The conservation of human functional variants and their effects across livestock species.
The conservation of human functional variants and their effects across livestock species.
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DOI：
10.1038/s42003-022-03961-1
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发表时间：
2022-09-21
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管人类功能变异的牲畜模型显然有潜力为驱动人类疾病和特征的生物机制提供重要的见解，但到目前为止，它们的使用一直受到限制。通过基因组编辑来生成这样的模型既昂贵又耗时，目前还不清楚哪些变异会在不同物种之间产生保守的影响。在这项研究中，我们通过研究人类功能变异的自然发生的牲畜模型来解决这些问题。我们发现，超过160万个人类变种的直系同源基因已经在驯化的哺乳动物物种中分离出来，其中包括数百个以前与人类特征和疾病直接相关的物种。与特定表型相关的变异模型，包括代谢紊乱和身高，在物种之间优先共享，这意味着在牲畜中研究这些表型的遗传基础特别容易。使用机器学习，我们证明了识别更有可能具有现有家畜同源基因的人类变体是可能的，重要的是，我们证明了功能变体的影响通常在家畜中是保守的，作用于具有相同影响方向的同源基因。因此，这项工作证明了自然产生的人类功能变异体的直系物牲畜携带者的巨大潜力，以解开它们的功能影响。对人类和牲畜物种中存在的遗传变异的调查支持了牲畜模型在提供对驱动人类疾病和特征的机制的洞察方面的明显潜力。
Despite the clear potential of livestock models of human functional variants to provide important insights into the biological mechanisms driving human diseases and traits, their use to date has been limited. Generating such models via genome editing is costly and time consuming, and it is unclear which variants will have conserved effects across species. In this study we address these issues by studying naturally occurring livestock models of human functional variants. We show that orthologues of over 1.6 million human variants are already segregating in domesticated mammalian species, including several hundred previously directly linked to human traits and diseases. Models of variants linked to particular phenotypes, including metabolomic disorders and height, are preferentially shared across species, meaning studying the genetic basis of these phenotypes is particularly tractable in livestock. Using machine learning we demonstrate it is possible to identify human variants that are more likely to have an existing livestock orthologue, and, importantly, we show that the effects of functional variants are often conserved in livestock, acting on orthologous genes with the same direction of effect. Consequently, this work demonstrates the substantial potential of naturally occurring livestock carriers of orthologues of human functional variants to disentangle their functional impacts. An investigation of genetic variants that exist across human and livestock species supports the clear potential of livestock models in providing insights into the mechanisms driving human diseases and traits.
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影响因子：
3.5
作者：
Lean, I. J.;Rabiee, A. R.
通讯作者：
Rabiee, A. R.
影响因子：
3.6
作者：
Kaser，Tobias
通讯作者：
Kaser，Tobias
影响因子：
16.6
作者：
Dutta P;Talenti A;Young R;Jayaraman S;Callaby R;Jadhav SK;Dhanikachalam V;Manikandan M;Biswa BB;Low WY;Williams JL;Cook E;Toye P;Wall E;Djikeng A;Marshall K;Archibald AL;Gokhale S;Kumar S;Hume DA;Prendergast JGD
通讯作者：
Prendergast JGD
影响因子：
14.9
作者：
Hinrichs AS;Karolchik D;Baertsch R;Barber GP;Bejerano G;Clawson H;Diekhans M;Furey TS;Harte RA;Hsu F;Hillman-Jackson J;Kuhn RM;Pedersen JS;Pohl A;Raney BJ;Rosenbloom KR;Siepel A;Smith KE;Sugnet CW;Sultan-Qurraie A;Thomas DJ;Trumbower H;Weber RJ;Weirauch M;Zweig AS;Haussler D;Kent WJ
通讯作者：
Kent WJ
影响因子：
30.8
作者：
Canela-Xandri O;Rawlik K;Tenesa A
通讯作者：
Tenesa A