scholarly journals Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice

2015 ◽  
Vol 25 (8) ◽  
pp. 1125-1134 ◽  
Author(s):  
Arikuni Uchimura ◽  
Mayumi Higuchi ◽  
Yohei Minakuchi ◽  
Mizuki Ohno ◽  
Atsushi Toyoda ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Laboratory Mice ◽  
Wild Type

scholarly journals Dynamics of mutation accumulation and adaptation during three years of evolution under long-term stationary phase

2020 ◽  
Author(s):  
Sophia Katz ◽  
Sarit Avrani ◽  
Meitar Yavneh ◽  
Sabrin Hilau ◽  
Jonathan Gross ◽  
...  
Keyword(s):  
Stationary Phase ◽  
Bacterial Species ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Single Population ◽  
E Coli ◽  
Mutational Spectra ◽  
Resource Exhaustion ◽  
Time Point

AbstractMany bacterial species that cannot sporulate, such as the model bacterium Escherichia coli, can nevertheless survive for years under resource exhaustion, in a state termed long-term stationary phase (LTSP). Here we describe the dynamics of E. coli adaptation during the first three years spent under LTSP. We show that during this time E. coli continuously adapts genetically, through the accumulation of mutations. For non-mutator clones, the majority of mutations accumulated appear to be adaptive under LTSP, reflected in an extremely convergent pattern of mutation accumulation. Despite the rapid and convergent manner in which populations adapt under LTSP, they continue to harbor extensive genetic variation. The dynamics of evolution of mutation rates under LTSP are particularly interesting. The emergence of mutators, affects overall mutation accumulation rates as well as the mutational spectra and the ultimate spectrum of adaptive alleles acquired under LTSP. With time, mutators can evolve even higher mutation rates, through the acquisition of additional mutation-rate enhancing mutations. Different mutator and non-mutator clones within a single population and time point can display extreme variation in their mutation rates, resulting in differences in both the dynamics of adaptation and their associated deleterious burdens. Despite these differences, clones that vary greatly in their mutation rates tend to co-exist within their populations for many years, under LTSP.

scholarly journals Mutator genomes decay, despite sustained fitness gains, in a long-term experiment with bacteria

2017 ◽  
Vol 114 (43) ◽  
pp. E9026-E9035 ◽  
Author(s):  
Alejandro Couce ◽  
Larissa Viraphong Caudwell ◽  
Christoph Feinauer ◽  
Thomas Hindré ◽  
Jean-Paul Feugeas ◽  
...  
Keyword(s):  
Evolutionary Biology ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Weak Selection ◽  
Bacterial Genomes ◽  
Random Drift ◽  
Strong Linkage ◽  
Term Experiment ◽  
Long Term Experiment

Understanding the extreme variation among bacterial genomes remains an unsolved challenge in evolutionary biology, despite long-standing debate about the relative importance of natural selection, mutation, and random drift. A potentially important confounding factor is the variation in mutation rates between lineages and over evolutionary history, which has been documented in several species. Mutation accumulation experiments have shown that hypermutability can erode genomes over short timescales. These results, however, were obtained under conditions of extremely weak selection, casting doubt on their general relevance. Here, we circumvent this limitation by analyzing genomes from mutator populations that arose during a long-term experiment with Escherichia coli, in which populations have been adaptively evolving for >50,000 generations. We develop an analytical framework to quantify the relative contributions of mutation and selection in shaping genomic characteristics, and we validate it using genomes evolved under regimes of high mutation rates with weak selection (mutation accumulation experiments) and low mutation rates with strong selection (natural isolates). Our results show that, despite sustained adaptive evolution in the long-term experiment, the signature of selection is much weaker than that of mutational biases in mutator genomes. This finding suggests that relatively brief periods of hypermutability can play an outsized role in shaping extant bacterial genomes. Overall, these results highlight the importance of genomic draft, in which strong linkage limits the ability of selection to purge deleterious mutations. These insights are also relevant to other biological systems evolving under strong linkage and high mutation rates, including viruses and cancer cells.

scholarly journals Stability across the Whole Nuclear Genome in the Presence and Absence of DNA Mismatch Repair

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1224
Author(s):  
Scott Alexander Lujan ◽  
Thomas A. Kunkel
Keyword(s):  
Cell Division ◽  
Cell Line ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Nuclear Genome ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Wild Type ◽  
Dna Mismatch ◽  
Chicken Cell

