of the overall strength of LD, the

fraction of complementary haplotypes was computed to

quantify different aspects of LD. This statistic further charac-

terizes the distribution of the individual Døij values. Haplo-

types for which DøijΩ 1 (the maximum value for the statistic)

are referred to as complementary haplotypes (6). For a given

locus pair, the complementary fraction (CF) is defined as the

fraction of haplotypes that are complementary. This statistic

was computed after applying a threshold of at least two esti-

mated copies to the set of haplotypes (28). In this way the

statistic is not influenced by haplotypes estimated to exist

with only one copy (singletons). For the purpose of compari-

sons across populations we focus on the Wn measure due to

the range of sample sizes present in the data and the effect of

the number of singleton haplotypes on the D’ measure.


Three types of tables are reported for each locus: a sum-

mary 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 haplotypes among regions, we used a threshold

frequency of 0.05 to identify higher frequency haplotypes in

a population sample. We refer to a haplotype that is found 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 a haplotype that was ob-

served 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,

a haplotype is classified as being either absent, present, or frequent

in a particular region.

Summary Table

The summary table contains statistics that summarize the dis-

tribution of haplotypes by region as well as across all regions.

The first column corresponds to all regions combined and is

followed by a separate column for each region. In this table

we report sample-size weighted averages over all populations

in each region where it is appropriate. Due to the presence

of a few very large samples, the following procedure was used

to modify the weights used. 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. Below is a description of each

statistic presented.


Table 4. Maximum frequency of ‘‘regionally frequent‘‘ haplotypes according to geographic region.The following notes apply to all of the ‘‘Table 4‘‘ set of haplotype summaries:i) A frequent haplotype is defined as one that exists with a frequency of at least 0.05 in at least one population.ii) An asterisk (*) next to a frequency indicates that the haplotype was found in only one population in that region.iii) A blank indicates that the haplotype was not found in any population in the region.

Table 4.1. Maximum frequency in each region for the regionally frequent HLA-A:B haplotypes

Populations sampled (number per region)A:B SSA NAF EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (10) (2) (7) (6) (21) (5) (3) (3) (4) (2) Frequent Present0101:0801 0.037 *0.022 0.115 0.02 *0.003 0.035 *0.003 0.032 1 80201:0702 0.019 0.052 0.02 *0.002 *0.015 0.017 *0.035 1 70201:1501 0.082 0.016 0.013 0.038 1 40201:1502 0.02 *0.188 1 20201:1504 0.106 1 10201:1525 *0.001 0.067 1 20201:2705 0.009 0.044 *0.011 *0.005 *0.005 *0.026 0.06 1 70201:3501 0.043 *0.008 0.019 0.045 0.01 0.017 0.055 *0.010 1 80201:3901 *0.004 *0.008 0.007 0.015 0.021 0.107 1 60201:4001 *0.004 0.03 *0.005 0.049 0.09 0.008 0.01 *0.012 *0.010 1 90201:4004 0.077 1 10201:4402 0.022 0.023 0.08 *0.030 *0.003 0.02 0.033 0.007 1 80201:4801 0.075 0.006 0.078 2 30201:5101 0.023 0.038 0.079 0.054 0.02 *0.005 0.03 0.019 0.038 2 90201:5102 *0.002 0.005 0.123 1 30201:5502 0.107 *0.010 *0.010 1 30202:5801 0.054 1 10203:3802 0.051 *0.041 *0.008 1 30203:4001 0.05 0.01 1 20206:4002 *0.003 0.007 0.011 0.051 1 40206:4801 0.006 0.073 0.008 *0.006 1 40206:5502 0.069 *0.059 *0.002 2 30207:4601 *0.007 0.102 0.011 0.035 1 40211:4006 0.056 0.005 *0.006 1 30301:0702 0.022 0.098 0.012 0.006 0.01 *0.020 *0.022 0.023 1 80301:3501 0.013 0.083 *0.020 0.003 *0.003 *0.010 1 61101:1301 0.031 0.049 0.045 0.101 1 41101:1502 *0.020 0.062 0.043 *0.005 1 41101:1513 0.016 0.051 1 21101:1525 0.338 *0.025 1 21101:3802 0.026 0.057 1 21101:4001 *0.004 0.009 *0.008 0.136 0.022 0.023 *0.011 1 71101:4002 *0.007 0.008 0.01 *0.010 0.087 *0.002 1 61101:4006 0.055 0.015 *0.002 1 31102:2704 0.082 *0.010 1 21102:3901 0.072 *0.005 1 22301:3501 0.06 1 12402:1301 *0.008 0.255 *0.027 0.071 2 42402:1501 0.006 0.012 0.06 *0.020 0.008 0.039 1 62402:1502 *0.010 0.137 *0.012 *0.002 1 42402:1506 0.134 1 12402:1525 0.01 0.06 *0.035 0.039 *0.003 1 52402:2703 *0.052 1 12402:2705 *0.003 0.014 *0.002 0.003 0.05 1 52402:3501 *0.006 *0.007 0.017 0.056 0.018 *0.005 0.033 0.158 2 82402:3802 0.11 0.034 1 22402:3901 *0.003 0.019 0.455 *0.020 0.021 *0.008 *0.009 1 72402:4001 *0.006 0.025 *0.006 0.274 0.125 0.128 0.022 0.031 3 82402:4002 0.23 0.04 0.078 0.053 0.191 4 52402:4005 0.092 1 12402:4006 *0.003 0.05 0.02 *0.031 0.017 1 52402:4801 0.229 0.08 *0.005 0.008 0.142 3 52402:5401 0.044 0.08 1 22402:5502 *0.002 *0.002 0.118 0.013 *0.005 1 52402:5601 *0.006 0.005 *0.180 0.046 *0.005 *0.002 1 62402:5602 0.003 0.233 0.055 2 32402:5901 0.058 1 12407:3505 0.045 0.064 1 22601:3901 0.116 *0.005 *0.010 1 32601:4001 *0.003 *0.003 0.056 *0.030 *0.024 1 52601:4002 0.011 0.051 0.01 0.015 1 42603:1501 0.077 1 13001:4201 0.116 *0.030 *0.002 *0.001 1 43002:5301 0.058 0.011 *0.002 1 33101:1504 0.087 1 13101:3901 0.003 *0.006 0.032 0.052 0.042 1 53101:3905 *0.003 0.025 0.101 1 33101:3906 0.017 0.037 0.082 1 33101:3909 0.069 1 1



Table 4. Continued

Populations sampled (number per region)A:B SSA NAF EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (10) (2) (7) (6) (21) (5) (3) (3) (4) (2) Frequent Present3101:4801 *0.031 0.058 1 23303:4403 0.032 0.044 *0.010 0.06 1 43303:5801 0.008 0.005 0.054 0.082 0.053 *0.005 0.062 4 73401:1301 *0.001 0.015 0.151 1 33401:1521 0.009 0.032 0.07 1 33401:4002 0.08 0.045 1 23401:5601 0.199 *0.033 0.142 2 33401:5602 *0.010 0.083 1 26801:3505 0.066 1 16801:5101 0.012 *0.007 0.014 0.029 *0.003 0.057 *0.010 1 7

O Number of populations typed

O Expected heterozygosity (gene diversity) at the haplotype

level.

O Number of different haplotypes (k) per region: This is the

number of haplotypes estimated with at least one copy in

the dataset.

O Range of values for k per population: The minimum and

maximum values of k for populations in the region are

reported.

O Number of different haplotypes needed to reach a fre-

quency of 0.5: This is the minimum number of different

haplotypes necessary to account for 50% of the haplotype

frequency. Small values correspond to datasets where a few

Table 4.2. Maximum frequency in each region for the regionally frequent HLA-A:DPB1 haplotypes

Populations sampled (number per region)A:DPB1 Haplotypes SSA (2) EUR (1) SEA (1) OCE (3) AUS (1) NAM (2) No. Regions Frequent No. Regions Present0101:0401 *0.002 *0.062 *0.031 1 30201:0401 *0.033 *0.187 *0.010 *0.008 0.177 2 50201:0402 0.018 *0.031 *0.010 0.218 1 40201:0501 *0.020 *0.018 *0.121 *0.015 1 40203:0501 *0.051 *0.047 1 20301:0401 *0.003 *0.072 1 20301:0402 *0.033 *0.056 1 21101:0101 0.118 1 11101:0401 *0.015 *0.051 0.071 2 31101:0501 *0.005 *0.038 0.073 *0.094 2 42301:0101 0.054 1 12402:0101 *0.005 0.089 1 22402:0201 *0.031 0.32 *0.017 0.086 2 42402:0401 *0.004 *0.021 0.227 *0.019 0.091 2 52402:0402 *0.002 *0.012 *0.020 *0.056 0.22 2 52402:0501 *0.061 0.19 *0.119 *0.006 3 42402:1301 *0.002 *0.051 *0.091 2 32402:2201 *0.080 1 12407:0101 *0.010 0.107 1 22407:0501 *0.034 0.075 1 23101:0401 *0.012 *0.005 0.117 1 33101:0402 *0.004 0.12 1 23303:0401 *0.051 *0.025 1 23401:0101 0.065 1 13401:0201 *0.014 *0.063 1 23401:0401 *0.004 *0.010 0.077 *0.038 1 43401:0501 0.06 *0.106 2 23401:1301 0.053 1 13401:2201 *0.074 1 17401:0402 0.052 1 1


haplotypes are present at high frequencies; high values are

observed in cases where haplotype frequencies are more

even, with several haplotypes at similar frequencies at the

high end of the spectrum.

O Number of regionally frequent haplotypes: This is the

number of haplotypes with a frequency of 0.05 or more

which are present in at least one population sample.

O Regionally frequent haplotypes that are frequent in only

one region: For each region, this specifies how many of

the frequent haplotypes have a frequency at or above the

threshold exclusively in that region.

O Fraction of haplotypes estimated with counts equal to one:

This is the number of singletons divided by the number

of different haplotypes. It indicates how many of the ob-


Table 4.3. Maximum frequency in each region for the regionally frequent HLA-B:DRB1 haplotypes

Populations sampled (number per region)B:DRB1 SSA NAF EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (2) (2) (3) (1) (14) (3) (1) (2) (2) (2) Frequent Present0702:1501 0.015 0.109 *0.016 *0.061 *0.006 2 50801:0301 0.082 0.13 *0.063 *0.036 *0.006 *0.004 3 61301:0803 0.048 *0.011 *0.095 1 31301:1101 0.073 *0.005 1 21301:1202 *0.010 0.245 *0.005 *0.010 1 41301:1401 0.07 *0.005 *0.036 1 31301:1502 *0.009 0.06 1 21501:0401 0.059 *0.003 *0.010 1 31502:1202 0.09 0.21 *0.005 2 31502:1502 *0.139 0.027 1 21504:1602 0.177 1 11506:0405 *0.055 1 11521:0803 *0.005 *0.120 1 21525:1401 *0.005 0.1 *0.014 1 31525:1602 0.3 0.03 1 21801:1502 *0.005 0.07 *0.010 1 32703:0401 *0.067 1 12704:0405 *0.059 *0.021 *0.003 1 33501:0101 *0.004 0.089 0.022 1 33501:0802 *0.005 *0.079 1 23501:1402 *0.003 0.158 1 23505:0802 0.059 1 13505:0901 0.073 1 13701:1001 0.005 *0.072 0.034 1 33802:1502 0.11 0.118 *0.010 2 33901:0404 *0.006 *0.010 0.052 1 33901:0802 *0.162 1 13901:0803 0.216 0.01 *0.010 1 33901:1202 0.244 *0.010 1 23901:1401 *0.005 0.098 *0.010 1 33901:1405 0.07 1 13905:1402 0.063 1 13906:1602 0.064 1 13909:1402 0.057 1 14001:0403 0.113 0.03 *0.003 1 34001:0404 *0.019 *0.005 *0.138 1 34001:0405 *0.005 0.156 0.01 *0.010 0.008 1 54001:0803 *0.000 0.093 0.03 *0.021 *0.003 1 54001:0901 0.078 0.011 *0.005 1 34001:1101 *0.005 0.118 *0.010 *0.020 1 44001:1301 0.056 *0.003 1 24001:1401 *0.001 0.176 0.05 2 34001:1501 *0.007 *0.003 0.109 *0.078 *0.005 *0.003 2 64002:0901 *0.010 *0.009 *0.063 1 34002:1101 *0.001 *0.005 0.099 *0.010 *0.008 *0.012 1 64002:1401 *0.000 0.22 *0.020 *0.008 *0.057 2 54002:1402 *0.010 0.081 1 24002:1502 0.01 0.1 1 24004:0807 0.076 1 14201:0804 0.1 1 14402:0401 0.054 *0.014 *0.002 1 34402:0402 0.067 1 14403:0701 0.022 0.052 *0.019 0.01 *0.011 0.028 1 64403:1302 *0.011 *0.060 *0.001 *0.035 1 44601:0901 0.069 *0.011 0.021 1 34801:0401 *0.005 *0.003 *0.078 1 34801:0404 *0.000 0.186 *0.002 1 34801:1101 0.074 0.03 *0.002 1 34801:1401 0.133 *0.003 1 24801:1501 0.05 *0.005 1 25101:1101 *0.002 0.024 *0.012 0.018 0.003 *0.077 1 65101:1301 0.028 *0.065 1 25101:1402 *0.028 0.057 1 25102:0802 *0.112 1 15201:1502 *0.002 *0.068 0.022 1 35301:1402 *0.003 *0.059 1 25502:1101 0.093 *0.010 1 25502:1401 0.078 1 15601:0803 *0.009 *0.014 *0.085 1 35601:1501 *0.006 *0.009 *0.066 1 35601:1502 0.184 *0.028 *0.031 1 35602:1407 *0.121 1 15801:0301 *0.015 *0.041 0.064 *0.032 *0.005 0.025 1 6



Table 4.4. Maximum frequency in each region for the regionally frequent HLA-B:DPB1 haplotypes

Populations sampled (number per region)B:DPB1 Haplotypes SSA (2) EUR (1) OCE (2) AUS (1) NAM (2) No. Regions Frequent No. Regions Present0702:0401 0.007 *0.082 *0.005 1 31301:0501 *0.029 *0.195 1 21506:0201 *0.063 *0.005 1 21521:2201 *0.005 *0.070 1 21525:0401 *0.053 1 12705:0402 *0.010 *0.072 1 23501:0201 *0.008 *0.022 *0.053 1 33501:0401 *0.012 0.059 1 23501:0402 *0.015 0.146 1 23802:0101 *0.106 1 13901:0401 *0.010 *0.135 1 24001:0201 *0.059 *0.032 1 24001:0401 *0.002 *0.025 *0.054 *0.029 1 44002:0101 *0.064 1 14002:0402 *0.005 0.064 1 24002:0501 0.016 *0.058 0.012 1 34005:0402 *0.092 1 14402:0401 *0.063 *0.005 1 24801:0402 0.123 1 15102:0401 0.062 1 15301:0402 0.021 *0.062 1 25601:0201 *0.064 1 15601:0401 *0.089 *0.046 1 25601:0501 *0.066 *0.072 2 25602:0201 *0.129 *0.005 1 25602:0401 *0.090 1 1

served haplotypes are at the lowest end of the frequency

spectrum.

O Total frequency of haplotypes estimated with count equal

to one: This statistic provides additional information about

the low end of the frequency spectrum by giving the total

frequency contribution of singletons.

O Wn and Dø These are measures of overall LD.

O Complementary Fraction: This is the fraction of haplotypes

for which DøijΩ1.

O FNF: This is the fraction of the number of haplotypes ex-

pected under linkage equilibrium that are not found in the

sample.

For the ‘‘number of populations typed’’ and frequent haplotypes

present and/or frequent in only one region, the value in the ‘‘All

Regions’’ category is the sum of the values across all regions.

This is not the case for the ‘‘number of different haplotypes’’

or ‘‘number of frequent haplotypes’’, due to the sharing of

haplotypes across regions. The averages reported in the ‘‘All

Regions’’ category for the previously mentioned statistics

were computed as sample size weighted averages over all

world populations that met the inclusion criteria.

Regional Table

Regional detail is provided in Table 4, which allows an assess-

ment of the degree of sharing of specific haplotypes found at

or above the threshold frequency of 0.05 in at least one popu-

lation sample (regionally frequent haplotypes). The statistic re-


ported in the tables is the maximum frequency for that haplo-

type 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 haplotypes.

Haplotypes that were observed in only one population sam-

ple in that region are marked with an asterisk, in order to

highlight regionally frequent haplotypes that were not shared

within the region. This table facilitates the identification of

specific haplotypes responsible for the patterns seen in the

summary table. The number of haplotypes listed is equal to

the total number of regionally frequent haplotypes indicated in

the summary table.

Population Table

Population level information is provided in Table 5, which

contains information about the distribution of specific haplo-

types at the individual population level. For this table, in addi-

tion to those haplotypes above the threshold frequency, the

superset of the three most frequent haplotypes found in each

population for a given region was used for the selection of

specific haplotypes. This set of haplotypes in each region en-

sures that each population within a region is represented.

Complete details for each population, including less frequent

haplotypes, can be found at the IHWG website (http://

www.ihwg.org/components/diversr.htm).


