Mutation rate, selection, and epistasis inferred from RNA virus haplotypes via neural posterior estimation

Caspi, Itamar; Meir, Moran; Nun, Nadav Ben; Rass, Reem Abu; Yakhini, Uri; Stern, Adi; Ram, Yoav

doi:10.1093/ve/vead033

Cited by 4 publications

(1 citation statement)

References 37 publications

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“…Despite this 𝑠 𝐶 δ 𝐶 under-confidence, the posterior distributions are narrow in biological terms: the 95% HDI represents less than an order of magnitude for both and . Thus, we did not apply post-training adjustments to the neural density estimator, such as 𝑠 𝐶 δ 𝐶 calibration (Cook et al, 2006) or ensembles (Caspi et al, 2023;Hermans et al, 2022).…”

Section: Breakpoint Analysis and Cnv Mechanism Inference In Sequenced...mentioning

confidence: 99%

DNA replication errors are a major source of adaptive gene amplification

Chuong,

Nun,

Suresh

et al. 2024

Preprint

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Detecting and understanding heritable changes in DNA that contribute to adaptive evolution is a primary goal of evolutionary biology. Copy number variants (CNVs) - gains and losses of genomic sequences - are an important source of genetic variation underlying rapid adaptation and genome evolution. However, despite their central role in evolution little is known about the factors that contribute to the structure, size, formation rate, and fitness effects of adaptive CNVs. Local genome elements are likely to be an important determinant of these properties. Whereas it is known that point mutation rates vary with genomic location and local sequence features, the role of genome architecture in the formation, selection, and the resulting evolutionary dynamics of CNVs is poorly understood. Previously, we have found that the GAP1 gene in Saccharomyces cerevisiae undergoes frequent and repeated amplification and selection under long-term experimental evolution in glutamine-limiting conditions. The GAP1 gene has a unique genomic architecture consisting of two flanking long terminal repeats (LTRs) and a proximate origin of DNA replication (autonomously replicating sequence, ARS), which are likely to promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution we performed experimental evolution in glutamine-limited chemostats using engineered strains lacking either the adjacent LTRs, ARS, or all elements. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. We find that although GAP1 CNVs repeatedly form and sweep to high frequency in all strains, removal of local DNA elements significantly impacts the rate and fitness effect of CNVs and the rate of adaptation. We performed genome sequence analysis to define the molecular mechanisms of CNV formation for 177 CNV lineages. We find that 49% of all GAP1 CNVs are mediated by the DNA replication-based mechanism Origin Dependent Inverted Repeat Amplification (ODIRA) regardless of background strain. In the absence of the local ARS, a distal ARS can mediate ODIRA CNV formation. In the absence of local LTRs homologous recombination mechanisms still mediate gene amplification following de novo insertion of retrotransposon elements at the locus. Our study demonstrates the remarkable plasticity of the genome and reveals that DNA replication errors are a predominant source of adaptive CNVs.

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Section: Breakpoint Analysis and Cnv Mechanism Inference In Sequenced...mentioning

confidence: 99%

DNA replication errors are a major source of adaptive gene amplification

Chuong,

Nun,

Suresh

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Navigating a fine balance: point-mutant cheater viruses disrupt the viral replication cycle

Meir,

Kahn,

Farage

et al. 2024

Preprint

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Cheater viruses, alternatively denoted as defective interfering viruses, cannot replicate on their own yet replicate faster than the wild type (WT) when the two viruses coinfect the same cell. Cheaters must possess dual genetic features: a defect, which leads to their inability to infect cells on their own, and a selective advantage over WT during co-infection. Previously, we have discovered two point-mutant cheaters of the MS2 bacteriophage. Here, we set out to discover the possible repertoire of cheater MS2 viruses by performing experimental evolution at a very high multiplicity of infection (MOI). Our results revealed a third point-mutant cheater that arose in eight biological replicas. Each of the three cheaters disrupts the fine balance necessary for phage replication, in different ways that create a defect + advantage. We found that over time, the point mutant cheaters accumulate additional "helper" mutations, which alter other stages of the viral replication cycle, complementing the disruptions created by the original cheater. Intriguingly, cheater and helper mutations almost always reside in very close proximity on the genome. This region encodes for multiple functions: overlapping reading frames as well as overlapping RNA structures critical for transitioning from one stage to another in the viral replication cycle. This region of overlap explains the dual functions of cheaters, as one mutation can have pleiotropic effects. Overall, these findings underscore how viruses, whose dense genomes often have overlapping functions, can easily evolve point-mutant cheaters, and how cheaters can evolve to alter the intricate balance of the viral replication cycle.

show abstract

DNA replication errors are a major source of adaptive gene amplification

Chuong,

Nun,

Suresh

et al. 2024

Preprint

View full text Add to dashboard Cite

Detecting and understanding heritable changes in DNA that contribute to adaptive evolution is a primary goal of evolutionary biology. Copy number variants (CNVs)—gains and losses of genomic sequences—are an important source of genetic variation underlying rapid adaptation and genome evolution. However, despite their central role in evolution little is known about the factors that contribute to the structure, size, formation rate, and fitness effects of adaptive CNVs. Local genome elements are likely to be an important determinant of these properties. Whereas it is known that point mutation rates vary with genomic location and local sequence features, the role of genome architecture in the formation, selection, and the resulting evolutionary dynamics of CNVs is poorly understood. Previously, we have found that the GAP1 gene in Saccharomyces cerevisiae undergoes frequent and repeated amplification and selection under long-term experimental evolution in glutamine-limiting conditions. The GAP1 gene has a unique genomic architecture consisting of two flanking long terminal repeats (LTRs) and a proximate origin of DNA replication (autonomously replicating sequence, ARS), which are likely to promote rapid GAP1 CNV formation. To test the role of these genomic elements on CNV-mediated adaptive evolution we performed experimental evolution in glutamine-limited chemostats using engineered strains lacking either the adjacent LTRs, ARS, or all elements. Using a CNV reporter system and neural network simulation-based inference (nnSBI) we quantified the formation rate and fitness effect of CNVs for each strain. We find that although GAP1 CNVs repeatedly form and sweep to high frequency in all strains, removal of local DNA elements significantly impacts the rate and fitness effect of CNVs and the rate of adaptation. We performed genome sequence analysis to define the molecular mechanisms of CNV formation for 177 CNV lineages. We find that 49% of all GAP1 CNVs are mediated by the DNA replication-based mechanism Origin Dependent Inverted Repeat Amplification (ODIRA) regardless of background strain. In the absence of the local ARS, a distal ARS can mediate ODIRA CNV formation. In the absence of local LTRs homologous recombination mechanisms still mediate gene amplification following de novo insertion of retrotransposon elements at the locus. Our study demonstrates the remarkable plasticity of the genome and reveals that DNA replication errors are a predominant source of adaptive CNVs.

show abstract

Mutation rate, selection, and epistasis inferred from RNA virus haplotypes via neural posterior estimation

Cited by 4 publications

References 37 publications

DNA replication errors are a major source of adaptive gene amplification

DNA replication errors are a major source of adaptive gene amplification

Navigating a fine balance: point-mutant cheater viruses disrupt the viral replication cycle

DNA replication errors are a major source of adaptive gene amplification

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