mutation accumulation
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Evolution ◽  
2022 ◽  
Author(s):  
Lindi M. Wahl ◽  
Deepa Agashe

2021 ◽  
Vol 2 ◽  
Author(s):  
Freek Manders ◽  
Ruben van Boxtel ◽  
Sjors Middelkamp

From conception to death, human cells accumulate somatic mutations in their genomes. These mutations can contribute to the development of cancer and non-malignant diseases and have also been associated with aging. Rapid technological developments in sequencing approaches in the last few years and their application to normal tissues have greatly advanced our knowledge about the accumulation of these mutations during healthy aging. Whole genome sequencing studies have revealed that there are significant differences in mutation burden and patterns across tissues, but also that the mutation rates within tissues are surprisingly constant during adult life. In contrast, recent lineage-tracing studies based on whole-genome sequencing have shown that the rate of mutation accumulation is strongly increased early in life before birth. These early mutations, which can be shared by many cells in the body, may have a large impact on development and the origin of somatic diseases. For example, cancer driver mutations can arise early in life, decades before the detection of the malignancy. Here, we review the recent insights in mutation accumulation and mutagenic processes in normal tissues. We compare mutagenesis early and later in life and discuss how mutation rates and patterns evolve during aging. Additionally, we outline the potential impact of these mutations on development, aging and disease.


2021 ◽  
Author(s):  
Sydney Kreutzmann ◽  
Elizabeth Pompa ◽  
Nhan Ngyuen ◽  
Liya Tilahun ◽  
Matthew Rutter ◽  
...  

Abstract Understanding the mechanisms by which mutations affect fitness and the distribution of mutational effects are central goals in evolutionary biology. Mutation accumulation (MA) lines have long been an important tool for understanding the effect of new mutations on fitness, phenotypic variation, and mutational parameters. However, there is a clear gap in predicting the effect of specific new mutations to their effects on fitness. Here, we complete gene ontology analysis and metabolomics experiments on Arabidopsis thaliana MA lines to determine how spontaneous mutations directly affect global metabolic output in lines that have measured fitness consequences. For these analyses, we compared three lines with relative fitness consistently higher than the unmutated progenitor and three lines with lower relative fitness as measured in four different field trials. In a gene ontology analysis, we find that the high fitness lines were significantly enriched in mutations in or near genes with transcription regulator activity. We also find that although they do not have an average difference in the number of mutations, low fitness lines have significantly more metabolic subpathways disrupted than high fitness lines. Taken together, these results suggest that the effect of a new mutation on fitness depends less on the specific metabolic pathways disrupted and more on the pleiotropic effects of those mutations, and that organisms can explore a considerable amount of physiological space with only a few mutations.


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 ◽  
Vol 12 ◽  
Author(s):  
Jia He ◽  
Jimin Han ◽  
Jia Liu ◽  
Ronghua Yang ◽  
Jingru Wang ◽  
...  

Chronic inflammation increases cancer risk, and cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations. During chronic inflammation, infectious agents and intrinsic mediators of inflammatory responses can induce genetic and epigenetic changes. This study tried to evaluate both the genetic and epigenetic influence of chronic inflammation on colon mucosa cells. Repetitive dextran sulfate sodium (DSS) treatment induced chronic colitis model. Whole-exome sequencing (WES) (200× coverage) was performed to detect somatic variations in colon mucosa cells. With the use of whole-genome bisulfite sequencing (BS) at 34-fold coverage (17-fold per strand), the methylome of both the colitis and control tissue was comparatively analyzed. Bioinformatics assay showed that there was no significant single-nucleotide polymorphism/insertion or deletion (SNP/InDel) mutation accumulation in colitis tissue, while it accumulated in aged mice. Forty-eight genes with SNP/InDel mutation were overlapped in the three colitis tissues, two (Wnt3a and Lama2) of which are in the cancer development-related signaling pathway. Differentially methylated region (DMR) assay showed that many genes in the colitis tissue are enriched in the cancer development-related signaling pathway, such as PI3K–AKT, Ras, Wnt, TGF-beta, and MAPK signaling pathway. Together, these data suggested that even though chronic inflammation did not obviously increase genetic mutation accumulation, it could both genetically and epigenetically alter some genes related to cancer development.


2021 ◽  
pp. 62-84
Author(s):  
Gary C. Howard

Why do we age? Aging has been an important issue in biology for many decades, and many questions remain unanswered. However, any explanation of aging must agree with Darwin’s theory of natural selection. Genes that benefit fitness early on in an individual’s lifetime will be favored. Ones that hinder fitness early on will be selected against because those individuals will reproduce less successfully. Genes that have an effect later in life (after the reproductive years) are not subject to natural selection. Thus, the force of natural selection is lost later in life. Three key theories have been proposed to explain how aging might have evolved: mutation accumulation theory, antagonistic pleiotrophy, and disposable soma. These three main theories are not mutually exclusive. Finally, is aging simply another disease?


2021 ◽  
Vol 129 (10) ◽  
Author(s):  
Nathan Keith ◽  
Craig E. Jackson ◽  
Stephen P. Glaholt ◽  
Kimberly Young ◽  
Michael Lynch ◽  
...  

2021 ◽  
Author(s):  
Lindi M Wahl ◽  
Deepa Agashe

Mutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes underlying evolution. In microbial populations, MA protocols typically involve a period of population growth between severe bottlenecks, such that a single individual can form a visible colony. While it has long been appreciated that the action of positive selection during this growth phase cannot be eliminated, it is typically assumed to be negligible. Here, we quantify the effect of both positive and negative selection in MA studies, demonstrating that selective effects can substantially bias the distribution of fitness effects (DFE) and mutation rates estimated from typical MA protocols in microbes. We then present a simple correction for this bias which applies to both beneficial and deleterious mutations, and can be used to correct the observed DFE in multiple environments. Finally, we use simulated MA experiments to illustrate the extent to which the MA-inferred DFE differs from the underlying true DFE, and demonstrate that the proposed correction accurately reconstructs the true DFE over a wide range of scenarios. These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters.


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