Abstract
The branch point sequence is a cis-acting intronic motif required for mRNA splicing. Despite their functional importance, branch point sequences are not routinely annotated. Here we predict branch point sequences in 179,476 bovine introns and investigate their variability using a catalogue of 29.4 million variants detected in 266 cattle genomes. We localize the bovine branch point within a degenerate heptamer “nnyTrAy”. An adenine residue at position 6, that acts as branch point, and a thymine residue at position 4 of the heptamer are more strongly depleted for mutations than coding sequences suggesting extreme purifying selection. We provide evidence that mutations affecting these evolutionarily constrained residues lead to alternative splicing. We confirm evolutionary constraints on branch point sequences using a catalogue of 115 million SNPs established from 3,942 human genomes of the gnomAD database.
Highlights
The branch point sequence is a cis-acting intronic motif required for mRNA splicing
Using a variant catalogue established from whole-genome sequencing of 266 cattle from 11 breeds (Fig. 1a, Supplementary Data 4) sequenced to an average 16.28 (±6.56)-fold coverage, we assessed the number of polymorphic sites overlapping these features
We used a catalogue of 29.4 million autosomal variants detected in 266 cattle to investigate evolutionary constraints on coding and noncoding features of the bovine genome
Summary
The branch point sequence is a cis-acting intronic motif required for mRNA splicing Despite their functional importance, branch point sequences are not routinely annotated. During pre-mRNA splicing, the branch point sequence undergoes base-pairing with a conserved 6-bp motif (GUAGUA) of the U2 snRNA. Mutations affecting the branch point sequence may compromise the assembly of the spliceosome, leading to dramatic changes in splicing and gene expression with disease consequences[10,13,14]. Despite their functional importance, branch point sequences are not systematically studied because they are not annotated in gene transfer files. Widely used tools to predict functional consequences of genetic variants such as Ensembl’s Variant Effect Predictor[15] are largely blind to branch point sequences
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
