Spontaneous mutation rate estimates for the principal malaria vectors Anopheles coluzzii and Anopheles stephensi

AbstractUsing high-depth whole genome sequencing of F0 mating pairs and multiple individual F1 offspring, we estimated the nuclear mutation rate per generation in the malaria vectors Anopheles coluzzii and Anopheles stephensi by detecting de novo genetic mutations. A purpose-built computer program was employed to filter actual mutations from a deep background of superficially similar artifacts resulting from read misalignment. Performance of filtering parameters was determined using software-simulated mutations, and the resulting estimate of false negative rate was used to correct final mutation rate estimates. Spontaneous mutation rates by base substitution were estimated at 1.00 × 10−9 (95% confidence interval, 2.06 × 10−10—2.91 × 10−9) and 1.36 × 10−9 (95% confidence interval, 4.42 × 10−10—3.18 × 10−9) per site per generation in A. coluzzii and A. stephensi respectively. Although similar studies have been performed on other insect species including dipterans, this is the first study to empirically measure mutation rates in the important genus Anopheles, and thus provides an estimate of µ that will be of utility for comparative evolutionary genomics, as well as for population genetic analysis of malaria vector mosquito species.

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First Estimation of the Spontaneous Mutation Rate in Diatoms

Genome Biology and Evolution ◽

10.1093/gbe/evz130 ◽

2019 ◽

Vol 11 (7) ◽

pp. 1829-1837 ◽

Cited By ~ 11

Author(s):

Marc Krasovec ◽

Sophie Sanchez-Brosseau ◽

Gwenael Piganeau

Keyword(s):

Mutation Rate ◽

Spontaneous Mutation ◽

Mutation Accumulation ◽

Mutation Rates ◽

Model Organisms ◽

Base Substitution ◽

Unicellular Eukaryote ◽

Fundamental Parameter ◽

Secondary Endosymbiosis ◽

Spontaneous Mutation Rate

Abstract Mutations are the origin of genetic diversity, and the mutation rate is a fundamental parameter to understand all aspects of molecular evolution. The combination of mutation–accumulation experiments and high-throughput sequencing enabled the estimation of mutation rates in most model organisms, but several major eukaryotic lineages remain unexplored. Here, we report the first estimation of the spontaneous mutation rate in a model unicellular eukaryote from the Stramenopile kingdom, the diatom Phaeodactylum tricornutum (strain RCC2967). We sequenced 36 mutation accumulation lines for an average of 181 generations per line and identified 156 de novo mutations. The base substitution mutation rate per site per generation is μbs = 4.77 × 10−10 and the insertion–deletion mutation rate is μid = 1.58 × 10−11. The mutation rate varies as a function of the nucleotide context and is biased toward an excess of mutations from GC to AT, consistent with previous observations in other species. Interestingly, the mutation rates between the genomes of organelles and the nucleus differ, with a significantly higher mutation rate in the mitochondria. This confirms previous claims based on indirect estimations of the mutation rate in mitochondria of photosynthetic eukaryotes that acquired their plastid through a secondary endosymbiosis. This novel estimate enables us to infer the effective population size of P. tricornutum to be Ne∼8.72 × 106.

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De Novo Mutation Rate Estimation in Wolves of Known Pedigree

Molecular Biology and Evolution ◽

10.1093/molbev/msz159 ◽

2019 ◽

Vol 36 (11) ◽

pp. 2536-2547 ◽

Cited By ~ 4

Author(s):

Evan M Koch ◽

Rena M Schweizer ◽

Teia M Schweizer ◽

Daniel R Stahler ◽

Douglas W Smith ◽

...

Keyword(s):

