Natural variation in the consequences of gene overexpression and its implications for evolutionary trajectories

Abstract

Copy number variation (CNV) through gene or chromosome amplification provides a route for rapid phenotypic variation and supports long-term evolution of gene functions. Although the evolutionary importance of CNV is known, little is understood about how genetic background influences CNV tolerance. Here, we measured fitness costs of over 4,000 over-expressed genes in 15 Saccharomyces cerevisiae strains representing different lineages, to explore natural variation in tolerating gene overexpression (OE). Strain-specific effects dominated the fitness costs of gene OE. We report global differences in the consequences of gene OE, independent of the amplified gene, as well as gene-specific effects that were dependent on the genetic background. Natural variation in the response to gene OE could be explained by several models, including strain-specific physiological differences, resource limitations, and regulatory sensitivities. This work provides new insight on how genetic background influences tolerance to gene amplification and the evolutionary trajectories accessible to different backgrounds.

The multiple fates of gene duplications: Deletion, hypofunctionalization, subfunctionalization, neofunctionalization, dosage balance constraints, and neutral variation

“…The complementary pattern of retained genes following WGD and segmental duplication is best explained by gene balance involving the stoichiometry of the interacting components of multicomponent cellular interactions, which if upset cause negative fitness consequences ( Veitia 2002 , 2003 , 2004 ; Papp et al, 2003 ; Schuster-Bockler et al, 2010 ; Makanae et al, 2013 ; Robinson et al, 2021 ). Other potential explanations do not predict a complementary pattern of gene functions.…”

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

“…One argument in this direction is that we and previous studies found smaller Leishmania chromosomes (with smaller numbers of genes) to be more frequently aneuploid, which matches observation in yeast and humans (chromosome 21 has the smallest number of genes in humans and the least severe autosomal aneuploid) [ 11 , 24 , 61 ]. Additionally, it has been shown in yeast that genes that are deleterious when overexpressed are enriched for protein complex subunits [ 62 ]. From this perspective, the situation in Leishmania could be similar to other single-celled organisms such as yeast, where the fitness benefits of aneuploidy must outweigh the fitness costs in a given environment [ 62 ].…”

“…Additionally, it has been shown in yeast that genes that are deleterious when overexpressed are enriched for protein complex subunits [ 62 ]. From this perspective, the situation in Leishmania could be similar to other single-celled organisms such as yeast, where the fitness benefits of aneuploidy must outweigh the fitness costs in a given environment [ 62 ].…”

Four layer multi-omics reveals molecular responses to aneuploidy in Leishmania

“…One argument in this direction is that we and previous studies found smaller Leishmania chromosomes to be more frequently aneuploid, which matches observation in yeast and humans (chromosome 21 has the smallest number of genes in humans and the least severe autosomal aneuploid) 10,23,58 . Additionally, it has been shown in yeast that genes that are deleterious when overexpressed are enriched for protein complex subunits 59 . Secondly, we observed a correlation between the degree of compensation and the cellular destination of the compensated protein.…”