Glenys Thomson - Academia.edu (original) (raw)
Papers by Glenys Thomson
The linkage disequilibrium patterns observed between tightly linked loci, such as the HLA loci, c... more The linkage disequilibrium patterns observed between tightly linked loci, such as the HLA loci, can indicate the nature of evolutionary events, particularly selection events, acting on the region. We have developed a method, disequilibrium pattern analysis, for examining the disequilibrium distribution of a population of two-locus haplotypes. Specific quantifiable patterns are predicted as a result of selective events.
PubMed, Sep 1, 1986
Genes comprising the major histocompatibility complex (MHC) play a central role in governing the ... more Genes comprising the major histocompatibility complex (MHC) play a central role in governing the immune response of vertebrates. A great deal of information has been revealed on the molecular biology and physiology of these loci, but three features-the high polymorphism, tight linkage among the loci, and the nonrandom association of alleles-make the system of particular interest from the perspective of population genetics. Information on the dynamic evolutionary forces that have acted on a locus can be inferred from the number and distribution of alleles that it carries. Ten loci from the HLA region of the human MHC, each sampled from several different populations, have been examined for departures from the expected value of homozygosity under the condition of selective neutrality. The homozygosities of five class I and II loci that code for membrane glycoproteins, HLA-A, -B, -C, -DR, and -DQ, and of glyoxylase I (GLO) were significantly less than the neutrality expectations. This suggests the presence of some form of balancing selection. In spite of being closely linked, in fact, located between the class I and class II histocompatibility loci, the homozygosities of the four class III or complement loci C2, Bf, C4A, and C4B, which are detected by electrophoresis, were indistinguishable from, or exceeded, that expected under neutrality. Although this conforms to the suggestion that, in general, electrophoretic variants are neutral, because of the tight linkage to loci demonstrating a history of selection, it is possible that the mechanism for generating variation in the class III loci may be different from that of the class I and class II loci.
Progress in clinical and biological research, 1989
Human Immunology, Apr 1, 1996
Springer eBooks, 1991
The record of non-random association of alleles between tightly linked loci in a population conta... more The record of non-random association of alleles between tightly linked loci in a population contains a wealth of information on the recent evolutionary past. Methods for the analysis of disequilibrium are presented and exemplified with application to HLA data.
Springer eBooks, 1984
The HLA region is a model system for the study of multilocus interactions. There are several well... more The HLA region is a model system for the study of multilocus interactions. There are several well-defined, tightly linked, highly polymorphic loci. The physiology of the gene products is relatively well understood, information is available on the history of past generations, including disease and migration patterns, and comparative studies (e.g., H-2 in mice) supply useful background data. With the Ninth Workshop we have the additional asset of pedigree data which permits the accurate scoring of haplotypes and the testing of selection components. Three separate approaches have been taken in the analysis of the population data from the Ninth Workshop: the level of homozygosity at each locus, an overall population measure of two-locus disequilibrium, and haplotype pattern analysis, which evaluates disequilibrium patterns to determine which haplotypes have been subject to selection.
Genetics, Nov 1, 1991
The HLA system has been extensively studied from an evolutionary perspective. Although it is clea... more The HLA system has been extensively studied from an evolutionary perspective. Although it is clear that selection has acted on the genes in the HLA complex, the nature of this selection has yet to be fully clarified. A study of constrained disequilibrium values is presented that is applicable to HLA and other less polymorphic systems with three or more linked loci, with the purpose of identifying selection events. The method uses the fact that three locus systems impose additional constraints on the range of possible disequilibrium values for any pair of loci. We have thus examined the behavior of the normalized pairwise disequilibrium measures using two locus (D'), and also three locus (D"), constraints on pairwise disequilibria in a three locus system when one of the three loci is under positive selection. The difference between these measures, 6 = ID' I-ID" I, has a distribution for the two unselected loci differing from that for the selected locus with either of the unselected loci (the hallmark is a high positive value of 6 for the two unselected loci). An examination of genetic drift indicates that positive 6 values are unlikely to be found in human populations in the absence of selection when recombination is greater than about 0.1%. This measure can thus provide insight into which allele of several linked loci might have been subject to selection. Application of this method to HLA haplotypes from a large French population study (Provinces Francaise) identifies selected alleles on particular haplotypes. Application of a complementary method, disequilibrium pattern analysis also confirms the action of selection on these haplotypes. ' To whom reprint requests should be sent.
Human Immunology, Apr 1, 1996
Human Immunology, Apr 1, 1996
Genetic Epidemiology, 1989
A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing ... more A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5′ insulin locus (INS) in insulin‐dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.