Table 4.5. Maximum frequency in each region for the regionally frequent HLA-C:B haplotypes

Populations sampled (number per region)C:B SSA EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (9) (5) (4) (18) (4) (3) (3) (2) (2) Frequent Present0102:1501 *0.003 0.005 0.06 0.009 0.042 1 50102:4002 *0.001 *0.010 0.062 1 30102:4601 0.163 0.02 0.05 2 30102:5401 0.034 0.01 0.087 1 30102:5502 *0.002 0.127 0.1 0.02 2 40102:5601 0.008 0.017 0.204 *0.010 0.171 0.006 *0.009 2 70102:5602 *0.001 *0.080 0.169 2 30102:5901 0.004 0.062 1 20202:1503 0.102 *0.004 1 20202:2705 0.01 0.039 0.018 *0.001 0.01 0.171 1 60202:4002 0.009 0.014 *0.050 0.004 1 40302:5801 0.042 0.005 0.045 0.109 0.064 0.057 3 60303:1501 0.016 0.089 0.015 *0.020 *0.006 0.086 0.04 *0.010 2 80303:1504 0.164 1 10303:3501 0.011 0.018 *0.011 0.101 1 40303:4001 0.011 0.01 0.01 0.151 0.005 *0.002 1 60303:4002 *0.005 0.137 *0.030 0.015 0.005 1 50303:5502 *0.002 *0.007 0.057 *0.010 *0.006 1 50304:1301 0.28 *0.027 0.012 0.01 1 40304:1510 0.065 *0.002 *0.002 1 30304:3511 *0.059 1 10304:4001 0.023 0.083 0.007 0.227 0.19 *0.003 0.039 0.037 *0.010 3 90304:4002 *0.003 0.011 0.15 *0.010 0.071 0.297 3 60304:4004 0.101 1 10304:5101 *0.005 *0.005 0.079 1 30304:5502 *0.002 0.059 1 20401:1301 *0.001 0.256 1 20401:1501 0.017 0.027 *0.005 0.052 0.007 1 50401:3501 0.073 0.106 0.045 0.027 *0.010 *0.006 0.024 0.207 *0.019 3 90401:3503 0.098 0.05 0.005 0.02 *0.006 *0.009 *0.007 2 70401:3505 *0.002 0.075 0.08 0.14 3 40401:4001 0.209 0.07 *0.006 *0.003 2 40401:5301 0.113 0.003 *0.015 *0.010 *0.018 0.085 2 60403:1521 0.043 0.059 0.145 2 30403:1525 0.4 0.062 *0.003 2 30403:4001 0.05 *0.020 1 20501:4402 0.025 0.116 *0.006 0.029 0.03 0.028 1 60602:1302 0.036 0.067 0.025 0.018 *0.010 0.045 *0.022 1 70602:5001 0.012 0.028 0.08 0.002 *0.015 0.003 1 60602:5701 0.025 0.04 0.096 0.016 0.02 0.017 0.033 *0.015 1 80602:5801 0.053 1 10602:5802 0.117 *0.002 1 20701:0801 0.053 0.16 0.021 *0.003 0.035 *0.003 0.037 2 70701:4403 0.023 *0.014 0.091 0.065 0.02 *0.025 *0.002 2 70702:0702 0.07 0.17 0.04 0.016 0.02 *0.041 0.068 0.07 *0.019 4 90702:0705 *0.008 0.011 0.054 0.021 1 40702:0801 0.02 *0.002 0.064 0.01 *0.006 *0.002 1 60702:1535 0.059 1 10702:3802 0.11 0.128 *0.012 2 30702:3901 *0.002 0.011 0.539 0.03 *0.021 0.067 0.158 0.049 3 80702:3905 *0.003 *0.004 0.108 1 30702:3906 *0.004 0.008 0.037 0.091 1 40702:3909 0.011 0.084 1 20702:4001 0.118 0.051 *0.017 *0.015 2 40704:1801 0.04 *0.011 0.081 0.07 *0.006 2 50801:1502 *0.002 *0.032 0.18 0.22 *0.005 2 50801:1513 0.075 0.112 2 20801:4006 0.02 *0.020 0.053 1 30801:4801 *0.000 0.26 0.1 *0.006 0.045 0.098 *0.010 3 70801:5102 0.134 1 10802:1404 *0.002 *0.056 1 20806:4801 *0.101 1 11202:2704 0.109 *0.010 1 21202:5201 0.009 0.01 0.074 0.016 0.02 0.03 *0.004 1 71402:5101 0.008 0.033 0.064 0.039 *0.016 0.1 *0.011 2 71502:4002 0.006 0.09 0.166 0.017 0.011 2 51502:4006 *0.003 0.085 0.022 *0.051 *0.006 2 51502:5101 0.009 0.023 0.045 0.013 *0.005 0.051 0.055 *0.010 2 81503:5104 0.067 1 11507:4006 0.091 *0.005 1 21601:4501 0.06 *0.002 0.007 1 31601:5201 0.085 1 11601:7801 0.07 1 11701:4101 0.027 0.017 0.05 *0.007 1 41701:4201 0.148 *0.003 *0.003 1 31801:5703 0.057 1 1



Results

In the subsections below we provide a brief overview of the

tables containing population summaries (Table 3) and the re-

gional details (Table 4). This overview highlights a few spe-

cific high frequency haplotypes that are either frequent (or

present) in most regions or unique to a certain region. For

two extremely polymorphic locus pairs with high degrees of

LD, HLA-C:B and DRB1:DQB1, we provide additional detail

about specific alleles at one locus that form haplotypes with

many alleles at the second locus.

A:B

A total of 63 population samples that met the inclusion criter-

ia were typed at both loci, with each region represented by

at least 2 population samples. There were 1798 different

Table 4.6. Maximum frequency in each region for the regionally frequent HLA-DRB1:DPB1 haplotypes

Populations sampled (number per region)DRB1:DPB1 SSA EUR SEA OCE AUS NAM SAM No. Regions No. RegionsHaplotypes (2) (2) (1) (3) (1) (3) (2) Frequent Present0101:0401 0.063 *0.020 1 20301:0401 0.057 *0.021 0.026 *0.016 *0.007 1 50302:0101 0.102 1 10302:0402 0.059 1 10403:0401 *0.005 *0.077 1 20403:0402 0.07 0.047 1 20404:0201 *0.010 *0.010 *0.054 1 30405:0101 *0.006 *0.011 *0.052 1 30405:0501 0.067 *0.059 2 20407:0401 0.081 1 10407:0402 *0.005 0.049 *0.146 1 30407:1401 *0.073 1 10411:0301 *0.020 0.071 1 20411:0402 *0.051 1 10411:1401 *0.006 *0.142 1 20701:0401 *0.028 0.087 *0.011 *0.016 *0.016 *0.031 1 60802:0401 *0.006 *0.240 1 20802:0402 0.2 *0.018 1 20803:0501 0.036 *0.158 1 20803:2201 *0.140 1 10807:0401 *0.152 1 10901:0201 *0.006 *0.021 *0.006 *0.071 1 41101:0101 0.063 *0.020 1 21101:0401 *0.020 0.053 *0.011 *0.012 1 41101:0402 0.064 *0.025 *0.008 1 31101:0501 *0.005 *0.021 0.062 1 31202:0402 *0.011 *0.052 1 21202:0501 *0.154 0.039 *0.005 1 31202:1301 *0.055 0.039 1 21302:0101 0.057 1 11402:0201 0.11 1 11402:0401 0.163 *0.024 1 21402:0402 0.143 *0.212 2 21402:0501 *0.055 0.03 1 21406:0401 *0.059 1 11407:0201 *0.093 1 11501:0201 *0.023 0.016 0.073 1 31501:0401 0.074 *0.042 *0.140 *0.007 *0.012 2 51502:0101 0.289 1 11502:0401 0.01 *0.011 0.076 *0.022 1 41502:0501 *0.026 0.208 *0.025 1 31502:1301 *0.005 *0.052 0.126 *0.005 2 41503:0201 *0.057 1 11602:0301 *0.069 *0.013 1 21602:0402 *0.004 0.156 0.245 2 3


haplotypes observed worldwide. The number of different

haplotypes per population ranged from 13 to 240. Of the 79

different regionally frequent haplotypes, four were frequent in at

least three regions (2402:4001, 2402:4002, 2402:4801, and

3303:5801). Averaged over all populations, 47% of the

haplotypes were estimated to exist as single copies. The total

frequency of these singletons was 17%. After correcting for

the number of comparisons, significant overall LD was found

in all but five populations (Georgian in EUR, American-Sa-

moa in OCE, Guarani-Nandeva in SAM, Paiwan-51 in SEA,

and Tamil in SWA). Significance at the 0.01 level prior to

correction was seen for all but the Georgian and Tamil popu-

lations. Regional average Wn values ranged from a low of 0.48

in SSA to a high of 0.68 in OCE.

The 0201:5101 haplotype was present in all regions with the

exception of AUS. Eight additional frequent haplotypes were pres-


Table 4.7. Maximum frequency in each region for the regionally frequent HLA-DRB1:DQB1 haplotypes

Populations sampled (number per region)DRB1:DQB1 SSA NAF EUR SWA SEA OCE AUS NAM SAM No. Regions No. RegionsHaplotypes (3) (3) (2) (1) (3) (4) (2) (5) (4) Frequent Present0101:0501 0.023 0.023 0.105 *0.045 *0.010 *0.011 *0.010 0.02 *0.019 1 90102:0501 0.075 0.066 *0.010 *0.005 *0.009 2 50301:0201 0.065 0.179 0.12 *0.090 0.098 0.048 *0.045 0.032 0.009 5 90302:0402 0.192 0.011 *0.009 1 30401:0301 *0.002 0.015 *0.006 0.227 1 40403:0302 0.026 *0.039 0.025 *0.032 *0.010 0.147 0.091 2 70404:0302 *0.006 0.025 *0.020 *0.010 *0.015 0.121 0.02 1 70405:0401 0.045 0.109 *0.020 1 30405:0402 *0.006 0.023 0.066 1 30407:0302 *0.002 0.142 0.227 2 30411:0302 *0.013 *0.015 *0.567 0.316 2 40411:0402 0.05 1 10412:0402 *0.110 1 10701:0201 0.081 0.209 0.126 *0.073 0.041 0.016 *0.025 *0.037 0.055 5 90802:0402 *0.005 *0.008 0.425 0.069 2 40803:0503 *0.040 0.085 1 20803:0601 0.025 0.048 0.273 1 30807:0402 0.224 1 10901:0303 *0.005 *0.010 0.141 0.043 0.078 0.097 3 61101:0301 0.103 0.092 0.06 *0.095 0.031 0.551 0.108 *0.009 6 81101:0602 0.094 *0.005 1 21104:0301 0.004 0.025 0.055 *0.063 *0.006 0.028 0.028 2 71201:0501 0.05 1 11202:0301 *0.005 *0.002 0.298 0.112 *0.005 2 51202:0502 0.055 0.088 2 21301:0603 0.043 0.011 0.087 *0.035 0.01 *0.005 0.015 *0.004 1 81302:0604 0.084 0.068 0.019 *0.035 *0.006 *0.005 2 61302:0605 0.052 0.031 *0.030 *0.010 0.015 *0.021 *0.005 1 71401:0502 *0.005 0.14 0.013 1 31401:0503 0.007 0.02 0.039 *0.049 0.034 *0.040 0.068 1 71402:0301 *0.010 0.071 0.338 0.255 3 41406:0301 0.09 1 11407:0503 *0.138 1 11408:0503 0.092 0.101 2 21409:0402 *0.220 1 11501:0602 0.058 0.074 0.102 *0.061 0.041 0.253 *0.040 0.026 5 81502:0501 0.082 0.222 *0.010 2 31502:0502 0.05 0.277 2 21502:0601 0.02 *0.015 *0.039 *0.020 0.17 0.134 2 61503:0602 0.152 *0.011 *0.006 *0.005 1 41601:0502 0.02 0.105 *0.059 2 31602:0301 0.18 0.351 2 21602:0502 0.009 *0.005 *0.005 0.188 0.263 0.012 2 6

ent in all but two regions (0101:0801, 0201:3501, 0201:4001,

0201:4402, 0201:5101, 0301:0702, 2402:3501, and 2402:

4001).

Twelve frequent haplotypes were present in only one region

(0202:5801 and 2301:3501 in SSA; 2402:1506 in OCE;

2402:5901 and 2603:1501 in NEA; 2402:2703 and

2402:4005 in NAM; 0201:1504, 0201:4004, 3101:1504,

3101:3909, and 6801:3505 in SAM).

C:B

A total of 51 population samples were typed at both loci,

including at least 2 populations from each region, except NAF

which was not sampled at these loci. There were 828 dif-

ferent haplotypes observed worldwide. The number of dif-

ferent haplotypes per population ranged from 10 to 145. Of

the 76 different regionally frequent haplotypes, eight were frequent

in at least three regions (0302:5801, 0304:4001, 0304:


4002, 0401:3501, 0401:3505, 0702:0702, 0702:3901, and



frequency of these singletons was 10%. Significant LD was

found in every population after correcting for the number of

comparisons. Regional average Wn values ranged from a low

of 0.72 in SWA to a high of 0.86 in AUS.

The 0304:4001, 0401:3501, and 0702:0702 haplotypes

were present in all sampled regions. Twelve additional frequent

haplotypes were present in all but two of the sampled regions

(0102:5601, 0303:1501, 0401:3503, 0602:1302, 0602:

5701, 0701:0801, 0701:4403, 0702:3901, 0801:4801,

1202:5201, 1402:5101, and 1502:5101). Eleven frequent

haplotypes were present in only one region (0602:5801,

1601:5201, 1601:7801, and 1801:5703 in SSA; 0702:1535

in OCE; 0801:5102 and 0806:4801 in NAM; 0303:1504,

0304:3511, 0304:4004, and 1503:5104 in SAM).


Table 4.8. Maximum frequency in each region for the regionally frequent HLA-A:C:B haplotypes

Populations sampled (number per region)A:C:B SSA EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (8) (5) (3) (18) (3) (3) (3) (2) (2) Frequent Present0101:0701:0801 0.034 0.115 *0.001 0.035 *0.003 0.028 1 60201:0102:5502 0.108 *0.010 1 20201:0303:1501 *0.009 0.06 0.015 *0.003 *0.009 1 50201:0303:1504 0.108 1 10201:0304:4001 *0.004 0.032 0.02 0.11 *0.003 *0.011 *0.010 1 70201:0304:4004 0.078 1 10201:0403:1525 *0.005 0.054 1 20201:0501:4402 0.016 0.083 *0.004 0.023 *0.020 0.011 1 60201:0702:0702 0.018 0.051 *0.001 *0.009 0.014 *0.036 1 60201:0704:1801 *0.015 0.005 *0.050 *0.006 1 40201:0801:1502 0.02 *0.187 1 20201:0801:4801 0.074 *0.004 1 20203:0403:4001 0.05 1 10206:0102:5502 0.069 *0.049 1 20206:0202:2705 *0.009 0.083 1 20206:0801:4801 0.072 0.008 *0.004 1 30207:0102:4601 0.092 *0.011 0.032 1 30301:0401:3501 0.012 0.083 *0.012 1 30301:0702:0702 0.022 0.1 *0.003 *0.010 *0.017 *0.023 0.024 1 71101:0304:4001 *0.004 0.007 0.055 *0.005 *0.009 1 51101:0401:1301 *0.009 0.109 1 21101:0403:1525 0.338 1 11101:0702:3802 0.027 0.059 1 21101:0702:4001 0.083 *0.021 *0.009 1 31101:0801:1502 0.053 *0.027 *0.005 1 31101:1202:5201 *0.009 0.005 0.057 *0.001 *0.005 *0.015 *0.002 1 71101:1502:4002 0.005 0.075 1 21102:0702:3901 0.069 *0.005 1 21102:1202:2704 0.082 *0.010 1 22301:1601:5201 *0.050 1 12402:0102:1501 *0.003 *0.005 0.06 *0.026 1 42402:0102:4002 *0.062 1 12402:0102:5401 0.02 0.071 1 22402:0102:5502 0.118 0.013 *0.005 1 32402:0102:5601 0.005 *0.010 0.084 *0.002 1 42402:0102:5602 *0.001 *0.025 *0.050 1 32402:0102:5901 0.058 1 12402:0202:2705 *0.001 0.068 1 22402:0303:4001 0.01 0.121 1 22402:0303:4002 0.128 *0.010 1 22402:0304:1301 0.257 *0.012 1 22402:0304:4001 *0.006 0.038 0.151 0.059 0.017 0.013 2 62402:0304:4002 0.15 *0.010 0.042 0.184 2 42402:0401:1301 0.073 1 12402:0401:3501 0.011 *0.038 0.01 0.009 0.062 1 52402:0401:4001 0.165 0.07 *0.006 2 32402:0403:1521 *0.005 0.03 0.06 1 32402:0403:1525 0.06 *0.008 1 22402:0702:3802 0.11 0.032 1 22402:0702:3901 *0.011 0.449 *0.020 *0.021 *0.005 *0.007 1 62402:0702:4001 0.1 *0.020 1 22402:0801:1502 0.137 *0.023 1 22402:0801:4801 0.224 0.08 0.009 0.007 2 42402:0806:4801 *0.101 1 12402:1502:4002 0.005 0.021 0.055 *0.012 0.008 1 52407:0401:3505 0.049 0.063 1 22601:0303:4002 0.052 0.005 1 22601:0702:3901 0.115 *0.010 1 22603:0303:1501 0.057 1 13001:1701:4201 0.105 *0.002 *0.001 1 33101:0702:3905 *0.003 0.098 1 23101:0702:3906 *0.002 0.084 1 23101:0702:3909 *0.002 0.069 1 23101:1503:1504 0.06 1 13303:0302:5801 0.004 0.005 *0.019 0.082 *0.053 0.054 3 63401:0102:5601 0.199 0.141 2 23401:0102:5602 0.085 1 13401:0401:1301 *0.001 0.151 1 23401:0403:1521 0.022 *0.032 0.07 1 33401:1502:4002 0.07 0.034 1 26601:0602:5802 0.051 1 16801:0304:4002 *0.002 *0.063 1 26801:0401:3505 0.066 1 1



