Fitness landscapes of human microsatellites

Advances in DNA sequencing technology and computation now enable genome-wide scans for natural selection to be conducted on unprecedented scales. By examining patterns of sequence variation among individuals, biologists are identifying genes and variants that affect fitness. Despite this progress, most population genetic methods for characterizing selection assume that variants mutate in a simple manner and at a low rate. Because these assumptions are violated by repetitive sequences, selection remains uncharacterized for an appreciable percentage of the genome. To meet this challenge, we focus on microsatellites, repetitive variants that mutate orders of magnitude faster than single nucleotide variants, can harbor substantial variation, and are known to influence biological function in some cases. We introduce four general models of natural selection that are each characterized by just two parameters, are easily simulated, and are specifically designed for microsatellites. Using a random forests approach to approximate Bayesian computation, we fit these models to carefully chosen microsatellites genotyped in 200 humans from a diverse collection of eight populations. Altogether, we reconstruct detailed fitness landscapes for 43 microsatellites we classify as targets of selection. Microsatellite fitness surfaces are diverse, including a range of selection strengths, contributions from dominance, and variation in the number and size of optimal alleles. Microsatellites that are subject to selection include loci known to cause trinucleotide expansion disorders and modulate gene expression, as well as intergenic loci with no obvious function. The heterogeneity in fitness landscapes we report suggests that genome-scale analyses like those used to assess selection targeting single nucleotide variants run the risk of oversimplifying the evolutionary dynamics of microsatellites. Moreover, our fitness landscapes provide a valuable visualization of the selective dynamics navigated by microsatellites.

Methods
Genotypes: Primers were developed by Prevention Genetics (Marshfield, WI). Prevention Genetics also performed electrophoretic determination of fragment lengths.

We determined absolute repeat legnths of microsatellites through comparison of raw genotypes to those available on the 1000 Genomes website. See Supplementary Information for a detailed example of this translation from raw to absolute genotypes.

Code: Developed solely by the authors.