Alu Recombination-Mediated Structural Deletions in the Chimpanzee Genome

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Abstract
With more than 1.2 million copies, Alu elements are one of the most important sources of structural variation in primate genomes. Here, we compare the chimpanzee and human genomes to determine the extent of Alu recombination-mediated deletion (ARMD) in the chimpanzee genome since the divergence of the chimpanzee and human lineages (∼6 million y ago). Combining computational data analysis and experimental verification, we have identified 663 chimpanzee lineage-specific deletions (involving a total of ∼771 kb of genomic sequence) attributable to this process. The ARMD events essentially counteract the genomic expansion caused by chimpanzee-specific Alu inserts. The RefSeq databases indicate that 13 exons in six genes, annotated as either demonstrably or putatively functional in the human genome, and 299 intronic regions have been deleted through ARMDs in the chimpanzee lineage. Therefore, our data suggest that this process may contribute to the genomic and phenotypic diversity between chimpanzees and humans. In addition, we found four independent ARMD events at orthologous loci in the gorilla or orangutan genomes. This suggests that human orthologs of loci at which ARMD events have already occurred in other nonhuman primate genomes may be “at-risk” motifs for future deletions, which may subsequently contribute to human lineage-specific genetic rearrangements and disorders. The recent sequencing of a number of primate genomes shows that small segments of DNA known as Alu elements are found repeatedly along all chromosomes, and indeed comprise ∼10% of the human genome. Although older Alu elements that have been in the genome for a long time accumulate some random mutations, overall these elements retain high levels of sequence identity among themselves. The presence of many near-identical Alu elements located close to each other makes primate genomes prone to DNA recombination events that generate genomic deletions of varying sizes. Here, by scanning the chimpanzee genome for such deletions, we determined the role of the Alu recombination-mediated deletion process in creating structural differences between the chimpanzee and human genomes. Using a combination of computational and experimental techniques, we identified 663 deletions, involving the removal of ∼771 kb of genomic sequence. Interestingly, about half of these deletions were located within known or predicted genes, and in several cases, the deletions removed coding exons from chimpanzee genes as compared to their human counterparts. Alu recombination-mediated deletion shows signs of being a major sculptor of primate genomes and may be responsible for generating some of the genetic differences between humans and chimpanzees.