The effects of microsatellite selection on linked sequence diversity

Abstract

The genome-wide scan for selection is an importantmethod for identifying loci involved in adaptive evolution. However, theory that underlies standard scans for selection assumes a simplemutationmodel. In particular, recurrent mutation of the selective target is not considered. Although this assumption is reasonable for single-nucleotide variants (SNVs), a microsatellite targeted by selection will reliably violate this assumption due to highmutation rate. Moreover, the mutation rate of microsatellites is generally high enough to ensure that recurrent mutation is pervasive rather than occasional. It is therefore unclear if positive selection targeting microsatellites can be detected using standard scanning statistics. Examples of functional variation at microsatellites underscore the significance of understanding thegenomiceffectsofmicrosatellite selection.Here,weinvestigate thejointeffectsof selectionandcomplexmutation on linked sequence diversity, comparing simulations of microsatellite selection and SNV-based selective sweeps. We find that selection on microsatellites is generally difficult to detect using popular summaries of the site frequency spectrum, and, under certain conditions,usingpopularmethods such as the integrated haplotype statistic and SweepFinder. However,comparisons of the number of haplotypes (K) and segregating sites (S) often provide considerable power to detect selection on microsatellites. We apply this knowledge to a scan of autosomes in the human CEU population (CEPH population sampled from Utah). In addition to the most commonly reported targets of selection in European populations, we identify numerous novel genomic regions that bear highly anomalous haplotype configurations.Using one of these regions-intron 1 ofMAGI2-asan example,we showthat the anomalous configuration is coincidentwith a perfectCArepeat of length 22.We conclude that standard genome-wide scans will commonly fail to detect mutationally complex targets of selection but that comparisons of K and Swill, in many cases, facilitate their identification. © The Author(s) 2014.