Gene clusters and the evolution of the major histocompatibility system

Bodmer, Walter F.; Trowsdale, John; Young, John A. T.; Bodmer, Julia G.

doi:10.1098/rstb.1986.0009

Cited by 25 publications

(5 citation statements)

References 14 publications

(10 reference statements)

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“…Haplotypes are combinations of alleles at different loci of phased DNA segregating together in multigenerational families (Bodmer et al, 1986;Lloyd et al, 2016;Alper and Larsen, 2017) essentially as DNA sequences that are identical by descent (IBD) via recent shared ancestry (Druet and Farnir, 2011;Browning and Browning, 2012;Thompson, 2013;Zhou et al, 2020b). The word haplotype (single, from haploid) was first introduced by Ruggero Ceppellini in 1966/67 to describe immunoglobin allotypes as corresponding "to the product of a single gene dose" and was appropriated almost immediately by immunogeneticists to describe the linked alleles in the highly polymorphic, multilocus human major histocompatibility complex (MHC) super locus on chromosome 6 (Bodmer, 2019) that consists of three distinct genomic regions, classes I, II and III with clusters of human leukocyte antigen (HLA) genes involved in the regulation of the innate and adaptive immune system, autoimmunity, and transplantation (Shiina et al, 2004(Shiina et al, , 2009Vandiedonck and Knight, 2009;Trowsdale, 2011).…”

Section: Introductionmentioning

confidence: 99%

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

2021

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The major histocompatibility complex (MHC) on chromosome 6p21 is one of the most single-nucleotide polymorphism (SNP)-dense regions of the human genome and a prime model for the study and understanding of conserved sequence polymorphisms and structural diversity of ancestral haplotypes/conserved extended haplotypes. This study aimed to follow up on a previous analysis of the MHC class I region by using the same set of 95 MHC haplotype sequences downloaded from a publicly available BioProject database at the National Center for Biotechnology Information to identify and characterize the polymorphic human leukocyte antigen (HLA)-class II genes, the MTCO3P1 pseudogene alleles, the indels of transposable elements as haplotypic lineage markers, and SNP-density crossover (XO) loci at haplotype junctions in DNA sequence alignments of different haplotypes across the extended class II region (∼1 Mb) from the telomeric PRRT1 gene in class III to the COL11A2 gene at the centromeric end of class II. We identified 42 haplotypic indels (20 Alu, 7 SVA, 13 LTR or MERs, and 2 indels composed of a mosaic of different transposable elements) linked to particular HLA-class II alleles. Comparative sequence analyses of 136 haplotype pairs revealed 98 unique XO sites between SNP-poor and SNP-rich genomic segments with considerable haplotype shuffling located in the proximity of putative recombination hotspots. The majority of XO sites occurred across various regions including in the vicinity of MTCO3P1 between HLA-DQB1 and HLA-DQB3, between HLA-DQB2 and HLA-DOB, between DOB and TAP2, and between HLA-DOA and HLA-DPA1, where most XOs were within a HERVK22 sequence. We also determined the genomic positions of the PRDM9-recombination suppression sequence motif ATCCATG/CATGGAT and the PRDM9 recombination activation partial binding motif CCTCCCCT/AGGGGAG in the class II region of the human reference genome (NC_ 000006) relative to published meiotic recombination positions. Both the recombination and anti-recombination PRDM9 binding motifs were widely distributed throughout the class II genomic regions with 50% or more found within repeat elements; the anti-recombination motifs were found mostly in L1 fragmented repeats. This study shows substantial haplotype shuffling between different polymorphic blocks and confirms the presence of numerous putative ancestral recombination sites across the class II region between various HLA class II genes.

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Section: Introductionmentioning

confidence: 99%

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

2021

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“…It remains uncertain whether the A#2 gene is expressed (16). The human class II MHC can be divided into the following five regions from the centromeric side of the chromosome: DP, DN (formerly DZ), DO, DQ, and DR (44,45). In the latest nomenclature, a-chain and (3-chain genes are designated as A and B respectively ( Table 1).…”

Section: Methodsmentioning

confidence: 99%

Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

Hughes

Nei

1989

Proc. Natl. Acad. Sci. U.S.A.

