Comparative sequencing of human and chimpanzee MHC class I regions unveils insertions/deletions as the major path to genomic divergence

Abstract

Despite their high degree of genomic similarity, reminiscent of their relatively recent separation from each other ( approximately 6 million years ago), the molecular basis of traits unique to humans vs. their closest relative, the chimpanzee, is largely unknown. This report describes a large-scale single-contig comparison between human and chimpanzee genomes via the sequence analysis of almost one-half of the immunologically critical MHC. This 1,750,601-bp stretch of DNA, which encompasses the entire class I along with the telomeric part of the MHC class III regions, corresponds to an orthologous 1,870,955 bp of the human HLA region. Sequence analysis confirms the existence of a high degree of sequence similarity between the two species. However, and importantly, this 98.6% sequence identity drops to only 86.7% taking into account the multiple insertions/deletions (indels) dispersed throughout the region. This is functionally exemplified by a large deletion of 95 kb between the virtual locations of human MICA and MICB genes, which results in a single hybrid chimpanzee MIC gene, in a segment of the MHC genetically linked to species-specific handling of several viral infections (HIV/SIV, hepatitis B and C) as well as susceptibility to various autoimmune diseases. Finally, if generalized, these data suggest that evolution may have used the mechanistically more drastic indels instead of the more subtle single-nucleotide substitutions for shaping the recently emerged primate species.

Fig. 1.

Comparative genomics of human and chimpanzee MHC class I region. The relative location of the 41 genes (orange box, MHC gene; red box, non-MHC gene) and 59 pseudogenes (purple box, MHC gene; gray box, non-MHC gene) for human (Bottom) and chimpanzee (Top) sequences are shown, left to right, in the direction from the centromere to the telomere, respectively. A total of 64 indels of >100 bp observed between the two sequences (chimpanzee serving as reference) are indicated by blue (deletions) and red (insertions) triangles or lines. One duplicated and one inverted region were indicated as a yellow triangle (duplication in chimpanzee) and a green box (inversion), respectively.

Fig. 2.

Structural analysis of MIC genes. (A) Evolutionary time line for duplication of the ancestral MICA and MICB genes, insertion of AluY and AluS elements, and separation of the human and chimpanzee lineages. The time line (millions of years ago) is shown along the vertical axis. (B) Comparative genomic map of the exon, intron, and retroelement (Alu, L1, LTR, and MIR) organization of human MICA, MICB, and Patr-MIC genes.

Fig. 3.

Differences in the coding genes between human and chimpanzee. Sequence differences for amino acid (blue) and nucleotide (purple) are indicated by percentages. MHC genes except MIC are shown in red, MIC (MICA/B fusion) in blue, and non-MHC genes in black.

Fig. 4.

Diversity profile between human and chimpanzee MHC. The aligned sequence (excluding indels) is shown along the horizontal axis and the percent nucleotide differences calculated per 1 kb of nonoverlapping windows are shown along the vertical axis. The relative positions of the coding (red box), noncoding (gray box), and MHC (blue box) sequences are shown along the horizontal axis.

Fig. 5.

Structural differences between human and chimpanzee sequences. (A) Diversity profile of nucleotide differences between the human and chimpanzee genomic sequences using a sliding window of 1,000 bp across the entire 1.68-Mb aligned genomic sequence, including single-nucleotide indels. The aligned sequence is shown along the horizontal axis, and the percent nucleotide differences calculated per 1 kb of nonoverlapping windows are shown along the vertical axis. Diversity profiles of a single-nucleotide indel and substitutions by transition and transversion are indicated by blue, pink, and yellow lines, respectively. The relative positions of the MHC class I (multicopy) gene (brown) and non-MHC (single copy) gene (light blue) regions are shown along the horizontal axis. (B) Alteration of percentages of continuous indels that override 2-bp length.

Fig. 6.

Grouping of nucleotide substitutions.