We describe the contribution of DNA mismatch repair (MMR) to the stability of the eukaryotic nuclear genome as determined by whole-genome sequencing. To date, wild-type nuclear genome mutation rates are known for over 40 eukaryotic species, while measurements in mismatch repair-defective organisms are fewer in number and are concentrated on Saccharomyces cerevisiae and human tumors. Well-studied organisms include Drosophila melanogaster and Mus musculus, while less genetically tractable species include great apes and long-lived trees. A variety of techniques have been developed to gather mutation rates, either per generation or per cell division. Generational rates are described through whole-organism mutation accumulation experiments and through offspring–parent sequencing, or they have been identified by descent. Rates per somatic cell division have been estimated from cell line mutation accumulation experiments, from systemic variant allele frequencies, and from widely spaced samples with known cell divisions per unit of tissue growth. The latter methods are also used to estimate generational mutation rates for large organisms that lack dedicated germlines, such as trees and hyphal fungi. Mechanistic studies involving genetic manipulation of MMR genes prior to mutation rate determination are thus far confined to yeast, Arabidopsis thaliana, Caenorhabditis elegans, and one chicken cell line. A great deal of work in wild-type organisms has begun to establish a sound baseline, but far more work is needed to uncover the variety of MMR across eukaryotes. Nonetheless, the few MMR studies reported to date indicate that MMR contributes 100-fold or more to genome stability, and they have uncovered insights that would have been impossible to obtain using reporter gene assays.

scholarly journals Germline mutation rates in young adults predict longevity and reproductive lifespan

2019 ◽  
Author(s):  
Richard M. Cawthon ◽  
Huong D. Meeks ◽  
Thomas A. Sasani ◽  
Ken R. Smith ◽  
Richard A. Kerber ◽  
...  
Keyword(s):  
Young Adults ◽  
Germline Mutation ◽  
Linear Regression Analysis ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Medical Institute ◽  
Accumulation Rates ◽  
Population Database ◽  
University Of Utah ◽  
The University

SUMMARYBACKGROUNDAnalysis of sequenced genomes from large three-generation families allows de novo mutations identified in Generation II individuals to be attributed to each of their parents’ germlines in Generation I. Because germline mutations increase with age, we hypothesized that they directly limit the duration of childbearing in women, and if correlated with mutation accumulation in somatic tissues, also reflect systemic aging in both sexes. Here we test whether the germline mutation rates of Generation I individuals when they were young adults predict their remaining survival, as well as the women’s reproductive lifespans.METHODSGermline autosomal mutation counts in 122 Generation I individuals (61 women, 61 men) from 41 three-generation Utah CEPH families were converted to germline mutation rates by normalizing each subject’s number of mutations to the callable portion of their genome. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Cancer Registry, and Utah Genetic Reference Project. Fertility analyses were restricted to the 53 women whose age at last birth (ALB) was at least 30 years, the approximate age when the decline in female fertility begins. Cox proportional hazard regression models were used to test the association of age-adjusted mutation rates (AAMRs) with aging-related outcomes. Linear regression analysis was used to estimate the age when adult germline mutation accumulation rates are established.FINDINGSQuartiles of increasing AAMRs were associated with increasing all-cause mortality rates in both sexes combined (test for trend, p=0.009); subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21-3.56; p=0.008; median survival difference = 4.7 years). Women with higher AAMRs had significantly fewer live births and a younger ALB. The analyses also indicate that adult germline mutation accumulation rates are established in adolescence, and that later menarche in women may delay mutation accumulation.INTERPRETATIONParental-age-adjusted germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic aging. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair genes’ expression levels are known to begin their lifelong decline.FUNDINGNIH R01AG038797 and R21AG054962 (to R.M.C.); University of Utah Program in Personalized Health (to H.D.M.); NIH T32GM007464 (to T.A.S.); NIH R01AG022095 (to K.R.S.); NIH R01HG006693, R01HG009141, and R01GM124355 (to A.R.Q.); NIH GM118335 and GM059290 (to L.B.J.); NIH P30CA2014 (to the Utah Population Database, a.k.a. the UPDB); National Center for Research Resources Public Health Services grant M01RR00064 (to the Huntsman General Clinical Research Center, University of Utah); National Center for Advancing Translational Sciences NIH grant UL1TR002538 (to the University of Utah’s Center for Clinical and Translational Science); Howard Hughes Medical Institute funding (to Ray White); gifts from the W.M. Keck Foundation (to Stephen M. Prescott and M.F.L.) and from the George S. and Delores Doré Eccles Foundation (to the University of Utah) that supported the Utah Genetic Reference Project (UGRP). Sequencing of the CEPH samples was funded by the Utah Genome Project, the George S. and Dolores Doré Eccles Foundation, and the H.A. and Edna Benning Foundation. We thank the Pedigree and Population Resource of the Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the UPDB.

scholarly journals Mutation accumulation and fitness in mutator subpopulations of Escherichia coli

