Inferring short tandem repeat variation from paired-end short reads

Abstract

The advances of high-throughput sequencing offer an unprecedented opportunity to study genetic variation. This is challenged by the difficulty of resolving variant calls in repetitive DNA regions. We present a Bayesian method to estimate repeat-length variation from paired-end sequence read data. The method makes variant calls based on deviations in sequence fragment sizes, allowing the analysis of repeats at lengths of relevance to a range of phenotypes. We demonstrate the method’s ability to detect and quantify changes in repeat lengths from short read genomic sequence data across genotypes. We use the method to estimate repeat variation among 12 strains of Arabidopsis thaliana and demonstrate experimentally that our method compares favourably against existing methods. Using this method, we have identified all repeats across the genome, which are likely to be polymorphic. In addition, our predicted polymorphic repeats also included the only known repeat expansion in A. thaliana, suggesting an ability to discover potential unstable repeats.

The overdue promise of short tandem repeat variation for heritability

“…The scientific community has tackled this problem in a flurry of recent studies describing methods for genotyping STRs genome-wide (Table 1). Specifically, in the last two years, several analytical tools have been developed to call STR genotypes from whole-genome-sequencing data [37–39]. These tools attempt to address the two major challenges for genotyping STRs: poor mappability due to low sequence complexity and high technical error rate due to amplification stutter.…”

“…Others have attempted to genotype STRs using whole-genome-sequencing data from paired-end reads (50bp) of size-selected genomic fragments [39], similar to strategies used to detect large insertions or deletions [77–80]. This approach is limited by the resolution of gel electrophoresis in the size selection of DNA fragments.…”

“…The broad interest in STR variation has led to the development of techniques for high-throughput genotyping of STRs [35,36] and an explosion of analysis tools for extracting STR variation from existing sequence data [37–39]. However, the precision of these methods remains limited, due to a combination of low effective coverage of STRs and the lack of robust models for distinguishing technical error from somatic variation.…”

0309 Systematic profiling of short tandem repeats in the cattle genome

“…In contrast to calling methods for single nucleotide polymorphisms (SNPs), insertions, deletions (indels) and copy number variations (CNVs), STRs are substantially more difficult to detect based on short reads produced by next generation sequencing (NGS); however, numerous methods have been recently developed to identify STR variants in human (Gymrek et al 2012;Tae et al 2013;Highnam et al 2013;Anvar et al 2014;Cao et al 2014;Fungtammasan et al 2015;Carlson et al 2015). These programs enable STR detection in NGS data by, among other features, carefully adjusting for high mismatch/indel levels in STRs during the mapping step (lobSTR) and guiding genotyping of STRs using informed error profiles (RepeatSeq) (Gymrek et al 2012;Highnam et al 2013).…”

Characterization and distribution of repetitive elements in association with genes in the human genome

“…Such fundamental studies have been performed in many different species including Escherichia Coli (Kawano et al, 2002), fish (Cioffi and Bertollo, 2012), and bovine (Adelson et al, 2009) genomes. Since a thorough study of repetitive elements will provide pivotal insights into genome functions and evolutionary process, there is no surprise that many computational (Jurka, 1998;Sharma et al, 2007;Wang and Xu, 2009) as well as experimental (Hormozdiari et al, 2011;Cao et al, 2014) approaches had been developed to identify novel repetitive elements using genomic sequences. For example, the L1Base provides the functional annotation and prediction of active LINE1 elements (Penzkofer et al, 2005) and the TRbase emphasizes tandem repeats related to disease genes in the human genome (Boby et al, 2005).…”