How does cryptic genetic variation influence the long-term fate of gene duplicates (paralogs)?
Our new study addresses this question by dissecting the evolutionary potential of redundant myosin paralogs in yeast nature.com/articles/s41... (1/12)

Fantastic study of the evolution of epistasis in paralogs!

n summary:
Cryptic genetic variation — both regulatory and coding variation— biases the future of redundant gene duplicates by altering the effects of new mutations (12/12) #evolution #epistasis #genetics

Our work underscores the importance of historical contingency in molecular evolution. Redundant paralogs are not evolutionary blank slates — they are subtly shaped by past substitutions and regulatory shifts that influence their future evolution (11/12)

Thus, cryptic divergence alters the functional landscape of gene duplicates. A mutation that is benign in one paralog can be deleterious in the other, thereby shaping asymmetric evolutionary trajectories and biasing the potential for subfunctionalization or loss of one of the paralogs (10/12)

To explore the origin of this divergence in effects, we introduced historical substitutions from one paralog into the other individually and in pairs. We found strong evidence of pairwise epistasis: certain mutations only impacted function in specific sequence contexts (9/12)

Approximately 15% of mutations showed divergence in functional effects between domains, which we refer to as contingent mutations, even when both domains were expressed at the same levels. These mutations were enriched at solvent-exposed, consistent with roles in binding specificity (8/12)

Not all mutations were globally destabilizing for all interactions. Some selectively impaired binding to a single interaction partner, suggesting that such changes could lead to subfunctionalization — the partitioning of ancestral functions between paralogs (7/12)

By swapping the SH3 domains between the two paralogs, we found that the expression level alone can modulate the severity of binding impairment. A mutation's impact is not fixed — it depends on the expression level of the protein in which it occurs (6/12)

We found the divergence in functional effects arose from two main sources:
1. Regulatory divergence — MYO5 is more highly expressed than MYO3, buffering it against deleterious mutations
2. Sequence divergence — cryptic amino acid substitutions that modulate mutational effects via epistasis (5/12)

We found that many mutations exhibited paralog-specific effects. Identical substitutions in the two SH3 domains led to divergent impacts on binding, demonstrating that even functionally redundant domains diverge in their evolutionary potential (4/12)

We combined saturated mutagenesis and CRISPR with high-throughput phenotyping of SH3 domains of MYO3 and MYO5 in S. cerevisiae, introducing all possible single amino acid substitutions, and assessed how these variants affected binding to 8 biologically relevant protein interaction partners (3/12)

Although paralogs like myosin-3 (MYO3) and myosin-5 (MYO5) often retain redundant functions, they gradually accumulate subtle changes in expression and sequence that do not immediately impact function, a phenomenon called cryptic divergence (2/12)

How does cryptic genetic variation influence the long-term fate of gene duplicates (paralogs)?
Our new study addresses this question by dissecting the evolutionary potential of redundant myosin paralogs in yeast nature.com/articles/s41... (1/12)

Welcome! Hi Harmit!!