804

396

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To study the mechanism of maintenance of polymorphism at major histocompatibility complex (MHC) loci, synonymous and nonsynonymous (amino, acid-altering) nucleotide substitutions in the putative antigen-recognition site (included in the first domain of the MHC molecule) and other regions of human and mouse class II genes were examined. In the putative antigen-recognition site, the rate of nonsynonymous substitution was found to exceed that of synonymous substitution, whereas in the second domain the former was significantly lower than the latter. In light of a previous theoretical study and parallel findings in class I MHC loci, we conclude that the unusually high degree of polymorphism at class II MHC loci is caused mainly by overdominant selection (heterozygote advantage) operating in the antigen-recognition site.The major histocompatibility complex (MHC) includes several genetic loci that are highly polymorphic in humans, mice, and other vertebrates (1). Four hypotheses have been proposed to account for this polymorphism: (i) an unusually high mutation rate (2), (ii) gene conversion or interlocus genetic exchange (3, 4), (iii) overdominant selection (5, 6), and (iv) frequency-dependent selection (7,8). To decide which of these hypotheses is correct, we previously studied rates of synonymous and nonsynonymous nucleotide substitution between alleles from human and mouse class I MHC loci and found that the nonsynonymous rate is higher than the synonymous rate in the 57 codons encoding the antigenrecognition site but is lower than the latter in other regions of the gene (9). Since overdominant selection is known to increase the rate of codon substitution as well as the extent of polymorphism (10), we concluded that class I polymorphism is caused mainly by overdominant selection that operates in the antigen-recognition site. Here we extend our analysis to class II MHC genes.Both class I and class II genes encode glycoproteins that are expressed on cell surfaces and that function to provide a context for recognition of intracellularly processed foreign peptides (antigens) by specific immune-system cells (1). Class I antigens are expressed on all nucleated cells, whereas class II antigens are expressed on antigen-presenting cells of the immune system, which present foreign antigens to helper T cells (1, 11). In the case of class I molecules, the amino acid residues involved in binding the foreign peptide and in T-cell recognition have been identified (12), making it possible to study the pattern of nucleotide substitution in the DNA region encoding the antigen-recognition site (ARS). In the case of class II molecules, the ARS has yet to be identified, but antigen recognition by helper T cells is known to be localized in the first domains of both a and (3 chains of the molecule, as opposed to the second domains (13,14).Furthermore, by analogy with the class I molecule, a putative ARS in domain 1 has been reported (15). In this paper we compare the rates of synonymous and nonsynonymous nucleotide substit...

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“…Ironically, the discovery of extensive protein polymorphisms in nature (Lewontin, 1974;Powell, 1975;Selander, 1976;Nevo, 1978;Nevo, Beiles & Ben-Shlomo, 1984a) reinforced the debate between the selectionist (Ayala, 1977;Milkman, 1978;Clarke, 1979;Wills, 1981) and neutralist (King & Jukes, 1969;Kimura, 1968Kimura, , 1969Kimura, , 1983Kimura & Ohta, 1971;Nei, 1975;Ohta, 1976;Nei & Graur, 1984) schools of opposing thought. Diverse attempts have been undertaken to resolve the problem statistically (Nei, 1975;Watterson, 1977Watterson, , 1978Gillespie, 1978Gillespie, , 1982Ewens, 1979;Nei & Graur, 1984;Manly, 1985), ecologically (Bryant, 1974;Christiansen & Frydenberg, 1974;McNaughton, 1974;Schaffer & Johnson, 1974;Hedrick, Ginevan & Ewing, 1976;Nevo, 1978Nevo, , 1983aNevo, et al, 1984a;Hedrick, 1986) biochemically, and physiologically (reviewed in Nevo, 198310: 260, and Hilbish & Koehn, 1985;Bodmer, Trowsdale, Young & Bodmer, 1986) as well as by direct controlled laboratory testing of the differential viability of allozyme genotypes (Nevo, Lavie & Ben-Shlomo, 1983;Nevo, Ben-Shlomo & Lavie, 1984b;Nevo, 1986a)…”

Section: Introductionmentioning

confidence: 99%

Genetic parallelism of protein polymorphism in nature: ecological test of the neutral theory of molecular evolution

Nevo

Beiles

1988

Biological Journal of the Linnean Society

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We have conducted an ecological test of protein polymorphism in 13 unrelated genera of plants, invertebrates and vertebrates, involving 21 species, 142 populations and 5474 individuals. Each was tested, on average, for 27 enzymatic gene loci. These species varied in population size and structure, life histories and biogeographical origins, but they largely share a geographically short (260 km) and ecologically stressful gradient of increasing aridity in Israel, both eastward and (mainly) southward. We found genetic parallelism across most taxa, and most loci. Observed average heterozygosity, H, and gene diversity, He, were positively and overall significantly correlated with rainfall variation. This result corroborates the environmental theory of genetic diversity, primarily the niche-width variation hypothesis in both space and time. Our results are inconsistent with the neutral theory of molecular evolution and suggest that natural selection appears to be an important differentiating evolutionary force at the protein level.

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Gene clusters and the evolution of the major histocompatibility system

Cited by 25 publications

References 14 publications

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection.

Genetic parallelism of protein polymorphism in nature: ecological test of the neutral theory of molecular evolution

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