Profiling of short-tandem-repeat disease alleles in 12,632 human whole genomes

Item Type:	Article
Title:	Profiling of short-tandem-repeat disease alleles in 12,632 human whole genomes
Creators Name:	Tang, H. and Kirkness, E.F. and Lippert, C. and Biggs, W.H. and Fabani, M. and Guzman, E. and Ramakrishnan, S. and Lavrenko, V. and Kakaradov, B. and Hou, C. and Hicks, B. and Heckerman, D. and Och, F.J. and Caskey, C.T. and Venter, J.C. and Telenti, A.
Abstract:	Short tandem repeats (STRs) are hyper-mutable sequences in the human genome. They are often used in forensics and population genetics and are also the underlying cause of many genetic diseases. There are challenges associated with accurately determining the length polymorphism of STR loci in the genome by next-generation sequencing (NGS). In particular, accurate detection of pathological STR expansion is limited by the sequence read length during whole-genome analysis. We developed TREDPARSE, a software package that incorporates various cues from read alignment and paired-end distance distribution, as well as a sequence stutter model, in a probabilistic framework to infer repeat sizes for genetic loci, and we used this software to infer repeat sizes for 30 known disease loci. Using simulated data, we show that TREDPARSE outperforms other available software. We sampled the full genome sequences of 12,632 individuals to an average read depth of approximately 30× to 40× with Illumina HiSeq X. We identified 138 individuals with risk alleles at 15 STR disease loci. We validated a representative subset of the samples (n = 19) by Sanger and by Oxford Nanopore sequencing. Additionally, we validated the STR calls against known allele sizes in a set of GeT-RM reference cell-line materials (n = 6). Several STR loci that are entirely guanine or cytosines (G or C) have insufficient read evidence for inference and therefore could not be assayed precisely by TREDPARSE. TREDPARSE extends the limit of STR size detection beyond the physical sequence read length. This extension is critical because many of the disease risk cutoffs are close to or beyond the short sequence read length of 100 to 150 bases.
Keywords:	Microsatellites, Short Tandem Repeats, Genotyping, Genome Sequencing, Trinucleotide Repeat Expansion, Genetic Disorder, Population Genetics
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	101
Number:	5
Page Range:	700-715
Date:	2 November 2017
Official Publication:	https://doi.org/10.1016/j.ajhg.2017.09.013
PubMed:	View item in PubMed

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