Deleterious recessive conditions have been primarily studied in the context of Mendelian diseases. Recently, several deleterious recessive mutations with large effects were discovered via non-additive genome-wide association studies (GWAS) of quantitative growth and developmental traits in cattle, which showed that quantitative traits can be used as proxies of genetic disorders when such traits are indicative of whole-animal health status. We reasoned that lactation traits in cattle might also reflect genetic disorders, given the increased energy demands of lactation and the substantial stresses imposed on the animal. In this study, we screened more than 124,000 cows for recessive effects based on lactation traits. We discovered five novel quantitative trait loci (QTL) that are associated with large recessive impacts on three milk yield traits, with these loci presenting missense variants in the DOCK8, IL4R, KIAA0556, and SLC25A4 genes or premature stop variants in the ITGAL, LRCH4, and RBM34 genes, as candidate causal mutations. For two milk composition traits, we identified several previously reported additive QTL that display small dominance effects. By contrasting results from milk yield and milk composition phenotypes, we note differing genetic architectures. Compared to milk composition phenotypes, milk yield phenotypes had lower heritabilities and were associated with fewer additive QTL but had a higher non-additive genetic variance and were associated with a higher proportion of loci exhibiting dominance. We identified large-effect recessive QTL which are segregating at surprisingly high frequencies in cattle. We speculate that the differences in genetic architecture between milk yield and milk composition phenotypes derive from underlying dissimilarities in the cellular and molecular representation of these traits, with yield phenotypes acting as a better proxy of underlying biological disorders through presentation of a larger number of major recessive impacts.

中文翻译：

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124,000 头牛泌乳性状的非加性 QTL 作图揭示了新的隐性基因座


有害的隐性病症主要是在孟德尔疾病的背景下进行研究的。最近，通过对牛数量生长和发育性状的非加性全基因组关联研究（GWAS）发现了几种具有巨大影响的有害隐性突变，这表明当数量性状具有指示性时，可以将其用作遗传性疾病的代表。整个动物的健康状况。我们推断，考虑到泌乳期能量需求的增加以及对动物造成的巨大压力，牛的泌乳特性也可能反映了遗传性疾病。在这项研究中，我们根据泌乳特性对超过 124,000 头奶牛进行了隐性效应筛查。我们发现了五个新的数量性状基因座（QTL），它们与三个产奶量性状的巨大隐性影响相关，这些基因座在 DOCK8、IL4R、KIAA0556 和 SLC25A4 基因中呈现错义变异，或在 ITGAL、LRCH4、和 RBM34 基因作为候选因果突变。对于两种牛奶成分性状，我们鉴定了几个先前报道的显示出较小显性效应的附加 QTL。通过对比产奶量和乳成分表型的结果，我们注意到不同的遗传结构。与乳成分表型相比，产奶量表型具有较低的遗传力，并且与较少的加性 QTL 相关，但具有较高的非加性遗传方差，并且与较高比例的表现出显性的基因座相关。我们鉴定出大效应隐性 QTL，它们在牛中以惊人的高频率分离。 我们推测，产奶量和奶成分表型之间遗传结构的差异源于这些性状的细胞和分子表征的潜在差异，产量表型通过呈现大量主要隐性基因，可以更好地代表潜在的生物疾病。影响。