W. Klitz - Academia.edu (original) (raw)
Papers by W. Klitz
PLoS Genetics, 2008
The large and diverse population of Latin America is potentially a powerful resource for elucidat... more The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.
Histocompatibility Testing 1984, 1984
Genetics, 1990
Copyright 0 1990 by the Genetics Society of America ... Gene Conversion in the Evolution of Both ... more Copyright 0 1990 by the Genetics Society of America ... Gene Conversion in the Evolution of Both the H-2 and Qu Class I Genes of the Murine Major Histocompatibility Complex ... Mary Kuhner,* Suzanne Watts: William Klitz,* Glenys Thornson* and Robert S. Goodenow+
Genetics, 1987
Disequilibrium pattern analysis, a general method for analyzing evolutionary events acting on pai... more Disequilibrium pattern analysis, a general method for analyzing evolutionary events acting on pairs of tightly linked polymorphic loci, is applied to a large sample of Danish individuals typed for A and B loci of the HLA (human leukocyte antigen) system. Cases of selection on particular haplotypes are revealed from patterns of linkage disequilibrium among the HLA haplotypes. These patterns cannot be explained by either population admixture or random genetic drift. Six haplotypes out of the total array of 273 haplotypes have been identified which show in varying extents the patterns indicating selection.
Blood, 2000
Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is... more Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)-documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P =.012), and the class II HLA-DRB1 (P =.0008) and DQB1 (P =.029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of s...
Genetics, 1998
Positive selection on a new mutant allele can increase the frequencies of closely linked alleles ... more Positive selection on a new mutant allele can increase the frequencies of closely linked alleles (through hitchhiking), as well as create linkage disequilibrium between them. Because this disequilibrium is induced by the selected allele, one may be able to identify loci under selection by measuring the influence of a candidate locus on pairwise disequilibrium values at nearby loci. The constrained disequilibrium values (CDV) method approaches this problem by examining differences in pairwise disequilibrium values, which have been normalized for two- and three-locus systems, respectively. We have investigated in detail the reliability of inferences based on CDV, using simulation and analytical methods. Our main results are (i) in some circumstances, CDV may not distinguish well between a selected locus and a neighboring neutral locus, but (ii) CDV seldom indicates "selection" in neutral haplotypes with moderate to large 4Nc. We conclude that, although the CDV method does no...
American journal of human genetics, 1994
We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population... more We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles a...
American journal of human genetics, 1995
DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals se... more DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals several lines of evidence that selection has operated to maintain and to diversify the existing level of polymorphism in the class II region. As has been noticed for other Native American groups, the overall level of polymorphism at the DRB1, DQA1, DQB1, and DPB1 loci is reduced relative to that found in other human populations. Nonetheless, the relative evenness in the distribution of allele frequencies at each of the four loci points to the role of balancing selection in the maintenance of the polymorphism. The DQA1 and DQB1 loci, in particular, have near-maximum departures from the neutrality model, which suggests that balancing selection has been especially strong in these cases. Several novel DQA1-DQB1 haplotypes and the discovery of a new DRB1 allele demonstrate an evolutionary tendency favoring the diversification of class II alleles and haplotypes. The recombination interval betwee...
American journal of human genetics, 1995
Disequilibrium between genetic markers is expected to decline monotonically with recombinational ... more Disequilibrium between genetic markers is expected to decline monotonically with recombinational map distance. We present evidence from the HLA class II region that seems to violate this principle. Pairwise disequilibrium values were calculated from six loci ranging in physical separation from 15 kb to 550 kb. The histocompatibility loci DRB1, DQA1, and DQB1, located on the distal end of the class II region, behave as a single evolutionary unit within which extremely high linkage disequilibrium exists. Lower but still significant levels of disequilibrium are present between these loci and DPB1, located at the proximal edge of the HLA complex. The peptide-transporter loci TAP1 and TAP2, located in the intervening region, reveal no disequilibrium with each other and low or negligible disequilibrium with the flanking loci. The action of two genetic process is required to account for this phenomenon: a recombinational hotspot operating between TAP1 and TAP2, to eliminate disequilibrium ...
