Profiling of Short-Tandem-Repeat Disease Alleles in 12,632 Human Whole Genomes

American Journal of Human Genetics
Haibao TangAmalio Telenti

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 si...Continue Reading

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Methods Mentioned

BETA
whole-genome shotgun sequencing
genotyping
Illumina sequencing
PCR

Software Mentioned

search
GATK
STRViper
ExpansionHunter
Manta
BWA aligner
BWA
EAGLE
ONP
Variant calling

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