Twin and multiple births are rare in cattle and have a negative impact on the performance and health of cows and calves. Therefore, selection against multiple birth would be desirable in dairy cattle breeds such as Holstein. We applied different methods to decipher the genetic architecture of this trait using de-regressed breeding values for maternal multiple birth of ~ 2500 Holstein individuals to perform genome-wide association analyses using ~ 600 K imputed single nucleotide polymorphisms (SNPs). In the population studied, we found no significant genetic trend over time of the estimated breeding values for multiple birth, which indicates that this trait has not been selected for in the past. In addition to several suggestive non-significant quantitative trait loci (QTL) on different chromosomes, we identified a major QTL on chromosome 11 for maternal multiple birth that explains ~ 16% of the total genetic variance. Using a haplotype-based approach, this QTL was fine-mapped to a 70-kb window on chromosome 11 between 31.00 and 31.07 Mb that harbors two functional candidate genes (LHCGR and FSHR). Analysis of whole-genome sequence data by linkage-disequilibrium estimation revealed a regulatory variant in the 5ʹ-region of LHCGR as a possible candidate causal variant for the identified major QTL. Furthermore, the identified haplotype showed significant effects on stillbirth and days to first service. QTL detection and subsequent identification of causal variants in livestock species remain challenging in spite of the availability of large-scale genotype and phenotype data. Here, we report for the first time a major QTL for multiple birth in Holstein cattle and provide evidence for a linked variant in the non-coding region of a functional candidate gene. This discovery, which is a first step towards the understanding of the genetic architecture of this polygenic trait, opens the path for future selection against this undesirable trait, and thus contributes to increased animal health and welfare.

中文翻译：

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荷斯坦牛多胎 LHCGR/FSHR 位点的主要 QTL

双胞胎和多胞胎在牛中很少见，会对奶牛和犊牛的生产性能和健康产生负面影响。因此，对于荷斯坦等奶牛品种来说，针对多胎的选择是可取的。我们采用不同的方法来破译该性状的遗传结构，使用约 2500 个荷斯坦个体的母体多胎的去回归育种值，并使用约 600 K 估算的单核苷酸多态性 (SNP) 进行全基因组关联分析。在所研究的群体中，我们发现多胞胎的估计育种值随着时间的推移没有显着的遗传趋势，这表明过去没有选择该性状。除了不同染色体上的几个暗示性的非显着数量性状位点 (QTL) 之外，我们还在 11 号染色体上确定了母体多胞胎的一个主要 QTL，它解释了约 16% 的总遗传变异。使用基于单倍型的方法，该 QTL 被精细定位到 11 号染色体上 31.00 至 31.07 Mb 之间的 70 kb 窗口，该窗口包含两个功能候选基因（LHCGR 和 FSHR）。通过连锁不平衡估计对全基因组序列数据进行分析，揭示了 LHCGR 5′区的调控变异，作为已确定的主要 QTL 的可能候选因果变异。此外，所鉴定的单倍型对死产和首次服务天数显示出显着影响。尽管可以获得大规模基因型和表型数据，但牲畜物种中的 QTL 检测和随后的因果变异鉴定仍然具有挑战性。在这里，我们首次报告了荷斯坦牛多胎的主要 QTL，并为功能候选基因非编码区的连锁变异提供了证据。这一发现是了解这种多基因性状遗传结构的第一步，为未来针对这种不良性状的选择开辟了道路，从而有助于提高动物健康和福利。