PT  - JOURNAL ARTICLE
AU  - Kachroo, Aashiq H.
AU  - Laurent, Jon M.
AU  - Yellman, Christopher M.
AU  - Meyer, Austin G.
AU  - Wilke, Claus O.
AU  - Marcotte, Edward M.
TI  - Systematic humanization of yeast genes reveals conserved functions and genetic modularity
AID  - 10.1126/science.aaa0769
DP  - 2015 May 22
TA  - Science
PG  - 921--925
VI  - 348
IP  - 6237
4099  - http://science.sciencemag.org/content/348/6237/921.short
4100  - http://science.sciencemag.org/content/348/6237/921.full
SO  - Science2015 May 22; 348
AB  - How far across evolution do families of genes retain their function? Yeast and humans are separated by roughly a billion years of evolutionary history, and yet genes from one can substitute for orthologous genes in the other. To study this effect systematically, Kachroo et al. replaced over 400 essential yeast genes with their human orthologs. Roughly half of the human genes could functionally replace their yeast counterparts. Genes being in the same pathway was as important as sequence or expression similarity in determining replaceability.Science, this issue p. 921To determine whether genes retain ancestral functions over a billion years of evolution and to identify principles of deep evolutionary divergence, we replaced 414 essential yeast genes with their human orthologs, assaying for complementation of lethal growth defects upon loss of the yeast genes. Nearly half (47%) of the yeast genes could be successfully humanized. Sequence similarity and expression only partly predicted replaceability. Instead, replaceability depended strongly on gene modules: Genes in the same process tended to be similarly replaceable (e.g., sterol biosynthesis) or not (e.g., DNA replication initiation). Simulations confirmed that selection for specific function can maintain replaceability despite extensive sequence divergence. Critical ancestral functions of many essential genes are thus retained in a pathway-specific manner, resilient to drift in sequences, splicing, and protein interfaces.