deleterious mutations
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Nature ◽  
2022 ◽  
Author(s):  
J. Grey Monroe ◽  
Thanvi Srikant ◽  
Pablo Carbonell-Bejerano ◽  
Claude Becker ◽  
Mariele Lensink ◽  
...  

AbstractSince the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences1. Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome—mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias2 reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.


Genetics ◽  
2022 ◽  
Author(s):  
Benjamin H Good

Abstract The statistical associations between mutations, collectively known as linkage disequilibrium (LD), encode important information about the evolutionary forces acting within a population. Yet in contrast to single-site analogues like the site frequency spectrum, our theoretical understanding of linkage disequilibrium remains limited. In particular, little is currently known about how mutations with different ages and fitness costs contribute to expected patterns of LD, even in simple settings where recombination and genetic drift are the major evolutionary forces. Here, I introduce a forward-time framework for predicting linkage disequilibrium between pairs of neutral and deleterious mutations as a function of their present-day frequencies. I show that the dynamics of linkage disequilibrium become much simpler in the limit that mutations are rare, where they admit a simple heuristic picture based on the trajectories of the underlying lineages. I use this approach to derive analytical expressions for a family of frequency-weighted LD statistics as a function of the recombination rate, the frequency scale, and the additive and epistatic fitness costs of the mutations. I find that the frequency scale can have a dramatic impact on the shapes of the resulting LD curves, reflecting the broad range of time scales over which these correlations arise. I also show that the differences between neutral and deleterious LD are not purely driven by differences in their mutation frequencies, and can instead display qualitative features that are reminiscent of epistasis. I conclude by discussing the implications of these results for recent LD measurements in bacteria. This forward-time approach may provide a useful framework for predicting linkage disequilibrium across a range of evolutionary scenarios.


2022 ◽  
Author(s):  
Kaichi Huang ◽  
Kate L Ostevik ◽  
Cassandra Elphinstone ◽  
Marco Todesco ◽  
Natalia Bercovich ◽  
...  

Recombination is critical both for accelerating adaptation and for the purging of deleterious mutations. Chromosomal inversions can act as recombination modifiers that suppress local recombination and, thus, are predicted to accumulate such mutations. In this study, we investigated patterns of recombination, transposable element abundance and coding sequence evolution across the genomes of 1,445 individuals from three sunflower species, as well as within nine inversions segregating within species. We also analyzed the effects of inversion genotypes on 87 phenotypic traits to test for overdominance. We found significant negative correlations of long terminal repeat retrotransposon abundance and deleterious mutations with recombination rates across the genome in all three species. However, we failed to detect an increase in these features in the inversions, except for a modest increase in the proportion of stop codon mutations in several very large or rare inversions. Moreover, there was little evidence of phenotypic overdominance in inversion heterozygotes, consistent with observations of minimal deleterious load. On the other hand, significantly greater load was observed for inversions in populations polymorphic for a given inversion compared to populations monomorphic for one of the arrangements, suggesting that the local state of inversion polymorphism affects deleterious load. These seemingly contradictory results can be explained by the geographic structuring and consequent excess homozygosity of inversions in wild sunflowers. Inversions contributing to local adaptation often exhibit geographic structure; such inversions represent ideal recombination modifiers, acting to facilitate adaptive divergence with gene flow, while largely averting the accumulation of deleterious mutations due to recombination suppression.


The Auk ◽  
2021 ◽  
Author(s):  
Charles Christian Riis Hansen ◽  
Sina Baleka ◽  
Sólveig Magnea Guðjónsdóttir ◽  
Jacob Agerbo Rasmussen ◽  
Jesus Adrian Chimal Ballesteros ◽  
...  

Abstract Using whole mitochondrial DNA sequences from 89 White-tailed Eagles (Haliaeetus albicilla) sampled from Iceland, Greenland, Norway, Denmark and Estonia between 1990 and 2018, we investigate the mitogenomic variation within and between countries. We show that there is a substantial population differentiation between the countries, reflecting similar major phylogeographic patterns obtained previously for the control region of the mitochondria, which suggested two main refugia during the last glacial period. Distinct mitogenomic lineages are observed within countries with divergence times exceeding the end of the last glacial period of the Ice Age. Deviations from neutrality indicate that these lineages have been maintained by natural selection and there is an excess of segregating amino acids in comparison with number of fixations suggesting a large load of deleterious mutations. The maintenance of the distinct mitogenic lineages within countries inflates our estimates of divergence times.


