Genomic Insertions, Deletions, Inversions and Single Nucleotide Changes

Single nucleotide changes are sequence alterations involving DNA transitions and transversions of single nucleotides. These changes may or may not produce a change in amino acid sequence, and occur in both coding and noncoding regions. Previous analyses of human and chimpanzee genomic data found that 1-2% of nucleotides in the human genome differ in identity from those in the genome of the chimpanzee; specifically, single nucleotide changes are present in 1.23% of nucleotide comparisons between human and chimpanzee, and 1.06% of nucleotides across the genome are thought to have fixed differences (are unique to one lineage or the other). As this is a comparison between only two species, though, the ancestral state of each change is not clear, and the substitution in question could have occurred in the human lineage or in the chimpanzee lineage. Additionally, many of the genes and gene families that have undergone human-specific changes involve changes of single nucleotides that substantially affect the protein product.

Humans also differ from other species at the genomic level by large-scale insertions, deletions and inversions. Insertions and deletions in this context refer primarily to changes of more than 1 kilobase. As for single base pair changes, most analyses looking at human-specific large-scale insertions and deletions have involved only the human and chimpanzee genomes. This is in part due to the fact that attempts to complete genomes for other primate species have been unable to determine sequences for more complicated regions, and thus comparison at the sequence level has not been feasible. The publication of the macaque genome provided an opportunity for a three-way comparison to determine whether many of the already discovered human-chimpanzee differences are human-specific or due to lineage-specific changes in other species, and to identify additional human-specific features. One study triangulating the macaque, chimpanzee and human genomes found 130 genomic breakpoints that are human-specific. 64 of these are due to human-specific insertions, two-thirds of which overlap with segmental duplications and appear to result from large-scale duplication events. Another 7 HLS breakpoints are due to deletions, and 16 to inversions (the sources of the final 43 breakpoints could not be determined). Another study using these three genomes to examine genes with human-specific elevated rates of single nucleotide changes found that 82 genes showed more elevated rates of single nucleotide substitutions in humans than in chimpanzees or macaques, involving 483 human-specific base changes, and that this pattern continued beyond the non-exonic regions surrounding the affected genes. While this study focused on a limited number of exonic regions, such a technique allows for further clarification of what differences between the human genome and related primate genomes are HLS.