scholarly journals Meiotic recombination counteracts male-biased mutation (male-driven evolution)

2016 ◽  
Vol 283 (1823) ◽  
pp. 20152691 ◽  
Author(s):  
Shuuji Mawaribuchi ◽  
Michihiko Ito ◽  
Mitsuaki Ogata ◽  
Hiroki Oota ◽  
Takafumi Katsumura ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Meiotic Recombination ◽  
Rate Ratio ◽  
Molecular Evidence ◽  
Nucleotide Substitution Rate ◽  
Type Group ◽  
Replication Errors ◽  
Two Factors ◽  
Dna Replication Errors ◽  
Male To Female

Meiotic recombination is believed to produce greater genetic variation despite the fact that deoxyribonucleic acid (DNA)-replication errors are a major source of mutations. In some vertebrates, mutation rates are higher in males than in females, which developed the theory of male-driven evolution (male-biased mutation). However, there is little molecular evidence regarding the relationships between meiotic recombination and male-biased mutation. Here we tested the theory using the frog Rana rugosa, which has both XX/XY- and ZZ/ZW-type sex-determining systems within the species. The male-to-female mutation-rate ratio ( α ) was calculated from homologous sequences on the X/Y or Z/W sex chromosomes, which supported male-driven evolution. Surprisingly, each α value was notably higher in the XX/XY-type group than in the ZZ/ZW-type group, although α should have similar values within a species. Interestingly, meiotic recombination between homologous chromosomes did not occur except at terminal regions in males of this species. Then, by subdividing α into two new factors, a replication-based male-to-female mutation-rate ratio ( β ) and a meiotic recombination-based XX-to-XY/ZZ-to-ZW mutation-rate ratio ( γ ), we constructed a formula describing the relationship among a nucleotide-substitution rate and the two factors, β and γ . Intriguingly, the β - and γ -values were larger and smaller than 1, respectively, indicating that meiotic recombination might reduce male-biased mutations.

scholarly journals The “false-positive” conundrum in the NTP 2-year rodent cancer study database

2018 ◽  
Vol 2 ◽  
pp. 239784731877283 ◽  
Author(s):  
Carr J. Smith ◽  
Thomas A. Perfetti
Keyword(s):  
Mutation Rate ◽  
Ames Test ◽  
Cellular Proliferation ◽  
Tumor Site ◽  
Routes Of Administration ◽  
Replication Errors ◽  
Background Mutation Rate ◽  
High Doses ◽  
Dna Replication Errors ◽  
Rats And Mice

In 1990, Ames and Gold described a conundrum of “too many carcinogens” among chemicals tested in rodent bioassays. Their proposed nongenotoxic carcinogenic mechanism was amplification of the background mutation rate via cytotoxicity induced by high doses of the test chemicals, thereby leading to increases in reparative cellular proliferation rates. Recently, we have statistically and mechanistically analyzed the entire 594-study (470 final reports) NTP 2-year rodent cancer database to better understand the conundrum posed by Ames and Gold. Our analysis provides several lines of evidence that support the contention of Ames and Gold. First, across different routes of administration, relatively phylogenetically similar rats and mice are nonetheless discordant for the development of tumors at similar organ sites. Tumor site concordance across sex within species is higher than tumor site concordance across species. Second, many chemicals negative in the Ames test nonetheless induce tumors in either rats or mice. Third, 11 out of 58 chemicals tested by the inhalation route induce lung tumors in mice and not rats, are negative in the Ames test, and exhibit hyperplasia. In 2017, Tomasetti et al. provided evidence for the clinical relevance in humans of the Ames and Gold mechanism regarding amplification of the background mutation rate by demonstrating that the majority of human tumors result from accumulated mutations due to DNA replication errors.

scholarly journals The Causes of Synonymous Rate Variation in the Rodent Genome: Can Substitution Rates Be Used to Estimate the Sex Bias in Mutation Rate?