2021 ◽  
Author(s):  
Milo Johnson ◽  
Michael M. Desai

As an adapting population traverses the fitness landscape, its local neighborhood (i.e., the collection of fitness effects of single-step mutations) can change shape because of interactions with mutations acquired during evolution. These changes to the distribution of fitness effects can affect both the rate of adaptation and the accumulation of deleterious mutations. However, while numerous models of fitness landscapes have been proposed in the literature, empirical data on how this distribution changes during evolution remains limited. In this study, we directly measure how the fitness landscape neighborhood changes during laboratory adaptation. Using a barcode-based mutagenesis system, we measure the fitness effects of 91 specific gene disruption mutations in genetic backgrounds spanning 8,000-10,000 generations of evolution in two constant environments. We find that the mean of the distribution of fitness effects decreases in one environment, indicating a reduction in mutational robustness, but does not change in the other. We show that these distribution-level patterns result from biases in variable patterns of epistasis at the level of individual mutations, including fitness-correlated and idiosyncratic epistasis.


2021 ◽  
Author(s):  
Aline Lefebvre ◽  
Julian Tillmann ◽  
Freddy Cliquet ◽  
Frederique Amsellem ◽  
Anna Maruani ◽  
...  

Abstract Background. Sensory processing atypicalities are part of the core symptoms of autism spectrum disorder (ASD) and could result from an excitation/inhibition imbalance. Yet, the convergence level of phenotypic sensory processing atypicalities with genetic alterations in GABA-ergic and glutamatergic pathways remains poorly understood. This study aimed to characterize the distribution of hypo/hyper-sensory profile among individuals with ASD and investigate the role of deleterious mutations in GABAergic and glutamatergic pathways related genes in sensory processing atypicalities. Method. From the Short Sensory Profile (SSP) questionnaire, we defined and explored a score – the differential Short Sensory Profile (dSSP) - as a normalized and centralized hypo/hypersensitivity ratio for 1136 participants (533 with ASD, 210 first-degree relatives, and 267 controls) from two independent study samples (PARIS and LEAP). We also performed an unsupervised item-based clustering analysis on SSP items scores to validate this new categorization in terms of hypo and hyper sensitivity. We then explored the link between the dSSP score and the burden of deleterious mutations in a subset of individuals for which whole-genome sequencing data were available. Results. We observed a mean dSSP score difference between ASD and controls, driven mostly by a high dSSP score variability among groups (PARIS: p<0.0001, η2 = 0.0001, LEAP: p<0.0001, Cohen’s d=3.67). First-degree relatives were with an intermediate distribution variability profile (p<0.0001). We also reported a positive developmental trajectory of the dSSP score (PARIS: p=0.0006, η2 = 0.02; LEAP: p=0.01, η2 = 0.01). Clusters were similarly characterized by hypo- and hyper-sensitivity items in both study samples (Cramer's V from 0.64 to 0.69, p<0.05). Our genetic analysis showed a trend only for an association with mutations of the GABAergic pathway.Limitations. The major limitation was the dSSP score difficulty to discriminate subjects with a similar quantum of hypo- and hyper- sensory symptoms to those with no such symptoms, resulting both in a similar ratio score of 0.Conclusion. The dSSP score could be a relevant clinical score of the hypo/hyper-sensory individual profile in subjects with ASD. Combined with additional sensory domain characteristics, genetics and endophenotypic substrates, the dSSP score will offer new avenues to explore the underlying neurobiological mechanisms of sensory processing atypicalities in ASD.


2021 ◽  
Author(s):  
Emma Berdan ◽  
Alexandre Blanckaert ◽  
Roger K Butlin ◽  
Thomas Flatt ◽  
Tanja Slotte ◽  
...  

