Loss-of-function mutation survey revealed that genes with background-dependent fitness are rare and functionally related in yeast

Caudal, Elodie; Friedrich, Anne; Jallet, Arthur J.; Garin, Marion; Hou, Jing; Schacherer, Joseph

doi:10.1073/pnas.2204206119

Cited by 17 publications

(14 citation statements)

References 42 publications

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“…The laboratory strain S288C, which was used in this study, has a hypomorphic allele of HAP1 (Gaisne et al 1999 ), which is a heme-responsive transcriptional activator of genes involved in respiration (Zhang and Hach 1999) (notably, genes with increased expression in CNV strains include siderophores, which chelate iron). Across many genetically distinct strains of yeast, genes involved in aerobic respiration and the electron transport chain vary more than any other category during growth in glucose-limited chemostats (Skelly et al 2013), and genes involved in mitochondrial function have continuous variation in fitness effects across different isolates (Caudal et al 2022). It would be instructive to study the relationship between mitochondrial function and CNV tolerance.…”

Section: Discussionmentioning

confidence: 99%

Copy number variants alter local and global mutational tolerance

Avecilla

Spealman

Matthews

et al. 2022

Preprint

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Copy number variants (CNVs), duplications and deletions of genomic content, contribute to evolutionary adaptation, but can also confer deleterious effects, and cause disease. Whereas the effects of amplifying individual genes or whole chromosomes (i.e., aneuploidy) have been studied extensively, much less is known about the genetic and functional effects of CNVs of differing sizes and structures. Here, we investigated Saccharomyces cerevisiae (yeast) strains that have CNVs of variable structures but with multiple copies of the gene GAP1. Although beneficial in glutamine-limited chemostats, CNVs result in decreased fitness compared with the euploid ancestor in rich media. We used transposon mutagenesis to investigate mutational tolerance and genetic interactions with CNVs. We find that CNVs confer novel mutational tolerance in amplified essential genes and novel genetic interactions. We validated a novel genetic interaction with BMH1. CNV strains have increased mutational tolerance in genes related to translation, and reduced mutational tolerance in genes related to mitochondrial function. We performed RNAseq and found that transcriptional dosage compensation does not affect the majority of genes amplified by CNVs. Furthermore, we do not find that CNV strains exhibit previously described transcriptional signatures of aneuploidy. Instead, CNV strains exhibit downregulation of genes involved in cellular respiration, nucleoside biosynthetic processes, and small molecule metabolism, and upregulation of genes involved in transposition, nucleic acid metabolic processes, and siderophore transport. Our study reveals the extent to which local and global mutational tolerance is modified by CNVs with implications for genome evolution and CNV associated diseases, such as cancer.

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Section: Discussionmentioning

confidence: 99%

Copy number variants alter local and global mutational tolerance

Avecilla

Spealman

Matthews

et al. 2022

Preprint

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“…Intra-specific HGT, mediated by plasmids, phage, and transduction account for most gene transfers into a genome. Though there has been some disagreement on the relative influences of random drift and natural selection on structuring pangenomes, a body of work has now shown that the presence or absence of specific genes (genetic background) can influence the presence or absence of others (Rosconi et al, 2022, Beavan and McInerney, 2022, Caudal et al, 2022). Consequently, the content of every contemporary prokaryotic genome is an outcome of its history of vertical and horizontal gene transmission and has emerged via a combination of internal (intragenomic) and external (ecological) fitness effects (McInerney, 2023) in addition to stochastic, non-adaptive evolution (genetic drift).…”

Section: Introductionmentioning

confidence: 99%

Contingency, Repeatability and Predictability in the Evolution of a Prokaryotic Pangenome