American journal of human genetics, 1997
Studies of linkage disequilibrium across the HLA class II region have been useful in predicting w... more Studies of linkage disequilibrium across the HLA class II region have been useful in predicting where recombination is most likely to occur. The strong associations between genes within the 85-kb region from DQB1 to DRB1 are consistent with low frequency of recombination in this segment of DNA. Conversely, a lack of association between alleles of TAP1 and TAP2 (approximately 15 kb) has been observed, suggesting that recombination occurs here with relatively high frequency. Much of the HLA class II region has now been sequenced, providing the tools to undertake detailed analysis of recombination. Twenty-seven families containing one or two recombinant chromosomes within the 500-kb interval between the DPB1 and DRB1 genes were used to determine patterns of recombination across this region. SSCP analysis and microsatellite typing yielded identification of 127 novel polymorphic markers distributed throughout the class II region, allowing refinement of the site of crossover in 30 class I...
Journal of immunology (Baltimore, Md. : 1950), 1992
Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individu... more Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or eq...
Tissue Antigens, 2003
A collaborative study involving a large sample of European Americans was typed for the histocompa... more 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.
Tissue Antigens, 2000
The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding seq... more The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding sequences in the human genome. High-resolution DNA-based HLA typing of population samples of the polymorphic class I loci, HLA-A, -B, and -C has only recently become feasible. Here, we report molecular HLA typing on family-based samples of European origin (the CEPH repository), which demonstrated very high polymorphism, with 20 A alleles, 38 B alleles and 19 C alleles in the sample of 248 independent haplotypes. In general, allele frequency distributions are consistently more even (lower observed homozygosity statistic) than expected from a past of selective neutrality suggesting a history of balancing selection. This was also true for the class II loci, DRB1, DQA1 and DQB1 in these samples, but not for the DPA1 and DPB1 loci, whose allelic frequency distributions were more skewed (higher observed homozygosity statistic) than expected under a neutral model. Although linkage disequilibrium is a prominent feature across the HLA region, only 19% of the eight locus haplotypes were sampled more than once. The relative age of some of the B alleles could be inferred from the pattern of B-C haplotypic associations. We suggest that the observed patterns of linkage disequilibrium reflect the operation of selection on nearly all HLA alleles.
Tissue Antigens, 2007
In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing re... more In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing results for the human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1, DQA1, DQB1, and DPB1) loci in 264 individuals of the Han ethnic group from the Canton region of southern China are presented. The data are examined at the allele, genotype, and haplotype level. Common alleles at each of the loci are in keeping with those observed in similar populations, while the high-resolution typing methods used give additional details about allele frequency distributions not shown in previous studies. Twenty distinct alleles are seen at HLA-A in this population. The locus is dominated by the A*1101 allele, which is found here at a frequency of 0.266. The next three most common alleles, A*2402, A*3303, and A*0203, are each seen at frequencies of greater than 10%, and together, these four alleles account for roughly two-thirds of the total for HLA-A in this population. Fifty alleles are observed for HLA-B, 21 of which are singleton copies. The most common HLA-B alleles are B*4001 (f= 0.144), B*4601 (f= 0.119), B*5801 (f= 0.089), B*1301 (f= 0.068), B*1502 (f= 0.073), and B*3802 (f= 0.070). At the HLA-C locus, there are a total of 20 alleles. Four alleles (Cw*0702, Cw*0102, Cw*0801, and Cw*0304) are found at frequencies of greater than 10%, and together, these alleles comprise over 60% of the total. Overall, the class II loci are somewhat less diverse than class I. Twenty-eight distinct alleles are seen at DRB1, and the most common three, DRB1*0901, *1202, and *1501, are each seen at frequencies of greater than 10%. The DR4 lineage also shows extensive expansion in this population, with seven subtypes, representing one quarter of the diversity at this locus. Eight alleles are observed at DQA1; DQA1*0301 and 