Genome-wide profiling of heritable and de novo STR variations

Willems, Thomas; Zielinski, Dina; Yuan, Jie; Gordon, Assaf; Gymrek, Melissa; Erlich, Yaniv

doi:10.1038/nmeth.4267

Cited by 235 publications

(351 citation statements)

References 28 publications

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“…After read alignment described in the previous section, we used the BAM files to run the software HipSTR in order to call STRs (31). STRs for the 14 substrains were jointly genotyped on a single node local server in batches of 500 STRs.…”

Section: Short Tandem Repeat (Str)mentioning

confidence: 99%

Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

Mortazavi

Ren

Saini

et al. 2020

Preprint

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C57BL/6J is the most widely used inbred mouse strain and is the basis for the mouse reference genome. In addition to C57BL/6J, several other C57BL/6 and C57BL/10 substrains exist. Previous studies have documented extensive phenotypic and genetic differences among these substrains, which are presumed to be due to the accumulation of new mutations. These differences can be used for genome wide association studies.They can also have unintended consequences for reproducibility when substrain differences are not properly accounted for. In this paper, we performed genomic sequencing and RNA-sequencing in the hippocampus of 9 C57BL/6 and 5 C57BL/10 substrains. We identified 985,329 SNPs, 150,344 Short Tandem Repeats (STR) and 896Structural Variants (SV), out of which 330,178 SNPs and 14,367 STRs differentiated the C57BL/6 and C57BL/10 groups. We found several regions that contained dense polymorphisms. We also identified 578 differentially expressed genes for C57BL/6 substrains and 37 differentially expressed genes for C57BL/10 substrains (FDR < 0.01).We then identified nearby SNPs, STRs and SVs that matched the gene expression patterns. In so doing, we identified SVs in coding regions of Wdfy1, Ide, Fgfbp3 and Btaf1 that explain the expression patterns observed. We replicated several previously reported gene expression differences between substrains (Nnt, Gabra2) as well as many novel gene expression differences (e.g. Kcnc2). Our results illustrate the impact of new mutations on gene expression among these substrains and provides a resource for future mapping studies.

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Section: Short Tandem Repeat (Str)mentioning

confidence: 99%

Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

Mortazavi

Ren

Saini

et al. 2020

Preprint

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“…Over the last several years, we and others have developed a series of tools for genome-wide genotyping of STRs [12,44,16,23] from short reads or targeted genotyping of VNTRs [4] from both short and long reads. These tools primarily rely on identifying reads that completely enclose the repeat of interest.…”

Section: Introductionmentioning

confidence: 99%

Profiling the genome-wide landscape of tandem repeat expansions

Mousavi

Shleizer-Burko

Gymrek

2018

Preprint

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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.

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“…We developed a novel method, MonSTR ( https://github.com/gymreklab/STRDenovoTools/ ), to identify de novo TR mutations from genome-wide TR genotypes obtained from GangSTR or HipSTR 52 . MonSTR is a model-based method that evaluates the joint likelihood of all genotypes of each parent-offspring trio and outputs a posterior estimate of a mutation occurring at each TR in each child.…”

Section: Identifying De Novo Tr Mutationsmentioning

confidence: 99%

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

Mitra

Huang

Mousavi

et al. 2020

Preprint

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Recent studies have demonstrated a strong contribution of germline de novo mutations to autism spectrum disorders (ASD). Tandem repeats (TRs), consisting of repeated sequence motifs of 1-20bp, comprise one of the largest sources of human genetic variation. Yet, the contribution of TR mutations to ASD has not been assessed on a genome-wide scale. Here, we leverage novel bioinformatics tools and~35 × whole genome sequencing of~1,600 families from the Simons Simplex Collection (SSC) to analyze germline de novo TR mutations at nearly 1 million loci in ASD-affected and unaffected siblings. We identify an average of 54 high-confidence mutations per child at an estimated true positive rate of 90%. We find novel genome-wide TR mutation patterns, including a bias toward larger mutations from the maternal compared with paternal germlines. We demonstrate a significant genome-wide excess of TR mutations in ASD probands, which are significantly larger than in controls, enriched in promoters of fetal brain expressed genes, and more strongly predicted to alter expression during brain development. Overall, our results indicate a significant, but so far overlooked, contribution of repetitive regions to ASD.

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Genome-wide profiling of heritable and de novo STR variations

Cited by 235 publications

References 28 publications

Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

Polymorphic SNPs, short tandem repeats and structural variants are responsible for differential gene expression across C57BL/6 and C57BL/10 substrains

Profiling the genome-wide landscape of tandem repeat expansions

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

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