Gene function & annotation

Confirmation and fine-mapping of a lethal recessive haplotype in Norwegian Red cattle

---

Abstract

This study aims to confirm and fine-map a previously identified recessive lethal haplotype and identify new candidates within the Norwegian Red (NR) cattle breed. In 2021, we conducted a preliminary search for potential lethal recessives in the NR cattle breed and identified a candidate haplotype on chromosome 8 (BTA8H). A haplotype test for this variant was subsequently implemented in the NR breeding programme. Since then, the number of available NR genotypes has doubled, thereby increasing the power to detect recessive lethal haplotypes. In the present study we performed a genome-wide search for lethal recessives using 240,279 NR genotypes imputed to 45,253 single nucleotide polymorphic (SNP) sites. A single SNP sliding window approach was applied to construct a haplotype library, with each haplotype consisting of 20 SNPs. Haplotypes were extracted and deviations between observed and expected homozygous counts were assessed using two binomial tests based on haplotype frequency, together with a pedigree-based test. Four haplotypes exhibited a binomial test q-value > 10 across all three tests. Out of these, three had some homozygous individuals observed, whereas BTA8H had none. To validate the effect of these four haplotypes, we analysed 4.8 million inseminations from 2004 to 2022 and evaluated the non-return rates at 35 (NRR35), 56 (NRR56), and 100 (NRR100) days. Two haplotypes, BTA8H and a haplotype on chromosome 12 (tagging a well known deletion causing late returns) showed reduced non-return rates for carrier matings. Carrier matings for BTA8H showed a reduced NRR56 (58.3%) compared with other matings (65.3%), confirming its negative impact on fertility. The NRR35 was also reduced, indicating that BTA8H is an early embryonic lethal. The highest significance on chromosome 8 was found in the region 69.5-70.5Mb and we did fine-mapping in a 3Mb region surrounding this interval. The BTA8H region contains 38 protein coding and 18 RNA genes of which four, CHMP7, POLR3D, SLC25A37, and XPO7, are embryonic lethal when knocked out in mouse. The POLR3D knockout in mice is early embryonic lethal, while the other three genes confer lethality at later development stages. We then extracted sequence variants in the region from 1000 Bulls Run 8 for 320 NR bulls and computed their correlation with BTA8H carrier status. The sequence variants with high correlation to BTA8H (r2 >0.95) includes a single variant (rs460084491) in POLR3D. This variant is a splice region variant and represents a compelling candidate for the causal mutation. By integrating large-scale genomic data with insemination records we confirmed BTA8H as a recessive lethal haplotype and identified a plausible candidate causal mutation in POLR3D.

Keywords: 2026

How to Cite:

Gjuvsland, A. & Jenko, J., (2026) “Confirmation and fine-mapping of a lethal recessive haplotype in Norwegian Red cattle”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2285396. doi: https://doi.org/10.31274/wcgalp.23681

Rights: 1