Mutation Rate ◽

De Novo ◽

Demographic History ◽

Full Range ◽

False Negative ◽

False Negative Rate ◽

De Novo Mutation ◽

Mutation Rates ◽

Point Estimate ◽

De Novo Mutations

Abstract Knowledge of mutation rates is crucial for calibrating population genetics models of demographic history in units of years. However, mutation rates remain challenging to estimate because of the need to identify extremely rare events. We estimated the nuclear mutation rate in wolves by identifying de novo mutations in a pedigree of seven wolves. Putative de novo mutations were discovered by whole-genome sequencing and were verified by Sanger sequencing of parents and offspring. Using stringent filters and an estimate of the false negative rate in the remaining observable genome, we obtain an estimate of ∼4.5 × 10−9 per base pair per generation and provide conservative bounds between 2.6 × 10−9 and 7.1 × 10−9. Although our estimate is consistent with recent mutation rate estimates from ancient DNA (4.0 × 10−9 and 3.0–4.5 × 10−9), it suggests a wider possible range. We also examined the consequences of our rate and the accompanying interval for dating several critical events in canid demographic history. For example, applying our full range of rates to coalescent models of dog and wolf demographic history implies a wide set of possible divergence times between the ancestral populations of dogs and extant Eurasian wolves (16,000–64,000 years ago) although our point estimate indicates a date between 25,000 and 33,000 years ago. Aside from one study in mice, ours provides the only direct mammalian mutation rate outside of primates and is likely to be vital to future investigations of mutation rate evolution.

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Genomic alterations and tumor mutational features of Chinese Xp11.2 translocation renal cell carcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.736 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 736-736

Author(s):

Yuan-Yuan Qu ◽

Hailiang Zhang ◽

Wenhao Xu ◽

Hongkai Wang ◽

Xi Tian ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

False Negative ◽

False Negative Rate ◽

Copy Number Variations ◽

Base Substitution ◽

Gene Fusions ◽

Genomic Alterations ◽

Xp11.2 Translocation

736 Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) is a rare subtype of RCC which occurs predominantly in children and adolescents. Xp11.2 RCC is characterized by the gene fusions of transcription factor E3 (TFE3). Since there is a high false-positive and false-negative rate of immunohistochemistry (IHC) for TFE3 and an uncertainty of TFE3 fusion partners by fluorescence in situ hybridization (FISH), a genetic approach, such as DNA sequencing, is necessary for auxiliary diagnosis. Methods: Thirty Chinese Xp11.2 RCC patients with positive TEF3 fusion diagnosed by FISH were involved in this analysis. Formalin-fixed, paraffin-embedded (FFPE) samples were collected for a next-generation sequencing (NGS)-based 576 gene panel assay. Genomic alterations including single base substitution, copy number variations, gene fusions, and rearrangements were assessed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were also analyzed by an NGS algorithm. Results: The 30 patients in the Xp11.2 RCC cohort included 13 males and 17 females, and had a median age of 30 years. TFE3 fusions of these patients were confirmed by both FISH and NGS. Out of the 30 Xp11.2 RCC patients, 2 patients (6.7%) showed negative TFE3 IHC expression and 4 patients (13.3%) showed equivocal TFE3 IHC expression. ASPL (9/30), PRCC (5/30), PSF (5/30), and NONO (3/30) were the most common partners of TFE3 fusion in this cohort. Moreover, we identified uncommon or novel partner genes by NGS, including ZNF627 (1/30), PTPN12 (1/30), PBM10 (1/30), PARP14 (1/30), MED15 (2/30), MATR3 (1/30), LUC7L3 (1/30), KHSRP (1/30), and EWSR1 (1/30). Based on the NGS results, several actionable genomic alterations including CDKN2A, BRCA2, and ATM were found in this study. All samples were identified as microsatellite stable (MSS). The median TMB of the entire cohort was 1.35 muts/Mb (range, 0-9.2 muts/Mb). Conclusions: In summary, we identified the partner genes of TFE3 fusion in 30 Chinese Xp11.2 RCC patients by NGS. Ten uncommon or novel partner genes (33.3%) of TFE3 were identified in this study. Overall, our results provide evidence for diagnosis and therapeutic strategies for Xp11.2 RCC patients.

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MUTATION RATES FOR ENZYME AND MORPHOLOGICAL LOCI IN BARLEY (HORDEUM VULGARE L.)

Genetics ◽

10.1093/genetics/106.4.729 ◽

1984 ◽

Vol 106 (4) ◽

pp. 729-734

Author(s):

A L Kahler ◽

R W Allard ◽

R D Miller

Keyword(s):

Mutation Rate ◽

Spontaneous Mutation ◽

Mutation Rates ◽

Isogenic Line ◽

Probability Level ◽

Short Term ◽

Hordeum Vulgare L ◽

Spontaneous Mutation Rate ◽

Enzyme Loci ◽

Morphological Variants

ABSTRACT Spontaneous mutation rates were estimated by assaying 84,126 seedlings of a highly homozygous barley line (isogenic line 2025) for five enzyme loci. No mutants were observed in 841,260 allele replications. This result excludes, at probability level 0.95, a spontaneous mutation rate larger than 3.56 x 10-6/locus/gamete/generation for these enzyme loci. Isogenic line 2025 also was scored for mutants at four loci governing morphological variants. No mutants were observed in 3,386,850 allele replications which indicates that the upper bound for the mutation rate for these loci is 8.85 x 10-7. It was concluded that, even though spontaneous mutation has been important in creating variability in the barley species at the loci scored, the rate is too low to have much affect on the short-term dynamics of barley populations.