Table 4.9. Maximum frequency in each region for the regionally frequent HLA-A:B: DRB1 haplotypes

Populations sampled (number per region)A:B: DRB1 SSA NAF EUR SWA SEA OCE AUS NEA NAM SAM No. Regions No. RegionsHaplotypes (2) (2) (3) (1) (14) (3) (1) (2) (1) (2) Frequent Present0101:0801:0301 *0.015 0.09 *0.036 *0.004 1 40201:1501:0401 0.05 1 10201:1502:1202 *0.020 *0.180 1 20201:1504:1602 0.096 1 10201:1801:1502 *0.050 1 10201:4004:0807 0.059 1 10201:4801:1101 0.073 1 10206:4801:1401 0.074 1 10206:4801:1501 *0.050 1 10301:0702:1501 0.056 *0.007 *0.005 *0.020 1 40301:3501:0101 0.078 1 11101:1525:1401 *0.086 1 11101:1525:1602 0.252 1 11101:4001:1401 0.057 *0.007 1 21101:4001:1501 *0.055 *0.016 *0.005 *0.003 1 42402:1301:1101 0.073 1 12402:1301:1202 0.245 1 12402:1301:1401 *0.080 1 12402:1502:1202 0.06 *0.030 1 22402:1502:1502 *0.110 *0.007 1 22402:1506:0405 *0.063 1 12402:1525:1602 0.06 1 12402:2704:0405 *0.059 1 12402:3802:1502 *0.110 0.057 2 22402:3901:0803 0.216 *0.008 1 22402:3901:1202 0.21 0.01 1 22402:4001:0403 0.088 0.03 *0.003 1 32402:4001:0404 *0.004 *0.110 1 22402:4001:0405 0.147 0.01 0.003 1 32402:4001:0803 0.069 *0.021 1 22402:4001:0901 0.068 *0.003 1 22402:4001:1101 *0.006 0.118 *0.010 1 32402:4001:1401 *0.001 0.103 1 22402:4001:1501 *0.001 0.029 *0.066 *0.003 1 42402:4002:1101 0.094 *0.003 *0.007 1 32402:4002:1401 0.22 *0.030 *0.003 *0.055 2 42402:4002:1402 *0.005 *0.063 1 22402:4801:0401 *0.003 *0.081 1 22402:4801:0404 0.166 1 12402:4801:1101 0.074 *0.011 1 22402:4801:1401 0.064 1 12402:4801:1502 0.06 1 12402:5502:1101 0.075 1 12402:5502:1401 *0.078 1 12402:5602:1407 *0.121 1 12601:3901:1405 0.073 1 13001:4201:0804 *0.075 1 13101:1504:1602 0.096 1 13101:3905:1402 0.061 1 13101:3906:1602 *0.058 1 13303:5801:0301 *0.036 0.055 *0.031 *0.005 0.022 1 53401:1521:0803 *0.009 *0.068 1 23401:4002:1502 0.07 1 13401:5601:0803 *0.055 1 13401:5601:1502 0.178 1 16801:3505:0901 *0.056 1 16801:5101:1101 *0.053 1 1

B alleles found in multiple C:B haplotypes

The B*3501 allele was found paired with the largest number of

C alleles in C:B haplotypes. It was found with 25 different C

alleles across all regions. Eleven of the 25 C:B*3501 haplotypes

had a frequency greater or equal to 0.01 in at least one popula-

tion. The diversity of pairings of B*3501 with C alleles was

greatest in SSA, EUR, SEA, and NEA. The 0401:3501 haplotype,

found in all of the sampled regions, had the highest frequencies

in NAM, EUR, SSA, and SWA, respectively. Bugawan et al.


(2000) found, in the CEPH data, that all B*35 alleles were

found on Cw*0401 C:B haplotypes. B*35 alleles in Asian and

North American populations were found on haplotypes with

additional other C alleles (7). Of the C:B haplotypes containing

a B*35 allele, the Cw*0401:B*35 haplotype had the highest

frequency in all but three populations. The Cw*0303:B*3501

haplotype had the highest frequency in the Korean, Okinawan,

and Pazeh population samples. This haplotype was also found

in OCE, SEA, and EUR. The Cw*0304:B*3511 haplotype had a


high frequency in the Guarani-Kaiowa population sample and

was only found in SAM.

B*5101 alleles were found on haplotypes with 22 different

C alleles. Sixteen of these C:B*5101 haplotypes had a fre-

quency of at least 0.01 in a population. The diversity of pair-

ings of B*5101 with C alleles was highest in EUR, SSA, and

SEA, respectively. The 1502:5101 haplotype was found in all

sampled regions with the exception of AUS and had highest

frequencies in NAM, NEA, and SWA, respectively.

B*4403 alleles were found paired with 21 different C allel-

es. Six of these C:B*4403 haplotypes reached a frequency of

at least 0.01 in at least one population. The diversity of pair-

ings of B*4403 with C alleles was highest in SSA, EUR, and

SEA, respectively.

B*1801 alleles were found on haplotypes with 20 different

C alleles. Eight of these C:B*1801 haplotypes had a frequency

of at least 0.01 in a population. The diversity of pairings of

B*5101 with C alleles was highest in SSA, EUR, and SWA,

respectively.

Additional B alleles that had a large number of pairings

Table 4.10. Maximum frequency in each region for the regionally frequent HLA-DRB1:DQA1:DQB1 haplotypes

Populations sampled (number per region)DRB1:DQA1:DQB1 SSA NAF EUR SWA OCE AUS NAM SAM No. Regions No. RegionsHaplotypes (2) (2) (2) (1) (2) (1) (4) (3) Frequent Present0101:0101:0501 0.02 0.023 0.105 *0.045 *0.010 0.02 *0.019 1 70102:0101:0501 *0.061 0.066 *0.010 *0.005 *0.009 2 50301:0501:0201 0.065 0.179 0.12 *0.090 *0.019 *0.045 0.032 0.009 4 80302:0401:0402 0.192 0.011 *0.009 1 30401:0301:0301 0.01 *0.006 0.246 1 30403:0301:0302 0.02 *0.039 *0.010 0.147 *0.091 2 50404:0301:0302 *0.006 0.025 *0.020 *0.015 0.121 *0.003 1 60405:0301:0401 0.104 *0.020 1 20405:0301:0402 *0.006 *0.023 *0.066 1 30407:0301:0302 *0.002 0.142 0.227 2 30410:0301:0402 *0.023 *0.025 *0.061 1 30411:0301:0302 *0.013 *0.015 *0.567 0.047 1 40411:0301:0402 0.05 1 10701:0201:0201 0.035 0.209 0.123 *0.073 *0.006 *0.025 *0.037 0.055 4 80802:0401:0402 *0.005 *0.008 0.19 0.069 2 40803:0103:0503 *0.023 *0.076 1 20803:0103:0601 0.023 *0.268 1 20807:0401:0402 0.101 1 10901:0301:0303 *0.005 *0.010 0.013 0.096 0.097 2 51101:0102:0602 0.099 1 11101:0501:0301 0.093 0.077 0.06 *0.095 0.095 0.096 *0.009 6 71104:0501:0301 *0.002 *0.023 0.055 *0.061 *0.006 0.025 0.028 2 71202:0102:0502 *0.088 1 11202:0601:0301 *0.051 *0.005 1 21301:0103:0603 *0.043 0.011 0.088 *0.035 *0.015 *0.009 1 61302:0102:0604 0.023 0.069 0.02 *0.033 1 41401:0101:0503 *0.007 0.02 0.039 *0.049 0.034 *0.040 *0.132 1 71402:0501:0301 *0.071 0.25 0.255 3 31406:0501:0301 0.09 1 11407:0101:0503 *0.138 1 11408:0101:0503 0.092 *0.101 2 21501:0102:0602 0.052 0.075 0.098 *0.057 0.253 *0.040 *0.026 5 71502:0101:0501 *0.183 *0.010 1 21502:0102:0502 *0.070 1 11502:0102:0601 0.176 *0.040 1 21503:0102:0602 *0.140 *0.011 *0.004 *0.005 1 41601:0102:0502 0.02 0.105 *0.059 2 31602:0501:0301 0.18 0.351 2 2


with different C alleles include B*4001 (19 pairings, 12 with

a frequency of at least 0.01 in a population), B*0702 (19,

4), B*1501 (14, 8), B*3801 (15, 4), B*4002 (14, 11),

B*4402 (17, 4), B*5301 (14,5), B*5501 (14, 5), and

B*5801 (16, 4).

B:DRB1


with each region represented by at least two population sam-

ples, except SWA and AUS which had only a single popula-

tion. There were 1164 different haplotypes observed

worldwide. The number of different haplotypes per popula-

tion ranged from 13 to 272. Of the 73 different regionally fre-

quent haplotypes, only 0801:0301 was frequent in at least three

regions. Six haplotypes were frequent in two regions

(0702:1501, 1502:1202, 3802:1502, 4001:1401, 4001:

1501, and 4002:1401). Averaged over all populations, 48%

of the haplotypes were estimated to exist as single copies. The

total frequency of these singletons was 19%. Significant LD

was found in every population after correcting for the


Table 5. Description of the 3 most frequent haplotypes identified among specific populations according to geographic region.The following notes apply to all of the ‘‘Table 5’’ set of haplotype summaries:i) A plus sign (π) next to a frequency indicates that this is a complementary haplotype (i.e., D’ijΩ1).ii) An asterisk (*) next to a frequency indicates that a single-d.f. chi-square test would be significant at the alphaΩ.0001 level.iii) A blank indicates that the haplotype was not found in that population.

Table 5.1a. Most frequent HLA-A:B haplotypes in Sub-Saharan Africa

Specific PopulationRegion: SSA Kenyan Kenyan North AmericaHLA-A:B Doggon Kenyan 142 Highlander Lowlander Mandenka (Af) Shona Ugandan Zambian Zulu2n 276 286 480 530 186 502 448 322 86 372ExpectedHeterozygosity 0.972 0.989 0.988 0.988 0.981 0.991 0.988 0.99 0.968 0.9830101:0801 0.014 *0.017 *0.028 *0.037 0.0120201:1503 0.008 *0.025 0.011 *0.034 0.02 0.012 0.0050201:3501 0.021 0.002 0.004 *0.043 0.011 0.002 0.0030202:5301 *0.043 0.016 0.006 *0.017 0.0060202:5801 0.007 0.01 0.002 *0.054 0.003 0.0020202:5802 0.014 *0.027 *0.015 0.002 *0.0192301:1503 0.015 0.01 0.011 0.012 0.027 *0.031 0.018 0.006 *0.0272301:3501 0.06 0.002 0.002 0.0032301:4403 0.004 0.002 0.006 0.005 0.01 *0.0252902:4201 0.01 0.014 *0.024 *0.026 *0.020 0.035 0.0272902:4403 *0.004 0.015 0.009 π*0.023 *0.0313001:4201 *0.104 *0.031 *0.029 *0.023 *0.025 *0.033 0.003 *0.116 *0.0603002:1801 0.004 0.017 0.004 *0.019 0.016 0.004 *0.030 0.009 0.0123002:3501 0.004 *0.048 0.0123002:5301 *0.017 0.008 0.008 0.003 0.0583002:5703 0.007 *0.006 0.005 0.019 0.003 0.047 0.0033601:5301 *0.035 π*0.012 *0.019 *0.022 *0.015 *0.009 0.023 *0.0036601:5802 0.004 *0.029 *0.049 0.004 *0.016 *0.019 π*0.012 *0.0136802:0702 *0.017 0.004 *0.011 *0.025 0.012 *0.023 0.016802:1510 0.007 0.007 *0.015 *0.013 *0.010 0.019 *0.009 *0.0437401:1503 0.011 0.004 0.004 *0.021 0.011 *0.014 *0.013 *0.028 π*0.023 *0.016

number of comparisons. Regional average Wn values ranged

from a low of 0.46 in SSA to a high of 0.65 in NAF.

Six haplotypes were present in six of the ten sampled regions

(0801:0301, 4001:1501, 4002:1101, 4403:0701, 5101:

1101, and 5801:0301). Sixteen frequent haplotypes were present

in only one region (4201:0804 in SSA; 4402:0402 in NAF;

3901:1405 and 5502:1401 in SEA; 1506:0405 and

5602:1407 in OCE; 2703:0401, 3901:0802, and 5102:0802

in NAM; 1504:1602, 3505:0802, 3505:0901, 3905:1402,

3906:1602, 3909:1402, and 4004:0807 in SAM).

A:DPB1

A total of ten population samples were typed at both loci.

These populations were from six regions, with three samples

from OCE; two samples from NAM; two samples from SSA;

and one sample from EUR, SEA, and AUS. There were 335

different haplotypes observed worldwide. The number of dif-

ferent haplotypes per population ranged from 14 to 126. Of

the 30 different regionally frequent haplotypes, only the

2402:0501 haplotype was frequent in at least three regions.

Eight were frequent in two regions (0201:0401, 1101:0401,

1101:0501, 2402:0201, 2402:0401, 2402:0402, 2402:

1301, and 3401:0501). Averaged over all populations, 42%


of the haplotypes were estimated to exist as single copies. The

total frequency of these singletons was 14%. Significant LD

was found in only two populations after correcting for the

number of comparisons (Cape York in AUS and Filipino in

OCE). LD was significant in the Czech population in EUR

prior to correction. Regional average Wn values ranged from

a low of 0.34 in SSA to a high of 0.54 in SEA.

There were three frequent haplotypes that were present in all

but one of the sampled regions (0201:0401, 2402:0401, and

2402:0402). Seven frequent haplotypes were present in only one

Table 5.1b. Most frequent HLA-A:B haplotypes in North Africa

Specific PopulationRegion: NAFHLA-A:B Chaouya Metalsa2n 132 134Expected Heterozygosity 0.985 0.9830101:4402 0.0340101:5001 0.03 0.0110201:4403 0.008 0.030201:5001 0.038 0.030201:5101 *0.038 0.0152301:4403 0.0372402:0801 0.015 *0.0302902:4403 *0.0303001:4201 π*0.030


Table 5.1c. Most frequent HLA-A:B haplotypes in Europe

Specific PopulationRegion: EURHLA-A:B Croatian Cuban(Eu) Czech Finn 90 Georgian Irish North America (Eu)2n 300 138 210 180 210 2000 574Expected Heterozygosity 0.983 0.984 0.98 0.959 0.98 0.967 0.9820101:0801 0.005 *0.043 *0.038 *0.072 *0.115 *0.0740201:0702 0.016 0.036 0.042 0.047 0.052 0.0320201:1501 0.033 0.007 0.033 0.082 0.033 0.015 0.0210201:1801 0.039 0.04 0.031 0.026 0.006 0.0050201:4402 0.031 0.036 0.035 0.022 0.01 *0.080 0.050201:5101 0.048 0.014 0.008 0.022 0.079 *0.014 0.0130301:0702 *0.053 0.029 0.059 *0.098 0.011 *0.067 *0.0460301:3501 *0.039 *0.083 0.033 0.012 0.020301:3503 0.009 0.037 0.0012902:4403 *0.036 *0.029 *0.017

region (2301:0101 and 7401:0402 in SSA; 1101:0101,

3401:0101, and 3401:1301 in OCE; 2402:2201 and

3401:2201 in AUS).

B:DPB1

A total of eight population samples were typed at both loci.

These populations were from five regions with two samples

from SSA, OCE, and NAM; and one sample from EUR and

AUS. There were 423 different haplotypes observed

worldwide. The number of different haplotypes per popula-

tion ranged from 32 to 134. Of the 26 different regionally

frequent haplotypes, none were frequent in at least three regions.

The 5601:0501 haplotype was frequent in both OCE and AUS.

Averaged over all populations, 47% of the haplotypes were

estimated to exist as single copies. The total frequency of

these singletons was 18%. Significant LD was found in all but

three of the populations after correcting for the number of

comparisons (Kenyan in SSA; Czech in EUR; and Canoncito

in NAM). Regional average Wn values ranged from a low of

0.42 in SSA to a high of 0.62 in AUS.

Table 5.1d. Most frequent HLA-A:B haplotypes in Southwest Asia

Specific PopulationRegion: SWAHLA-A:B Arab Druze Israeli Jews New Delhi Omani South Indian Tamil2n 200 184 124 236 168 98Expected Heterozygosity 0.985 0.988 0.976 0.979 0.977 0.9770101:3701 *0.0480101:5701 0.011 *0.016 0.004 *0.030 0.0460101:5703 π*0.0330201:5101 0.01 0.005 0.016 0.054 0.030205:5001 *0.035 *0.021 0.0040211:4006 0.016 0.012 0.0561101:3503 0.048 0.0061101:4006 0.046 *0.055 0.0281101:5101 *0.035 0.048 0.0241101:5201 *0.033 0.048 0.008 0.048 0.012402:3501 0.011 *0.0562402:4006 0.008 0.05 0.0362601:0801 *0.048 *0.045 *0.030 π*0.0202901:0702 *0.0403201:5101 *0.0483303:1404 *0.0333303:5801 *0.032 *0.016 *0.054 π*0.020


The 4001:0401 haplotype was present in four of the five

sampled regions. Three additional frequent haplotypes were pres-

ent in two of the sampled regions (0702:0401, 3501:0201,

and 4002:0501). Eight frequent haplotypes were present in only

one region (1525:0401, 3802:0101, 4002:0101, 5601:

0201, and 5602:0401 in OCE; 4005:0402, 4801:0402, and

5102:0401 in NAM).

