STRetch: detecting and discovering pathogenic short tandem repeat expansions

Harriet Dashnow,Daniel G Macarthur,Alicia Oshlack,Phillipa Lamont,Monkol Lek,Andrew Lonsdale,Simon Sadedin,Joshua S Clayton,Andreas Halman,Belinda Phipson,Mark Davis,Nigel G Laing

doi:10.1186/s13059-018-1505-2

Abstract

Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch.

Highlights

Short tandem repeats (STRs), known as microsatellites, are a set of short (1–6 bp) DNA sequences repeated consecutively
We show that STRetch can detect pathogenic STR expansions in short-read polymerase chain reaction (PCR)-free whole-genome sequencing (WGS) data and can detect expansions at STR loci not known to be pathogenic
Here we have introduced STRetch, a method to test for rare STR expansions from WGS data

Summary

Introduction

Short tandem repeats (STRs), known as microsatellites, are a set of short (1–6 bp) DNA sequences repeated consecutively. 3% of the human genome consists of STRs [1]. These loci are prone to frequent mutations and high polymorphism, with mutation rates 10–100,000 times higher than average rates throughout the genome [2]. Dozens of neurological and developmental disorders have been attributed to STR expansions [3]. STR expansions have been identified as the causal DNA mutation in almost 30 Mendelian human diseases [6]. Many of these conditions affect the nervous system, including Huntington’s disease, spinocerebellar ataxias, spinal-bulbar muscular atrophy, Friedreich’s ataxia, fragile X syndrome, and polyalanine disorders [7]. Most tandem repeat expansion disorders show dominant inheritance, with disease mechanisms varying from expansion of a peptide repeat and subsequent disruption

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Discussion

Conclusion