Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in humans via hitchhiking diversity

Abstract

A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC class I region (coding units or full contigs) in several human and nonhuman primate haplotypes allowed an analysis of single nucleotide variations (SNV) across this entire segment. This diversity was not evenly distributed. It was rather concentrated within two gene-rich clusters. These were each centered, but importantly not limited to, the antigen-presenting HLA-A and HLA-B/-C loci. Rapid evolution of MHC-I alleles, as evidenced by an unusually high number of haplotype-specific (hs) and hypervariable (hv) (which could not be traced to a single species or haplotype) SNVs within the classical MHC-I, seems to have not only hitchhiked alleles within nearby genes, but also hitchhiked deleterious mutations in these same unrelated loci. The overrepresentation of a fraction of these hvSNV (hv1SNV) along with hsSNV, as compared to those that appear to have been maintained throughout primate evolution (trans-species diversity; tsSNV; included within hv2SNV) tends to establish that the majority of the MHC polymorphism is de novo (species specific). This is most likely reminiscent of the fact that these hsSNV and hv1SNV have been selected in adaptation to the constantly evolving microbial antigenic repertoire.

Figure 1.—

An operational map of long-range PCR regions spanning from the HLA-F to LTB. Solid and open boxes indicate expressed genes and potential coding regions or pseudogenes, respectively. Striped lines around the HLA-A gene indicate the deleted segment of LKT3 and AKIBA haplotypes.

Figure 2.—

Genomic diversity plot of the human and chimpanzee MHC class I region. Diversity plot drawn upon comparison of six human haplotypes (red) and four chimpanzee haplotypes (blue). Arrows below the plot depict the location of identified disease susceptibility genes. Arrows above the plot indicate “hitchhiked” regions for each species.

Figure 3.—

Definition of SNV categories in a sample sequence. a, b, c, d, e, hv1, and hv2 indicate SNV generated after birth of human haplotypes; SNV generated in humans after speciation of humans and chimpanzees but before birth of human haplotypes; SNV generated in chimpanzees after speciation of humans and chimpanzees; SNV generated before speciation of human- and chimpanzee- or macaque-specific SNV and hypervariable SNV, respectively. A total of seven SNV are shown (position nos. 2, 5, 8, 11, 14, 17, and 20). There is one “a” stage SNV (position no. 2) (LKT3 = 0 AKIBA = 0 JPKO = 0 COX = 1 PGF = 0 QBL = 0); hence (0 + 0 + 0 + 1 + 0 + 0)/6 sequence = 0.17 average SNV; 0.17 SNV/21 bp × 100 = 0.81 SNV% (the DI). For “b,” there is one location (position no. 5): 1 SNV/21 bp × 100 = 4.76% SNV (DI). For the “c” stage, there is one location (position no. 8) (Ericka = C/A Borie = C/C); hence (0 + 1 + 0 + 0)/4 sequence = 0.25 average SNV; 0.25 SNV/21 bp × 100 = 1.19 SNV% (DI) in stage c. For the “d” stage, there is also one location (position no. 11): 1 SNV/21 bp × 100 = 4.76% SNV (DI). For the “e” stage, there is also one variation (position no. 14) 1 SNV/21 bp × 100 = 4.76% SNV (DI). Finally, for hvSNV there are two locations (position nos. 17 and 20): 2 SNV/21 bp × 100 = 9.52% SNV (DI) at this level. To be comprehensive, the large-scale analysis of hvSNV depicted in Figure 6 was accomplished while dividing the observed hvSNV into two categories: hv1 and hv2. hv1 refers to situations similar to those seen in position 17 of this figure, where there is a patent case for de novo generation of the diversity in Homo, whereas for hv2 (equivalent to position 20 in this hypothetical sequence) the question (i.e., the molecular genealogy of the diversity) can be definitely settled only once the syntenic segment in the most recent common ancestor of humans and chimpanzees has been sequenced.

Figure 4.—

Comparative genomic map of HLA, Patr, and Mamu class I regions. Lines show orthologous relationship. Mamu-B region from 300 to 1200 kb and Mamu-A, -G, -F region from 2400 to 3285 kb were shown only with respect to Mamu class I loci. Arrows show segments used for calculating genomic diversity analysis shown in Figure 5.

Figure 5.—

SNV vs. indels in the MHC class I region. The aligned sequence (excluding indels) is shown along the horizontal axis and the percentage of nucleotide differences calculated per 1 kb of nonoverlapping windows is shown along the vertical axis. (A) Human vs. human (1.24 Mb). (B) Human vs. chimpanzee (1.26 Mb). (C) Human vs. macaque (1.38 Mb). Deep red, deep blue, and green lines show nucleotide substitution (%) whereas light red, light blue, and sky blue refer to indel percentages.

Figure 6.—

Classification of SNV by species and gene category unveils the origin of MHC diversity. Red designates SNVs generated after birth of four human haplotypes; purple those generated after speciation of chimpanzees and humans but prior to divergence of the six human haplotypes; dark blue designates SNVs generated after birth of four chimpanzee haplotypes; light blue highlights the chimpanzee “counterparts” generated after human–chimpanzee speciation; and yellow and orange refer to hvSNV. (A) Total SNV content. (B) MHC (classical and nonclassical) vs. nonMHC SNVs. For definition of hv1 and hv2 SNV, see legend of Figure 3.