DRB1: DQB1


including at least 2 populations from each region, with the

exception of SWA, which had one sampled population, and

NEA, which was not sampled. There were 307 different


haplotypes per population ranged from nine to 94. Of the 43

different regionally frequent haplotypes, 6 were frequent in at least

three regions (0301:0201, 0701:0201, 0901:0303, 1101:

0301, 1402:0301, and 1501:0602). Averaged over all popu-

lations, 40% of the haplotypes were estimated to exist as

single copies. The total frequency of these singletons was 7%.


Table 5.1e. Most frequent HLA-A:B haplotypes in Southeast Asia

Specific PopulationHan- Han- North

Region: SEA Chinese Chinese America Paiwan PuyumaHLA-A:B Ami 97 Atayal Bunun Chinese Hakka 149 572 Malay Minnan (As) 51 Pazeh 492n 196 212 202 560 110 298 1138 200 204 792 102 110 100ExpectedHeterozygosity 0.831 0.88 0.89 0.974 0.953 0.97 0.971 0.983 0.956 0.984 0.828 0.953 0.9230201:4801 0.02 0.004 0.001 0.005 *0.010 0.01 0.010201:5502 0.021 0.02 0.002 0.005 0.002 0.01 *0.0180203:3802 *0.034 *0.018 *0.033 *0.036 0.005 *0.049 *0.017 π*0.018 π*0.0100203:4001 0.014 0.01 0.012 0.015 0.01 *0.0500206:4801 0.01 *0.073 0.005 0.003 0.002 *0.018 0.050206:5502 0.005 *0.069 0.002 *0.010 0.003 0.010207:4601 π*0.005 *0.068 *0.073 *0.071 *0.094 π*0.015 *0.093 *0.046 *0.0351101:1301 0.005 0.029 0.045 0.034 *0.043 *0.035 0.046 *0.024 0.0311101:1502 *0.052 0.009 0.027 *0.062 0.027 0.031 *0.031 0.0271101:1525 *0.015 *0.024 *0.059 0.009 0.002 0.005 0.005 0.081 0.011101:4001 0.005 0.023 0.035 0.053 0.136 *0.088 0.059 0.015 *0.118 0.04 0.0741102:2704 π*0.010 *0.037 *0.004 π*0.009 0.003 *0.009 *0.005 *0.015 *0.082 0.0271102:3901 0.01 0.0012402:1301 *0.243 0.016 0.009 0.024 0.012 0.01 0.005 0.008 0.255 0.078 0.172402:1501 0.005 0.005 0.009 0.004 0.011 0.011 0.0392402:1502 0.004 0.004 0.013 0.025 0.01 0.1372402:1525 0.01 0.005 0.006 0.01 0.01 0.062402:3802 0.014 0.004 0.02 0.0192402:3901 0.077 0.156 0.086 0.007 0.003 0.029 0.009 0.052402:4001 0.254 0.269 0.132 0.046 0.073 0.03 0.031 0.01 0.057 0.033 0.275 0.097 0.052402:4002 0.046 0.005 0.005 0.007 0.009 0.005 0.025 0.014 0.137 0.027 0.052402:4801 *0.229 *0.053 0.084 0.003 0.005 0.003 0.015 0.006 0.078 0.036 0.062402:5502 0.006 0.083 *0.018 0.002 0.009 0.01 0.002 0.002 0.039 0.032407:3505 π*0.007 *0.003 *0.004 *0.0452601:3901 0.036 0.052 0.018 *0.004 *0.0152601:4001 0.046 0.008 0.009 0.005 0.005 0.001 0.039 0.022601:4002 *0.014 0.003 0.001 0.01 0.002 0.013303:4403 *0.011 0.003 *0.007 *0.044 *0.0343303:5801 *0.077 π*0.082 *0.080 *0.064 *0.040 *0.078 *0.062 π*0.0363401:5601 *0.199 *0.001 π*0.010 π*0.040

Specific PopulationRegion: SEAHLA-A:B Rukai Saisiat Singapore (Chinese) Siraya Thai Toroko Tsou Yami2n 100 102 158 102 196 110 102 100ExpectedHeterozygosity 0.882 0.762 0.971 0.947 0.97 0.893 0.874 0.8050201:4801 0.02 π*0.0750201:5502 0.01 0.01 0.01 *0.1070203:3802 π*0.010 *0.051 0.01 0.010203:4001 0.025 0.0150206:4801 π*0.020 0.0430206:5502 π*0.0300207:4601 *0.082 0.02 *0.1021101:1301 0.019 0.049 0.045 0.0111101:1502 0.046 0.01 0.026 0.01 0.0111101:1525 *0.029 0.006 0.039 π*0.049 *0.3381101:4001 0.011 0.066 0.059 0.025 0.026 π*0.073 0.0491102:2704 π*0.006 0.027 *0.020 π*0.009 π*0.0301102:3901 0.072 0.009 0.012402:1301 0.255 0.019 0.078 0.005 0.176 0.0292402:1501 0.06 0.009 0.0292402:1502 0.043 0.0892402:1525 0.041 *0.0522402:3802 0.015 0.112402:3901 0.082 *0.455 0.094 0.2252402:4001 0.113 0.113 0.017 0.074 0.219 0.108 0.032402:4002 0.119 0.154 0.005 0.021 0.059 π*0.2302402:4801 0.07 0.013 0.049 0.072 0.0882402:5502 0.02 0.039 0.1182407:3505 π*0.006 0.0052601:3901 0.048 *0.115 0.012601:4001 0.056 0.049 0.006 0.0512601:4002 0.011 0.0513303:4403 π*0.0313303:5801 *0.051 *0.029 *0.0713401:5601



Table 5.1f. Most frequent HLA-A:B haplotypes in Oceania

Specific PopulationRegion: OCEHLA-A:B American Samoa Filipino Indonesian Ivatan PNG Highlander2n 100 188 98 100 150ExpectedHeterozygosity 0.956 0.974 0.978 0.925 0.8720201:1502 *0.1880201:4001 0.09 0.005 0.02 0.0320203:3802 *0.0410206:5502 *0.0591101:1513 0.011 0.0511101:3802 0.057 0.0152402:1506 0.005 0.1342402:4001 0.119 0.016 0.041 0.105 0.1252402:4801 0.064 0.021 π*0.0802402:5601 0.182402:5602 0.023 0.2332407:1513 0.0412407:3505 *0.064 0.02 π*0.0603303:5801 *0.053 0.023401:4002 π*0.030 *0.048 *0.080 0.013

Significant LD was found in every population after correcting

for the number of comparisons. Regional average Wn values

ranged from a low of 0.70 in SSA to a high of 0.94 in SAM.

Haplotypes 0101:0501, 0301:0201, and 0701:0201 were

present in all nine of the sampled regions. Three additional

frequent haplotypes were present in all but two of the sampled

regions (1101:0301, 1301:0603, and 1501:0602). Seven fre-

quent haplotypes were present in only one region (1201:0501

in SSA; 1407:0503 in OCE; 0412:0402 in AUS; 0411:0402

and 1406:0301 in NAM; 0807:0402 in SAM).

DRB1 alleles found in multiple DRB1: DQB1 haplotypes

The DRB1*1301 and DRB1*1302 alleles were found paired

with the largest number of DQB1 alleles in DRB1: DQB1

haplotypes. Each was found with 13 different DQB1 alleles

across all regions. Eight of the 13 DRB1*1301:DQB1 haplo-

types had frequencies greater or equal to 0.01 in at least one

population. The diversity of pairings of DRB1*1301 and

DRB1*1302 with DQB1 alleles was greatest in SSA and NAF.

Table 5.1g. Most frequent HLA-A:B haplotypes in North Africa

Specific PopulationRegion: AUSHLA-A:B Cape_York Groote Eylandt Yuendumu2n 198 150 382ExpectedHeterozygosity 0.959 0.922 0.9350201:1525 *0.067 0.0181101:1301 0.071 0.101 0.0061101:4002 0.008 0.087 *0.0642402:1301 0.059 0.064 0.0712402:4001 0.017 *0.128 0.0082402:4002 0.022 0.078 0.0582402:5602 0.025 0.0553401:1301 0.079 0.068 *0.1513401:1521 0.057 0.045 0.073401:5601 0.062 *0.142 0.0643401:5602 0.02 0.083


The 1301:0603 haplotype was found in all regions except

SAM and had the highest frequencies in EUR, SSA, and SWA,

respectively. Only four of the DRB1*1302:DQB1 haplotypes

reached a frequency of at least 0.01 in a population. The

1302:0604 and 1302:0605 haplotypes were found in the

largest number of regions and in high frequency in SSA and

NAF.

DRB1*0405 alleles were found on haplotypes with 12 dif-

ferent DQB1 alleles. Four of these DRB1*0405:DQB1 haplo-

types had a frequency of at least 0.01 in a population. The

diversity of pairings of DRB1*0405 with DQB1 alleles was

highest in NAF. However, among haplotypes with frequency

at least 0.01 the diversity was greatest in OCE.

DRB1*1101 alleles were found paired with ten different

DQB1 alleles. Four of these DRB1*1101:DQB1 haplotypes

reached a frequency of at least 0.01 in at least one population.

The diversity of pairings of DRB1*1101 with DQB1 alleles

was highest in SSA. The 1101:0301 haplotype had a moderate

to high frequency in nearly all regions. It was not found in

Table 5.1h. Most frequent HLA-A:B haplotypes in Northeast Asia

Specific PopulationRegion: NEAHLA-A:B Korean 200 Okinawan Tuva2n 400 208 356ExpectedHeterozygosity 0.978 0.967 0.9810201:4402 0.002 *0.0332402:4002 0.007 0.047 *0.0532402:5101 0.042 0.032 0.0172402:5401 0.024 *0.080 0.0142402:5901 0.008 *0.0582603:1501 0.005 *0.0773001:1302 *0.042 π*0.0033303:4403 *0.060 *0.0143303:5801 *0.052 *0.062


Table 5.1i. Most frequent HLA-A:B haplotypes in North America

Specific PopulationRegion: NAMHLA-A:B Amerindian Canoncito Pima 99 Yupik2n 468 82 162 504ExpectedHeterozygosity 0.985 0.932 0.943 0.9190201:0702 *0.0350201:1501 0.038 0.012 0.0060201:2705 0.008 0.012 0.06 0.0020201:3501 0.037 0.049 0.055 0.010201:3901 0.016 0.1070201:4801 0.04 0.0780201:5102 0.004 0.085 *0.1230206:4002 *0.024 0.022 0.0512402:2703 0.0522402:2705 0.015 0.014 0.052402:3501 0.029 *0.159 0.056 0.0562402:4002 *0.032 0.012 0.022 0.1912402:4005 0.004 0.0922402:4801 0.009 0.088 *0.1423101:3901 0.007 0.0523101:4801 0.058 0.0076801:5101 *0.020 *0.057

Table 5.1j. Most frequent HLA-A:B haplotypes in South America

Specific PopulationRegion: SAMHLA-A:B Guarani-Kaiowa Guarani-Nandeva2n 286 104Expected Heterozygosity 0.952 0.9570201:1504 0.028 0.1060201:4004 *0.077 0.0773101:1504 0.083 0.0873101:3905 *0.101 π*0.0873101:3906 *0.082 0.013101:3909 0.069 0.016801:3505 *0.066 0.01

Table 5.1k. Most frequent HLA-A:B haplotypes in other regions

Specific PopulationNorth

Region: OTH Brazilian AmericaHLA-A:B Brazilian (Af Eu) Mexican (Hi)2n 178 136 80 480ExpectedHeterozygosity 0.987 0.989 0.978 0.9910101:0702 0.029 0.0020101:0801 *0.034 0.022 π*0.025 *0.0180101:0805 0.0220101:1402 0.007 *0.038 0.0020201:1801 0.034 0.015 0.038 0.010201:3501 0.05 0.0150201:3512 0.062 *0.0190201:4402 0.011 0.022 0.0160201:5001 π*0.034 0.010201:5101 0.034 0.015 0.025 0.0270301:0702 0.006 0.015 0.012 *0.0252402:3501 0.006 0.022 0.0092902:4403 *0.011 0.007 *0.029

AUS and was found at low frequency in one SAM pop. In

contrast with other studies (14) this haplotype had a high

frequency in NAM.

DRB1*1502 alleles were found on haplotypes with ten dif-

ferent DQB1 alleles. Six of these DRB1*1502:DQB1 haplo-


Table 5.2a. Most frequent HLA-A:B:DRB1 haplotypes in Sub-SaharanAfrica

Specific PopulationRegion: SSAHLA-A:B:DRB1 Doggon Shona2n 276 448Expected Heterozygosity 0.986 0.9940202:5301:0804 0.0292301:5201:1303 0.0332301:5301:0806 0.0292902:4501:1102 0.0163001:4201:0804 0.0753002:1801:1101 0.0186802:0702:1503 0.004 0.025

Table 5.2b. Most frequent HLA-A:B:DRB1 haplotypes in North Africa

Specific PopulationRegion: NAFHLA-A:B:DRB1 Chaouya Metalsa2n 132 132Expected Heterozygosity 0.989 0.9870101:4402:0402 0.0380101:5001:0301 0.0230201:4402:0402 0.023 0.0150201:5001:0701 0.030201:5101:1501 0.032301:4403:0405 0.032402:0801:0301 0.015 0.03

Table 5.2c. Most frequent HLA-A:B:DRB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-A:B:DRB1 Czech Finn 90 Irish2n 204 180 2000

0.989 0.975 0.984Expected Heterozygosity0101:0801:0301 0.034 0.061 0.090201:1501:0401 0.015 0.05 0.0070201:4402:0401 0.011 0.040301:0702:1501 0.039 0.056 0.0480301:3501:0101 0.029 0.078 0.007

Table 5.2d. Most frequent HLA-A:B:DRB1 haplotypes in SouthwestAsia

Specific PopulationRegion: SWAHLA-A:B:DRB1 South_Indian2n 166

0.987Expected Heterozygosity0101:3701:1001 0.0421101:5201:1502 0.033303:5801:0301 0.036

types had a frequency greater than 0.01 in at least one popu-

lation. The diversity of pairings of DRB1*1502 with DQB1

alleles was greatest in SEA and OCE.

Among the DRB1 alleles that were paired with the largest

number of DQB1 alleles across all regions, the number of

different pairings of specific DRB1 alleles with DQB1 alleles

was usually highest in SSA and NAF. In some cases this was

due to several haplotypes found in only one population at


Table 5.2e. Most frequent HLA-A:B:DRB1 haplotypes in Southeast Asia

Specific PopulationRegion: SEA Paiwan PuyumaHLA-A:B:DRB1 Ami 97 Atayal Bunun Hakka Minnan 51 Pazeh 49 Rukai Saisiat Siraya Toroko Tsou Yami2n 196 212 202 110 204 102 110 100 100 102 102 110 102 100ExpectedHeterozygosity 0.9 0.954 0.935 0.982 0.986 0.899 0.972 0.957 0.926 0.917 0.97 0.956 0.9 0.8570201:4801:1101 0.011 0.01 0.01 0.01 0.0730206:4801:1401 0.01 0.074 0.009 0.014 0.0450206:4801:1501 0.050207:4601:0901 0.044 0.009 0.011101:1301:1501 0.027 0.005 0.0271101:1525:1401 0.0861101:1525:1602 0.015 0.024 0.05 0.082 0.01 0.01 0.02 0.039 0.2521101:4001:0803 0.009 0.045 0.025 0.021101:4001:0901 0.0271101:4001:1401 0.009 0.0571101:4001:1501 0.0551101:4601:1201 0.0272402:1301:1101 0.073 0.04 0.0112402:1301:1202 0.188 0.245 0.04 0.202 0.059 0.167 0.0292402:1301:1401 0.082402:1502:1202 0.01 0.062402:1502:1502 0.112402:1525:1602 0.01 0.009 0.06 0.04 0.0482402:2704:0405 0.0592402:3802:1502 0.112402:3901:0803 0.005 0.047 0.056 0.029 0.01 0.048 0.103 0.036 0.2162402:3901:1202 0.075 0.022 0.01 0.21 0.0182402:4001:0403 0.057 0.073 0.088 0.02 0.02 0.029 0.009 0.022402:4001:0404 0.112402:4001:0405 0.147 0.009 0.009 0.01 0.03 0.027 0.022402:4001:0803 0.006 0.029 0.009 0.0692402:4001:0901 0.068 0.015 0.027 0.029 0.01 0.03 0.029 0.0182402:4001:1101 0.01 0.02 0.118 0.027 0.0182402:4001:1401 0.01 0.094 0.025 0.018 0.103 0.01 0.082 0.0782402:4002:1101 0.015 0.005 0.005 0.049 0.02 0.094 0.029 0.012402:4002:1401 0.02 0.009 0.005 0.078 0.018 0.01 0.088 0.027 0.049 0.222402:4801:0404 0.166 0.012402:4801:1101 0.011 0.074 0.039 0.03 0.07 0.039 0.0492402:4801:1401 0.043 0.053 0.005 0.039 0.045 0.03 0.0642402:5502:1101 0.075 0.0452402:5502:1401 0.0782601:3901:1405 0.005 0.0732901:0705:1001 0.0273303:5801:0301 0.055 0.039 0.036 0.023303:5801:1302 0.027 0.034 0.013401:5601:1502 0.178 0.01 0.04

low frequency. In the case of DRB1*1502, which was not

found in SSA, the greatest diversity of pairings was in SEA

and OCE. When restricting to higher frequency haplotypes

there was often a greater diversity of pairings in SEA and OCE.

