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Researchers Search for Sites of Balancing Selection in Primate Genomes

NEW YORK (GenomeWeb News) – In a study published in the early, online edition of Science today, researchers from the University of Chicago, the University of Oxford, and elsewhere sorted through genome sequences for dozens of humans and chimpanzees to look for signs of balancing selection — represented, in this case, by sets of genetic variants that have been maintained in both primate species.

Along with previously known sites of balancing selection in the human genome — namely the ABO blood group locus and the major histocompatibility complex, or MHC, locus — the team pulled out hundreds of shared coding SNPs and 125 larger haplotypes in allele patterns that appear to persevere as a result of balancing selection.

In half a dozen instances, the sets of polymorphisms shared the same linkage disequilibrium patterns in the human and chimpanzee genomes, suggesting that these regions represented ancestral forms of genetic variation that have been preserved via balancing selection.

In addition, authors of the new study explained, sites in the primate genomes that appeared most prone to balancing selection in the current analysis tended to coincide with sequences involved in the formation or regulation of glycoproteins or other players in host responses to potential pathogens.

"Our results imply that dynamic co-evolution of human hosts and their pathogens has played an important role in shaping human variation," the University of Chicago's Molly Przeworski, senior author on the study, said in a statement. "This highlights the importance of a different kind of selection pressure in human evolution."

Unlike forms of selection that weed out certain alleles and push others toward fixation in a population or species, balancing selection acts to preserve variation, Przeworski and her co-authors noted, resulting in sets of alternative alleles that stick around over very long stretches of time, evolutionarily speaking.

Because these variants are interspersed between parts of the genome that have been subjected to more neutral selection pressure, they continued, it's possible to pick out potential targets of balancing selection by considering allele frequency and other patterns across the genome.

To protect against finding false-positive cases of balancing selection, the team went a step further for its analyses, focusing on identical allele groupings in humans and chimpanzees that are expected to extend back to the shared ancestor of both species.

"We conducted a genome-wide scan for long-lived balancing selection by looking for combinations of SNPs shared between humans and chimpanzees," authors of the new study noted, adding that "the recent availability of genome sequences for multiple humans and chimpanzees provides an opportunity to search comprehensively and with greater power for ancient balancing selection."

Using existing genome sequence data representing 59 individuals from Sub-Saharan Africa and 10 Western chimpanzees, researchers worked their way down from more than 33,900 and 490 autosomal and X-linked SNPs, respectively. In particular, they scrutinized shared human-chimpanzee SNPs sets within protein-coding sequences as well as haplotypes that appeared to have been maintained since the species' shared ancestor.

Within the MHC, a locus in the human genome long-lauded for its balancing selection-based variability, the group saw several synonymous and non-synonymous SNPs that were the same in the chimp genome as in the human genome. And despite the fact that the chimpanzee blood system does not include the B blood type, researchers detected a pair of overlapping chimpanzee and human SNPs at the ABO blood locus.

"Neither shared SNP is non-synonymous … and they do not meet our criteria for creating shared haplotypes," they noted, "but there is a peak of diversity around them within both humans and chimpanzees, suggesting that they may be ancient variants."

Across the broader genome, meanwhile, investigators identified 125 regions that seemed to have similar or overlapping haplotypes, including six regions that appear especially likely to harbor ancient polymorphisms that have been maintained through balancing selection since the time of the chimpanzee-human ancestor.

Almost all of these shared haplotypes fell outside of coding sequences, the study's authors noted, hinting that balancing selection can influence what sorts of regulatory variants stick around in the genome.

Glycoprotein-coding genes appeared to be enriched in and around suspected sites of balancing selection, the researchers reported, consistent with the notion that balancing selection is being used, in part, to combat potential pathogens. Coding SNPs common to both humans and chimpanzees seemed especially apt to fall in glycoprotein or cell adhesion-related genes, too, bolstering that idea.

"Given that viruses frequently utilize host glycans to gain entry into host cells and some bacteria imitate host glycans to evade the host immune system," the researchers elaborated, "these enrichments suggest that the targets of balancing selection that we identified likely evolved in response to pressures exerted by human and chimpanzee pathogens, mirroring what is known about other genes under balancing selection in humans."

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