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人类功能丧失的遗传变异可用于评估药物靶标
2020-05-29 13:22

近日,美国麻省总医院Daniel G. MacArthur、Eric Vallabh Minikel等研究人员合作发现,人类功能丧失的遗传变异可用于评估药物靶标。这一研究成果发表在2020年5月27日出版的国际学术期刊《自然》上。

研究人员报道了有关使用人类功能丧失型变体评估候选药物靶标的三个关键发现。首先,即使是不容忍功能丧失变异的必需基因,也可以作为抑制药物的靶标。其次,在大多数基因中,功能丧失的变异非常罕见。第三,自动的变体注释和过滤功能强大,但是手动管理对于消除缺陷仍然至关重要。
 
这些结果为人类基因敲除研究提供了路线图,并能够指导药物开发中对于功能丧失型变异的理解。
 
据了解,自然发生的人类遗传变异(可能会导致蛋白质编码基因失活)提供了人类基因失活的体内模型,这可以补充细胞和模型生物的基因敲除研究。
 
附:英文原文

Title: Evaluating drug targets through human loss-of-function genetic variation

Author: Eric Vallabh Minikel, Konrad J. Karczewski, Hilary C. Martin, Beryl B. Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alfldi, Richard C. Trembath, David A. van Heel, Mark J. Daly, Stuart L. Schreiber, Daniel G. MacArthur

Issue&Volume: 2020-05-27

Abstract: Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous ‘knockout’ humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.

DOI: 10.1038/s41586-020-2267-z

Source: https://www.nature.com/articles/s41586-020-2267-z

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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