Table 5.2f. Most frequent HLA-A:B:DRB1 haplotypes in Oceania

Specific PopulationRegion: OCEHLA-A:B:DRB1 Filipino Ivatan PNG_Highlander2n 188 100 142Expected Heterozygosity 0.983 0.943 0.9620201:1502:1202 0.180201:1801:1502 0.051101:3802:1502 0.034 0.022402:1506:0405 0.0632402:3802:1502 0.057 0.022402:4001:1501 0.0662402:4801:1502 0.005 0.062402:5602:1407 0.1212407:3505:1202 0.037 0.033401:4002:1502 0.027 0.07 0.007


It should be noted that the number of populations per region

typed for both DRB1 and DQB1 was relatively constant across

the different regions, minimizing the likelihood that this fac-

tor influenced the diversity of pairings.

DRB1:DPB1

A total of 14 population samples were typed at both loci.

These populations were from seven regions with three sam-

Table 5.2g. Most frequent HLA-A:B:DRB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-A:B:DRB1 Cape_York2n 192Expected Heterozygosity 0.9762402:1521:0803 0.0473401:1521:0803 0.0683401:5601:0803 0.055


ples from OCE and NAM; two samples from EUR and SAM;

and one sample from SEA and AUS. There were 360 different



different regionally frequent haplotypes, none were frequent in at

least three regions. Five were frequent in two regions

(0405:0501, 1402:0402, 1501:0401, 1502:1301, and

Table 5.2h. Most frequent HLA-A:B:DRB1 haplotypes in Northeast Asia

Specific PopulationRegion: NEAHLA-A:B:DRB1 Korean 200 Tuva2n 398 356Expected Heterozygosity 0.99 0.9911101:1501:0406 0.032402:0702:1501 0.0263001:1302:0701 0.0293101:4801:1201 0.0253303:5801:1302 0.033 0.034

Table 5.2i. Most frequent HLA-A:B:DRB1 haplotypes in North America

Specific PopulationRegion: NAMHLA-A:B:DRB1 Yupik2n 504Expected Heterozygosity 0.9692402:4002:1401 0.0552402:4002:1402 0.0632402:4801:0401 0.0816801:5101:1101 0.053

Table 5.2j. Most frequent HLA-A:B:DRB1 haplotypes in South America

Specific PopulationRegion: SAMHLA-A:B:DRB1 Guarani-Kaiowa Guarani-Nandeva2n 286 104Expected Heterozygosity 0.967 0.9730201:1504:1602 0.027 0.0960201:4004:0807 0.059 0.0160201:5101:1402 0.004 0.0483101:1504:1602 0.096 0.0643101:3905:1402 0.061 0.013101:3906:1602 0.0586801:3505:0901 0.056

Table 5.2k. Most frequent HLA-A:B:DRB1 haplotypes in other regions

Specific PopulationRegion: OTHHLA-A:B:DRB1 Brazilian(Af_Eu)2n 134Expected Heterozygosity 0.9910101:0801:0301 0.0220101:0805:0301 0.0220201:0803:1501 0.0150201:1801:1104 0.0150201:4402:0411 0.0150201:5101:1301 0.0150202:3501:1302 0.0152402:0702:1302 0.0153301:1402:0101 0.0153303:5101:1301 0.015




frequency of these singletons was 13%. Significant LD was

found in all but four populations (Czech and Slovenian in

EUR; Malay in SEA; and East Timorese in OCE). Regional

average Wn values ranged from a low of 0.42 in EUR to a

high of 0.57 in NAM.

Haplotype 0701:0401 was present in six of the seven sam-

pled regions. Two additional frequent haplotypes were present in

five of the sampled regions (1501:0401 and 0301:0401).

Thirteen frequent haplotypes were present in only one region

(0302:0101, 0302:0402, 1302:0101, and 1503:0201 in

SSA; 1407:0201 and 1502:0101 in OCE; 0803:2201 in AUS;

0407:0401, 1402:0201, and 1406:0401 in NAM; 0407:

1401, 0411:0402, and 0807:0401 in SAM).

A:C:B

A total of 47 population samples were typed at all three loci,

including at least 2 populations from each region represented.

Eighteen of these populations were from SEA. There were

2790 different haplotypes observed worldwide. The number

of different haplotypes per population ranged from 15 to

323. Of the 73 different regionally frequent haplotypes, one was

frequent in at least three regions (3303:0302:5801). Five were

frequent in two regions (2402:0304:4001, 2402:0304:4002,

2402:0801:4801, 2402:0401:4001, and 3401:0102:5601).

Averaged over all populations, 56% of the haplotypes were

estimated to exist as single copies. The total frequency of

these singletons was 24%.

Three haplotypes were present in seven of the nine sampled re-

gions (0201:0304:4001, 0301:0702:0702, and 1101:1202:

5201). Six additional frequent haplotypes were present in six of

the sampled regions (3303:0302:5801, 2402:0304:4001,

0101:0701:0801, 0201:0501:4402, 0201:0702:0702, and

2402:0702:3901). Of the 30 haplotypes found in only two

regions, 15 were frequent in SEA. Fourteen frequent haplotypes

were present in only one region (2301:1601:5201 and 6601:

0602:5802 in SSA; 0203:0403:4001 and 1101:0403:1525

in SEA; 2402:0102:4002, 2402:0401:1301, and 3401:0102:

5602 in AUS; 2402:0102:5901 and 2603:0303:1501 in

NEA; 2402:0806:4801 in NAM; 0201:0303:1504, 0201:

0304:4004, 3101:1503:1504, and 6801:0401:3505 in

SAM).

A:B:DRB1


including at least 2 populations from each of the ten regions

represented, with the exception of SWA, AUS, and NAM,


Table 5.3a. Most frequent HLA-A:C:B haplotypes in Sub-Saharan Africa

Specific PopulationRegion: SSAHLA-A:C:B Doggon Kenyan 142 Kenyan Highlander Kenyan Lowlander North America (Af) Shona Ugandan Zulu2n 258 224 480 530 502 446 322 192ExpectedHeterozygosity 0.975 0.989 0.989 0.989 0.992 0.989 0.991 0.9830101:0701:0801 0.028 0.0340201:0202:1503 0.004 0.022 0.011 0.034 0.025 0.009 0.0050201:1601:4501 0.035 0.01 0.013 0.016 0.022 0.019 0.010202:0602:5802 0.013 0.027 0.013 0.002 0.002 0.0192301:0202:1503 0.011 0.009 0.011 0.013 0.032 0.021 0.007 0.0312301:1601:5201 0.052902:1701:4201 0.012 0.018 0.025 0.026 0.02 0.0313001:1701:4201 0.105 0.027 0.029 0.021 0.026 0.033 0.003 0.0623001:1701:4202 0.009 0.009 0.0313002:0704:1801 0.018 0.004 0.017 0.027 0.0063601:0401:5301 0.036 0.012 0.019 0.022 0.009 0.009 0.0056601:0602:5802 0.029 0.051 0.006 0.016 0.019 0.0217401:0202:1503 0.012 0.004 0.004 0.019 0.014 0.011 0.027 0.0267401:0602:5802 0.031 0.002 0.01

which had one population each. There were 2601 different



different regionally frequent haplotypes, only two were frequent in

two regions (2402:4002:1401 and 2402:3802:1502). None

were frequent in more than two regions. Averaged over all

populations, 62% of the haplotypes were estimated to exist

as single copies. The total frequency of these singletons was

33%.

The 3303:5801:0301 haplotype was present in five of the

ten sampled regions. Five additional frequent haplotypes were

present in four of the sampled regions (2402:4002:1401,

0101:0801:0301, 0301:0702:1501, 1101:4001:1501, and

2402:4001:1501). Thirty two frequent haplotypes were present

in only one region (3001:4201:0804 in SSA; 0201:

1501:0401 and 0301:3501:0101 in EUR; 0201:4801:1101,

0206:4801:1401, 0206:4801:1501, 1101:1525:1401, 1101:

Most frequent HLA-A:C:B haplotypes in North AfricaNo data

Table 5.3b. Most frequent HLA-A:C:B haplotypes in Europe

Specific PopulationNorth

Region: EUR AmericaHLA-A:C:B Czech Finn 90 Georgian Irish (Eu)2n 208 180 208 2000 574ExpectedHeterozygosity 0.984 0.964 0.989 0.967 0.9830101:0701:0801 0.038 0.072 0.115 0.0740201:0303:1501 0.007 0.06 0.006 0.0130201:0401:3503 0.037 ∞0.001 0.0070201:0501:4402 0.024 0.017 0.01 0.083 0.0490201:0702:0702 0.014 0.024 0.051 0.0320201:1203:1501 0.024 ∞0.0010301:0401:3501 0.041 0.083 0.029 0.012 0.0170301:0401:3503 0.024 0.0010301:0702:0702 0.06 0.1 0.014 0.066 0.0442402:0602:1302 0.01 0.024


1525:1602, 2402:1301:1101, 2402:1301:1202, 2402:1301:

1401, 2402:1525:1602, 2402:2704:0405, 2402:4801:0404,

2402:4801:1401, 2402:5502:1101, 2402:5502:1401, 2601:

3901:1405, and 3401:5601:1502 in SEA; 0201:1801:1502,

2402:1506:0405, 2402:4801:1502, 2402:5602:1407, and

3401:4002:1502 in OCE; 3401:5601:0803 in AUS; 6801:

5101:1101 in NAM; 0201:1504:1602, 0201:4004:0807,

3101:1504:1602, 3101:3905:1402, 3101:3906:1602, and

6801:3505:0901 in SAM).

DRB1:DQA1:DQB1


including at least 2 populations from each of the eight re-

gions represented, with the exception of SWA and AUS,

which had one population each. There were 275 different



different regionally frequent haplotypes, two were frequent in at

least five regions (1101:0501:0301 and 1501:0102:0602).

Two were frequent in four regions (0301:0501:0201 and

Table 5.3c. Most frequent HLA-A:C:B haplotypes in Southwest Asia

Specific PopulationRegion: SWAHLA-A:C:B Arab Druze Israeli Jews New Delhi2n 200 134 106ExpectedHeterozygosity 0.987 0.988 0.9790101:0602:5703 0.0370205:0602:5001 0.03 0.0221101:1202:5201 0.03 0.0571101:1402:5101 0.005 0.0381101:1502:5101 0.031101:1507:4006 0.0472402:0401:3501 0.0382601:0702:0801 0.0382901:0702:0702 0.043303:0802:1404 0.03


Table 5.3d. Most frequent HLA-A:C:B haplotypes in Southeast Asia

Specific PopulationRegion: SEA NorthAmerica Paiwan Puyuma

HLA-A:C:B Ami 97 Atayal Bunun Chinese Hakka Malay Minnan (As) 51 Pazeh 49 Rukai Saisiat Siraya Thai Toroko Tsou

2n 196 212 202 558 110 184 204 786 102 110 100 100 102 102 184 110 102ExpectedHeterozygosity 0.864 0.928 0.902 0.978 0.965 0.982 0.967 0.987 0.883 0.963 0.925 0.883 0.78 0.958 0.974 0.92 0.8790201:0102:5502 0.018 0.015 0.001 0.009 0.1080201:0801:4801 0.021 0.004 0.005 0.008 0.01 0.02 0.0740203:0403:4001 0.004 0.050206:0102:5502 0.069 0.002 0.0010206:0801:4801 0.01 0.072 0.005 0.009 0.05 0.02 0.0430207:0102:4601 0.005 0.069 0.073 0.016 0.084 0.047 0.034 0.01 0.0921101:0304:1301 0.005 0.03 0.045 0.027 0.044 0.017 0.031 0.049 0.0271101:0304:4001 0.005 0.006 0.055 0.013 0.048 0.055 0.021101:0403:1525 0.015 0.024 0.059 0.005 0.005 0.079 0.01 0.03 0.038 0.0491101:0702:0705 0.001 0.0431101:0702:4001 0.009 0.043 0.082 0.083 0.022 0.055 0.01 0.019 0.029 0.011 0.0291101:0801:1502 0.053 0.009 0.033 0.034 0.032 0.027 0.01 0.022 0.011102:0702:3901 0.005 0.01 0.069 0.009 0.011102:1202:2704 0.01 0.037 0.004 0.009 0.015 0.082 0.027 0.029 0.022 0.0092402:0102:1501 0.005 0.005 0.004 0.039 0.062402:0102:5502 0.006 0.034 0.016 0.003 0.02 0.1182402:0303:4002 0.031 0.005 0.005 0.002 0.009 0.015 0.098 0.018 0.05 0.118 0.127 0.021 0.0592402:0304:1301 0.244 0.013 0.009 0.008 0.255 0.078 0.17 0.257 0.078 0.1762402:0304:4001 0.092 0.151 0.058 0.022 0.045 0.029 0.012 0.134 0.043 0.02 0.116 0.056 0.02 0.118 0.0882402:0304:4002 0.015 0.004 0.033 0.029 0.0052402:0401:4001 0.165 0.057 0.049 0.004 0.005 0.005 0.078 0.03 0.029 0.039 0.012402:0403:1525 0.01 0.005 0.01 0.011 0.06 0.042402:0702:3802 0.014 0.02 0.022402:0702:3901 0.079 0.15 0.083 0.029 0.05 0.079 0.449 0.094 0.2252402:0702:4001 0.066 0.03 0.017 0.018 0.02 0.014 0.069 0.036 0.034 0.12402:0801:1502 0.002 0.016 0.015 0.001 0.1372402:0801:4801 0.224 0.051 0.084 0.003 0.01 0.009 0.078 0.036 0.06 0.07 0.049 0.074 0.0882407:0401:3505 0.007 0.0492601:0303:4002 0.014 0.01 0.012 0.0522601:0702:3901 0.036 0.055 0.018 0.01 0.051 0.115 0.013303:0302:5801 0.075 0.082 0.043 0.078 0.062 0.036 0.029 0.0713303:0701:4403 0.009 0.048 0.011 0.0333401:0102:5601 0.199 0.01 0.04

0701:0201:0201). Averaged over all populations, 41% of the


frequency of these singletons was 7%.

Two haplotypes were present in each of the eight sampled

regions (0301:0501:0201 and 0701:0201:0201). Seven ad-

ditional frequent haplotypes were present in seven of the sampled

regions (1101:0501:0301, 1501:0102:0602, 1104:0501:

0301, 0101:0101:0501, and 1401:0101:0503). Of the eight

Table 5.3e. Most frequent HLA-A:C:B haplotypes in Oceania

Specific PopulationRegion: OCEHLA-A:C:B American_Samoa Filipino Ivatan2n 100 188 100ExpectedHeterozygosity 0.967 0.977 0.9330201:0304:4001 0.11 0.030201:0704:1801 0.050201:0801:1502 0.1871101:0702:3802 0.059 0.012402:0304:4001 0.059 0.022402:0401:4001 0.03 0.016 0.072402:0801:4801 0.063 0.021 0.082407:0401:3505 0.063 0.063303:0302:5801 0.0533401:1502:4002 0.037 0.07


haplotypes found in only two regions, seven were found only

in OCE and AUS (1408:0101:0503 0405:0301:0401, 0803:

0103:0503, 0803:0103:0601, 1202:0601:0301, 1502:0101:

0501, and 1502:0102:0601). The eighth, 1602:0501:0301,

was found with high frequency in both NAM and SAM. Seven

frequent haplotypes were present in only one region (1101:

Table 5.3f. Most frequent HLA-A:C:B haplotypes in Australia

Specific PopulationRegion: AUSHLA-A:C:B Cape York Groote Eylandt Yuendumu2n 172 146 380ExpectedHeterozygosity 0.957 0.928 0.9410201:0403:1525 0.054 0.0181101:0401:1301 0.081 0.109 0.0061101:1502:4002 0.075 0.0622402:0102:4002 0.0622402:0102:5601 0.084 0.016 0.0352402:0102:5602 0.052402:0303:4001 0.012 0.121 0.0112402:0401:1301 0.03 0.073 0.0722402:0403:1521 0.06 0.0162402:1502:4002 0.024 0.009 0.0553401:0102:5601 0.044 0.141 0.0213401:0102:5602 0.023 0.014 0.0853401:0401:1301 0.089 0.051 0.1513401:0403:1521 0.059 0.048 0.07


Table 5.3g. Most frequent HLA-A:C:B haplotypes in Northeast Asia

Specific PopulationRegion: NEAHLA-A:C:B Korean 200 Okinawan Tuva2n 400 208 332ExpectedHeterozygosity 0.982 0.975 0.9852402:0102:5401 0.025 0.071 0.0152402:0102:5901 0.008 0.0582402:0304:4002 0.005 0.023 0.0422402:1402:5101 0.046 0.0282603:0303:1501 0.005 0.0573001:0602:1302 0.042 0.0033101:0801:4801 0.005 0.033303:0302:5801 0.052 0.054

Table 5.3h. Most frequent HLA-A:C:B haplotypes in North America

Specific PopulationRegion: NAMHLA-A:C:B Amerindian Yupik2n 458 298Expected Heterozygosity 0.989 0.9280201:0702:0702 0.0360206:0202:2705 0.025 0.0832402:0202:2705 0.011 0.0682402:0304:4002 0.031 0.1842402:0401:3501 0.032 0.0622402:0806:4801 0.1016801:0304:4002 0.063

Table 5.3i. Most frequent HLA-A:C:B haplotypes in South America

Specific PopulationRegion: SAMHLA-A:C:B Guarani-Kaiowa Guarani-Nandeva2n 284 102Expected Heterozygosity 0.957 0.960201:0303:1504 0.023 0.1080201:0304:4004 0.077 0.0783101:0702:3905 0.098 0.0883101:0702:3906 0.084 0.013101:0702:3909 0.069 0.0293101:1503:1504 0.025 0.066801:0401:3505 0.066 0.01

Table 5.3j. Most frequent HLA-A:C:B haplotypes in other regions

Specific PopulationRegion: OTHHLA-A:C:B Brazilian (Af Eu) North America (Hi)2n 134 480Expected Heterozygosity 0.991 0.9930101:0701:0801 0.015 0.0180101:0701:5801 0.0150101:0702:0702 0.03 0.0040201:0401:0702 0.015 0.0020201:0401:3512 0.0190201:0401:4402 0.0150301:0702:0702 0.0250301:0702:3501 0.0152902:1601:4403 0.007 0.0293001:1701:4202 0.015

0102:0602 in SSA; 1202:0102:0502, 1407:0101:0503, and

1502:0102:0502 in OCE; 0411:0301:0402 and 1406:0501:

0301 in NAM; 0807:0401:0402 in SAM).


