Large-scale analysis of tandem repeat variability in the human genome

Abstract

Tandem repeats are short DNA sequences that are repeated head-to-tail with a propensity to be variable. They constitute a significant proportion of the human genome, also occurring within coding and regulatory regions. Variation in these repeats can alter the function and/or expression of genes allowing organisms to swiftly adapt to novel environments. Importantly, some repeat expansions have also been linked to certain neurodegenerative diseases. Therefore, accurate sequencing of tandem repeats could contribute to our understanding of common phenotypic variability and might uncover missing genetic factors in idiopathic clinical conditions. However, despite long-standing evidence for the functional role of repeats, they are largely ignored because of technical limitations in sequencing, mapping and typing. Here, we report on a novel capture technique and data filtering protocol that allowed simultaneous sequencing of thousands of tandem repeats in the human genomes of a three generation family using GS-FLX-plus Titanium technology. Our results demonstrated that up to 7.6% of tandem repeats in this family (4% in coding sequences) differ from the reference sequence, and identified a de novo variation in the family tree. The method opens new routes to look at this underappreciated type of genetic variability, including the identification of novel disease-related repeats.

MIPSTR: a method for multiplex genotyping of germline and somatic STR variation across many individuals

“…5), a substantially better agreement than previously observed (Duitama et al 2014). However, this correlation was substantially weaker among coding STRs (r = 0.46) than among noncoding STRs (r = 0.75).…”

“…We observed ratios as close as 49.9/50.1 (761 tag-defined read groups/764) and as far as 36/74 (40/71) for the three ascertained duplicate loci across three Col-0 siblings. These results suggest that with sufficient coverage, MIPSTR can readily identify heterozygous and somatic STR variants, which have been largely inaccessible by previous analytical or empirical methods (Gymrek et al 2012;Guilmatre et al 2013;Highnam et al 2013;Duitama et al 2014;Willems et al 2014). …”

“…Such strategies were recently applied to the human genome, using STRtargeted microarray capture or RNA probe capture prior to sequencing (Guilmatre et al 2013;Duitama et al 2014). However, these STR capture methods produced only limited enrichment for STR-containing reads with flanking sequence, i.e., 2.2% of mappable reads (Guilmatre et al 2013) and 25% of mappable reads (Duitama et al 2014), and only marginally improved STR coverage for unit number calls (Table 1).…”

“…More than 2000 STR loci are accessible by MIPSTR in A. thaliana, and many more accessible STR loci exist in humans (Molla et al 2009;Guilmatre et al 2013;Duitama et al 2014;Willems et al 2014). Our preliminary results, considering only a fraction of the accessible A. thaliana STR loci, highlight the promise of STRs to contribute to the variation and heritability of quantitative traits (Press et al 2014).…”

Genetic polymorphisms of loci D18S53, D18S59, and D18S488 in fetuses from a Chinese Tianjin Han population

“…STRs contain a wealth of polymorphisms, which may indicate regional and ethnic differences (Duitama et al, 2014). STRs, also known as satellite DNA, constitute about 10% of the human genome.…”