Genome-wide mapping of large deletions and their population-genetic properties in dairy cattle

Abstract

Large genomic deletions are potential candidate for loss-of-function, which could be lethal as homozygote. Analysing whole genome data of 175 cattle, we report 8,480 large deletions (199 bp–773 KB) with an overall false discovery rate of 8.8%; 82% of which are novel compared with deletions in the dbVar database. Breakpoint sequence analyses revealed that majority (24 of 29 tested) of the deletions contain microhomology/homology at breakpoint, and therefore, most likely generated by microhomology-mediated end joining. We observed higher differentiation among breeds for deletions in some genic-regions, such as ABCA12, TTC1, VWA3B, TSHR, DST/BPAG1, and CD1D. The genes overlapping deletions are on average evolutionarily less conserved compared with known mouse lethal genes (P-value = 2.3 × 10−6). We report 167 natural gene knockouts in cattle that are apparently nonessential as live homozygote individuals are observed. These genes are functionally enriched for immunoglobulin domains, olfactory receptors, and MHC classes (FDR = 2.06 × 10−22, 2.06 × 10−22, 7.01 × 10−6, respectively). We also demonstrate that deletions are enriched for health and fertility related quantitative trait loci (2-and 1.5-fold enrichment, Fisher’s P-value = 8.91 × 10−10 and 7.4 × 10−11, respectively). Finally, we identified and confirmed the breakpoint of a ∼525 KB deletion on Chr23:12,291,761-12,817,087 (overlapping BTBD9, GLO1 and DNAH8), causing stillbirth in Nordic Red Cattle.

Functional and population genetic features of copy number variations in two dairy cattle populations

“…Taken together, the studies that focused on mid-sized CNVs [62][63][64] are in line with our findings, whereas studies based on tiling oligonucleotide microarrays [65] and whole genome sequencing data [5,66], which can provide rather complete genome-wide coverage with a various size range of CNVs [4], show different results.…”

“…Also, a deletion variant overlapping with ADAMTS17 was shown to be highly diverged between HOL and JER in a previous study [66]. Given that CNVR 1452 we found is a duplication locus, it might be a different mutation than the one found by Mesbah-Uddin et al [66]. Nonetheless, our and the previous findings revealed that CNVs overlapping with ADAMTS17 gene to be diverged between HOL and JER.…”

“…Among these genes, ADAMTS17 has been reported as one of the height determining genes in various species, such as cattle, horse, and human [46][47][48]. Also, a deletion variant overlapping with ADAMTS17 was shown to be highly diverged between HOL and JER in a previous study [66]. Given that CNVR 1452 we found is a duplication locus, it might be a different mutation than the one found by Mesbah-Uddin et al [66].…”

“…These studies were based on medium-to-large size human CNVs, and rat CNVs were found from exome arrays (CNV length ranged between 5 and 256 kb). However, more recent studies, based on a finer resolution of CNVs, concluded that CNVs are biased away from genes and functional elements [5,[65][66][67].…”

Functional and population genetic features of copy number variations in two dairy cattle populations

“…These studies were based on medium-to-large size human CNVs, and rat CNVs were found from exome arrays (CNV length ranged between 5 and 256 kb). However, more recent studies, based on a finer resolution of CNVs, concluded that CNVs are biased away from genes and functional elements [5,[65][66][67].…”