Biological Journal of The Linnean Society, Aug 1, 1987
... test does not examine deviations from Hardy-Weinberg proportions but examines the allelic fre... more ... test does not examine deviations from Hardy-Weinberg proportions but examines the allelic frequency array expected under neutrality.) Using this ... including maternal-foetal effects (eg, Clarke & Kirby, 1966; Warburton, 1968), segregation distortion (Alper, Awdeh, Raun & Yunis ...
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.
Genetic Epidemiology, 1986
We have used the large, ethnically homogeneous French and German IDDM family files from the Genet... more We have used the large, ethnically homogeneous French and German IDDM family files from the Genetic Analysis Workshop IV to clarify the contribution of the HLA region to IDDM pathogenesis. Our analysis has considered the relative predispositional effects of the DR ...
Human Immunology, Feb 1, 1987
Segregation distortion, the non-Mendelian segregation of gametes, has been well documented among ... more Segregation distortion, the non-Mendelian segregation of gametes, has been well documented among diverse groups of organisms. These cases are characterized by extreme segregation ratios found only in males. Previous reports have suggested the existence of segregation distortion operating in the HLA system of humans, a tightly linked complex of genes which regulates the immune system. In mice, some alleles of the T/t complex, which is linked to H-2 (the HLA homologue of mice), cause extreme segregation distortion in wild mice populations. Here we report on the examination of a large body of pedigree data on non-diseased families, scored for the alleles of five HLA region loci. We searched for segregation distortion on the basis of five different models of inheritance: allelic, haplotypic, genotypic, diffuse occurrence in families, and autosomal effects on the sex ratio. There was no clear evidence for segregation distortion. In particular, the possibility of extreme levels of segregation distortion was firmly rejected in the populations examined, thus reducing the likelihood of common distortion-causing HLA associated haplotypes in our species.
Tissue Antigens, May 1, 1997
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
Genetics, May 1, 1999
Analysis of the highly polymorphic 1 domains of the HLA class II molecules encoded by the DRB1, ... more Analysis of the highly polymorphic 1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P Ͻ 10 Ϫ4), DRB1 shows some evidence of balancing selection (P Ͻ 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P Ͻ 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigenbinding pocket-and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket-and non-pocketforming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.
Philosophical Transactions of the Royal Society B, Mar 19, 2012
Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers ... more Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.
Human Immunology, Apr 1, 1996
Genetic Epidemiology, 1986
The linkage disequilibrium patterns observed between tightly linked loci, such as the HLA loci, c... more The linkage disequilibrium patterns observed between tightly linked loci, such as the HLA loci, can indicate the nature of evolutionary events, particularly selection events, acting on the region. We have developed a method, disequilibrium pattern analysis, for examining the disequilibrium distribution of a population of two-locus haplotypes. Specific quantifiable patterns are predicted as a result of selective events.
PubMed, Sep 1, 1986
Genes comprising the major histocompatibility complex (MHC) play a central role in governing the ... more Genes comprising the major histocompatibility complex (MHC) play a central role in governing the immune response of vertebrates. A great deal of information has been revealed on the molecular biology and physiology of these loci, but three features-the high polymorphism, tight linkage among the loci, and the nonrandom association of alleles-make the system of particular interest from the perspective of population genetics. Information on the dynamic evolutionary forces that have acted on a locus can be inferred from the number and distribution of alleles that it carries. Ten loci from the HLA region of the human MHC, each sampled from several different populations, have been examined for departures from the expected value of homozygosity under the condition of selective neutrality. The homozygosities of five class I and II loci that code for membrane glycoproteins, HLA-A, -B, -C, -DR, and -DQ, and of glyoxylase I (GLO) were significantly less than the neutrality expectations. This suggests the presence of some form of balancing selection. In spite of being closely linked, in fact, located between the class I and class II histocompatibility loci, the homozygosities of the four class III or complement loci C2, Bf, C4A, and C4B, which are detected by electrophoresis, were indistinguishable from, or exceeded, that expected under neutrality. Although this conforms to the suggestion that, in general, electrophoretic variants are neutral, because of the tight linkage to loci demonstrating a history of selection, it is possible that the mechanism for generating variation in the class III loci may be different from that of the class I and class II loci.
Progress in clinical and biological research, 1989
Human Immunology, Apr 1, 1996
Springer eBooks, 1991
The record of non-random association of alleles between tightly linked loci in a population conta... more The record of non-random association of alleles between tightly linked loci in a population contains a wealth of information on the recent evolutionary past. Methods for the analysis of disequilibrium are presented and exemplified with application to HLA data.
