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通过人类功能丧失的遗传变异来评估药物点
Eric Vallabh Minikel1,2,3,4,5,6,7,8, Konrad J Karczewski9,10, Hilary C Martin11
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. eminikel@broadinstitute.org.
Nature
|May 29, 2020
概括
人类遗传变异为基因功能和药物开发提供了洞察力. 重要基因可能是药物点,
科学领域:
- 遗传学
- 药理学
- 人类生物学
背景情况:
- 自然存在的人类遗传变异作为基因失活的体内模型.
- 这些变体补充了细胞和模型生物系统的传统淘汰研究.
- 评估候选药物标可以通过人类功能丧失变体获得信息.
研究的目的:
- 评估人类功能丧失变体在确定和验证药物标中的有用性.
- 探索重要基因的潜力, 即使是那些不能容忍功能丧失的基因,
- 评估基于基因型识别人类基因淘汰的可行性.
主要方法:
- 对自然发生的人类遗传变异的分析预测会使蛋白质编码基因失活.
- 对基本基因作为抑制药物的标的评估.
- 基于基因型确定同卵性或复合异卵性个体的变异性稀有性的评估.
- 使用自动化变体注释和过,并补充手动策划.
主要成果:
- 尽管对功能丧失有不耐受性, 但基本基因可以成为有效的药物标.
- 识别同卵性或复合异卵性"淘汰"人类需要显著更大的样本大小 (目前的1,000倍),除非专注于同血族群.
- 自动变体注释很强大,但手动策划对于准确性和基因型回忆研究至关重要.
结论:
- 人类功能丧失的变种对于药物标的评估有价值.
- 提供了人类淘汰研究的路线图,指导药物开发的解释.
- 这项研究强调了在药物研究中利用遗传变异的策略.
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