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Spontaneous Mutation Rate of Measles Virus: Direct Estimation Based on Mutations Conferring Monoclonal Antibody Resistance

Journal of Virology ◽

10.1128/jvi.73.1.51-54.1999 ◽

1999 ◽

Vol 73 (1) ◽

pp. 51-54 ◽

Cited By ~ 64

Author(s):

Stephanie J. Schrag ◽

Paul A. Rota ◽

William J. Bellini

Keyword(s):

Monoclonal Antibody ◽

Mutation Rate ◽

Measles Virus ◽

Spontaneous Mutation ◽

Single Point ◽

Test Method ◽

Mutation Rates ◽

Viral Population ◽

Single Point Mutation ◽

Direct Estimate

ABSTRACT High mutation rates typical of RNA viruses often generate a unique viral population structure consisting of a large number of genetic microvariants. In the case of viral pathogens, this can result in rapid evolution of antiviral resistance or vaccine-escape mutants. We determined a direct estimate of the mutation rate of measles virus, the next likely target for global elimination following poliovirus. In a laboratory tissue culture system, we used the fluctuation test method of estimating mutation rate, which involves screening a large number of independent populations initiated by a small number of viruses each for the presence or absence of a particular single point mutation. The mutation we focused on, which can be screened for phenotypically, confers resistance to a monoclonal antibody (MAb 80-III-B2). The entire H gene of a subset of mutants was sequenced to verify that the resistance phenotype was associated with single point mutations. The epitope conferring MAb resistance was further characterized by Western blot analysis. Based on this approach, measles virus was estimated to have a mutation rate of 9 × 10−5 per base per replication and a genomic mutation rate of 1.43 per replication. The mutation rates we estimated for measles virus are comparable to recent in vitro estimates for both poliovirus and vesicular stomatitis virus. In the field, however, measles virus shows marked genetic stability. We briefly discuss the evolutionary implications of these results.

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The Rate and Character of Spontaneous Mutation in an RNA Virus

Genetics ◽

10.1093/genetics/162.4.1505 ◽

2002 ◽

Vol 162 (4) ◽

pp. 1505-1511 ◽

Cited By ~ 1

Author(s):

José M Malpica ◽

Aurora Fraile ◽

Ignacio Moreno ◽

Clara I Obies ◽

John W Drake ◽

...

Keyword(s):

Mutation Rate ◽

Movement Protein ◽

Rna Viruses ◽

Rna Virus ◽

Spontaneous Mutation ◽

Mutation Rates ◽

Lower Side ◽

Mutation Process ◽

Spontaneous Mutation Rate ◽

Mutant Frequency

Abstract Estimates of spontaneous mutation rates for RNA viruses are few and uncertain, most notably due to their dependence on tiny mutation reporter sequences that may not well represent the whole genome. We report here an estimate of the spontaneous mutation rate of tobacco mosaic virus using an 804-base cognate mutational target, the viral MP gene that encodes the movement protein (MP). Selection against newly arising mutants was countered by providing MP function from a transgene. The estimated genomic mutation rate was on the lower side of the range previously estimated for lytic animal riboviruses. We also present the first unbiased riboviral mutational spectrum. The proportion of base substitutions is the same as that in a retrovirus but is lower than that in most DNA-based organisms. Although the MP mutant frequency was 0.02-0.05, 35% of the sequenced mutants contained two or more mutations. Therefore, the mutation process in populations of TMV and perhaps of riboviruses generally differs profoundly from that in populations of DNA-based microbes and may be strongly influenced by a subpopulation of mutator polymerases.

