The distribution of fitness effects among synonymous mutations in a gene under directional selection

Lebeuf-Taylor, Eleonore; McCloskey, Nick; Bailey, Susan F.; Hinz, Aaron; Kassen, Rees

doi:10.7554/elife.45952

Cited by 91 publications

(94 citation statements)

References 44 publications

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“…Only 11 of these 89 outlier SNPs matched P. monodon transcriptome contigs [ 72 ] with subsequent protein translation of eight outlier SNPs demonstrating more non-synonymous changes than synonymous changes across all six reading frames. Despite the greater likelihood that non-synonymous mutations will have functional implications [ 73 , 74 ], all 11 of these outlier SNPs with P. monodon transcriptome matches should be considered as candidates for future research into divergent selection driven local adaptation among these geographically discrete populations [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

Fine-scale population structure and evidence for local adaptation in Australian giant black tiger shrimp (Penaeus monodon) using SNP analysis

Zenger

Guppy

et al. 2020

BMC Genomics

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Background Restrictions to gene flow, genetic drift, and divergent selection associated with different environments are significant drivers of genetic differentiation. The black tiger shrimp (Penaeus monodon), is widely distributed throughout the Indian and Pacific Oceans including along the western, northern and eastern coastline of Australia, where it is an important aquaculture and fishery species. Understanding the genetic structure and the influence of environmental factors leading to adaptive differences among populations of this species is important for farm genetic improvement programs and sustainable fisheries management. Results Based on 278 individuals obtained from seven geographically disparate Australian locations, 10,624 high-quality SNP loci were used to characterize genetic diversity, population structure, genetic connectivity, and adaptive divergence. Significant population structure and differentiation were revealed among wild populations (average FST = 0.001–0.107; p < 0.05). Eighty-nine putatively outlier SNPs were identified to be potentially associated with environmental variables by using both population differentiation (BayeScan and PCAdapt) and environmental association (redundancy analysis and latent factor mixed model) analysis methods. Clear population structure with similar spatial patterns were observed in both neutral and outlier markers with three genetically distinct groups identified (north Queensland, Northern Territory, and Western Australia). Redundancy, partial redundancy, and multiple regression on distance matrices analyses revealed that both geographical distance and environmental factors interact to generate the structure observed across Australian P. monodon populations. Conclusion This study provides new insights on genetic population structure of Australian P. monodon in the face of environmental changes, which can be used to advance sustainable fisheries management and aquaculture breeding programs.

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Section: Discussionmentioning

confidence: 99%

Fine-scale population structure and evidence for local adaptation in Australian giant black tiger shrimp (Penaeus monodon) using SNP analysis

Zenger

Guppy

et al. 2020

BMC Genomics

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“…However, more recent studies have revealed that synonymous changes have an underestimated effect on fitness through their perturbances before and during translation. Synonymous sequence variance can impact fitness by changing the stability of mRNA (Kudla et al 2009;Kristofich et al 2018;Lebeuf-Taylor et al 2019) and altering codons to perturb or better match the codonanticodon ratio (Frumkin et al 2018). To our knowledge, we have shown here for the first time that synonymous sequence can also be essential for realising extreme parallel evolution.…”

Section: Discussionmentioning

confidence: 84%

A mutational hotspot that determines highly repeatable evolution can be built and broken by silent genetic changes

Horton

Flanagan

Jackson

et al. 2021

Preprint

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There is a growing need for accurate evolutionary forecasting, but we must first understand how possible evolutionary paths can be constrained by silent genetic features. Here we show that synonymous sequence variation determines extreme parallel evolution during the evolutionary rescue of flagellar motility. An immotile variant of the soil microbe, Pseudomonas fluorescens, swiftly recovers flagellum-dependent motility through parallel de novo mutation. This typically manifests within 96 h under strong selection through repeatable mutation within the nitrogen pathway’s histidine kinase gene, ntrB. We found that evolution was parallel to nucleotide resolution in over 95% of cases in minimal medium (M9), with lineages repeatedly fixing an identical mutation (ntrB A289C). There was no evidence that this substitution is context-specific, as repeatable de novo mutation was robust to nutrient condition despite evidence for antagonistic pleiotropy. Competition assays against alternative motile alleles revealed some evidence for selection enforcing repeated fixation of ntrB mutants, but there was no evidence for clonal interference driving parallel evolution to nucleotide resolution. Instead, the introduction of 6 synonymous substitutions surrounding the mutational hotspot reduced parallel evolution from >95% to 0% at the site. In a reciprocal experiment, we introduced 6 synonymous substitutions into a homologous strain that did not ancestrally evolve in parallel and observed that parallel evolution at the site rose from 0% to 80%. We propose that these silent mutations facilitate extremely localised heterogeneity in de novo mutation. Our results reveal that unique quirks in how DNA is structured at specific loci can strongly bias evolutionary outcomes.

