Haplotype frequencies and linkage disequilibrium among classical HLA genes (original) (raw)
Related papers
2001
The HLA system is the most polymorphic of all human genetic systems. The frequency of HLA class I alleles and their linkage disequilibrium patterns differ significantly among human populations as shown in studies using serologic methods. Many DNA-defined alleles with identical serotypes may have variable frequencies in different populations. We typed HLA-A, B, and C loci at the allele level by PCR-based methods in 1,296 unrelated subjects from five major outbred groups living in the U.S.A (African, AFAM; Caucasians, CAU; Asian, ORI; Hispanic, HIS, and North American Natives, NAI). We detected 46, 100 and 32 HLA-A, B, and C alleles, respectively. ORI and HIS presented more alleles at each of these loci. There was lack of correlation between the levels of heterozygosity and the number of alleles detected in each population. In AFAM, heterozygosity (Ͼ90%) is maximized at all class I loci. HLA-A had the lowest heterozygosity in all populations but CAU. Tight LD was observed between HLA-B and C alleles. AFAM had weaker or nonexistent associations between alleles of HLA-A and B than other populations. Analysis of the genetic distances between these and other populations showed a close relationship between specific US populations and a population from their original continents. ORI exhibited the largest genetic distance with all the other U.S. groups and were closer to NAI. Evidence of admixture with CAU was observed for AFAM and HIS. HIS also had significant frequencies of AFAM and Mexican Indian alleles. Differences in both LD and heterozygosity levels suggest distinct evolutionary histories of the HLA loci in the geographical regions from where the U.S. populations originated.
Worldwide genetic diversity at the HLA-DQA1 locus
American Journal of Human Biology, 1997
Genotype, gene, or phenotype frequency data, obtained by PCR analysis with sequence specific oligonucleotide probes at the HLA-DQA1 locus, in 176 population samples, each consisting of 30 or more individuals, from all around the world were analyzed. The sampled populations were assigned to the following nine groups: African, Afro-American, American Native, American Mestizo, Asian, American Caucasian, European Caucasian, Caucasian from other regions, and Pacific Islanders. Observed genotype proportions agreed with Hardy-Weinberg expectations (HWE) in 90 of the 102 populations for which genotype data are available. The 12 discordant population samples were of substantial mixed origin. For these discordant populations, 41 of the 252 (population by genotype) data points showed significant departures of the observed frequencies in comparison to their HWE predictions. The deviations, by and large (38 of the 41), were in the direction of HWE over-estimating the actual genotype frequencies. Total heterozygosity (H T ) at a worldwide level was 79%, and varied from 56% in American Natives to >80% in Caucasians. Of the total diversity, 94.4% was due to intrapopulation and 5.6% to inter-population variation (F ST ), partitioned into 3.0% inter-population within groups and 2.6% inter-group variation. F ST for the locus was high among Africans and American Natives (>9%) and low in Afro-Americans and American Caucasians (<0.5%). The range for allele specific F ST was 0.2% to 5.9%, and the lowest value did not correspond to the same allele in all nine groups. A variance component analysis of allele frequencies showed no relationship of the ratio of between/within group variation with the world average frequency of the respective alleles. The first three principal components explained 36.2%, 27.5%, and 22.9% of the total allelic diversity, respectively. analyses indicate that genetic drift in contrast to natural selection, more readily explains the pattern of worldwide diversity at the HLA-DQA1 locus.
The HLA-A,B gene frequencies in the world: Migration or selection
Human Immunology, 1980
Multivariate methods make it p~sible to condense much of the information araila61¢ /~r a large number of alleles into one or a few synthetic variables. The geographic distributi~ synthetic variables can b~ analyzed and plotted by the same technique used an analyzing and mapping the gene frequency of a singl~ allele. The i~formation contained in 21 HLASA and HLA-B alleles from 116 world populations is ce.~densed in principal components and discrimiuant functions which describe the global variation of gene frequencies along longitudes and al~ latitudes. Most genetfi" variation is associated with longitude and shows a center of symmetry in Asia. Thus Asia, or some part of it, may haw been the center, both geographically and historically. *f late Pleist~'ene migrations. However, l~,titude also plays a significant role (perhaps IOe~ *f t~e o, enetic mriation). A remarkable symn:et~ of the latitude variation in opposite euortG aFid southJ hemiJpheres suggests that climatic factors exer,'ise sele, tive pressure for certaiu HLA alleles. More specifically AI, A3, BT. B8, and B27 show about equally high correlati~ coefficients (between 0,45 and 0.55J u'J:th distance from equator. This result supports the id, a that the well-known linkage disequilibria between A 1 and B8, A3 and B7 are prdaably kepe l~ selective pressure, ABBREVIATIONS HLA human leukocyte
International Journal of Immunogenetics, 2012
We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of welldefined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The GENE[RATE] computer tools were combined to create a GENE[RATE] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution.
International Journal of Immunogenetics
We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May-June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well-defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA-NET recommendations. The new data included, among others, large sets of welldefined populations from north-east Europe and West Asia, as well as many donor registry data from European countries. The GENE[RATE] computer tools were combined to create a GENE[RATE] computer pipeline to automatically (i) estimate allele frequencies by an expectation-maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy-Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th-15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA-A, -B and -DRB1 loci but not for HLA-DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south-east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian-speaking South-East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution.
Tissue Antigens, 2003
A collaborative study involving a large sample of European Americans was typed for the histocompatibility loci of the HLA DR-DQ region and subjected to intensive typing validation measures in order to accurately determine haplotype composition and frequency. The resulting tables have immediate application to HLA typing and allogeneic transplantation. The loci within the DR-DQ region are especially valuable for such an undertaking because of their tight linkage and high linkage disequilibrium. The 3798 haplotypes, derived from 1899 unrelated individuals, had a total of 75 distinct DRB1-DQA1-DQB1 haplotypes. The frequency distribution of the haplotypes was right skewed with haplotypes occurring at a frequency of less than 1% numbering 59 and yet constituting less than 12% of the total sample. Given DRB1 typing, it was possible to infer the exact DQA1 and DQB1 composition of a haplotype with high confidence (>90% likelihood) in 21 of the 35 highresolution DRB1 alleles present in the sample. Of the DRB1 alleles without high reliability for DQ haplotype inference, only *0401, *0701 and *1302 were common, the remaining 11 DRB1 alleles constituting less than 5% of the total sample. This approach failed for the 13 serologically equivalent DR alleles in which only 33% of DQ haplotypes could be reliably inferred. The 36 DQA1-DQB1 haplotypes present in the total sample conformed to the known pattern of permissible heterodimers. Four DQA1-DQB1 haplotypes, all rare, are reported here for the first time. The haplotype frequency tables are suitable as a reference standard for HLA typing of the DR and DQ loci in European Americans.