Genetics ◽  
1999 ◽  
Vol 152 (2) ◽  
pp. 661-673 ◽  
Author(s):  
Nick G C Smith ◽  
Laurence D Hurst
Keyword(s):  
Mutation Rate ◽  
Rate Ratio ◽  
Synonymous Substitution ◽  
Sex Bias ◽  
Imprinted Genes ◽  
Rate Variation ◽  
Substitution Rates ◽  
Synonymous Substitution Rates ◽  
Male To Female ◽  
Different Parts

Abstract Miyata et al. have suggested that the male-to-female mutation rate ratio (α) can be estimated by comparing the neutral substitution rates of X-linked (X), Y-linked (Y), and autosomal (A) genes. Rodent silent site X/A comparisons provide very different estimates from X/Y comparisons. We examine three explanations for this discrepancy: (1) statistical biases and artifacts, (2) nonneutral evolution, and (3) differences in mutation rate per germline replication. By estimating errors and using a variety of methodologies, we tentatively reject explanation 1. Our analyses of patterns of codon usage, synonymous rates, and nonsynonymous rates suggest that silent sites in rodents are evolving neutrally, and we can therefore reject explanation 2. We find both base composition and methylation differences between the different sets of chromosomes, a result consistent with explanation 3, but these differences do not appear to explain the observed discrepancies in estimates of α. Our finding of significantly low synonymous substitution rates in genomically imprinted genes suggests a link between hemizygous expression and an adaptive reduction in the mutation rate, which is consistent with explanation 3. Therefore our results provide circumstantial evidence in favor of the hypothesis that the discrepancies in estimates of α are due to differences in the mutation rate per germline replication between different parts of the genome. This explanation violates a critical assumption of the method of Miyata et al., and hence we suggest that estimates of α, obtained using this method, need to be treated with caution.

Potential problems in estimating the male-to-female mutation rate ratio from DNA sequence data

1993 ◽  
Vol 37 (2) ◽  
pp. 160-166 ◽  
Author(s):  
Lawrence C. Shimmin ◽  
Benny Hung-Junn Chang ◽  
David Hewett-Emmett ◽  
Wen-Hsiung Li
Keyword(s):  
Dna Sequence ◽  
Mutation Rate ◽  
Rate Ratio ◽  
Sequence Data ◽  
Dna Sequence Data ◽  
Potential Problems ◽  
Male To Female

scholarly journals 3′ → 5′ Exonucleases of DNA Polymerases ϵ and δ Correct Base Analog Induced DNA Replication Errors on Opposite DNA Strands in Saccharomyces cerevisiae

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 717-726 ◽  
Author(s):  
Polina V Shcherbakova ◽  
Youri I Pavlov
Keyword(s):  
Dna Replication ◽  
Dna Polymerases ◽  
Replication Errors ◽  
Dna Strands ◽  
Base Analog ◽  
Chromosome Iii ◽  
Dna Strand ◽  
Dna Replication Errors ◽  
Yeast Mutants ◽  
Lagging Strand

Abstract The base analog 6-N-hydroxylaminopurine (HAP) induces bidirectional GC → AT and AT → GC transitions that are enhanced in DNA polymerase ϵ and δ 3′ → 5′ exonuclease-deficient yeast mutants, pol2-4 and pol3-01, respectively. We have constructed a set of isogenic strains to determine whether the DNA polymerases δ and ϵ contribute equally to proofreading of replication errors provoked by HAP during leading and lagging strand DNA synthesis. Site-specific GC → AT and AT → GC transitions in a Pol→, pol2-4 or pol3-01 genetic background were scored as reversions of ura3 missense alleles. At each site, reversion was increased in only one proofreading-deficient mutant, either pol2-4 or pol3-01, depending on the DNA strand in which HAP incorporation presumably occurred. Measurement of the HAP-induced reversion frequency of the ura3 alleles placed into chromosome III near to the defined active replication origin ARS306 in two orientations indicated that DNA polymerases ϵ and δ correct HAP-induced DNA replication errors on opposite DNA strands.

scholarly journals Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors

1997 ◽  
Vol 74 (3) ◽  
pp. 330-334 ◽  
Author(s):  
Rafael Rosell ◽  
Alex Pifarré ◽  
Mariano Monzó ◽  
Julio Astudillo ◽  
M. Paz López-Cabrerizo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Replication ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Stage I ◽  
Small Cell Lung ◽  
Replication Errors ◽  
Dna Replication Errors

scholarly journals Linkage disequilibrium, mutational analysis and natural selection in the repetitive region of the clock gene, period, in Drosophila melanogaster

1997 ◽  
Vol 69 (2) ◽  
pp. 89-99 ◽  
Author(s):  
EZIO ROSATO ◽  
ALEXANDRE A. PEIXOTO ◽  
RODOLFO COSTA ◽  
CHARALAMBOS P. KYRIACOU
Keyword(s):  
Drosophila Melanogaster ◽  
Mutation Rate ◽  
Clock Gene ◽  
Mutational Analysis ◽  
Pedigree Analysis ◽  
Nucleotide Substitution Rate ◽  
Repetitive Region ◽  
Linkage Disequilibria ◽  
Direct Measurements ◽  
Polymerase Chain

