小柯机器人

使用替代表型的非添加关联分析鉴定新型牛综合征，这一成果由新西兰梅西大学Mathew D. Littlejohn研究组经过不懈努力而取得。该研究成果于2021年5月27日发表在国际学术期刊《自然-遗传学》上。

在本研究中，研究人员报道了迄今为止最大的牛序列解析筛选之一，该筛选旨在发现和验证130,725只动物中的非添加效应。研究人员重点介绍了六个新发现的隐性基因座，其影响超过了从全基因组关联研究中确定的最大效应变异体，并发现了与人类疾病和迄今未知疾病有关的类似物。这些基因座表现出显著的错义（PLCD4、MTRF1和DPF2）、过早终止（MUS81）和剪接破坏（GALNT2和FGD4）突变，这共同解释了近交下降的实质性比例。

这些结果表明，对选定物种进行有害等位基因频率分布分析可提供能直接绘制新型疾病图谱的信息，从而提供了将遗传疾病发生率降至最低的机会。 

研究人员表示，每种哺乳动物个体都携带约100个功能丧失变体，其中有1-5个影响必需基因并在纯合时引起胚胎致死或严重疾病。尽管科学家认为这些变体以不太明显的方式影响适应性，但其余变体的功能仍难解析。

附：英文原文

Title: Non-additive association analysis using proxy phenotypes identifies novel cattle syndromes

Author: Edwardo G. M. Reynolds, Catherine Neeley, Thomas J. Lopdell, Michael Keehan, Keren Dittmer, Chad S. Harland, Christine Couldrey, Thomas J. J. Johnson, Kathryn Tiplady, Gemma Worth, Mark Walker, Stephen R. Davis, Richard G. Sherlock, Katie Carnie, Bevin L. Harris, Carole Charlier, Michel Georges, Richard J. Spelman, Dorian J. Garrick, Mathew D. Littlejohn

Issue&Volume: 2021-05-27

Abstract: Mammalian species carry ~100 loss-of-function variants per individual1,2, where ~1–5 of these impact essential genes and cause embryonic lethality or severe disease when homozygous3. The functions of the remainder are more difficult to resolve, although the assumption is that these variants impact fitness in less manifest ways. Here we report one of the largest sequence-resolution screens of cattle to date, targeting discovery and validation of non-additive effects in 130,725 animals. We highlight six novel recessive loci with impacts generally exceeding the largest-effect variants identified from additive genome-wide association studies, presenting analogs of human diseases and hitherto-unrecognized disorders. These loci present compelling missense (PLCD4, MTRF1 and DPF2), premature stop (MUS81) and splice-disrupting (GALNT2 and FGD4) mutations, together explaining substantial proportions of inbreeding depression. These results demonstrate that the frequency distribution of deleterious alleles segregating in selected species can afford sufficient power to directly map novel disorders, presenting selection opportunities to minimize the incidence of genetic disease.

DOI: 10.1038/s41588-021-00872-5

Source: https://www.nature.com/articles/s41588-021-00872-5

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex