MyJournals Home  

RSS FeedsPathogenicity and selective constraint on variation near splice sites [RESEARCH] (Genome Research)


2 february 2019 12:00:38

Pathogenicity and selective constraint on variation near splice sites [RESEARCH] (Genome Research)

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. By using mutational burden analyses in this large cohort of proband–parent trios, we could estimate in an unbiased manner the relative contributions of mutations at canonical dinucleotides (73%) and flanking noncanonical positions (27%), and calculate the positive predictive value of pathogenicity for different classes of mutations. We identified 18 patients with likely diagnostic de novo mutations in dominant DD-associated genes at noncanonical positions in splice sites. We estimate 35%–40% of pathogenic variants in noncanonical splice site positions are missing from public databases. Digg Facebook Google StumbleUpon Twitter
55 viewsCategory: Bioinformatics, Genetics, Genomics
Where is genomics going next? (Genome Biology)
Systematic interrogation of human promoters [RESEARCH] (Genome Research)
blog comments powered by Disqus
The latest issues of all your favorite science journals on one page


Register | Retrieve



Use these buttons to bookmark us: Digg Facebook Google StumbleUpon Twitter

Valid HTML 4.01 Transitional
Copyright © 2008 - 2020 Indigonet Services B.V.. Contact: Tim Hulsen. Read here our privacy notice.
Other websites of Indigonet Services B.V.: Nieuws Vacatures News Tweets Travel Photos Nachrichten Indigonet Finances Leer Mandarijn