Researchers: Gene Variation Adds to Breakdown Risk

While their paper still faces peer review, a group of researchers have concluded that their study indicates a gene variation may contribute to catastrophic breakdown risk in horses. According to a June 18 preprint in bioRxiv, which bills itself as the preprint server for biology, researchers found that a functional single nucleotide polymorphism, or gene variation, upstream of the collagen type III gene may contribute to catastrophic fracture risk in Thoroughbred horses. The abstract offered the following conclusion, "This approach provides a powerful means to identify novel DNA variants and understand their mechanism of action to enable the development of new ways to identify and treat horses at high risk of a catastrophic fracture." The full preprint offered a more detailed conclusion. "In conclusion, we have established a cell-based system to allow us to study the genetic basis of fracture in Thoroughbred horses. In support of previous work identifying a fracture-associated region on ECA18 (Blott et al. 2014; Tozaki et al. 2020), we demonstrated that one of the genes within this region, COL3A1, is differentially expressed in cells from horses at high and low risk of fracture and that this may in part be due to the presence of an associated SNP in the COL3A1 promoter," the study found. "The SNP may affect SOX11 binding, and we demonstrate that SOX11 modulates COL3A1 expression. These findings support future work using this system to identify other genes that are differently expressed across the genome and other SNPs that are involved in fracture risk. "This approach has the potential to be very valuable in teasing apart the complexity of the genetic basis for fracture risk." Researchers said the risk of such fractures has been shown to be influenced by both environmental and genetic factors but, to date, no specific genetic mechanisms underpinning fracture have been identified. The study's aim was to use a genome-wide polygenic risk score to establish an in vitro cell system to study bone gene regulation in horses at high and low genetic risk of fracture. Candidate gene expression analysis revealed differential expression of COL3A1 and STAT1 genes in osteoblasts derived from high- and low-risk horses. "Whole genome sequencing of fracture case and control horses revealed a single nucleotide polymorphism (SNP) upstream of COL3A1 that was confirmed in a larger cohort to be significantly associated with fracture," said the study abstract. The study's authors are Esther Palomino Lago and Amy C. Ross of Royal Veterinary College, Arabella Baird and Rhona McPhail of Animal Health Trust, Sarah Blott of the University of Nottingham, Sian Durward-Arkhurst of the University of Minnesota, and corresponding author Debbie Guest. Before formal publication in a scholarly journal, scientific and medical articles are traditionally certified by "peer review." In this process, the journal's editors take advice from various experts—called "referees"—who have assessed the paper and may identify weaknesses in its assumptions, methods, and conclusions. Typically, a journal will only publish an article once the editors are satisfied that the authors have addressed referees' concerns and that the data presented support the conclusions drawn in the paper. Because this process can be lengthy, authors use the bioRxiv service to make their manuscripts available as "preprints" before certification by peer review, allowing other scientists to see, discuss, and comment on the findings immediately.