TRTools: a toolkit for genome-wide analysis of tandem repeats

Mousavi, Nima; Margoliash, Jonathan; Pusarla, Neha; Saini, Shubham; Yanicky, Richard; Gymrek, Melissa

doi:10.1101/2020.03.17.996033

Cited by 6 publications

(1 citation statement)

References 8 publications

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“…Short tandem repeats (STRs) were called from aligned WGS data with GangSTR v.2.4 (42), using the GangSTR hg19 reference file v.13.1. The calls were filtered and analyzed using three tools from the STR analysis toolkit TRTools (43). First, dumpSTR was used to filter for quality of calls using the following parameters: read depth >20, read depth <1000, QUAL >0.9, spanbound only (calls that are spanned by reads), and filter bad confidence intervals (filtered calls whose maximum likelihood estimates were not within the confidence interval).…”

Section: Methodsmentioning

confidence: 99%

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

Jensen

Tyryshkina

Pizzo

et al. 2021

Preprint

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Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in >90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional "second-hit" variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed expression changes that were inherited as well as de novo compared with their parents, which matched with 39/47 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of "second-hit" variants in genes with expression changes, where 7/25 variant classes were only enriched when inherited from the non-carrier parent, including missense SNVs and large deletions. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited "second-hits" in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying "second-hits" and genes with transcriptome alterations, including differential expression, alternative splicing, and allele-specific expression. Our study shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

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Section: Methodsmentioning

confidence: 99%

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

Jensen

Tyryshkina

Pizzo

et al. 2021

Preprint

View full text Add to dashboard Cite

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Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes

2022

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When present in coding regions, tandem repeats (TRs) may have large effects on protein structure and function contributing to health and disease. We use a family-based design to identify de novo TRs and assess their impact at the population level in 148,607 European ancestry participants from the UK Biobank. The 427 loci with de novo TR mutations are enriched for targets of microRNA-184 (21.1-fold, P = 4.30 × 10−5, FDR = 9.50 × 10−3). There are 123 TR-phenotype associations with posterior probabilities > 0.95. These relate to body structure, cognition, and cardiovascular, metabolic, psychiatric, and respiratory outcomes. We report several loci with large likely causal effects on tissue microstructure, including the FAN1-[TG]N and carotid intima-media thickness (mean thickness: beta = 5.22, P = 1.22 × 10−6, FDR = 0.004; maximum thickness: beta = 6.44, P = 1.12 × 10−6, FDR = 0.004). Two exonic repeats FNBP4-[GGT]N and BTN2A1-[CCT]N alter protein structure. In this work, we contribute clear and testable hypotheses of dose-dependent TR implications linking genetic variation and protein structure with health and disease outcomes.

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Patterns of de novo tandem repeat mutations and their role in autism

Mitra

Huang

Mousavi

et al. 2021

Nature

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Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors 1,2 . Family studies demonstrate that ASD has a significant genetic basis with contributions both from inherited and de novo variants 3,4 . It has been estimated that de novo mutations may contribute to 30% of all Reprints and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http:// www.nature.com/authors/editorial_policies/license.html#terms

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TRTools: a toolkit for genome-wide analysis of tandem repeats

Cited by 6 publications

References 8 publications

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes

Patterns of de novo tandem repeat mutations and their role in autism

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