Springer eBooks, 1984
The HLA region is a model system for the study of multilocus interactions. There are several well... more The HLA region is a model system for the study of multilocus interactions. There are several well-defined, tightly linked, highly polymorphic loci. The physiology of the gene products is relatively well understood, information is available on the history of past generations, including disease and migration patterns, and comparative studies (e.g., H-2 in mice) supply useful background data. With the Ninth Workshop we have the additional asset of pedigree data which permits the accurate scoring of haplotypes and the testing of selection components. Three separate approaches have been taken in the analysis of the population data from the Ninth Workshop: the level of homozygosity at each locus, an overall population measure of two-locus disequilibrium, and haplotype pattern analysis, which evaluates disequilibrium patterns to determine which haplotypes have been subject to selection.
Genetics, Nov 1, 1991
The HLA system has been extensively studied from an evolutionary perspective. Although it is clea... more The HLA system has been extensively studied from an evolutionary perspective. Although it is clear that selection has acted on the genes in the HLA complex, the nature of this selection has yet to be fully clarified. A study of constrained disequilibrium values is presented that is applicable to HLA and other less polymorphic systems with three or more linked loci, with the purpose of identifying selection events. The method uses the fact that three locus systems impose additional constraints on the range of possible disequilibrium values for any pair of loci. We have thus examined the behavior of the normalized pairwise disequilibrium measures using two locus (D'), and also three locus (D"), constraints on pairwise disequilibria in a three locus system when one of the three loci is under positive selection. The difference between these measures, 6 = ID' I-ID" I, has a distribution for the two unselected loci differing from that for the selected locus with either of the unselected loci (the hallmark is a high positive value of 6 for the two unselected loci). An examination of genetic drift indicates that positive 6 values are unlikely to be found in human populations in the absence of selection when recombination is greater than about 0.1%. This measure can thus provide insight into which allele of several linked loci might have been subject to selection. Application of this method to HLA haplotypes from a large French population study (Provinces Francaise) identifies selected alleles on particular haplotypes. Application of a complementary method, disequilibrium pattern analysis also confirms the action of selection on these haplotypes. ' To whom reprint requests should be sent.
Human Immunology, Apr 1, 1996
Human Immunology, Apr 1, 1996
Genetic Epidemiology, 1989
A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing ... more A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5′ insulin locus (INS) in insulin‐dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.
Biological Journal of The Linnean Society, Aug 1, 1987
... test does not examine deviations from Hardy-Weinberg proportions but examines the allelic fre... more ... test does not examine deviations from Hardy-Weinberg proportions but examines the allelic frequency array expected under neutrality.) Using this ... including maternal-foetal effects (eg, Clarke & Kirby, 1966; Warburton, 1968), segregation distortion (Alper, Awdeh, Raun & Yunis ...
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.
Genetic Epidemiology, 1986
We have used the large, ethnically homogeneous French and German IDDM family files from the Genet... more We have used the large, ethnically homogeneous French and German IDDM family files from the Genetic Analysis Workshop IV to clarify the contribution of the HLA region to IDDM pathogenesis. Our analysis has considered the relative predispositional effects of the DR ...
Human Immunology, Feb 1, 1987
Segregation distortion, the non-Mendelian segregation of gametes, has been well documented among ... more Segregation distortion, the non-Mendelian segregation of gametes, has been well documented among diverse groups of organisms. These cases are characterized by extreme segregation ratios found only in males. Previous reports have suggested the existence of segregation distortion operating in the HLA system of humans, a tightly linked complex of genes which regulates the immune system. In mice, some alleles of the T/t complex, which is linked to H-2 (the HLA homologue of mice), cause extreme segregation distortion in wild mice populations. Here we report on the examination of a large body of pedigree data on non-diseased families, scored for the alleles of five HLA region loci. We searched for segregation distortion on the basis of five different models of inheritance: allelic, haplotypic, genotypic, diffuse occurrence in families, and autosomal effects on the sex ratio. There was no clear evidence for segregation distortion. In particular, the possibility of extreme levels of segregation distortion was firmly rejected in the populations examined, thus reducing the likelihood of common distortion-causing HLA associated haplotypes in our species.
Tissue Antigens, May 1, 1997
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
Genetics, May 1, 1999
Analysis of the highly polymorphic 1 domains of the HLA class II molecules encoded by the DRB1, ... more Analysis of the highly polymorphic 1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P Ͻ 10 Ϫ4), DRB1 shows some evidence of balancing selection (P Ͻ 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P Ͻ 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigenbinding pocket-and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket-and non-pocketforming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.
Philosophical Transactions of the Royal Society B, Mar 19, 2012
Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers ... more Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans.
Human Immunology, Apr 1, 1996
Genetic Epidemiology, 1986