Beavan

Domingo-Sananes

McInerney

2023

Preprint

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Pangenomes exhibit remarkable variability in many prokaryotic species. This variation is maintained through the processes of horizontal gene transfer and gene loss. Repeated acquisitions of near-identical homologs can easily be observed across pangenomes, leading to the question of whether these parallel events potentiate similar evolutionary trajectories, or whether the remarkably different genetic background of the recipients mean that post-acquisition evolutionary trajectories end up being quite different. In this study, we present a machine learning method that predicts the presence or absence of genes in individual genomes of a 2,500 genome sample of the Escherichia coli pangenome, based on the presence or absence of other accessory genes within the same genome. We are, in effect, asking whether gene acquisitions potentiate similar evolutionary trajectories or not. We found that the presence or absence of a substantial set of genes is highly predictable, from other genes alone, indicating that natural selection potentiates and maintains gene-gene co-occurrence and avoidance relationships deterministically over long-term bacterial evolution, despite differences in host evolutionary history. We propose that the pangenome can be understood as a set of genes with relationships that govern their likely cohabitants, analogous to an ecosystem's set of interacting organisms. Our findings highlight intra-genomic gene fitness effects as key drivers of prokaryotic evolution, with ensuing pangenome-wide emergence of repeated patterns of community structure.

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“…In these cells, despite a strongly deleterious effect on organismal fitness, copies of the mitochondrial genome deleted at loci essential for respiration may outcompete healthy copies thanks to their higher replication origin density ( de Zamaroczy et al 1981 ; Mangin et al 1983 ; Bernardi 2005 ). Furthermore, deletion screens in yeasts have also repeatedly identified signals of frequent essentiality switching among genes involved in mitochondrial functions, both across ( Kim et al 2010 ) and within species ( Caudal et al 2022 ; Chen et al 2022 ), suggesting enhanced evolvability at these loci. In summary, because of unique characteristics and selection pressures, the rate of evolution tends to be higher in the mitochondrial genome than in the nuclear genome, with a critical influence on genetic divergence, speciation, reproductive strategies, and morphology ( Hill 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Trajectories are Contingent on Mitonuclear Interactions

Biot-Pelletier

Bettinazzi

Gagnon‐Arsenault

et al. 2023

Molecular Biology and Evolution

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Critical mitochondrial functions, including cellular respiration, rely on frequently interacting components expressed from both the mitochondrial and nuclear genomes. The fitness of eukaryotic organisms depends on a tight collaboration between both genomes. In the face of an elevated rate of evolution in mtDNA, current models predict that maintenance of mitonuclear compatibility relies on compensatory evolution of the nuclear genome. Mitonuclear interactions would therefore exert an influence on evolutionary trajectories. One prediction from this model is that the same nuclear genome evolving with different mitochondrial haplotypes would follow distinct molecular paths towards higher fitness. To test this prediction, we submitted 1344 populations derived from seven mitonuclear genotypes of Saccharomyces cerevisiae to more than 300 generations of experimental evolution in conditions that either select for a mitochondrial function, or that do not strictly require respiration for survival. Performing high-throughput phenotyping and whole-genome sequencing on independently evolved individuals, we identified numerous examples of gene-level evolutionary convergence among populations with the same mitonuclear background. Phenotypic and genotypic data on strains derived from this evolution experiment identify the nuclear genome and the environment as the main determinants of evolutionary divergence, but also show a modulating role for the mitochondrial genome exerted both directly and via interactions with the two other components. We finally recapitulated a subset of prominent loss-of-function alleles in the ancestral backgrounds and confirmed a generalized pattern of mitonuclear-specific and highly epistatic fitness effects. Together, these results demonstrate how mitonuclear interactions can dictate evolutionary divergence of populations with identical starting nuclear genotypes.

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Loss-of-function mutation survey revealed that genes with background-dependent fitness are rare and functionally related in yeast

Cited by 17 publications

References 42 publications

Copy number variants alter local and global mutational tolerance

Copy number variants alter local and global mutational tolerance

Contingency, Repeatability and Predictability in the Evolution of a Prokaryotic Pangenome

Evolutionary Trajectories are Contingent on Mitonuclear Interactions

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