Table 5.4a. Most frequent HLA-A:DPB1 haplotypes in Sub-SaharanAfrica

Specific PopulationRegion: SSAHLA-A:DPB1 Kenyan 142 Shona2n 246 448ExpectedHeterozygosity 0.985 0.9810201:0401 *0.0330301:0402 *0.0332301:0101 0.007 0.0543002:0101 0.02 0.0476802:0101 0.012 0.0367401:0402 0.052 0.017

Most frequent HLA-A:DPB1 haplotypes in North AfricaNo data

Table 5.4b. Most frequent HLA-A:DPB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-A:DPB1 Malay2n 98Expected Heterozygosity 0.9720101:0401 0.0620201:0401 *0.1870301:0401 0.0720301:0402 0.056

Most frequent HLA-A:DPB1 haplotypes in Southwest AsiaNo data

Table 5.4c. Most frequent HLA-A:DPB1 haplotypes in Southeast Asia

Specific PopulationRegion: SEAHLA-A:DPB1 Malay2n 98Expected Heterozygosity 0.9720203:0501 0.0511101:0401 0.0512402:0501 0.0612402:1301 0.0513303:0401 *0.051

Table 5.4d. Most frequent HLA-A:DPB1 haplotypes in Oceania

Specific PopulationRegion: OCEHLA-A:DPB1 East Timorese Filipino PNG Highlander2n 106 188 176ExpectedHeterozygosity 0.927 0.941 0.8141101:0101 0.019 0.1181101:0401 0.019 0.0711101:0501 0.056 0.073 0.0112402:0101 0.089 0.0172402:0201 0.021 0.322402:0401 0.037 *0.2272402:0402 0.0562402:0501 0.19 0.086 0.1232402:1301 0.0912407:0101 0.019 0.1072407:0501 0.075 0.0183401:0101 0.065 0.0063401:0401 0.035 0.018 0.0773401:0501 0.06 0.025 0.0253401:1301 0.053 0.005


Table 5.4e. Most frequent HLA-A:DPB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-A:DPB1 Cape_York2n 192Expected Heterozygosity 0.9280201:0501 0.1211101:0501 0.0942402:0501 0.1192402:2201 0.083401:0201 0.0633401:0501 0.1063401:2201 0.074

Most frequent HLA-A:DPB1 haplotypes in Northeast AsiaNo data

Table 5.4f. Most frequent HLA-A:DPB1 haplotypes in North America

Specific PopulationRegion: NAMHLA-A:DPB1 Canoncito Pima 992n 80 168Expected Heterozygosity 0.876 0.8670201:0401 0.177 0.1510201:0402 0.156 0.2182402:0201 0.086 0.0182402:0401 0.019 0.0912402:0402 0.17 0.223101:0401 0.117 0.0223101:0402 0.12 0.026

Most frequent HLA-A:DPB1 haplotypes in South AmericaNo data

Most frequent HLA-A:DPB1 haplotypes in other regionsNo data

Table 5.5a. Most frequent HLA-B:DPB1 haplotypes in Sub-SaharanAfrica

Specific PopulationRegion: SSAHLA-B:DPB1 Kenyan 142 Shona2n 246 450Expected Heterozygosity 0.987 0.9831503:0101 0.028 0.0381510:0101 0.004 0.0481510:0402 0.03 0.0184201:0101 0.043 0.0295301:0101 0.016 0.0375801:0402 0.032

Most frequent HLA-B:DPB1 haplotypes in North AfricaNo data

Table 5.5b. Most frequent HLA-B:DPB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-B:DPB1 Czech2n 204Expected Heterozygosity 0.9760702:0401 0.0821801:0401 0.0344402:0401 0.0635701:0401 0.034


Most frequent HLA-B:DPB1 haplotypes in Southwest AsiaNo data

Most frequent HLA-B:DPB1 haplotypes in Southeast AsiaNo data

Table 5.5c. Most frequent HLA-B:DPB1 haplotypes in Oceania

Specific PopulationRegion: OCEHLA-B:DPB1 Filipino PNG Highlander2n 188 142Expected Heterozygosity 0.969 0.941506:0201 0.0631525:0401 0.0533505:0101 0.0453802:0101 *0.1064001:0201 0.0594001:0401 0.0544002:0101 0.0645601:0201 0.0645601:0401 0.0895601:0501 0.0665602:0201 0.1295602:0401 0.09

Table 5.5d. Most frequent HLA-B:DPB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-B:DPB1 Cape_York2n 186Expected Heterozygosity 0.9331301:0501 *0.1951521:2201 0.074002:0501 0.0585601:0501 0.072

Most frequent HLA-B:DPB1 haplotypes in Northeast AsiaNo data

Table 5.5e. Most frequent HLA-B:DPB1 haplotypes in North America

Specific PopulationRegion: NAMHLA-B:DPB1 Canoncito Pima 992n 80 174Expected Heterozygosity 0.937 0.9472705:0402 0.0723501:0201 0.0533501:0401 0.014 0.0593501:0402 0.146 0.0453901:0401 *0.1354002:0402 0.025 0.0644005:0402 0.0924801:0402 0.016 0.1235102:0401 0.052 0.0625301:0402 0.062

Discussion

Haplotype frequencies and differentiation among regions

We investigated the degree to which haplotypes were shared

among regions; graphical summaries are given in Figure 1

for C:B and DRB1:DQB1 haplotypes. For each region there

are two columns. The first column depicts the fraction of


Most frequent HLA-B:DPB1 haplotypes in South AmericaNo data

Most frequent HLA-B:DPB1 haplotypes in other regionsNo data

Table 5.6a. Most frequent HLA-B:DRB1 haplotypes in Sub-SaharanAfrica

Specific PopulationRegion: SSAHLA-B:DRB1 Doggon Shona2n 276 452Expected Heterozygosity 0.975 0.9880702:1503 0.004 *0.0281503:1101 *0.018 *0.0374201:0804 *0.1 0.0044501:0102 *0.0265201:1303 *0.0475301:0804 0.04 0.011

Table 5.6b. Most frequent HLA-B:DRB1 haplotypes in North Africa

Specific PopulationRegion: NAFHLA-B:DRB1 Chaouya Metalsa2n 136 134Expected Heterozygosity 0.984 0.9730801:0301 *0.045 π*0.0821801:0701 *0.0374402:0402 *0.022 π*0.0674403:0405 *0.029 0.0224403:1302 *0.0604501:1302 *0.0295001:0701 0.0295101:1501 *0.029 0.015

haplotypes 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 haplotypes

in each category to the overall haplotype frequency in that

region (i.e., a frequency weighted version of the first col-

umn). Although the fraction of haplotypes exclusive to a re-

gion may be large (e.g., more than 40% in many cases and

more than 60% in some), especially for locus pairs involving

a class I and a class II locus, the population frequency of these

exclusive haplotypes is usually substantially lower (e.g., below

25% in most cases). This pattern is observed among most

regions and loci, and reflects the fact that exclusive haplotypes

are in general the rare ones. Exceptions include loci paired

with B, especially in the SAM region. Specific exclusive haplo-

types that are present with a frequency above 0.05 can be

identified in Table 4. Graphs of haplotype sharing for other

pairs of loci can be found at the IHWG website under the

Anthropology component (www.ihwg.org/components/di-

versr.htm).

It is interesting to note in Figure 1 that SSA and SAM had

similar fractions of exclusive C:B haplotypes, while the total

frequency of these was much higher in SAM. In contrast,


Table 5.6c. Most frequent HLA-B:DRB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-B:DRB1 Czech Finn 90 Irish2n 206 180 2000ExpectedHeterozygosity 0.98 0.963 0.9610702:1501 *0.078 *0.083 *0.1090801:0301 *0.049 *0.072 *0.1301302:0701 *0.049 *0.011 *0.0111501:0401 *0.013 *0.059 *0.0103501:0101 *0.029 *0.089 *0.0214001:1301 *0.056 0.0054402:0401 0.012 *0.0544403:0701 0.024 0.006 *0.052

Table 5.6d. Most frequent HLA-B:DRB1 haplotypes in Southwest Asia

Specific PopulationRegion: SWAHLA-B:DRB1 South_Indian2n 206Expected Heterozygosity 0.9730801:0301 *0.0633701:1001 *0.0725101:1301 *0.0655201:1502 *0.068

the total frequency of exclusive DRB1: DQB1 haplotypes was

similar for theses two regions, but the unweighted fraction

of exclusive haplotypes was much higher in SSA.

Population samples from the SSA region had the largest

number of different haplotypes for most locus pairs (Table

3). The rare cases for which a non-SSA population had the

highest number of haplotypes were in the Irish sample (for

A: B and B: DRB1 haplotypes), and the North American Asian

population in SEA (for A: B and C:B haplotypes). One reason

for these exceptions is the large sample size for these popula-

tions, relative to that of the SSA datasets. We compared the

median number of haplotypes found among populations in

each region; in only two instances did non-SSA populations

have the highest number of haplotypes (NEA for B: DRB1,

SWA for DRB1: DQB1). A similar pattern was seen when re-

stricting to the number of different non-singleton haplotypes.

High levels of haplotype heterozygosity were found for each

locus pair (Table 3). With few exceptions the values were

ordered in the following manner: (SSA, NAF, EUR, SWA) ±(SEA, OCE, AUS) ± (NAM, SAM). This pattern is similar to

the ordering found for the individual loci (Meyer et al., 2004

in this volume) and also to that found in non-HLA data (15).

Overall LD and significance

Figure 2 shows the LD measures Dø and Wn averaged over all

populations, using the aforementioned sample size weights.

Moderate to high LD can be seen for all locus pairs. Differ-


Table 5.6e. Most frequent HLA-B:DRB1 haplotypes in Southeast Asia

Specific PopulationRegion: SEAPaiwan Puyuma

HLA-B:DRB1 Ami 97 Atayal Bunun Hakka Minnan 51 Pazeh 49 Rukai Saisiat Siraya Toroko Tsou Yami2n 196 212 202 110 204 102 110 100 100 102 102 110 102 100ExpectedHeterozygosity 0.879 0.933 0.919 0.975 0.978 0.894 0.96 0.947 0.911 0.864 0.961 0.935 0.899 0.8261301:1101 *0.073 0.049 0.011 0.011301:1202 *0.196 0.02 *0.245 0.009 0.04 *0.220 0.01 *0.069 *0.167 π*0.0401301:1401 0.009 0.07 0.011301:1501 *0.045 0.015 0.027 *0.0191502:1202 0.009 *0.034 *0.026 0.01 0.01 0.01 *0.0901502:1502 *0.1391525:1401 0.01 0.01 0.11525:1602 π*0.026 π*0.028 *0.053 π*0.109 π*0.070 π*0.050 *0.029 π*0.039 π*0.32704:0405 *0.0593802:1502 0.009 *0.010 π*0.1103901:0404 0.052 π*0.0103901:0803 π*0.010 0.079 *0.095 *0.027 0.008 π*0.049 π*0.018 *0.020 0.07 π*0.167 π*0.010 0.063 *0.2163901:1202 π*0.080 0.02 0.009 0.01 *0.244 0.035 0.013901:1401 0.015 0.015 0.098 0.0283901:1405 0.005 0.07 0.014001:0403 *0.074 *0.113 0.026 π*0.088 0.02 0.02 0.02 0.02 0.027 0.0394001:0404 0.1384001:0405 *0.156 0.014 0.045 0.025 0.01 0.009 0.02 0.02 0.036 π*0.0204001:0803 0.048 0.02 0.036 0.034 0.069 0.093 0.01 0.024001:0901 0.078 0.012 0.045 0.036 0.01 0.03 0.029 0.039 0.0184001:1101 0.015 0.01 0.027 0.025 0.118 0.064 0.012 0.027 0.049 0.022 0.0394001:1401 0.007 0.082 0.03 0.016 0.018 0.055 *0.176 0.022 0.055 0.0694001:1501 0.005 0.033 0.015 0.018 0.013 0.026 0.05 0.02 0.02 *0.109 π*0.0104002:1101 0.015 0.005 0.01 0.015 0.049 0.04 *0.099 0.0294002:1401 *0.025 0.005 0.005 0.009 0.005 *0.078 0.018 0.01 *0.125 0.027 0.059 *0.2204601:0901 0.045 *0.069 *0.045 0.014801:0404 *0.186 0.014801:1101 0.008 0.016 *0.074 0.049 0.029 π*0.070 *0.029 *0.039 0.065 *0.049 π*0.0404801:1401 0.061 *0.133 0.005 0.039 π*0.055 0.013 0.01 *0.1264801:1501 0.01 *0.0505502:1101 0.006 *0.093 0.01 0.02 *0.0915502:1401 0.009 0.006 0.025 0.014 0.009 0.027 *0.0785601:1502 *0.184 π*0.010 π*0.0405801:0301 *0.064 *0.049 π*0.010 π*0.036 π*0.039

ences between the two measures are also evident, with higher

values for Dø than Wn, a result similar to that obtained by

Weiss and Clark (33) for biallelic loci. Over 90% of all locus

pairs in all population samples showed significant LD. Of the

499 comparisons of locus pairs, only 45 were non-significant

Table 5.6f. Most frequent HLA-B:DRB1 haplotypes in Oceania

Specific PopulationRegion: OCEHLA-B:DRB1 Filipino Ivatan PNG Highlander2n 188 100 142ExpectedHeterozygosity 0.968 0.923 0.9571301:1502 0.021 0.06 0.021502:1202 0.027 *0.2101506:0405 0.0551535:1502 0.047 0.011801:1502 0.021 0.073505:1202 *0.048 0.033802:1502 *0.118 0.054001:1401 0.05 0.0074001:1501 0.0784002:1502 0.041 0.1 0.0145601:1501 0.0665602:1407 *0.121


at the 0.05 significance level prior to correction for multiple

comparisons. All but 11 locus pairs with non-significant LD

involved either the DPA1 or DPB1 locus.

Significant LD across large physical distances in the MHC

region is well documented (1, 8, 29). In the 13th IHW data,

significant LD was common even between loci that were dis-

tant from each other (e.g., class I loci and either DPA1 or

DPB1). Twenty of the 35 locus pairs at these large physical

distances were in significant LD at the 0.05 significance level

(nine after correcting for the 35 tests). LD between A and

DPB1 was significant, prior to correction, in three of the 10

Table 5.6g. Most frequent HLA-B:DRB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-B:DRB1 Cape_York2n 192Expected Heterozygosity 0.9551301:0803 0.0951521:0803 *0.1205601:0803 0.085


Table 5.6h. Most frequent HLA-B:DRB1 haplotypes in Northeast Asia

Specific PopulationRegion: NEAHLA-B:DPB1 Korean 200 Tuva2n 398 358Expected Heterozygosity 0.984 0.9840702:1501 *0.0611501:0406 *0.0402705:0101 *0.0383701:1001 π*0.008 *0.0344403:1302 *0.0355801:1302 *0.035 *0.036

Table 5.6i. Most frequent HLA-B:DRB1 haplotypes in North America

Specific PopulationRegion: NAMHLA-B:DRB1 Canoncito Yupik2n 80 504Expected Heterozygosity 0.92 0.9532703:0401 *0.0673501:0802 *0.0793501:1402 *0.158 0.0123901:0802 π*0.1624002:0901 *0.0634002:1401 *0.0574002:1402 0.017 0.0814801:0401 *0.0785101:1101 *0.0775102:0802 0.1125301:1402 0.059

populations typed at both loci (Cape York in AUS, Filipino in

OCE, and Czech in EUR). LD was not significant in the Czech

population after correcting the significance level for the 10

comparisons.

Figure 1A. Barplots of the degree of sharingof HLA-C:B haplotypes among regions. Foreach region there are two columns. The firstdepicts the fraction of haplotypes in a regionwhich are either exclusively found in thatregion (black), shared by two (dark gray),three (light gray), or more than three regions(white). The second column shows thecontribution of the haplotypes in eachcategory to the overall haplotype frequencyin that region (i.e., a frequency weightedversion of the first column). The totalnumber of haplotypes is indicated at the topof each set of columns.


