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 (Ϸ6 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 insertions͞deletions (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 (HIV͞SIV, 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 singlenucleotide substitutions for shaping the recently emerged primate species.

Genomic evolution of MHC class I region in primates

“…Recently, we have sequenced the complete MHC class I genome regions of humans, Homo sapiens (21), and chimpanzees, Pan troglodytes (22), and a part of the counterpart of rhesus monkeys, Macaca mulatta. ʈ The genomic regions of the three species include a large number of orthologous (23) genes and of repeated sequences such as short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs).…”

Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex

“…The remainder of the gene content of some 140 genes appears unaltered, with expected coding-sequence divergence. All comparisons with the human MHC are largely paralleled with any of the chimpanzee, as a recent analysis confirmed the existence of a high degree of sequence similarity between the human and chimpanzee class I regions (Anzai et al 2003).…”

Gene evolution at the ends of wheat chromosomes

“…Gene evolution appears to occur nonuniformly across the genome (16)(17)(18)(19). Recent comparison of human with chimpanzee genomes revealed regions of disproportionate gene divergence (20,21). Other comparative studies suggest that regions of chromosomal instability, often located near the telomeres, are hot spots of chromosome evolution (22), harboring extensive rearrangements (23) and segmental gene duplications (22).…”