GenPhySE, Université de Toulouse, INRAE, ENVT, 31326, Castanet-Tolosan, France.
CDEO, Quartier Ahetzia, 64130, Ordiarp, France.
Genet Sel Evol. 2024 Feb 29;56(1):16. doi: 10.1186/s12711-024-00886-7.
Recessive deleterious variants are known to segregate in livestock populations, as in humans, and some may be lethal in the homozygous state.
We used phased 50 k single nucleotide polymorphism (SNP) genotypes and pedigree data to scan the genome of 6845 Manech Tête Rousse dairy sheep to search for deficiency in homozygous haplotypes (DHH). Five Manech Tête Rousse deficient homozygous haplotypes (MTRDHH1 to 5) were identified, with a homozygous deficiency ranging from 84 to 100%. These haplotypes are located on Ovis aries chromosome (OAR)1 (MTRDHH2 and 3), OAR10 (MTRDHH4), OAR13 (MTRDHH5), and OAR20 (MTRDHH1), and have carrier frequencies ranging from 7.8 to 16.6%. When comparing at-risk matings between DHH carriers to safe matings between non-carriers, two DHH (MTRDHH1 and 2) were linked with decreased insemination success and/or increased stillbirth incidence. We investigated the MTRDHH1 haplotype, which substantially increased stillbirth rate, and identified a single nucleotide variant (SNV) inducing a premature stop codon (p.Gln409*) in the methylmalonyl-CoA mutase (MMUT) gene by using a whole-genome sequencing approach. We generated homozygous lambs for the MMUT mutation by at-risk mating between heterozygous carriers, and most of them died within the first 24 h after birth without any obvious clinical symptoms. Reverse transcriptase-qPCR and western blotting on post-mortem liver and kidney biological samples showed a decreased expression of MMUT mRNA in the liver and absence of a full-length MMUT protein in the mutant homozygous lambs.
We identified five homozygous deficient haplotypes that are likely to harbor five independent deleterious recessive variants in sheep. One of these was detected in the MMUT gene, which is associated with lamb lethality in the homozygous state. A specific management of these haplotypes/variants in the MTR dairy sheep selection program would help enhance the overall fertility and lamb survival.
与人类一样，隐性有害变异在畜群中也会发生分离，其中一些在纯合状态下可能是致命的。
我们使用相配套的 50k 单核苷酸多态性（SNP）基因型和系谱数据，对 6845 只曼尼彻特罗塞乳羊进行扫描，以寻找纯合单倍型（DHH）缺失。鉴定出 5 种曼尼彻特罗塞纯合缺失单倍型（MTRDHH1 至 5），纯合缺失率为 84%至 100%。这些单倍型位于绵羊 Ovis aries 染色体（OAR）1（MTRDHH2 和 3）、OAR10（MTRDHH4）、OAR13（MTRDHH5）和 OAR20（MTRDHH1）上，携带频率为 7.8%至 16.6%。当比较 DHH 携带者的风险交配与非携带者的安全交配时，两种 DHH（MTRDHH1 和 2）与授精成功率降低和/或死产发生率增加相关。我们研究了 MTRDHH1 单倍型，它显著增加了死产率，并通过全基因组测序方法确定了一个导致甲基丙二酰辅酶 A 变位酶（MMUT）基因过早终止密码子（p.Gln409*）的单核苷酸变异（SNV）。我们通过杂合子携带者之间的风险交配产生了 MMUT 突变的纯合羔羊，其中大多数在出生后 24 小时内死亡，没有任何明显的临床症状。对死后肝脏和肾脏生物样本的逆转录酶-qPCR 和 Western blot 分析显示，肝脏中 MMUT mRNA 的表达降低，突变纯合羔羊中不存在全长 MMUT 蛋白。
我们鉴定了 5 种纯合缺失单倍型，它们可能在绵羊中携带 5 种独立的隐性有害突变。其中一种在 MMUT 基因中被检测到，与纯合状态下羔羊的致死性有关。在 MTR 乳羊选择计划中对这些单倍型/变异体进行特定的管理，将有助于提高整体繁殖力和羔羊存活率。