Table 5.6j. Most frequent HLA-B:DRB1 haplotypes in South America

Specific PopulationRegion: SAMHLA-B:DRB1 Guarani-Kaiowa Guarani-Nandeva2n 288 106Expected Heterozygosity 0.951 0.951504:1602 π*0.125 *0.1773505:0802 *0.059 *0.0383505:0901 *0.073 *0.0283905:1402 *0.063 0.0273906:1602 *0.064 0.0093909:1402 *0.057 0.0284004:0807 *0.076 0.0285101:1402 0.003 π*0.0575104:1402 0.01 0.047

Table 5.6k. Most frequent HLA-B:DRB1 haplotypes in other regions

Specific PopulationRegion: OTHHLA-B:DRB1 Brazilian(Af_Eu)2n 136Expected Heterozygosity 0.9880702:1302 *0.0290801:0301 *0.0370805:0301 π*0.0375101:1301 *0.029

For a given pair of loci, there is a large amount of variation

in LD across population samples within a region. Some of

this variation is due to differences in sample sizes, population

complexity levels, and typing methods. In the discussion of

the results that follows, we have attempted to account for

these effects.


Table 5.7a. Most frequent HLA-C:B haplotypes in Sub-Saharan Africa

Specific PopulationRegion: SSA Kenyan Kenyan NorthHLA-C:B Doggon Kenyan 142 Highlander Lowlander America (Af) Shona Ugandan Zambian Zulu2n 258 224 480 530 502 448 322 88 196Expected Heterozygosity 0.936 0.969 0.966 0.959 0.968 0.962 0.976 0.945 0.9440202:1503 *0.050 *0.040 *0.062 *0.075 *0.068 π*0.076 *0.056 π*0.057 *0.1020304:1510 *0.012 *0.036 *0.015 π*0.036 *0.014 *0.065 π*0.025 π*0.045 *0.0360401:3501 *0.073 *0.018 *0.016 *0.021 *0.041 0.009 *0.028 0.0110401:5301 *0.113 *0.067 *0.044 *0.051 *0.087 *0.065 *0.040 π*0.102 0.0050602:5801 *0.053 0.017 0.002 0.008 0.004 0.003 0.0050602:5802 *0.062 π*0.085 *0.117 π*0.034 *0.060 π*0.043 π*0.023 *0.0970701:0801 π*0.004 0.018 0.015 *0.040 *0.020 *0.053 π*0.034 *0.0360702:0702 π*0.047 *0.027 π*0.008 *0.023 *0.070 *0.040 *0.056 *0.034 *0.0311601:4501 *0.058 *0.036 *0.015 *0.028 *0.028 *0.060 *0.019 π*0.045 π*0.0411601:5201 π*0.085 *0.014 0.0061601:7801 π*0.070 π*0.0081701:4201 π*0.140 *0.076 π*0.069 *0.074 π*0.056 π*0.069 π*0.012 π*0.148 π*0.1431801:5703 *0.013 0.004 *0.006 0.002 *0.031 *0.006 π*0.057

Table 5.7b. Most frequent HLA-C:B haplotypes in Europe

Specific PopulationRegion: EURHLA-C:B Czech Finn 90 Georgian Irish North America (Eu)2n 210 180 214 2000 574Expected Heterozygosity 0.963 0.937 0.97 0.918 0.9520303:1501 *0.019 *0.089 *0.023 *0.021 *0.0380304:4001 π*0.024 *0.083 π*0.019 *0.053 *0.0640401:3501 *0.057 *0.105 *0.061 *0.052 *0.0630401:3503 π*0.010 *0.098 *0.004 *0.0100501:4402 *0.038 *0.039 π*0.028 *0.116 *0.0890602:1302 π*0.067 π*0.017 *0.051 *0.016 π*0.0140701:0801 π*0.052 π*0.089 0.009 *0.160 *0.1060702:0702 *0.110 *0.139 π*0.033 *0.170 π*0.110

Figure 1B. Barplots of the degree of sharingof HLA-DRB1:DQB1haplotypes amongregions.For each region there are twocolumns. The first depicts the fraction ofhaplotypes in a region which are eitherexclusively found in that region (black), sharedby two (dark gray), three (light gray), or morethan three regions (white). The second columnshows the contribution of the haplotypes ineach category to the overall haplotypefrequency in that region (i.e., a frequencyweighted version of the first column). The totalnumber of haplotypes is indicated at the topof each set of columns.



Figure 2. Sample size weighted averagevalues for Wn and Dø over all populations.

LD and physical distance

We examined the decay of LD with distance using the Wn meas-

ure (Figure 3). It should be noted that this type of information

is more commonly presented in the literature as scatterplots of

LD versus distance for a large number of locus pairs (usually

SNPs) in a single population. Here we display LD values for all

possible pairs among seven loci for a large number of popula-

Figure 3. Boxplots of Wn vs. distance. Each box represents the middle half of the data with a line at the median. The spread of the central half of the data iscalled the interquartile range (IQR). The dashed lines extend to the most extreme data point that is no further from the central box than 1.5 times the IQR. Observationsbeyond this point are identified with circles. On the horizontal axis results are grouped into six categories based on physical distance. Interlocus distances are used on thehorizontal axis in (a). Locus pairs are listed in rank order according to the interlocus distance (not to scale) to facilitate their identification in (b).


tions. Less than ten populations of sufficient size were typed at

DPA1, so this locus was excluded from these analyses. The de-

cay has an overall negative exponential pattern with a large de-

gree of scatter, and levels off at the larger interlocus distances.

At distances beyond approximately 1Mb there is no longer a

strong effect due to increasing distance between loci. Similar

results were found using the overall Dø measure.


Table 5.7c. Most frequent HLA-C:B haplotypes in Southwest Asia

Specific PopulationRegion: SWAHLA-C:B Arab Druze Israeli Jews New Delhi Tamil2n 200 144 110 94ExpectedHeterozygosity 0.969 0.982 0.956 0.9620202:4002 π*0.0500401:3503 π*0.050 π*0.014 0.027 0.0210602:5001 *0.080 *0.035 0.009 0.0110602:5701 π*0.015 0.007 π*0.045 π*0.0960602:5703 *0.0350701:4403 0.007 *0.091 *0.0430702:0801 *0.064 *0.0430802:1404 *0.0561202:5201 π*0.010 *0.056 π*0.064 *0.0741402:5101 π*0.005 *0.064 π*0.0211502:4006 0.018 *0.0851507:4006 *0.091 0.0111701:4101 *0.050 π*0.014 π*0.009

We assigned the locus pairs to six distance categories, de-

fined by the physical distance between the constituent loci.

Values for Wn ranged from 0.63 to 1.0 in the shortest distance

category (interlocus distances between 0.02 and 0.09 Mb)

with a median value of 0.82. In the second category (0.42 to

0.49 Mb) the range was from 0.26 to 0.82 with a median of

0.41. The third distance category (1.17 to 1.33 Mb) had Wn

values with a range of 0.30 to 0.85 and a median of 0.56. In

the fourth category (1.48 to1.75 Mb) the range was from

0.30 to 0.81 with a median of 0.55. The range of values in

the fifth category (2.74 to 2.81 Mb) was from 0.25 to 0.76

Table 5.7d. Most frequent HLA-C:B haplotypes in Southeast Asia

Specific Population

NorthRegion: SEA America Paiwan PuyumaHLA-C:B Ami 97 Atayal Bunun Chinese Hakka Malay Minnan (As) 51 Pazeh 49 Rukai Saisiat Siraya Thai Toroko Tsou Yami

2n 196 212 202 558 110 186 204 786 102 110 100 100 102 102 184 110 102 100ExpectedHeterozygosity 0.822 0.87 0.861 0.95 0.935 0.959 0.943 0.972 0.867 0.929 0.893 0.849 0.669 0.94 0.946 0.832 0.858 0.78

0102:1501 0.005 0.005 0.005 0.005 0.005 π*0.039 0.009 π*0.0600102:4601 π*0.005 *0.115 π*0.136 π*0.016 *0.137 *0.066 π*0.082 *0.029 π*0.1630102:5502 0.015 *0.052 *0.104 0.009 0.009 0.01 *0.019 0.009 *0.010 0.02 *0.127 π*0.1180102:5601 π*0.204 0.005 *0.008 0.018 π*0.006 π*0.010 π*0.0400302:5801 π*0.088 π*0.109 π*0.048 π*0.088 *0.073 π*0.010 π*0.036 π*0.049 *0.0870303:4002 *0.036 π*0.019 π*0.025 *0.005 0.009 *0.015 π*0.098 0.018 π*0.060 π*0.130 π*0.010 *0.137 π*0.073 π*0.088 π*0.0800303:5502 0.005 *0.057 *0.030 0.002 0.009 0.005 0.018 0.0180304:1301 π*0.267 *0.075 *0.055 *0.032 *0.064 *0.029 π*0.255 π*0.118 π*0.170 π*0.280 0.029 π*0.127 *0.049 π*0.176 π*0.0400304:4001 *0.107 *0.193 0.069 *0.042 *0.1 0.016 0.039 *0.030 0.174 0.064 0.09 0.15 *0.147 0.049 0.011 π*0.227 *0.127 0.020304:4002 0.015 0.005 0.009 *0.025 *0.016 0.032 0.009 0.029 0.011 *0.1500304:5502 0.005 0.059 0.040401:3505 π*0.007 π*0.075 π*0.005 0.001 π*0.0090401:4001 π*0.209 π*0.071 π*0.114 0.01 0.011 0.015 0.008 0.078 0.03 0.02 0.039 0.039 0.018 0.01 π*0.0100403:1525 π*0.026 π*0.028 π*0.064 *0.009 π*0.011 π*0.005 *0.003 π*0.010 π*0.109 π*0.070 π*0.070 π*0.049 *0.011 π*0.049 π*0.40403:4001 0.004 0.003 0.050701:4403 *0.011 π*0.009 π*0.065 *0.014 π*0.0330702:0705 0.004 0.003 *0.0540702:3802 *0.070 0.036 *0.054 π*0.061 0.011 0.01 0.01 π*0.029 π*0.038 π*0.1100702:3901 π*0.102 π*0.198 π*0.149 0.002 0.036 0.015 *0.019 π*0.049 0.01 π*0.050 π*0.130 *0.539 0.01 0.016 π*0.218 π*0.2450702:4001 0.005 0.075 0.03 *0.082 0.109 *0.108 *0.047 0.069 *0.115 0.01 *0.118 0.039 0.021 0.1 0.0290704:1801 *0.005 *0.081 *0.006 *0.0270801:1502 π*0.072 π*0.027 *0.075 π*0.059 *0.050 π*0.036 π*0.180 0.01 *0.054 0.01 π*0.1200801:1513 π*0.075 π*0.003 π*0.0160801:4801 π*0.260 π*0.170 π*0.089 π*0.016 *0.015 *0.018 π*0.088 π*0.055 *0.110 π*0.070 π*0.039 π*0.049 π*0.191 π*0.088 π*0.0401202:2704 π*0.010 π*0.080 *0.011 π*0.009 *0.020 *0.001 π*0.109 π*0.090 π*0.069 π*0.027 π*0.009 π*0.029 π*0.030


Table 5.7e. Most frequent HLA-C:B haplotypes in Oceania

Specific PopulationRegion: OCE AmericanHLA-C:B Samoa Filipino Indonesian Ivatan2n 100 188 98 100ExpectedHeterozygosity 0.929 0.953 0.957 0.9070102:5502 *0.1 π*0.0110102:5602 *0.0800302:5801 π*0.064 π*0.0310304:4001 *0.190 0.006 0.02 *0.0800401:3505 *0.080 π*0.051 π*0.0600401:4001 0.04 0.027 0.070403:1521 π*0.030 π*0.059 π*0.020 π*0.0100702:1535 *0.059 0.020702:3802 π*0.128 π*0.071 π*0.0600702:4001 0.02 0.051 0.020704:1801 *0.016 *0.041 π*0.0700801:1502 *0.037 π*0.082 π*0.2200801:1513 π*0.032 *0.1120801:4801 π*0.1 *0.027 π*0.0801502:4002 *0.064 π*0.0901502:4006 π*0.051

with a median of 0.47. In the last distance category (3.32

Mb) the range was from 0.28 to 0.54 with a median of 0.40.

Evidence of the recombination hotspots between DPB1 and

DQB1 is visible in the second distance category, which con-

tains DPA1 and DPB1 paired with other class II loci. The pres-

ence of hotspots near RING3, TAP2, and DQB3, identified by

Cullen et al. (2), causes a sudden drop in the strength of LD

for locus pairs in this distance category.

Of the 79 datasets with locus pairs involving DPB1, 54 had


significant LD at the 0.05 level of significance prior to correc-

tion for multiple tests (31 after correction for the 79 tests).

This result differs from those in Sanchez-Mazas et al. (2000),

where no significant LD among locus pairs involving DPB1

in CEPH data was found.

Variation in LD among populations and regions

Figure 4 displays a plot of LD versus distance for each geo-

graphic region. These plots characterize some of the vari-

Table 5.7f. Most frequent HLA-C:B haplotypes in Australia

Specific PopulationRegion: AUSHLA-C:B Cape York Groote Eylandt Yuendumu2n 172 146 384Expected Heterozygosity 0.883 0.87 0.8590102:4002 0.012 0.062 *0.0100102:5601 *0.128 *0.171 *0.0600102:5602 π*0.035 0.021 *0.1690303:4001 π*0.029 π*0.151 *0.0390401:1301 *0.256 *0.233 π*0.2450403:1521 π*0.145 *0.048 π*0.1250403:1525 *0.062 0.0231502:4002 *0.064 *0.109 *0.167

Table 5.7g. Most frequent HLA-C:B haplotypes in Northeast Asia

Specific PopulationRegion: NEAHLA-C:B Korean 200 Okinawan Tuva2n 400 208 336Expected Heterozygosity 0.963 0.948 0.9690102:4601 *0.050 0.01 *0.0090102:5401 π*0.048 *0.087 π*0.0240102:5901 π*0.010 π*0.0620302:5801 π*0.055 π*0.0570303:1501 0.018 *0.086 *0.0240303:3501 *0.040 *0.101 0.0180304:4002 *0.030 *0.058 *0.0710401:1501 *0.052 *0.029 0.0030702:0702 π*0.038 0.01 *0.0680702:3901 *0.015 *0.067 0.0030801:4006 *0.030 *0.0531402:5101 *0.1 π*0.072 π*0.0091502:5101 *0.015 0.005 *0.051

Table 5.7h. Most frequent HLA-C:B haplotypes in North America

Specific PopulationRegion: NAMHLA-C:B Amerindian Canoncito Yupik2n 458 82 298Expected Heterozygosity 0.966 0.885 0.8550202:2705 *0.065 π*0.037 *0.1710304:4002 *0.039 π*0.049 *0.2970304:5101 0.008 *0.0790401:3501 *0.094 π*0.207 *0.0730401:5301 0.004 π*0.0850702:0702 π*0.070 π*0.0200702:3901 *0.035 π*0.1590801:4801 *0.013 π*0.098 0.0070801:5102 π*0.007 π*0.1340806:4801 π*0.1011502:5101 *0.055 π*0.049 0.012


ability seen in Figure 3. While there is still a large amount of

scatter in the degree of LD within regions (Figure 4), differ-

ences among regions are evident. In order to help visualize

overall differences among regions we present lowess curves

(locally weighted robust regression (3)) for several regions

Table 5.7i. Most frequent HLA-C:B haplotypes in South America

Specific PopulationRegion: SAMHLA-C:B Guarani-Kaiowa Guarani-Nandeva2n 286 104Expected Heterozygosity 0.927 0.9350303:1504 *0.070 *0.1630304:3511 π*0.0590304:4004 π*0.101 *0.0960401:3505 *0.139 π*0.0580702:3905 π*0.108 π*0.0960702:3906 π*0.091 0.010702:3909 π*0.084 0.0291503:5104 *0.042 π*0.067

Table 5.7j. Most frequent HLA-C:B haplotypes in other regions

Specific PopulationRegion: OTHHLA-C:B Brazilian (Af Eu) North America (Hi)2n 136 480Expected Heterozygosity 0.985 0.9790401:3501 0.021 *0.0560701:0801 π*0.044 *0.0350701:0805 0.0290702:0702 *0.051 *0.0650802:1402 *0.015 *0.042

Table 5.8a. Most frequent HLA- DRB1:DPB1 haplotypes in Sub-Sahar-an Africa

Specific PopulationRegion: SSAHLA-DRB1:DPB1 Shona Zulu2n 456 174Expected Heterozygosity 0.978 0.9640302:0101 *0.048 0.1020302:0402 0.003 0.0591101:0101 0.05 0.0631101:0402 0.036 0.0641302:0101 0.029 0.0571503:0201 *0.057

Most frequent HLA- DRB1:DPB1 haplotypes in North AfricaNo data

Table 5.8b. Most frequent HLA- DRB1:DPB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-DRB1:DPB1 Czech Slovenian2n 198 200Expected Heterozygosity 0.973 0.970101:0401 0.016 0.0630301:0401 0.011 0.0570701:0401 0.087 0.030701:1701 π*0.035 0.0051101:0401 0.02 0.0531501:0401 0.074 0.069


Most frequent HLA- DRB1:DPB1 haplotypes in Southwest AsiaNo data

Table 5.8c. Most frequent HLA- DRB1:DPB1 haplotypes in SoutheastAsia

Specific PopulationRegion: SEAHLA-DRB1:DPB1 Malay2n 94Expected Heterozygosity 0.9561202:0501 0.1541202:1301 0.0551502:1301 0.052

Table 5.8d. Most frequent HLA- DRB1:DPB1 haplotypes in Oceania

Specific PopulationRegion: OCE East PNGHLA-DRB1:DPB1 Timorese Filipino Highlander2n 158 188 168Expected Heterozygosity 0.923 0.89 0.9420405:0101 0.0520405:0501 0.019 0.007 *0.0671101:0501 0.062 0.028 0.0061202:0402 *0.0521407:0201 0.0931501:0201 0.006 0.0731501:0401 0.141502:0101 0.014 *0.289 0.0061502:0401 0.046 0.007 0.0761502:0501 0.208 0.1181502:1301 0.126 0.014

