Dataset Information

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

ABSTRACT: Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

SUBMITTER: Bishop MR

PROVIDER: S-EPMC7332647 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Bishop Madison R MR Diaz Perez Kimberly K KK Sun Miranda M Ho Samantha S Chopra Pankaj P Mukhopadhyay Nandita N Hetmanski Jacqueline B JB Taub Margaret A MA Moreno-Uribe Lina M LM Valencia-Ramirez Luz Consuelo LC Restrepo Muñeton Claudia P CP Wehby George G Hecht Jacqueline T JT Deleyiannis Frederic F Weinberg Seth M SM Wu-Chou Yah Huei YH Chen Philip K PK Brand Harrison H Epstein Michael P MP Ruczinski Ingo I Murray Jeffrey C JC Beaty Terri H TH Feingold Eleanor E Lipinski Robert J RJ Cutler David J DJ Marazita Mary L ML Leslie Elizabeth J EJ

American journal of human genetics 20200622 1

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expre ...[more]

PMID: 32574564

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Project description:MotivationWhole-genome and -exome sequencing on parent-offspring trios is a powerful approach to identifying disease-associated genes by detecting de novo mutations in patients. Accurate detection of de novo mutations from sequencing data is a critical step in trio-based genetic studies. Existing bioinformatic approaches usually yield high error rates due to sequencing artifacts and alignment issues, which may either miss true de novo mutations or call too many false ones, making downstream validation and analysis difficult. In particular, current approaches have much worse specificity than sensitivity, and developing effective filters to discriminate genuine from spurious de novo mutations remains an unsolved challenge.ResultsIn this article, we curated 59 sequence features in whole genome and exome alignment context which are considered to be relevant to discriminating true de novo mutations from artifacts, and then employed a machine-learning approach to classify candidates as true or false de novo mutations. Specifically, we built a classifier, named De Novo Mutation Filter (DNMFilter), using gradient boosting as the classification algorithm. We built the training set using experimentally validated true and false de novo mutations as well as collected false de novo mutations from an in-house large-scale exome-sequencing project. We evaluated DNMFilter's theoretical performance and investigated relative importance of different sequence features on the classification accuracy. Finally, we applied DNMFilter on our in-house whole exome trios and one CEU trio from the 1000 Genomes Project and found that DNMFilter could be coupled with commonly used de novo mutation detection approaches as an effective filtering approach to significantly reduce false discovery rate without sacrificing sensitivity.AvailabilityThe software DNMFilter implemented using a combination of Java and R is freely available from the website at http://humangenome.duke.edu/software.

Dataset Information

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Publications

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

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