PT  - JOURNAL ARTICLE
AU  - Melissa Gymrek
AU  - Thomas Willems
AU  - David Reich
AU  - Yaniv Erlich
TI  - Interpreting short tandem repeat variations in humans using mutational constraint
AID  - 10.1101/092734
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 092734
4099  - http://biorxiv.org/content/early/2017/05/01/092734.short
4100  - http://biorxiv.org/content/early/2017/05/01/092734.full
AB  - Identifying regions of the genome that are depleted of mutations can reveal potentially deleterious variants. Short tandem repeats (STRs), also known as microsatellites, are among the largest contributors of de novo mutations in humans and are implicated in a variety of human disorders. However, because of the challenges STRs pose to bioinformatics tools, per-locus studies of STR mutations have been limited to highly ascertained panels of several dozen loci. Here, we harnessed bioinformatics tools and a novel analytical framework to estimate mutation parameters for each STR in the human genome by correlating STR genotypes with local sequence heterozygosity. We applied our method to obtain robust estimates of the impact of local sequence features on mutation parameters and used this to create a framework for measuring constraint at STRs by comparing observed vs. expected mutation rates. Constraint scores identified known pathogenic variants with early onset effects. Our constraint metrics will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies.