Département de Biologie, Université Laval, Québec, QC, Canada.
Département de Biochimie, Microbiologie et Bio-Informatique, Université Laval, Québec, QC, Canada.
Mol Syst Biol. 2019 Sep;15(9):e8871. doi: 10.15252/msb.20198871.
The protective redundancy of paralogous genes partly relies on the fact that they carry their functions independently. However, a significant fraction of paralogous proteins may form functionally dependent pairs, for instance, through heteromerization. As a consequence, one could expect these heteromeric paralogs to be less protective against deleterious mutations. To test this hypothesis, we examined the robustness landscape of gene loss-of-function by CRISPR-Cas9 in more than 450 human cell lines. This landscape shows regions of greater deleteriousness to gene inactivation as a function of key paralog properties. Heteromeric paralogs are more likely to occupy such regions owing to their high expression and large number of protein-protein interaction partners. Further investigation revealed that heteromers may also be under stricter dosage balance, which may also contribute to the higher deleteriousness upon gene inactivation. Finally, we suggest that physical dependency may contribute to the deleteriousness upon loss-of-function as revealed by the correlation between the strength of interactions between paralogs and their higher deleteriousness upon loss of function.
同源基因的保护冗余部分依赖于它们独立发挥功能这一事实。然而，相当一部分同源蛋白可能形成功能依赖的对，例如通过异源二聚化。因此，人们可能会预期这些异源二聚体同源基因对有害突变的保护作用较弱。为了验证这一假设，我们通过 CRISPR-Cas9 在超过 450 个人类细胞系中检测了基因功能丧失的稳健性景观。该景观显示了随着关键同源基因属性的变化，基因失活的有害性更大的区域。由于异源二聚体同源基因的高表达和大量的蛋白质-蛋白质相互作用伙伴，它们更有可能占据这些区域。进一步的研究表明，异源二聚体也可能受到更严格的剂量平衡的影响，这也可能导致基因失活时的更高有害性。最后，我们认为，物理依赖性可能会导致功能丧失时的有害性，正如同源基因之间相互作用的强度与其功能丧失时的更高有害性之间的相关性所揭示的那样。