0102 are the most common alleles, with frequencies over 20%. The DQB1 locus is dominated by four alleles of the 03 lineage, which make up nearly half of the total. The two most common DQB1 alleles in this population are DQB1*0301 (f= 0.242) and DQB1*0303 (f= 0.15). Eighteen alleles are observed at DPB1; DPB1*0501 is the most common allele, with a frequency of 37%. The class I allele frequency distributions, expressed in terms of Watterson's (homozygosity) F-statistic, are all within expectations under neutrality, while there is evidence for balancing selection at DRB1, DQA1, and DQB1. Departures from Hardy-Weinberg expectations are observed for HLA-C and DRB1 in this population. Strong individual haplotypic associations are seen for all pairs of loci, and many of these occur at frequencies greater than 5%. In the class I region, several examples of HLA-B and -C loci in complete or near complete linkage disequilibrium (LD) are present, and the two most common, B*4601-Cw*0102 and B*5801-Cw*0302 account for more than 20% of the B-C haplotypes. Similarly, at class II, nearly all of the most common DR-DQ haplotypes are in nearly complete LD. The most common DRB1-DQB1 haplotypes are DRB1*0901-DQB1*0303 (f= 0.144) and DRB1*1202-DQB1*0301 (f= 0.131). The most common four locus class I and class II combined haplotypes are A*3303-B*5801-DRB1*0301-DPB1*0401 (f= 0.028) and A*0207-B*4601-DRB1*0901-DPB1*0501 (f= 0.026). The presentation of complete DNA typing for the class I loci and haplotype analysis in a large sample such as this can provide insights into the population history of the region and give useful data for HLA matching in transplantation and disease association studies in the Chinese population.
Tissue Antigens, 2001
HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain ... more HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) and/or DNA sequencing in 126 healthy individuals in Cameroon. Eighteen DRB1, 11 DQA1, and 18 DQB1 alleles were observed. The most common alleles at each locus were DRB1*1503 (29%), DRB1*1301 (13%); DQA1*0102 (38%), DQA1*0302 (11%), DQA1*0401 (11%); and DQB1*0602 (31%), DQB1*0301 (13%), DQB1*0501 (12%). Forty-four different haplotypes were identified including 12 novel haplotypes demonstrating the HLA class II diversity resulting from allele combinations in this population. A single predominant DRB1*1503-DQA1*0102-DQB1*0602 haplotype was observed with a frequency of 27%. In summary, this study of HLA class II polymorphism in Cameroon demonstrates the extent of diversity in this population.
Tissue Antigens, 1996
Molecular genetic techniques were used to type nine loci in the HLA class I1 region in 241 unrela... more Molecular genetic techniques were used to type nine loci in the HLA class I1 region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class I1 alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class I1 region. The African-American DRB I allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRBl allele frequencies (specifically DRB 1* 1501) and some haplotypes of DRB 1-DPB 1 were different in our NYC and the 1 1 th International Histocompatibility Workshop (IHW) samples of African-Arnericans. The high level of allele and haplotype diversity found in African-Arnericans has important implications for the construction of pools of unrelated J. J. Just1u2, M . 4 . King's3
Tissue Antigens, 1992
HLA class I1 region and susceptibility to Kawasaki disease.
PLoS Genetics, 2008
The large and diverse population of Latin America is potentially a powerful resource for elucidat... more The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region.
Histocompatibility Testing 1984, 1984
Genetics, 1990
Copyright 0 1990 by the Genetics Society of America ... Gene Conversion in the Evolution of Both ... more Copyright 0 1990 by the Genetics Society of America ... Gene Conversion in the Evolution of Both the H-2 and Qu Class I Genes of the Murine Major Histocompatibility Complex ... Mary Kuhner,* Suzanne Watts: William Klitz,* Glenys Thornson* and Robert S. Goodenow+
Genetics, 1987
Disequilibrium pattern analysis, a general method for analyzing evolutionary events acting on pai... more Disequilibrium pattern analysis, a general method for analyzing evolutionary events acting on pairs of tightly linked polymorphic loci, is applied to a large sample of Danish individuals typed for A and B loci of the HLA (human leukocyte antigen) system. Cases of selection on particular haplotypes are revealed from patterns of linkage disequilibrium among the HLA haplotypes. These patterns cannot be explained by either population admixture or random genetic drift. Six haplotypes out of the total array of 273 haplotypes have been identified which show in varying extents the patterns indicating selection.
