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Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees.

ABSTRACT: MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A, -B, and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. Therefore the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on the present results and the fact that chimpanzees have a natural resistance to the development of AIDS, we hypothesize that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus (SIVcpz), the closest relative of HIV-1, or a closely related retrovirus. Hence, the contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of a HIV-like pandemic that took place in the distant past.

SUBMITTER: de Groot NG

PROVIDER: S-EPMC129340 | biostudies-literature | 2002 Sep

REPOSITORIES: biostudies-literature

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Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees.

de Groot Natasja G NG Otting Nel N Doxiadis Gaby G M GG Balla-Jhagjhoorsingh Sunita S SS Heeney Jonathan L JL van Rood Jon J JJ Gagneux Pascal P Bontrop Ronald E RE

Proceedings of the National Academy of Sciences of the United States of America 20020819 18

MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, the present comparison of MHC class I gene intron variation revealed that chimpanzees have experienced a severe repertoire reduction at the orthologues of the HLA-A, -B, and -C loci. The loss of variability predates the (sub)speciation of chimpanzees and did not effect other known gene systems. There ...[more]

PMID: 12186979

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Project description:BACKGROUND:Lymphotoxin-? (LT?), located in the Major Histocompatibility Complex (MHC) class III region on chromosome 6, encodes a cytotoxic protein that mediates a variety of antiviral responses among other biological functions. Furthermore, several genotypes at this gene have been implicated in the onset of a number of complex diseases, including myocardial infarction, autoimmunity, and various types of cancer. However, little is known about levels of nucleotide variation and linkage disequilibrium (LD) in and near LT?, which could also influence phenotypic variance. To address this gap in knowledge, we examined sequence variation across ~?10 kilobases (kbs), encompassing LT? and the upstream region, in 2039 individuals from the 1000 Genomes Project originating from 21 global populations. RESULTS:Here, we observed striking patterns of diversity, including an excess of intermediate-frequency alleles, the maintenance of multiple common haplotypes and a deep coalescence time for variation (dating >?1.0 million years ago), in global populations. While these results are generally consistent with a model of balancing selection, we also uncovered a signature of positive selection in the form of long-range LD on chromosomes with derived alleles primarily in Eurasian populations. To reconcile these findings, which appear to support different models of selection, we argue that selective sweeps (particularly, soft sweeps) of multiple derived alleles in and/or near LT? occurred in non-Africans after their ancestors left Africa. Furthermore, these targets of selection were predicted to alter transcription factor binding site affinity and protein stability, suggesting they play a role in gene function. Additionally, our data also showed that a subset of these functional adaptive variants are present in archaic hominin genomes. CONCLUSIONS:Overall, this study identified candidate functional alleles in a biologically-relevant genomic region, and offers new insights into the evolutionary origins of these loci in modern human populations.

Dataset Information

Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees.

Publications

Evidence for an ancient selective sweep in the MHC class I gene repertoire of chimpanzees.

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