Decoupling gene functions from knockout effects by evolutionary analyses

• 作者: Di Zhang Jing Yang Li Liu Mengdi Liu Piaopiao Chen Shanjun Deng Xionglei He Yunhan Xie
• 来源期刊: 国家科学评论（英文版）
• 关键词: pleiotropy mutational effects heritability reverse genetics gene function
• 年，卷（期）: 2020,（7）
• 页码范围: 1169-1180
• 页数: 12页
• 语种: 英文
• DOI: 10.1093/nsr/nwaa079

摘要

Genic functions have long been confounded by pleiotropic mutational effects.To understand such genetic effects,we examine HAP4,a well-studied transcription factor in Saccharomyces cerevisiae that functions by forming a tetramer with HAP2,HAP3 and HAP5.Deletion of HAP4 results in highly pleiotropic gene expression responses,some of which are clustered in related cellular processes (clustered effects) while most are distributed randomly across diverse cellular processes (distributed effects).Strikingly,the distributed effects that account for much of HAP4 pleiotropy tend to be non-heritable in a population,suggesting they have few evolutionary consequences.Indeed,these effects are poorly conserved in closely related yeasts.We further show substantial overlaps of clustered effects,but not distributed effects,among the four genes encoding the HAP2/3/4/5 tetramer.This pattern holds for other biochemically characterized yeast protein complexes or metabolic pathways.Examination of a set of cell morphological traits of the deletion lines yields consistent results.Hence,only some deletion effects of a gene support related biochemical understandings with the rest being often pleiotropic and evolutionarily decoupled from the gene's normal functions.This study suggests a new framework for reverse genetic analysis.