Blood, 2000
Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is... more Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)-documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P =.012), and the class II HLA-DRB1 (P =.0008) and DQB1 (P =.029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of s...
Genetics, 1998
Positive selection on a new mutant allele can increase the frequencies of closely linked alleles ... more Positive selection on a new mutant allele can increase the frequencies of closely linked alleles (through hitchhiking), as well as create linkage disequilibrium between them. Because this disequilibrium is induced by the selected allele, one may be able to identify loci under selection by measuring the influence of a candidate locus on pairwise disequilibrium values at nearby loci. The constrained disequilibrium values (CDV) method approaches this problem by examining differences in pairwise disequilibrium values, which have been normalized for two- and three-locus systems, respectively. We have investigated in detail the reliability of inferences based on CDV, using simulation and analytical methods. Our main results are (i) in some circumstances, CDV may not distinguish well between a selected locus and a neighboring neutral locus, but (ii) CDV seldom indicates "selection" in neutral haplotypes with moderate to large 4Nc. We conclude that, although the CDV method does no...
American journal of human genetics, 1994
We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population... more We have analyzed the distribution of HLA class II alleles and haplotypes in a Filipino population by PCR amplification of the DRB1, DQB1, and DPB1 second-exon sequences from buccal swabs obtained from 124 family members and 53 unrelated individuals. The amplified DNA was typed by using nonradioactive sequence-specific oligonucleotide probes. Twenty-two different DRB1 alleles, including the novel Filipino *1105, and 46 different DRB1/DQB1 haplotypes, including the unusual DRB1*0405-DQB1*0503, were identified. An unusually high frequency (f = .383) of DPB1*0101, a rare allele in other Asian populations, was also observed. In addition, an unusual distribution of DRB1 alleles and haplotypes was seen in this population, with DR2 (f = .415) and DRB1*1502-DQB1*0502 (f = .233) present at high frequencies. This distribution of DRB1 alleles differs from the typical HLA population distribution, in which the allele frequencies are more evenly balanced. The distribution of HLA class II alleles a...
American journal of human genetics, 1995
DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals se... more DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals several lines of evidence that selection has operated to maintain and to diversify the existing level of polymorphism in the class II region. As has been noticed for other Native American groups, the overall level of polymorphism at the DRB1, DQA1, DQB1, and DPB1 loci is reduced relative to that found in other human populations. Nonetheless, the relative evenness in the distribution of allele frequencies at each of the four loci points to the role of balancing selection in the maintenance of the polymorphism. The DQA1 and DQB1 loci, in particular, have near-maximum departures from the neutrality model, which suggests that balancing selection has been especially strong in these cases. Several novel DQA1-DQB1 haplotypes and the discovery of a new DRB1 allele demonstrate an evolutionary tendency favoring the diversification of class II alleles and haplotypes. The recombination interval betwee...
American journal of human genetics, 1995
Disequilibrium between genetic markers is expected to decline monotonically with recombinational ... more Disequilibrium between genetic markers is expected to decline monotonically with recombinational map distance. We present evidence from the HLA class II region that seems to violate this principle. Pairwise disequilibrium values were calculated from six loci ranging in physical separation from 15 kb to 550 kb. The histocompatibility loci DRB1, DQA1, and DQB1, located on the distal end of the class II region, behave as a single evolutionary unit within which extremely high linkage disequilibrium exists. Lower but still significant levels of disequilibrium are present between these loci and DPB1, located at the proximal edge of the HLA complex. The peptide-transporter loci TAP1 and TAP2, located in the intervening region, reveal no disequilibrium with each other and low or negligible disequilibrium with the flanking loci. The action of two genetic process is required to account for this phenomenon: a recombinational hotspot operating between TAP1 and TAP2, to eliminate disequilibrium ...