2013 ◽  
Vol 9 (1) ◽  
pp. 20120961 ◽  
Author(s):  
Ram P. Maharjan ◽  
Bin Liu ◽  
Yang Li ◽  
Peter R. Reeves ◽  
Lei Wang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Significant Proportion ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Deleterious Mutations ◽  
Wild Type ◽  
Beneficial Mutations ◽  
Bacterial Populations ◽  
Neutral Mutations ◽  
Over Time

Bacterial populations in clinical and laboratory settings contain a significant proportion of mutants with elevated mutation rates (mutators). Mutators have a particular advantage when multiple beneficial mutations are needed for fitness, as in antibiotic resistance. Nevertheless, high mutation rates potentially lead to increasing numbers of deleterious mutations and subsequently to the decreased fitness of mutators. To test how fitness changed with mutation accumulation, genome sequencing and fitness assays of nine Escherichia coli mutY mutators were undertaken in an evolving chemostat population at three time points. Unexpectedly, the fitness in members of the mutator subpopulation became constant despite a growing number of mutations over time. To test if the accumulated mutations affected fitness, we replaced each of the known beneficial mutations with wild-type alleles in a mutator isolate. We found that the other 25 accumulated mutations were not deleterious. Our results suggest that isolates with deleterious mutations are eliminated by competition in a continuous culture, leaving mutators with mostly neutral mutations. Interestingly, the mutator–non-mutator balance in the population reversed after the fitness plateau of mutators was reached, suggesting that the mutator–non-mutator ratio in populations has more to do with competition between members of the population than the accumulation of deleterious mutations.

An ER–Golgi Tethering Factor SLOH4/MIP3 Is Involved in Long-term Heat Tolerance of Arabidopsis

2020 ◽  
Author(s):  
Kazuho Isono ◽  
Ryo Tsukimoto ◽  
Satoshi Iuchi ◽  
Akihisa Shinozawa ◽  
Izumi Yotsui ◽  
...  
Keyword(s):  
Heat Stress ◽  
Heat Tolerance ◽  
Secretory Proteins ◽  
Wild Type ◽  
Additional Function ◽  
Transcript Levels ◽  
Unfolded Protein ◽  
In The Wild ◽  
Protein Response

Abstract Plants are often exposed not only to short-term (S-) heat stress but also to diurnal long-term (L-) heat stress over several consecutive days. To reveal the mechanisms underlying L-heat stress tolerance, we here used a forward genetic screening for sensitive to long-term heat (sloh) mutants and isolated sloh4. The mutant was hypersensitive to L- but not S-heat stress. The causal gene of sloh4 was identical to MIP3 encoding a member of the MAIGO2 (MAG2) tethering complex, which is composed of the MAG2, MIP1, MIP2, and MIP3 subunits and is localized at the endoplasmic reticulum (ER) membrane. Although sloh4/mip3 was hypersensitive to L-heat stress, the sensitivity of the mag2-3 and mip1–1 mutants was similar to that of the wild type. Under L-heat stress, the ER stress and the following unfolded protein response (UPR) were more pronounced in sloh4 than in the wild type. Transcript levels of bZIP60-regulated UPR genes were strongly increased in sloh4 under L-heat stress. Two processes known to be mediated by INOSITOL REQUIRING ENZYME1 (IRE1)—accumulation of the spliced bZIP60 transcript and a decrease in the transcript levels of PR4 and PRX34, encoding secretory proteins—were observed in sloh4 in response to L-heat stress. These findings suggest that misfolded proteins generated in sloh4 under L-heat stress may be recognized by IRE1 but not bZIP28, resulting in initiation of the UPR via activated bZIP60. Therefore, it would be possible that only MIP3 in MAG2 complex has an additional function in L-heat tolerance, which is not related to the ER–Golgi vesicle tethering.

scholarly journals Nature of Deleterious Mutation Load in Drosophila

Genetics ◽  
1996 ◽  
Vol 144 (4) ◽  
pp. 1993-1999 ◽  
Author(s):  
Peter D Keightley
Keyword(s):  
Deleterious Mutation ◽  
Spontaneous Mutation ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Mutation Load ◽  
Spontaneous Mutation Rate ◽  
A Minor ◽  
Chromosome I ◽  
Balancer Chromosomes ◽  
Balancer Chromosome

