Fine mapping genetic variants affecting birth weight in sheep: a GWAS of 3007 individuals using low-coverage whole genome sequencing

Abstract

Birth weight is a critical economic trait in livestock production. However, its genetic architecture remains poorly understood due to historical limitations in sample size and reliance on low-density SNP arrays. In this study, we utilized low-coverage whole-genome sequencing (lcWGS) to genotype 3,007 Hu sheep, bypassing the cost and resolution constraints of conventional genotyping arrays while achieving scalable genome-wide variant detection. LcWGS with high imputation accuracy (97.8% allelic concordance) enabled genome-wide association studies (GWAS) identifying two novel quantitative trait loci (QTLs) on chromosomes 6 and 9. The chromosome 9 QTL encompassed a regulatory region functionally linked to PLAG1 expression through expression quantitative trait locus (eQTL) mapping. Compared with wild-type homozygotes, heterozygous carriers of the lead SNP (chr9:g.35920172A > G) presented a 9.85% increase in birth weight (3.35 kg vs. 3.68 kg; Δ = 0.33 kg). Notably, the derived allele of this SNP exhibited low frequencies of < 0.1 across most global sheep breeds except Dorper, highlighting its potential for selective breeding applications. Leveraging lcWGS data, haplotype-based fine-mapping prioritized three candidate causal variants. A secondary QTL on chromosome 6 colocalized with the FecB mutation, a well-established locus associated with increased litter size. Intriguingly, individuals carrying one FecB allele showed a 6.18% reduction (0.22 kg) in birth weight, which tentatively indicates potential pleiotropic influences on both growth and reproductive traits. This study demonstrates the utility of lcWGS as a cost-effective, high-resolution tool for dissecting complex traits in livestock. Our findings not only advance the understanding of birth weight genetics in sheep but also offer a blueprint for accelerating genetic improvement programs in global livestock production through cost-effective, genome-wide approaches.