American journal of human genetics, 1997
Studies of linkage disequilibrium across the HLA class II region have been useful in predicting w... more Studies of linkage disequilibrium across the HLA class II region have been useful in predicting where recombination is most likely to occur. The strong associations between genes within the 85-kb region from DQB1 to DRB1 are consistent with low frequency of recombination in this segment of DNA. Conversely, a lack of association between alleles of TAP1 and TAP2 (approximately 15 kb) has been observed, suggesting that recombination occurs here with relatively high frequency. Much of the HLA class II region has now been sequenced, providing the tools to undertake detailed analysis of recombination. Twenty-seven families containing one or two recombinant chromosomes within the 500-kb interval between the DPB1 and DRB1 genes were used to determine patterns of recombination across this region. SSCP analysis and microsatellite typing yielded identification of 127 novel polymorphic markers distributed throughout the class II region, allowing refinement of the site of crossover in 30 class I...
Journal of immunology (Baltimore, Md. : 1950), 1992
Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individu... more Thirty-nine CEPH (Centre d'Etude du Polymorphisme Humain) families, comprised of 502 individuals, have been typed for the HLA class II genes DRB1, DQA1, DQB1, and DPB1 using nonradioactive sequence-specific oligonucleotide probes to analyze polymerase chain reaction amplified DNA. This population, which consists of 266 independent chromosomes, contains 27 DRB1, 7 DQA1, 12 DQB1, and 17 DPB1 alleles. Analysis of the distribution of allele frequencies using the homozygosity statistic, which gives an indication of past selection pressures, suggests that balancing selection has acted on the DRB1, DQA1, and DQB1 loci. The distribution of DPB1 alleles, however, suggests a different evolutionary past. Family data permits the estimation of recombination rates and the unambiguous assignment of haplotypes. No recombinants were found between DRB1, DQA1, and DQB1; however, recombinants were detected between DQB1 and DPB1, resulting in an estimated recombination fraction of greater than or eq...
Tissue Antigens, 2003
A collaborative study involving a large sample of European Americans was typed for the histocompa... more 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.
Tissue Antigens, 2000
The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding seq... more The HLA region on the short arm of chromosome 6 (6p21.3) contains the most polymorphic coding sequences in the human genome. High-resolution DNA-based HLA typing of population samples of the polymorphic class I loci, HLA-A, -B, and -C has only recently become feasible. Here, we report molecular HLA typing on family-based samples of European origin (the CEPH repository), which demonstrated very high polymorphism, with 20 A alleles, 38 B alleles and 19 C alleles in the sample of 248 independent haplotypes. In general, allele frequency distributions are consistently more even (lower observed homozygosity statistic) than expected from a past of selective neutrality suggesting a history of balancing selection. This was also true for the class II loci, DRB1, DQA1 and DQB1 in these samples, but not for the DPA1 and DPB1 loci, whose allelic frequency distributions were more skewed (higher observed homozygosity statistic) than expected under a neutral model. Although linkage disequilibrium is a prominent feature across the HLA region, only 19% of the eight locus haplotypes were sampled more than once. The relative age of some of the B alleles could be inferred from the pattern of B-C haplotypic associations. We suggest that the observed patterns of linkage disequilibrium reflect the operation of selection on nearly all HLA alleles.