Supergenes offer some of the most spectacular examples of long-term balancing selection in nature but their origin and maintenance remain a mystery. A critical aspect of supergenes is reduced recombination between arrangements. Reduced recombination protects adaptive multi-trait phenotypes, but can also lead to degeneration through mutation accumulation. Mutation accumulation can stabilize the system through the emergence of associative overdominance (AOD), destabilize the system, or lead to new evolutionary outcomes. One such outcome is the formation of balanced lethal systems, a maladaptive system where both supergene arrangements have accumulated deleterious mutations to the extent that both homozygotes are inviable, leaving only heterozygotes to reproduce. Here, we perform a simulation study to understand the conditions under which these different outcomes occur, assuming a scenario of introgression after allopatric divergence. We found that AOD aids the invasion of a new supergene arrangement and the establishment of a polymorphism. However, this polymorphism is easily destabilized by further mutation accumulation. While degradation may strengthen AOD, thereby stabilizing the supergene polymorphism, it is often asymmetric, which is the key disrupter of the quasi-equilibrium state of the polymorphism. Furthermore, mechanisms that accelerate degeneration also tend to amplify asymmetric mutation accumulation between the supergene arrangements and vice versa. As the evolution of a balanced lethal system requires symmetric degradation of both arrangements, this leaves highly restricted conditions under which such a system could evolve. We show that small population size and low dominance coefficients are critical factors, as these reduce the efficacy of selection. The dichotomy between the persistence of a polymorphism and degradation of supergene arrangements likely underlies the rarity of balanced lethal systems in nature.


2021 ◽  
Author(s):  
Brian Charlesworth

The effects of selection on variability at linked sites have an important influence on levels and patterns of within-population variation across the genome. Most theoretical models of these effects have assumed that selection is sufficiently strong that allele frequency changes at the loci concerned are largely deterministic. These models have led to the conclusion that directional selection for new selectively favorable mutations, or against recurrent deleterious mutations, reduces nucleotide site diversity at linked neutral sites. Recent work has shown, however, that fixations of weakly selected mutations, accompanied by significant stochastic changes in allele frequencies, can sometimes cause higher diversity at linked sites when compared with the effects of fixations of neutral mutations. The present paper extends this work by deriving approximate expressions for the mean times to loss and fixation of mutations subject to selection, and analysing the conditions under which selection increases rather than reduces these times. Simulations are used to examine the relations between diversity at a neutral site and the fixation and loss times of mutations at a linked site subject to selection. It is shown that the long-term level of neutral diversity can be increased over the equilibrium expectation in the absence of selection by recurrent fixations and losses of linked, weakly selected dominant or partially dominant favorable mutations, and by linked recessive or partially recessive deleterious mutations. The results are used to examine the conditions under which associative overdominance, as opposed to background selection, is likely to operate.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qian Ma ◽  
Congcong Cao ◽  
Changshui Zhuang ◽  
Xiaomin Luo ◽  
Xiaofeng Li ◽  
...  

AbstractSpermiogenesis is a complex process depending on the sophisticated coordination of a myriad of testis-enriched gene regulations. The regulatory pathways that coordinate this process are not well understood, and we demonstrate here that AXDND1, as a novel testis-enriched gene is essential for spermiogenesis and male fertility. AXDND1 is exclusively expressed in the round and elongating spermatids in humans and mice. We identified two potentially deleterious mutations of AXDND1 unique to non‐obstructive azoospermia (NOA) patients through selected exonic sequencing. Importantly, Axdnd1 knockout males are sterile with reduced testis size caused by increased germ cell apoptosis and sloughing, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. Axdnd1 mutated late spermatids showed head deformation, outer doublet microtubules deficiency in the axoneme, and loss of corresponding accessory structures, including outer dense fiber (ODF) and mitochondria sheath. These phenotypes were probably due to the perturbed behavior of the manchette, a dynamic structure where AXDND1 was localized. Our findings establish AXDND1 as a novel testis-enrich gene essential for spermiogenesis and male fertility probably by regulating the manchette dynamics, spermatid head shaping, sperm flagellum assembly.


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