PT  - JOURNAL ARTICLE
AU  - Li Liu
AU  - Mengdi Liu
AU  - Di Zhang
AU  - Shanjun Deng
AU  - Piaopiao Chen
AU  - Jing Yang
AU  - Yunhan Xie
AU  - Xionglei He
TI  - Decoupling gene knockout effects from gene functions by evolutionary analyses
AID  - 10.1101/688358
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 688358
4099  - http://biorxiv.org/content/early/2020/03/25/688358.short
4100  - http://biorxiv.org/content/early/2020/03/25/688358.full
AB  - 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 little 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 gene deletion effects support related biochemical understandings with the rest being pleiotropic and evolutionarily decoupled from the gene’s normal functions.