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“…Although this finding contradicts the intuition that so-called silent mutations should not imbue significant downstream impacts, it is less surprising in light of prior work demonstrating that these mutations can indeed enact non-trivial effects on splicing, transcript folding/stability, translational rates, co-translational folding/stability, and degradation 53,54 . Although NF1 splice mutations are often mistaken for silent mutations by sequencing methods 55,56 , evidence that synonymous mutations of the NF1 gene are selected in cancers such as T-cell acute lymphoblastic leukemia 57 signals a need for more research in this area.…”

Section: Subgroupings Outperform Mutation Subsets Chosen Using Varianmentioning

confidence: 99%

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

Grzadkowski

Manning

Somers

et al. 2020

Preprint

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6Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor 7 cohorts within which they are frequently mutated. We sought to identify the downstream expres-8 sion effects of these perturbations and to find whether or not this heterogeneity at the genomic 9 level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel 10 hierarchical framework for organizing the mutations present in a cohort along with machine learn-11 ing pipelines trained on sample expression profiles we systematically interrogated the signatures 12 associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue 13 the mutations with discernible downstream expression effects across a number of tumor cohorts 14 as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are 15 clearly divergent in their function from the remaining mutations of the gene. 16 Each tumor faces a common set of obstacles arising from internal dynamics and external de-18 fense mechanisms 1 . Tumor cohorts, however, are replete with diverse yet recurrent tactics for 19 overcoming these shared obstacles. Tumorigenesis can thus be perceived as a landscape within 20 which each tumor navigates a unique, multidimensional path, weaving between segments trodden 21 by other tumors. A number of the early breakthroughs in cancer treatment directly resulted from 22 coarse demarcations of these paths into distinct subtypes based on "landmarks"-usually defined 23 by mutations and/or markers derived from proteomic or transcriptomic data-that were then used 24 to engineer subtype-specific treatments [2][3][4] . 25 Although these biomarker-based treatment matching criteria have proven effective in some 26 precision medicine applications, there is a sizable subset of patients whose tumors harbor no dis-27 cernible drug targets, thus diminishing their likelihood of successful treatment and survival [5][6][7][8] . 28 Developing a more thorough understanding of the downstream effects of landmark events could 29 therefore improve tailored treatment design outcomes. In particular, we envision a tactic which de-30 tects whether two genomic alterations (or combinations thereof) have a shared downstream effect, 31 and can therefore be grouped together when weighing treatment options. This type of approach 32 should also be able to detect whether two such alterations or groupings result in divergent tran-33 scriptional programs and can therefore be considered distinct. Despite recent efforts to profile the 34 downstream effects of mutations recurrent in cancer, for most mutations we still know little about 35 the programs they trigger. As a result, most clinical guidelines depend on only a limited sub-36 set of specific perturbations within a gene or on other coarse biomarker-based demarcations 9,10 . 37A clearer discernment of the convergences and divergences between the downstream programs 38 present within cancer genes is thus a crucial prerequisi...

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The distribution of fitness effects among synonymous mutations in a gene under directional selection

Cited by 91 publications

References 44 publications

Fine-scale population structure and evidence for local adaptation in Australian giant black tiger shrimp (Penaeus monodon) using SNP analysis

Fine-scale population structure and evidence for local adaptation in Australian giant black tiger shrimp (Penaeus monodon) using SNP analysis

A mutational hotspot that determines highly repeatable evolution can be built and broken by silent genetic changes

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

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