Gene function & annotation

Updated genome scan for homozygous haplotype depletion identifies a POMT2 nonsense mutation causing stillbirth and embryonic loss in Normande cattle

---

Abstract

Genome-wide detection of homozygous genotype depletion among animals genotyped for genomic evaluation is a proven strategy to uncover recessive loci causing either embryonic lethality or early juvenile mortality. Here, we present an updated analysis based on the largest dataset assembled to date for the Normande breed, including 239,675 genotyped animals with available ancestor genotype information.By analyzing sliding windows of 20 markers across more than 44,000 phased and imputed SNPs from the Illumina BovineSNP50 array, we identified two significant signals. The strongest signal, located on chromosome 11 (one homozygote observed vs. 119 expected; Bonferroni-adjusted Poisson P (Padj) = 1.8 à— 10⁻⁵⁰), corresponded to a previously reported missense variant in the CAD gene. The second most significant signal (Padj = 6.0 x 10-18) on chromosome 10 showed only one observed vs. 54 expected for its lead haplotype.Analysis of juvenile mortality revealed a highly significant effect on stillbirth, with dead calf ratios of 33.1% versus 9.6% (χ² p = 3.1 à— 10⁻²⁵) in 181 and 7,433 offspring from at-risk matings (carrier sire à— carrier dam) and matched control matings (carrier sire à— non-carrier dam), respectively. Regarding fertility, the analysis of conception rate and 56-day non-return rate in 742 at-risk matings compared with 24,648 controls revealed significantly reduced performance (−5.1% and −5.6%; χ² p = 6.1 à— 10⁻³ and 2.0 à— 10⁻², respectively), although the effects were of lower magnitude.A search for candidate variants, leveraging whole-genome sequences of 5 Normande heterozygous bulls, 154 Normande wild-type bulls, and 1,006 individuals from 19 additional breeds, identified a single deleterious candidate variant: a stop-gain mutation in the Protein O-Mannosyltransferase 2 gene (POMT2; Chr10:g.88499167C >T; POMT2 p.W334X).The POMT2 gene encodes an enzyme involved in the glycosylation of α-dystroglycan. This process is essential for maintaining the stability of muscle fibres and ensuring normal brain development. Notably, several deleterious missense variants in POMT2 have been associated with congenital muscular dystrophy and brain defects in humans, whereas complete knockout of the gene results in embryonic lethality in mice. If expressed, the mutant protein would be truncated by approximately 62% and would lack several essential functional domains.Large-scale genotyping of the POMT2 variant in 94,727 Normande cattle using the custom Illumina EuroGMD revealed an absence of homozygotes. The allele frequency was estimated to be 1.8%. Among 1,275,893 additional animals from 20 breeds, all were wild type except nine Holsteins, which had some degree of Normande ancestry.In conclusion, we report a novel recessive genetic defect in Normande cattle, primarily responsible for stillbirth and, to a lesser extent, reduced fertility. The identification of the likely causative variant, now included on the genomic evaluation array, will allow efficient monitoring and help prevent future at-risk matings.

Keywords: 2026

How to Cite:

Roy, C., Barbat, A., Besnard, F., Hozé, C., Escouflaire, C., Boussaha, M., Grohs, C., Minéry, S., Boichard, D., Vinet, A., Fritz, S. & Capitan, A., (2026) “Updated genome scan for homozygous haplotype depletion identifies a POMT2 nonsense mutation causing stillbirth and embryonic loss in Normande cattle”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2286433. doi: https://doi.org/10.31274/wcgalp.24004

Rights: 1