Exploring whole-genome duplicate gene retention (new paper in Science)

Here’s the lay(ish) summary:

The fate of genes after duplication

Gene duplication within an organism is a relatively common event during evolution. However, we cannot predict the fate of the duplicated genes: Will they be lost, evolve, or overlap in function within an organismal lineage or species? Kuzmin et al. explored the fate of duplicated gene function within the yeast Saccharomyces cerevisiae (see the Perspective by Ehrenreich). They examined how experimental deletions of one or two duplicated genes (paralogs) affected yeast fitness and were able to determine which genes have likely evolved new essential functions and which retained functional overlap, a condition the authors refer to as entanglement. On the basis of these results, they propose how entanglement affects the evolutionary trajectory of gene duplications.

Among other things, a nice new use of the word ‘entanglement’. Structured abstract:


Whole-genome duplication (WGD) events are pervasive in eukaryotes, shaping the genomes of simple single-celled organisms, such as yeast, as well as those of more complex metazoans, including humans. Most duplicated genes are eliminated after WGD because one copy accumulates deleterious mutations, leading to its loss. However, a significant proportion of duplicates persists, and factors that result in duplicate gene retention are poorly understood but critical for understanding the evolutionary forces that shape genomes.


Quantifying the functional divergence of paralog pairs is of particular interest because of the strong selection against functional redundancy. Negative genetic interactions identify functional relationships between genes and provide a means to directly capture the functional relationship between duplicated genes. Genetic interactions occur when the phenotype associated with a combination of mutations in two or more different genes deviates from the expected combined effect of the individual mutations. A negative genetic interaction refers to a combination of mutations that generates a stronger fitness defect than expected, such as synthetic lethality. Here, we used systematic analysis of digenic and trigenic interaction profiles to assess the functional relationship of retained duplicated genes.


To map both digenic and trigenic interactions of duplicated genes, we profiled query strains carrying single-deletion mutations and the corresponding double-deletion mutations for 240 different dispensable paralog pairs originating from the yeast WGD event. In total, we tested ~550,000 double and ~260,000 triple mutants for genetic interactions, and identified ~4700 negative digenic interactions and ~2500 negative trigenic interactions. We quantified the trigenic interaction fraction, defined as the ratio of negative trigenic interactions to the total number of interactions associated with the paralog pair. The distribution of the resulting trigenic interaction fractions was distinctly bimodal, with two-thirds of paralogs exhibiting a low trigenic interaction fraction (diverged paralogs) and one-third showing a high trigenic interaction fraction (functionally redundant paralogs). Paralogs with a high trigenic interaction fraction showed a relatively low asymmetry in their number of digenic interactions, low rates of protein sequence divergence, and a negative digenic interaction within the gene pair.

We correlated position-specific evolutionary rate patterns between paralogs to assess constraints acting on their evolutionary trajectories. Paralogs with a high trigenic interaction fraction showed more correlated evolutionary rate patterns and thus were more evolutionarily constrained than paralogs with a low trigenic interaction fraction. Computational simulations that modeled duplicate gene evolution revealed that as the extent of the initial entanglement (overlap of functions) of paralogs increased, so did the range of functional redundancy at steady state. Thus, the bimodal distribution of the trigenic interaction fraction may reflect that some paralogs diverged, primarily evolving distinct functions without redundancy, while others converged to an evolutionary steady state with substantial redundancy due to their structural and functional entanglement.


We propose that the evolutionary fate of a duplicated gene is dictated by an interplay of structural and functional entanglement. Paralog pairs with high levels of entanglement are more likely to revert to a singleton state. In contrast, unconstrained paralogs will tend to partition their functions and adopt divergent roles. Intermediately entangled paralog pairs may partition or expand nonoverlapping functions while also retaining some common, overlapping functions, such that they can both adopt paralog-specific roles and maintain functional redundancy at an evolutionary steady state.