Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing

Doi, Kouki; Monjo, Taku; Hoang, Pham Huy; Yoshimura, Junichi; Yurino, Hideaki; Mitsui, Jun; Ishiura, Hiroyuki; Takahashi, Yūji; Ichikawa, Yaeko; Goto, Jun; Tsuji, Shoji; Morishita, Shinichi

doi:10.1093/bioinformatics/btt647

Cited by 60 publications

(49 citation statements)

References 37 publications

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“…Furthermore, many sequencing technologies have a limited ability to genotype some 385 tandem repeat variants [27,[41][42][43][44], so our results apply to any data that is limited to…”

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confidence: 99%

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Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

Sawaya

Jones

2015

Preprint

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Some diseases are caused by genetic loci with a high rate of change, and heritability in complex traits is likely to be partially caused by variation at these loci. These hypermutable elements, such as tandem repeats, change at rates that are orders of magnitude higher than the rates at which most single nucleotides mutate. However, single nucleotide polymorphisms, or SNPs, are currently the primary focus of genetic studies of human disease. Here we quantify the degree to which SNPs are correlated with hypermutable loci by examining a range of mutation rates. We use established population genetics theory to relate mutation rates to recombination rates and compare the theoretical predictions to simulations. Both simulations and theory agree that, at the highest mutation rates, almost all correlation is lost between a hypermutable locus and surrounding SNPs. The theoretical predictions break down as the mutation rate increases, and consequently differ widely from the simulated results. The simulation results suggest that some correlation remains between SNPs and hypermutable loci when mutation rates are on the lower end of the mutation spectrum. Consequently, in some cases SNPs can tag variation caused by some hypermutable loci. We also examine the linkage between SNPs and other SNPs and uncover ways in which the linkage disequilibrium of rare SNPs differs from that of hypermutable loci.

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“…Furthermore, many sequencing technologies have a limited ability to genotype some 385 tandem repeat variants [27,[41][42][43][44], so our results apply to any data that is limited to…”

mentioning

confidence: 99%

“…Recent advances in sequencing technology [42,43,45] and tandem repeat 387 genotyping [6,44,46,47] provide hope that some hypermutable elements will be included 388 in future studies of genetic heritability and genetic disease. Nevertheless, some of the often caused by expansion [14,18].…”

mentioning

confidence: 99%

Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

Sawaya

Jones

2015

Preprint

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“…The recent development of single-molecule sequencing platform produces reads that are sufficiently long to span the entire gene or small viral genome. It not only benefits the assembly of genomic regions with tendem repeat [23][24][25], but also offers the opportunity to examine the genetic linkage between mutations. In fact, it is shown that the long read in single-molecule sequencing aids haplotype phasing in diploid genome [26], and in polyploid genome [27].…”

Section: Discussionmentioning

confidence: 99%

Long single-molecule reads can resolve the complexity of the Influenza virus composed of rare, closely related mutant variants

Artyomenko

Mangul

et al. 2016

Preprint

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Abstract. As a result of a high rate of mutations and recombination events, an RNA-virus exists as a heterogeneous "swarm" of mutant variants. The long read length offered by single-molecule sequencing technologies allows each mutant variant to be sequenced in a single pass. However, high error rate limits the ability to reconstruct heterogeneous viral population composed of rare, related mutant variants. In this paper, we present 2SNV, a method able to tolerate the high error-rate of the single-molecule protocol and reconstruct mutant variants. 2SNV uses linkage between single nucleotide variations to efficiently distinguish them from read errors. To benchmark the sensitivity of 2SNV, we performed a single-molecule sequencing experiment on a sample containing a titrated level of known viral mutant variants. Our method is able to accurately reconstruct clone with frequency of 0.2% and distinguish clones that differed in only two nucleotides distantly located on the genome. 2SNV outperforms existing methods for full-length viral mutant reconstruction. The open source implementation of 2SNV is freely available for download at

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“…This error rate might not be acceptable for individuals at the edge of one of the repeat ranges. In the future, HD genetic testing might require a two-tier approach using an additional long-read sequencing platform such as PacBio [34, 35] for persons with CAG lengths in the equivocal ranges (i.e., within 2 CAG repeats of another range).…”

Section: Discussionmentioning

confidence: 99%

Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD

Downing

Lourens

Soriano

et al. 2016

JHD

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Background: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. Objective: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional and imaging outcomes between persons with CAG repeats in four ranges: normal (≤ 26), intermediate (27–35), reduced penetrance (36–39), and full penetrance (≥ 40). Methods: We examined longitudinal data from 1379 participants (280 normal [NA], 21 intermediate [IA], 88 reduced penetrance [RP], and 986 full penetrance [FP] allele ranges). We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. Results: Model 3 was the best fitting model for most outcome variables. Differences between the NA and the FP group account for the majority of significant findings. Some differences between the RP and NA groups were significant. While there were baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, we found no significant differences between the NA and IA groups. Conclusions: We did not find evidence to support differences in the IA group compared to the nongene-expanded controls. These findings are limited by a small IA sample size.

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Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing

Cited by 60 publications

References 37 publications

Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

Linkage disequilibrium between single nucleotide polymorphisms and hypermutable loci

Long single-molecule reads can resolve the complexity of the Influenza virus composed of rare, closely related mutant variants

Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD

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