Profiling the genome-wide landscape of tandem repeat expansions

Abstract

Tandem Repeat (TR) expansions have been implicated in dozens of genetic diseases, including Huntington's Disease, Fragile X Syndrome, and hereditary ataxias. Furthermore, TRs have recently been implicated in a range of complex traits, including gene expression and cancer risk. While the human genome harbors hundreds of thousands of TRs, analysis of TR expansions has been mainly limited to known pathogenic loci. A major challenge is that expanded repeats are beyond the read length of most next-generation sequencing (NGS) datasets and are not profiled by existing genome-wide tools. We present GangSTR, a novel algorithm for genome-wide genotyping of both short and expanded TRs. GangSTR extracts information from paired-end reads into a unified model to estimate maximum likelihood TR lengths. We validate GangSTR on real and simulated data and show that GangSTR outperforms alternative methods in both accuracy and speed. We apply GangSTR to a deeply sequenced trio to profile the landscape of TR expansions in a healthy family and validate novel expansions using orthogonal technologies. Our analysis reveals that healthy individuals harbor dozens of long TR alleles not captured by current genome-wide methods. GangSTR will likely enable discovery of novel disease-associated variants not currently accessible from NGS.

ExpansionHunter: A sequence-graph based tool to analyze variation in short tandem repeat regions

“…ExpansionHunter was the first computational method for genotyping STRs from short-read sequencing data capable of consistently genotyping repeats longer than the read length and, hence, detecting pathogenic repeat expansions (Dolzhenko et al 2017). Since the initial release of ExpansionHunter, several other methods have been developed and were shown to accurately identify long (greater than read length) repeat expansions (Dashnow et al 2018;Tang et al 2017;Mousavi, Shleizer-Burko, and Gymrek 2018;Tankard et al 2018 An even more extreme example is the CAGG repeat in the CNBP gene whose expansions cause Myotonic Dystrophy type 2 (DM2). This repeat is adjacent to polymorphic CA and CAGA repeats (Liquori et al 2001) making it particularly difficult to accurately align reads to this locus.…”

Genome-wide patterns ofde novotandem repeat mutations and their contribution to autism spectrum disorders

“…Probands were selected to be negative for syndromic forms of ASD and most known pathogenic mutations including large CNVs and de novo point mutations in coding regions 5 , thus enriching for probands with other classes of pathogenic mutations. We used GangSTR 25 to estimate diploid repeat lengths at 1,131,232 autosomal TRs with repeat unit lengths 1-20bp in each sample. Resulting genotypes were subject to stringent filtering to remove low-quality calls ( Methods ).…”

ExpansionHunter Denovo: A computational method for locating known and novel repeat expansions in short-read sequencing data

“…To demonstrate the feasibility of such analyses, we analyzed 91 Coriell samples with experimentally-confirmed expansions in repeats associated with Friedreich's ataxia (FRDA; N=25), Myotonic Dystrophy type 1 (DM1; N=17), Huntington disease (HD; N=14), and fragile X syndrome (FXS; N=35). This dataset has been previously used to benchmark the performance of existing methods [23][24][25] .…”

“…Existing methods for repeat expansion detection rely upon predefined repeat catalogs [22][23][24][25][26]38 . Although these methods can analyze user-defined catalogs, defining the genomic locations of repeats is a complex task and there is a risk of missing many potentially-pathogenic loci.…”

“…Several recently-developed tools can detect REs longer than the standard short read sequencing read length of 150 bp [22][23][24][25][26][27] . These tools have all been demonstrated to be capable of accurately detecting pathogenic expansions of simple short tandem repeats (STRs).…”