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A CASE OF HIGH RATE OF SPONTANEOUS MUTATION AFFECTING VIABILITY IN DROSOPHILA MELANOGASTER

Genetics ◽

10.1093/genetics/75.1.133 ◽

1973 ◽

Vol 75 (1) ◽

pp. 133-153

Author(s):

Margaret Gale Kidwell ◽

J F Kidwell ◽

M Nei

Keyword(s):

Mutation Rate ◽

Spontaneous Mutation ◽

High Rate ◽

Mutation Rates ◽

Genetic Constitution ◽

Isogenic Line ◽

Frequency Distributions ◽

The Third ◽

Lethal Mutations ◽

Very High

ABSTRACT A spontaneous lethal mutation rate approximately twenty to thirty times greater than normal has been discovered in second and third chromosomes derived from an irradiated isogenic line and paired with marked inversion chromosomes. Mutations resulting in reductions of viability of varying magnitude short of complete lethality apparently also occur at a very high rate in the third but not in the second chromosome. The pattern of accumulation of lethal mutations over several generations and viability frequency distributions within generations have been studied in a number of independent experiments. High mutation rate occurs in heterozygous isogenic-derived second and third chromosomes, either together or apart, irrespective of the genetic constitution of nonhomologous chromosomes. High mutation rates were not observed using the same methods with chromosomes of an inbred line from a different source. The possible mechanisms responsible for these results are discussed.

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MUTATOR ACTIVITY OF PETITE STRAINS OF SACCHAROMYCES CEREVISIAE

Genetics ◽

10.1093/genetics/83.4.645 ◽

1976 ◽

Vol 83 (4) ◽

pp. 645-653

Author(s):

Fred Flury ◽

R C von Borstel ◽

D H Williamson

Keyword(s):

Saccharomyces Cerevisiae ◽

Mitochondrial Dna ◽

Mutation Rate ◽

Frameshift Mutation ◽

Spontaneous Mutation ◽

Nuclear Genes ◽

Mutation Rates ◽

Spontaneous Mutation Rate ◽

Mutator Activity ◽

Missense Allele

ABSTRACT Petite strains in Saccharomyces exhibit enhanced spontaneous mutation rates of nuclear genes regardless of whether they are cytoplasmically or nuclearly inherited, or whether or not the cytoplasmic petite strains have mitochondrial DNA. In petite strains, the mutation rate for the nonsense allele lys1-1 is enhanced by a factor of 3-6 and for the missense allele his1-7 by a factor of 2 as compared with their grande counterparts. The reversion of a third allele, the putative frameshift mutation, hom3-10, is not enhanced in a petite background. The results indicate that the spontaneous mutation rate of an organism can be altered by indirect intracellular influences.

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High and Highly Variable Spontaneous Mutation Rates in Daphnia

Molecular Biology and Evolution ◽

10.1093/molbev/msaa142 ◽

2020 ◽

Vol 37 (11) ◽

pp. 3258-3266 ◽

Cited By ~ 3

Author(s):

Eddie K H Ho ◽

Fenner Macrae ◽

Leigh C Latta ◽

Peter McIlroy ◽

Dieter Ebert ◽

...

Keyword(s):

Intraspecific Variation ◽

Sequence Data ◽

Spontaneous Mutation ◽

Nuclear Genome ◽

Mutation Accumulation ◽

Whole Genome Sequence ◽

Critical Parameters ◽

Mutation Rates ◽

Base Substitution ◽

Conversion Rates

Abstract The rate and spectrum of spontaneous mutations are critical parameters in basic and applied biology because they dictate the pace and character of genetic variation introduced into populations, which is a prerequisite for evolution. We use a mutation–accumulation approach to estimate mutation parameters from whole-genome sequence data from multiple genotypes from multiple populations of Daphnia magna, an ecological and evolutionary model system. We report extremely high base substitution mutation rates (µ-n,bs = 8.96 × 10−9/bp/generation [95% CI: 6.66–11.97 × 10−9/bp/generation] in the nuclear genome and µ-m,bs = 8.7 × 10−7/bp/generation [95% CI: 4.40–15.12 × 10−7/bp/generation] in the mtDNA), the highest of any eukaryote examined using this approach. Levels of intraspecific variation based on the range of estimates from the nine genotypes collected from three populations (Finland, Germany, and Israel) span 1 and 3 orders of magnitude, respectively, resulting in up to a ∼300-fold difference in rates among genomic partitions within the same lineage. In contrast, mutation spectra exhibit very consistent patterns across genotypes and populations, suggesting the mechanisms underlying the mutational process may be similar, even when the rates at which they occur differ. We discuss the implications of high levels of intraspecific variation in rates, the importance of estimating gene conversion rates using a mutation–accumulation approach, and the interacting factors influencing the evolution of mutation parameters. Our findings deepen our knowledge about mutation and provide both challenges to and support for current theories aimed at explaining the evolution of the mutation rate, as a trait, across taxa.

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