本期文章：《科学》：Volume 380 Issue 6648

美国Illumina公司Kyle Kai-How Farh等研究人员合作绘制出人类和灵长类动物中可容忍的遗传变异景观。该研究于2023年6月2日发表于国际一流学术期刊《科学》。

为了系统地解读人类遗传变异的影响，研究人员获得了来自233种灵长类动物的809只个体的全基因组测序数据，并确定了430万个常见的改变蛋白质的变异体与人类的直系同源物。结果表明，根据这些变体在其他灵长类动物种群中的高等位基因频率，可以推断它们在人类中具有非致畸作用。研究人员利用这一资源将所有可能的人类蛋白改变变体中的6%归类为可能是良性的，并通过深度学习推断其余94%的变体的致病性，这在诊断遗传病患者的致病变体方面达到了最先进的准确性。

据了解，个性化的基因组测序揭示了个体之间数以百万计的遗传差异，但人们对其临床相关性的理解在很大程度上仍然不完整。

附：英文原文

Title: The landscape of tolerated genetic variation in humans and primates

Author: Hong Gao, Tobias Hamp, Jeffrey Ede, Joshua G. Schraiber, Jeremy McRae, Moriel Singer-Berk, Yanshen Yang, Anastasia S. D. Dietrich, Petko P. Fiziev, Lukas F. K. Kuderna, Laksshman Sundaram, Yibing Wu, Aashish Adhikari, Yair Field, Chen Chen, Serafim Batzoglou, Francois Aguet, Gabrielle Lemire, Rebecca Reimers, Daniel Balick, Mareike C. Janiak, Martin Kuhlwilm, Joseph D. Orkin, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rousselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, R. Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S. Chuma, Julie E. Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Fabiano R. de Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, Joo Valsecchi do Amaral, Mariluce Messias, Maria N. F. da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J. Rabarivola, Alphonse Zaramody, Clifford J. Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H. Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D. Keyyu, Sascha Knauf, Minh D. Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Thomas Bataillon, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C. Kitchener, Dietmar Zinner, Ivo Gut, Amanda Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M. D. Beck, Govindhaswamy Umapathy, Christian Roos, Jean P. Boubli, Monkol Lek, Shamil Sunyaev, Anne O’Donnell-Luria, Heidi L. Rehm, Jinbo Xu, Jeffrey Rogers, Tomas Marques-Bonet, Kyle Kai-How Farh

Issue&Volume: 2023-06-02

Abstract: Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.

DOI: abn8197