Structural variants and short tandem repeats impact gene expression and splicing in bovine testis tissue

Abstract

Structural variants (SVs) and short tandem repeats (STRs) are significant sources of genetic variation. However, the impacts of these variants on gene regulation have not been investigated in cattle. Here, we genotyped and characterized 19,408 SVs and 374,821 STRs in 183 bovine genomes and investigated their impact on molecular phenotypes derived from testis transcriptomes. We found that 71% STRs were multiallelic. The vast majority (95%) of STRs and SVs were in intergenic and intronic regions. Only 37% SVs and 40% STRs were in high LD (R2 > 0.8) with surrounding SNPs/Indels, indicating that SNP-based association testing and genomic prediction are blind to a non-negligible portion of genetic variation. We showed that both SVs and STRs were more than two-fold enriched among expression and splicing QTL (e/sQTL) relative to SNPs/Indels and were often associated with differential expression and splicing of multiple genes. Deletions and duplications had larger impacts on splicing and expression than any other type of structural variant. Exonic duplications predominantly increased gene expression either through alternative splicing or other mechanisms, whereas expression- and splicing-associated STRs primarily resided in intronic regions and exhibited bimodal effects on the molecular phenotypes investigated. Most e/sQTL resided within 100 kb of the affected genes or splicing junctions. We pinpoint candidate causal STRs and SVs associated with the expression of SLC13A4 and TTC7B, and alternative splicing of a lncRNA and CAPP1. We provide a catalogue of STRs and SVs for taurine cattle and show that these variants contribute substantially to gene expression and splicing variation.

Pangenome-genotyped structural variation improves molecular phenotype mapping in cattle

“…SVs, such as indels >50 bp, have thus been predominantly neglected in GWAS and e/sQTL studies, despite contributing substantially to phenotype variation ( Alonge et al 2020 ; Scott et al 2021 ). Some recent work has used short reads from various cattle breeds to call SVs ( Zhou et al 2022a ; Bhati et al 2023 ; Lee et al 2023 ) but was primarily restricted to deletions and duplications and required extreme filtering to remove false positives. Long and accurate sequencing reads, like Pacific Biosciences (PacBio) HiFi and those produced with Oxford Nanopore Technologies (ONT) r10 chemistries, have the potential to access both small variants (including SNPs and indels <50 bp) and SVs but are costly when sequencing entire mapping cohorts.…”