Much population genetics and evolution theory depends on knowledge of genomic mutation rates and distributions of mutation effects for fitness, but most information comes from a few mutation accumulation experiments in Drosophila in which replicated chromosomes are sheltered from natural selection by a balancer chromosome. I show here that data from these experiments imply the existence of a large class of minor viability mutations with approximately equivalent effects. However, analysis of the distribution of viabilities of chromosomes exposed to EMS mutagenesis reveals a qualitatively different distribution of effects lacking such a minor effects class. A possible explanation for this difference is that transposable element insertions, a common class of spontaneous mutation event in Drosophila, frequently generate minor viability effects. This explanation would imply that current estimates of deleterious mutation rates are not generally applicable in evolutionary models, as transposition rates vary widely. Alternatively, much of the apparent decline in viability under spontaneous mutation accumulation could have been nonmutational, perhaps due to selective improvement of balancer chromosomes. This explanation accords well with the data and implies a spontaneous mutation rate for viability two orders of magnitude lower than previously assumed, with most mutation load attributable to major effects.

scholarly journals A Replication-Defective Gammaherpesvirus Efficiently Establishes Long-Term Latency in Macrophages but Not in B Cells In Vivo

2008 ◽  
Vol 82 (17) ◽  
pp. 8500-8508 ◽  
Author(s):  
Haiyan Li ◽  
Kazufumi Ikuta ◽  
John W. Sixbey ◽  
Scott A. Tibbetts
Keyword(s):  
B Cells ◽  
Viral Genome ◽  
Lytic Replication ◽  
Mutant Virus ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Virus Latency

ABSTRACT Murine gammaherpesvirus 68 (γHV68 or MHV68) is genetically related to the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), providing a useful system for in vivo studies of the virus-host relationship. To begin to address fundamental questions about the mechanisms of the establishment of gammaherpesvirus latency, we previously generated a replication-defective γHV68 lacking the expression of the single-stranded DNA binding protein encoded by orf6. In work presented here, we demonstrate that this mutant virus established a long-term infection in vivo that was molecularly identical to wild-type virus latency. Thus, despite the absence of an acute phase of lytic replication, the mutant virus established a chronic infection in which the viral genome (i) was maintained as an episome and (ii) expressed latency-associated, but not lytic replication-associated, genes. Macrophages purified from mice infected with the replication-defective virus harbored viral genome at a frequency that was nearly identical to that of wild-type γHV68; however, the frequency of B cells harboring viral genome was greatly reduced in the absence of lytic replication. Thus, this replication-defective gammaherpesvirus efficiently established in vivo infection in macrophages that was molecularly indistinguishable from wild-type virus latency. These data point to a critical role for lytic replication or reactivation in the establishment or maintenance of latent infection in B cells.

scholarly journals Bisecting GlcNAc structure is implicated in suppression of stroma-dependent haemopoiesis in transgenic mice expressing N-acetylglucosaminyltransferase III

1998 ◽  
Vol 331 (3) ◽  
pp. 733-742 ◽  
Author(s):  
Masafumi YOSHIMURA ◽  
Yoshito IHARA ◽  
Tetsuo NISHIURA ◽  
Yu OKAJIMA ◽  
Megumu OGAWA ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Stromal Cells ◽  
Bone Marrow Cells ◽  
Adherent Cell ◽  
Wild Type ◽  
Spleen Cells ◽  
Bisecting Glcnac ◽  
Marrow Cells

Several sugar structures have been reported to be necessary for haemopoiesis. We analysed the haematological phenotypes of transgenic mice expressing β-1,4 N-acetylglucosaminyltransferase III (GnT-III), which forms bisecting N-acetylglucosamine on asparagine-linked oligosaccharides. In the transgenic mice, the GnT-III activity was elevated in bone marrow, spleen and peripheral blood and in isolated mononuclear cells from these tissues, whereas no activity was found in these tissues of wild-type mice. Stromal cells after long-term cultures of transgenic-derived bone marrow and spleen cells also showed elevated GnT-III activity, compared with an undetectable activity in wild-type stromal cells. As judged by HPLC analysis, lectin blotting and lectin cytotoxicity assay, bisecting GlcNAc residues were increased on both blood cells and stromal cells from bone marrow and spleen in transgenic mice. The transgenic mice displayed spleen atrophy, hypocellular bone marrow and pancytopenia. Bone marrow cells and spleen cells from transgenic mice produced fewer haemopoietic colonies. After lethal irradiation followed by bone marrow transplantation, transgenic recipient mice showed pancytopenia compared with wild-type recipient mice. Bone marrow cells from transgenic donors gave haematological reconstitution at the same level as wild-type donor cells. In addition, non-adherent cell production was decreased in long-term bone marrow cell cultures of transgenic mice. Collectively these results indicate that the stroma-supported haemopoiesis is compromised in transgenic mice expressing GnT-III, providing the first demonstration that the N-glycans have some significant roles in stroma-dependent haemopoiesis.

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