We have used the method of disequilibrium pattern analysis to examine associations between the threonine-glycine (Thr-Gly) encoding repeat region of the clock gene period (per) of Drosophila melanogaster, and polymorphic sites both upstream and downstream of the repeat, in a number of European fly populations. The results are consistent with the view that selection may be operating on various haplotypes which share the Thr-Gly length alleles encoding 17, 20 and 23 dipeptide pairs, and that the repeat itself may be the focus for selection. These conclusions lend support to a number of other population and behavioural investigations which have provided evidence that selection is acting on the Thr-Gly region. The linkage analysis was also used to infer an approximate mutation rate (μ) for the repeat, of 10−5<μ<4×10−5 per gamete per generation. Direct measurements of the mutation rate using the polymerase chain reaction in a pedigree analysis of tens of thousands of individuals do not contradict this value. Consequently, the Thr-Gly repeat does not have a mutation rate that is as high as some of the non-coding minisatellites, but it is several orders of magnitude higher than the nucleotide substitution rate. The implications of this elevated mutation rate for linkage disequilibria and selection are discussed.

Brain tumor-polyposis syndrome: two genetic diseases?

1997 ◽  
Vol 15 (7) ◽  
pp. 2744-2758 ◽  
Author(s):  
F Paraf ◽  
S Jothy ◽  
E G Van Meir
Keyword(s):  
Colorectal Cancer ◽  
Brain Tumor ◽  
Genetic Diseases ◽  
Skin Lesions ◽  
Colorectal Adenomas ◽  
Syndrome Type ◽  
Dna Mismatch ◽  
Replication Errors ◽  
Café Au Lait Spots ◽  
Dna Replication Errors

PURPOSE AND DESIGN This report presents a comprehensive and statistical analysis of the brain tumor-polyposis (BTP) cases referred to as Turcot's syndrome in the literature. RESULTS BTP patients encompass a heterogeneous group that can be classified into two statistically distinct clinical entities based on phenotype of the polyps (P = .0001), presence of colorectal cancer (P = .0001), type of brain neoplasm, ie, glioma or medulloblastoma (P = .0001), presence of skin lesions (P = .0004) and cafe-au-lait spots (P = .0008), as well as consanguinity (P = .0135). CONCLUSION The first entity (BTP syndrome type 1) consists of patients who have glioma and colorectal adenomas without polyposis (non-FAP cases), and their siblings with glioma and/or colorectal adenomas. For these patients, we show that the patient's age at malignant glioma occurrence is less than 20 years (50 to 80 years in the general population), which strongly supports the existence of an underlying genetic cause. The neoplasms of these patients show DNA replication errors, which suggests a relationship with hereditary nonpolyposis colorectal cancer (HNPCC), a disease characterized by germline alterations in DNA mismatch repair genes. The second entity (BTP syndrome type 2) consists of patients with a CNS tumor that occurs in a familial adenomatous polyposis kindred (FAP cases). These patients carry germline mutations in the APC gene, which suggests that mutations in this gene might predispose to brain tumors. Risk analysis shows increased incidence of medulloblastoma in FAP patients, but APC mutations are not found in sporadic glioma or medulloblastoma. Therefore, further investigations should establish whether the occurrence of medulloblastoma in an FAP family represents a variant of FAP.

scholarly journals DNA Mismatch Repair in Eukaryotes and Bacteria

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Kenji Fukui
Keyword(s):  
Mismatch Repair ◽  
Molecular Mechanisms ◽  
Dna Mismatch Repair ◽  
Repair System ◽  
Dna Mismatch ◽  
Replication Errors ◽  
Colon Cancers ◽  
Basic Features ◽  
Almost All ◽  
Dna Replication Errors

DNA mismatch repair (MMR) corrects mismatched base pairs mainly caused by DNA replication errors. The fundamental mechanisms and proteins involved in the early reactions of MMR are highly conserved in almost all organisms ranging from bacteria to human. The significance of this repair system is also indicated by the fact that defects in MMR cause human hereditary nonpolyposis colon cancers as well as sporadic tumors. To date, 2 types of MMRs are known: the human type andEscherichia colitype. The basic features of the former system are expected to be universal among the vast majority of organisms including most bacteria. Here, I review the molecular mechanisms of eukaryotic and bacterial MMR, emphasizing on the similarities between them.

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