Abstract
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.
Highlights
After a gene duplication event and before they become functionally distinct, paralogs are redundant and can mask each other’s inactivating mutations (Pickett & Meeks-Wagner, 1995; Brookfield, 1997; Diss et al, 2014)
Paralogous genes protect against the effect of gene LOF across all cell lines We used two datasets of paralogous genes, one of relatively young paralogs, largely derived from small-scale duplications (Lan & Pritchard, 2016) and another set of relatively old paralogs most likely derived from whole-genome duplication (Data ref: Ohnolog, 2018; total of 3,132 pairs of paralogs, see Materials and Methods, Dataset EV1)
We first examined whether paralogous genes protect against the deleterious effects of LOF mutations in a set of 455 human cell lines from three independent CRISPR-Cas9 genome-wide LOF screens (Table EV1)
Summary
After a gene duplication event and before they become functionally distinct, paralogs are redundant and can mask each other’s inactivating mutations (Pickett & Meeks-Wagner, 1995; Brookfield, 1997; Diss et al, 2014). A parallel observation in humans showed that genes are less likely to be involved in diseases if they have a paralog, and the probability of disease association for a gene decreases with increasing sequence similarity with its closest homolog in the genome (Hsiao & Vitkup, 2008). These observations, along with smaller scale observations made in classical genetics (Pickett & Meeks-Wagner, 1995; Diss et al, 2014), strongly demonstrate that redundancy allows paralogs to compensate for each other’s LOF at the molecular level
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