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Nat Genet. 2017 Oct;49(10):1495-1501. doi: 10.1038/ng.3952. Epub 2017 Sep 11.

Interpreting short tandem repeat variations in humans using mutational constraint.

Gymrek M1,2,3,4, Willems T2,5, Reich D6,7, Erlich Y2,8.

Author information

1
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
New York Genome Center, New York, New York, USA.
3
Department of Medicine, University of California, San Diego, La Jolla, California, USA.
4
Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA.
5
Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
6
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
7
Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
8
Department of Computer Science, Fu Foundation School of Engineering, Columbia University, New York, New York, USA.

Abstract

Identifying regions of the genome that are depleted of mutations can distinguish potentially deleterious variants. Short tandem repeats (STRs), also known as microsatellites, are among the largest contributors of de novo mutations in humans. However, 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 these estimates to create a framework for measuring constraint at STRs by comparing observed versus expected mutation rates. Constraint scores identified known pathogenic variants with early-onset effects. Our metric will provide a valuable tool for prioritizing pathogenic STRs in medical genetics studies.

PMID:
28892063
PMCID:
PMC5679271
DOI:
10.1038/ng.3952
[Indexed for MEDLINE]
Free PMC Article

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