Tissue Antigens, 2007
In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing re... more In this study, polymerase chain reaction-sequence-specific oligonucleotide prode (SSOP) typing results for the human leukocyte antigen (HLA) class I (A, B, and C) and class II (DRB1, DQA1, DQB1, and DPB1) loci in 264 individuals of the Han ethnic group from the Canton region of southern China are presented. The data are examined at the allele, genotype, and haplotype level. Common alleles at each of the loci are in keeping with those observed in similar populations, while the high-resolution typing methods used give additional details about allele frequency distributions not shown in previous studies. Twenty distinct alleles are seen at HLA-A in this population. The locus is dominated by the A*1101 allele, which is found here at a frequency of 0.266. The next three most common alleles, A*2402, A*3303, and A*0203, are each seen at frequencies of greater than 10%, and together, these four alleles account for roughly two-thirds of the total for HLA-A in this population. Fifty alleles are observed for HLA-B, 21 of which are singleton copies. The most common HLA-B alleles are B*4001 (f= 0.144), B*4601 (f= 0.119), B*5801 (f= 0.089), B*1301 (f= 0.068), B*1502 (f= 0.073), and B*3802 (f= 0.070). At the HLA-C locus, there are a total of 20 alleles. Four alleles (Cw*0702, Cw*0102, Cw*0801, and Cw*0304) are found at frequencies of greater than 10%, and together, these alleles comprise over 60% of the total. Overall, the class II loci are somewhat less diverse than class I. Twenty-eight distinct alleles are seen at DRB1, and the most common three, DRB1*0901, *1202, and *1501, are each seen at frequencies of greater than 10%. The DR4 lineage also shows extensive expansion in this population, with seven subtypes, representing one quarter of the diversity at this locus. Eight alleles are observed at DQA1; DQA1*0301 and 0102 are the most common alleles, with frequencies over 20%. The DQB1 locus is dominated by four alleles of the 03 lineage, which make up nearly half of the total. The two most common DQB1 alleles in this population are DQB1*0301 (f= 0.242) and DQB1*0303 (f= 0.15). Eighteen alleles are observed at DPB1; DPB1*0501 is the most common allele, with a frequency of 37%. The class I allele frequency distributions, expressed in terms of Watterson's (homozygosity) F-statistic, are all within expectations under neutrality, while there is evidence for balancing selection at DRB1, DQA1, and DQB1. Departures from Hardy-Weinberg expectations are observed for HLA-C and DRB1 in this population. Strong individual haplotypic associations are seen for all pairs of loci, and many of these occur at frequencies greater than 5%. In the class I region, several examples of HLA-B and -C loci in complete or near complete linkage disequilibrium (LD) are present, and the two most common, B*4601-Cw*0102 and B*5801-Cw*0302 account for more than 20% of the B-C haplotypes. Similarly, at class II, nearly all of the most common DR-DQ haplotypes are in nearly complete LD. The most common DRB1-DQB1 haplotypes are DRB1*0901-DQB1*0303 (f= 0.144) and DRB1*1202-DQB1*0301 (f= 0.131). The most common four locus class I and class II combined haplotypes are A*3303-B*5801-DRB1*0301-DPB1*0401 (f= 0.028) and A*0207-B*4601-DRB1*0901-DPB1*0501 (f= 0.026). The presentation of complete DNA typing for the class I loci and haplotype analysis in a large sample such as this can provide insights into the population history of the region and give useful data for HLA matching in transplantation and disease association studies in the Chinese population.
Tissue Antigens, 2001
HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain ... more HLA-DRB1, -DQA1 and -DQB1 allele frequencies were determined by high-resolution polymerase chain reaction using sequence-specific oligonucleotide probes (PCR-SSOP) and/or DNA sequencing in 126 healthy individuals in Cameroon. Eighteen DRB1, 11 DQA1, and 18 DQB1 alleles were observed. The most common alleles at each locus were DRB1*1503 (29%), DRB1*1301 (13%); DQA1*0102 (38%), DQA1*0302 (11%), DQA1*0401 (11%); and DQB1*0602 (31%), DQB1*0301 (13%), DQB1*0501 (12%). Forty-four different haplotypes were identified including 12 novel haplotypes demonstrating the HLA class II diversity resulting from allele combinations in this population. A single predominant DRB1*1503-DQA1*0102-DQB1*0602 haplotype was observed with a frequency of 27%. In summary, this study of HLA class II polymorphism in Cameroon demonstrates the extent of diversity in this population.
Tissue Antigens, 1996
Molecular genetic techniques were used to type nine loci in the HLA class I1 region in 241 unrela... more Molecular genetic techniques were used to type nine loci in the HLA class I1 region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class I1 alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class I1 region. The African-American DRB I allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRBl allele frequencies (specifically DRB 1* 1501) and some haplotypes of DRB 1-DPB 1 were different in our NYC and the 1 1 th International Histocompatibility Workshop (IHW) samples of African-Arnericans. The high level of allele and haplotype diversity found in African-Arnericans has important implications for the construction of pools of unrelated J. J. Just1u2, M . 4 . King's3
Tissue Antigens, 1992
HLA class I1 region and susceptibility to Kawasaki disease.