Table 5.8e. Most frequent HLA- DRB1:DPB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-DRB1:DPB1 Cape_York2n 192Expected Heterozygosity 0.9360405:0501 0.0590803:0501 0.1580803:2201 *0.1401402:0501 0.055

Most frequent HLA- DRB1:DPB1 haplotypes in Northeast AsiaNo data

Table 5.8f. Most frequent HLA- DRB1:DPB1 haplotypes in NorthAmerica

Specific PopulationRegion: NAMHLA-DRB1:DPB1 Canoncito Sioux Zuni2n 80 162 100Expected Heterozygosity 0.857 0.962 0.8790403:0401 0.0770403:0402 0.048 0.070404:0201 0.0540407:0401 0.081 0.0140802:0401 *0.2400802:0402 0.197 0.034 0.21402:0201 0.11 0.0261402:0401 0.06 0.013 0.1631402:0402 0.143 0.035 0.1271406:0401 0.0591602:0301 *0.0691602:0402 0.085 0.03 0.156


Table 5.8g. Most frequent HLA- DRB1:DPB1 haplotypes in SouthAmerica

Specific PopulationRegion: SAMHLA-DRB1:DPB1 Ticuna Central American2n 98 110Expected Heterozygosity 0.876 0.8830407:0402 0.1450407:1401 0.0730411:0301 π*0.071 0.0090411:0402 0.0510411:1401 *0.1420807:0401 *0.1520901:0201 π*0.0711402:0402 0.2121602:0402 π*0.245 0.193

Table 5.9a. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in Sub-Saharan Africa

Specific PopulationRegion: SSAHLA-DRB1:DQA1:DQB1 Shona Zulu2n 458 172Expected Heterozygosity 0.947 0.9290102:0101:0501 0.0610301:0501:0201 0.065 0.0470302:0401:0402 0.063 0.1921101:0102:0602 0.071 0.0991101:0501:0301 0.064 0.0931501:0102:0602 0.002 0.0521503:0102:0602 0.14

Table 5.9b. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes inNorth Africa

Specific PopulationRegion: NAFHLA-DRB1:DQA1:DQB1 Moroccan 98 Moroccan 992n 196 174Expected Heterozygosity 0.902 0.9360102:0101:0501 0.066 0.0520301:0501:0201 0.179 0.1550701:0201:0201 0.209 0.1261101:0501:0301 0.077 0.0171302:0102:0604 0.026 0.0691501:0102:0602 0.056 0.075

Table 5.9c. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in Eur-ope

Specific PopulationRegion: EURHLA-DRB1:DQA1:DQB1 Czech Slovenian2n 204 200Expected Heterozygosity 0.942 0.9410101:0101:0501 0.074 0.1050301:0501:0201 0.069 0.120701:0201:0201 0.123 0.0651101:0501:0301 0.049 0.061104:0501:0301 0.044 0.0551301:0103:0603 0.088 0.0451501:0102:0602 0.098 0.071601:0102:0502 0.025 0.105


Table 5.9d. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes inSouthwest Asia

Specific PopulationRegion: SWAHLA-DRB1:DQA1:DQB1 Turk2n 490Expected Heterozygosity 0.9540301:0501:0201 0.090701:0201:0201 0.0731101:0501:0301 0.0951104:0501:0301 0.0611501:0102:0602 0.0571601:0102:0502 0.059

Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in Southeast AsiaNo data

Table 5.9e. Most frequent HLA- DRB1:DPB1 haplotypes in Oceania

Specific PopulationRegion: OCE East PNGHLA-DRB1:DPB1 Timorese Highlander2n 158 174Expected Heterozygosity 0.905 0.8840405:0301:0401 0.013 0.1031101:0501:0301 0.095 0.0061202:0102:0502 0.0881202:0601:0301 0.0511407:0101:0503 0.1381408:0101:0503 0.013 0.0921501:0102:0602 0.019 0.2531502:0101:0501 0.1831502:0102:0502 0.071502:0102:0601 0.176 0.086

Table 5.9f. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in Aus-tralia

Specific PopulationRegion: AUSHLA-DRB1:DQA1:DQB1 Cape_York2n 198Expected Heterozygosity 0.8920405:0301:0402 0.0660803:0103:0503 0.0760803:0103:0601 0.2681402:0501:0301 0.0711408:0101:0503 0.101

Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in Northeast AsiaNo data

Table 5.9g. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes inNorth America

Specific PopulationRegion: NAMHLA-DRB1:DQA1:DQB1 Lacandon Sioux Yupik Zuni2n 324 190 114 100Expected Heterozygosity 0.652 0.916 0.861 0.8510401:0301:0301 0.011 0.2460403:0301:0302 0.044 0.147 0.026 0.070404:0301:0302 0.068 0.1210407:0301:0302 0.096 0.142 0.010410:0301:0402 0.0610411:0301:0302 0.5670411:0301:0402 0.007 0.050802:0401:0402 0.058 0.114 0.190901:0301:0303 0.026 0.096 0.021101:0501:0301 0.016 0.0961401:0101:0503 0.1321402:0501:0301 0.074 0.079 0.149 0.251406:0501:0301 0.046 0.091602:0501:0301 0.046 0.11 0.053 0.18


Table 5.9h. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes inSouth America

Specific PopulationRegion: SAM Guarani- Guarani- CentralHLA-DRB1:DQA1:DQB1 Kaiowa Nandeva American2n 288 106 110Expected Heterozygosity 0.8 0.809 0.8330403:0301:0302 0.0910407:0301:0302 0.087 0.019 0.2270701:0201:0201 0.009 0.0550802:0401:0402 0.069 0.0660807:0401:0402 0.101 0.0660901:0301:0303 0.097 0.0471402:0501:0301 0.205 0.255 0.2361602:0501:0301 0.351 0.33 0.209

Table 5.9i. Most frequent HLA-DRB1:DQA1:DQB1 haplotypes in otherregions

Specific PopulationRegion: OTHHLA-DRB1:DQA1:DQB1 Mexican2n 408Expected Heterozygosity 0.9470407:0301:0302 0.1320701:0201:0201 0.0540802:0401:0402 0.121406:0501:0301 0.059

Table 5.10a. Most frequent HLA-DRB1:DQB1 haplotypes in Sub-Sahar-an Africa

Specific PopulationRegion: SSAHLA-DRB1:DQB1 Rwandan Shona Zulu2n 560 458 172Expected Heterozygosity 0.944 0.945 0.9210102:0501 *0.075 π*0.0610301:0201 *0.054 *0.065 *0.0460302:0402 *0.024 *0.063 π*0.1920701:0201 *0.050 π*0.046 π*0.0811101:0301 *0.057 *0.064 *0.1031101:0602 0.032 *0.074 0.0941201:0501 π*0.021 *0.050 π*0.0471302:0604 *0.084 *0.013 *0.0231302:0605 *0.048 π*0.022 *0.0521501:0602 0.002 π*0.0581503:0602 *0.152 *0.140

Table 5.10b. Most frequent HLA-DRB1:DQB1 haplotypes in NorthAfrica

Specific PopulationRegion: NAF Algerian Moroccan MoroccanHLA-DRB1:DQB1 99 98 992n 198 196 176Expected Heterozygosity 0.951 0.899 0.9340102:0501 *0.010 π*0.066 π*0.0570301:0201 *0.141 π*0.179 π*0.1590701:0201 *0.116 *0.209 π*0.1251101:0301 *0.071 π*0.092 π*0.0231302:0604 *0.025 π*0.026 *0.0681501:0602 *0.020 *0.061 π*0.074


Table 5.10c. Most frequent HLA-DRB1:DQB1 haplotypes in Europe

Specific PopulationRegion: EURHLA-DRB1:DQB1 Czech Slovenian2n 206 200Expected Heterozygosity 0.94 0.9390101:0501 π*0.073 *0.1050301:0201 *0.068 π*0.1200701:0201 *0.126 *0.0701101:0301 *0.058 *0.0601104:0301 *0.044 *0.0551301:0603 π*0.087 *0.0451501:0602 *0.102 *0.0701601:0502 π*0.024 *0.105

Table 5.10d. Most frequent HLA-DRB1:DQB1 haplotypes in SouthwestAsia

Specific PopulationRegion: SWAHLA-DRB1:DQB1 Turk2n 490Expected Heterozygosity 0.9530301:0201 π*0.0900701:0201 *0.0731101:0301 *0.0951104:0301 *0.0631501:0602 *0.0611601:0502 *0.059

on the same plot of Wn versus distance (Figure 5) after omit-

ting locus pairs that include DPB1. The lowess curves display

a non-parametric robust local smoothing of the scatter plot

data where the smoothness of the fit depends on the fraction

of the data used to compute the mean at each value on the

horizontal axis.

Figure 4. Scatterplot matrix of Wn vs.physical distance for each region. Results foreach geographic region are in separate panelswith points representing a single population/locus pair combination in that region.


Table 5.10e. Most frequent HLA-DRB1:DQB1 haplotypes in SoutheastAsia

Specific PopulationRegion: SEAHLA-DRB1:DPB1 Kinh Malay Muong2n 198 98 164Expected Heterozygosity 0.875 0.898 0.9150301:0201 π*0.040 *0.041 *0.0980701:0201 *0.025 0.041 0.0060901:0303 π*0.141 0.02 *0.0671202:0301 *0.298 *0.282 0.0371202:0502 0.021 0.0551401:0502 π*0.030 0.01 *0.1401501:0602 *0.015 *0.041 0.0061502:0501 *0.061 *0.082 *0.0661502:0502 0.015 0.051602:0502 π*0.010 0.01 *0.188

Examining all locus pairs, we find that LD is lowest in SSA

and highest in the Americas. Between these two extremes we

find (ordered by increasing LD) EUR, the Asian regions, AUS,

and OCE. This result is similar to those found between mark-

ers separated by comparatively shorter physical distances, out-

side the HLA region (15, 16, 31).

In a study of European individuals, Jeffreys et al. (12) used

sperm typing techniques to directly measure recombination

rates among SNPs in the HLA class II region. The authors

found several recombination hotspots between DPB1 and

other classical HLA loci, a result that was concordant with the

pattern of LD showing a marked discontinuity across the re-

gion containing these hotspots. In the present study, we inves-

tigated whether the LD pattern expected in the presence of


Figure 5. Smoothed plot of Wn vs. distancefor a subset of regions. Smoothing is basedupon a locally weighted robust regression(lowess), in which the degree of smoothingdepends on the fraction of the data used tocompute the mean at each value on thehorizontal axis. A separate lowess curve wasestimated for each region using a data-fractionof 2/3 (4, 20).

this hotspot is found for populations from other regions of

the world. The result in Figure 4 shows that the decrease in

LD between DPB1 and the other classical loci is found in

populations from all world regions. This suggests that these

recombination hotspots are shared by human populations,

and not population specific.

Effects of admixture and polymorphism on LD

Extent of recent admixture is a potential source of LD among

populations. We investigated the relationship between admix-

ture and LD, using population complexity as a proxy for ad-

mixture. Higher complexity levels correspond to more ad-

mixed populations (see reference 19 in this volume for a de-

scription of the three complexity levels). We compared levels

of LD in populations of unequal complexity in the SEA re-

Table 5.10f. Most frequent HLA-DRB1:DQB1 haplotypes in Oceania

Specific PopulationRegion: OCE East PNG PNG Low-HLA-DRB1:DPB1 Timorese Filipino Highlander lander 952n 158 188 174 156ExpectedHeterozygosity 0.89 0.876 0.876 0.6050405:0401 π*0.013 π*0.016 *0.1091101:0301 π*0.095 *0.043 π*0.006 π*0.5511202:0301 0.051 *0.112 π*0.0061202:0502 *0.088 0.0051407:0503 π*0.1381408:0503 π*0.013 π*0.0921501:0602 π*0.019 π*0.2531502:0501 π*0.222 *0.1491502:0502 0.083 *0.277 0.0061502:0601 *0.170 0.016 *0.115 *0.1471602:0502 π*0.044 *0.023 *0.263


gion, the only region that had a sufficiently large number of

sampled populations to allow such a comparison. For these

populations, higher complexity level was not associated with

higher LD. One interpretation of this result is that the ob-

served LD patterns carry information about the long-term

demographic history of the populations, and are not just a

reflection of sampling effects. This suggests that admixture

induced LD alone does not explain the observed results.

Several papers have remarked on the relationship between

LD and locus polymorphism (18, 24, 29), finding higher LD

for loci with higher heterozygosity. The 13th IHW data pro-

vides a unique opportunity to investigate this relationship

across a large number of populations typed at the same loci

with varying degrees of polymorphism. Sanchez-Mazas et al.

(29) found that less polymorphic loci were in significant LD

with fewer other loci. In the 13th IHW data, the strength

of LD, rather than statistical significance, appears to be more

strongly influenced by marker characteristics such as the

Table 5.10g. Most frequent HLA-DRB1:DQB1 haplotypes in Australia

Specific PopulationRegion: AUSHLA-DRB1:DQB1 Cape_York Kimberley2n 198 82Expected Heterozygosity 0.889 0.8720405:0402 *0.066 0.0490412:0402 0.110803:0503 0.076 0.0850803:0601 *0.273 *0.1711402:0301 π*0.071 0.0121408:0503 π*0.101 π*0.0851409:0402 π*0.2201502:0601 0.04 π*0.134


Most frequent HLA-DRB1:DQB1 haplotypes in Northeast AsiaNo data

Table 5.10h. Most frequent HLA-DRB1:DQB1 haplotypes in North America

Specific PopulationRegion: NAMHLA-DRB1:DQB1 Canoncito Lacandon Sioux Yupik Zuni2n 80 324 190 502 100Expected Heterozygosity 0.691 0.652 0.914 0.856 0.8370401:0301 0.011 *0.2270403:0302 0.044 *0.147 π*0.030 π*0.0700404:0302 0.068 *0.121 π*0.0020407:0302 *0.025 0.096 π*0.142 π*0.002 0.010411:0302 *0.5670411:0402 0.007 0.050802:0402 π*0.425 π*0.074 π*0.131 π*0.2100901:0303 π*0.012 *0.026 π*0.078 π*0.0201101:0301 0.016 π*0.1081401:0503 π*0.025 π*0.0681402:0301 π*0.338 π*0.074 *0.078 *0.221 0.261406:0301 0.012 π*0.046 0.091602:0301 0.112 π*0.046 *0.110 0.046 0.18

number of alleles or heterozygosity for certain measures. The

Dø measure was positively correlated with locus heterozygosi-

ty (measured as either maximum or average heterozygosity

for the pair of loci involved) for most locus pairs. This pattern

was most notable for the higher values of heterozygosity. It

was not seen for locus pairs with very high degrees of LD

(e.g., C:B and DRB1:DQB1). We found that for Wn there was

little to no relationship with heterozygosity.

The number and total frequency of singleton haplotypes is a

consequence of the degree of polymorphism at the constituent

loci. The observed effect of polymorphism on singleton fre-

quency is accentuated as a consequence of the estimation of

haplotype frequencies. For locus pairs in distance categories

two through six (defined in figure 3), the total frequency of

singletons is positively correlated with the measure of LD. This

correlation is much higher for the Dø measure than for the Wn

measure (e.g., A:B haplotypes: rΩ0.71 for Dø, rΩ0.13 for Wn;

Table 5.10i. Most frequent HLA-DRB1:DQB1 haplotypes in SouthAmerica

Specific PopulationRegion: SAM Guarani- Guarani- CentralHLA-DRB1:DQA1:DQB1 Kaiowa Nandeva Ticuna American2n 288 106 98 110ExpectedHeterozygosity 0.8 0.809 0.782 0.830403:0302 0.041 π*0.0910407:0302 π*0.087 π*0.019 π*0.2270411:0302 π*0.042 π*0.047 π*0.316 0.0090701:0201 π*0.009 π*0.0550802:0402 *0.069 *0.066 0.0310807:0402 π*0.101 π*0.066 π*0.2240901:0303 π*0.097 π*0.047 π*0.0511402:0301 π*0.205 π*0.255 π*0.2361602:0301 π*0.351 π*0.330 π*0.245 π*0.218


B:DRB1 haplotypes: rΩ0.43 for Dø, rΩ0.17 for Wn). For the

closest pairs of loci the correlation is of a lower magnitude and

is negative. Locus pairs in the first distance category have the

highest levels of LD and the lowest number and total frequency

of singletons. Characteristics such as these need to be consid-

ered when comparing the degree of LD across different pairs of

loci for highly polymorphic data.

In this paper we described patterns of LD among the HLA

class I and class II genes and gave an overview of the distribu-

tion of haplotype frequencies. Although the intra regional

variation in measures of LD is high and differences in sample

sizes and population complexity levels complicate inter-

pretations, certain patterns were evident. LD was significant

even for HLA loci separated by large physical distances. At the

population level LD was highest in the SAM and NAM re-

gions, and lowest in SSA populations; SSA also showed the

largest numbers of haplotypes. Region specific haplotypes are

commonly at low frequencies; the large number of such

haplotypes results in a sizeable contribution of region specific

haplotypes to overall haplotypic diversity.

Table 5.10j. Most frequent HLA-DRB1:DQB1 haplotypes in other re-gions

Specific PopulationRegion: OTHHLA-DRB1:DQB1 Mexican2n 408Expected Heterozygosity 0.9420407:0302 *0.1370701:0201 *0.0560802:0402 π*0.1251406:0301 π*0.0591602:0301 π*0.051


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Haplotype frequencies and linkage disequilibrium among classical HLA genes