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PubMed1999

The approach to mutation-selection balance in an infinite asexual population, and the evolution of mutation rates.

A method is described for calculating the dynamics of the distribution of fitness in an infinite asexual population which is subject to unconditionally deleterious mutations with independent effects. This method is applied to the problem of calculating the frequency of a mutator subpopulation, at equilibrium between mutation and indirect selection due to association with deleterious mutations. Many mutator alleles are produced by loss-of-function mutations in polymerase or mismatch repair genes. Previous calculations have ignored the fact that this creates a flux of higher fitness individuals into the mutator subpopulation. This flux raises the mean fitness of the mutator subpopulation, and when this factor is taken into account, the frequency of the mutator may be more than an order of magnitude greater than recent theoretical work has suggested.

Alleles↗
PubMed2003

Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis.

HYPOTHESIS: Breast cancer gene (BRCA) mutation status affects patients' surgical decisions when genetic cancer risk assessment is offered at the time of breast cancer diagnosis, prior to definitive treatment. PATIENTS AND INTERVENTIONS: Outcomes following genetic cancer risk assessment were studied for women newly diagnosed as having breast cancer who were prospectively enrolled in an institutional review board-approved hereditary cancer registry during a 1-year sampling frame. BRCA gene analysis was offered to subjects with a calculated mutation probability of 10% or higher. Review of medical records and telephone survey were used to document surgical treatment decisions following genetic cancer risk assessment. RESULTS: Thirty-seven of 233 women in the registry were enrolled at the time of a breast cancer diagnosis. The interval from diagnosis to genetic cancer risk assessment ranged from 3 to 60 days. The mean calculated probability of a BRCA gene mutation was 21% across the cohort. Two women were not tested because of low prior probabilities of mutation detection, and 3 declined owing to intercurrent psychological stressors. Of the remaining 32 patients, no BRCA gene mutation was detected in 22 (69%), 3 (9%) were found to carry a variant of uncertain significance, and 7 (22%) had a deleterious mutation. All 7 subjects with a deleterious mutation opted for bilateral mastectomy, whereas 20 of 22 patients with negative test results chose stage-appropriate treatment (P<.001). CONCLUSIONS: Genetic cancer risk assessment at the time of breast cancer diagnosis significantly affected women's treatment decisions. Although need and feasibility are demonstrated, the logistics of genetic cancer risk assessment during breast cancer diagnosis prove challenging.

Adult↗
PubMed1996

Mutation accumulation in transfer RNAs: molecular evidence for Muller's ratchet in mitochondrial genomes.

The accumulation of deleterious mutations is thought to be a major factor preventing the long-term persistence of obligately asexual lineages relative to their sexual ancestors. This phenomenon is also of potential relevance to sexual species that harbor asexually propagating organelle genomes. A comparative study of the transfer RNA genes in animal mitochondrial and nuclear genomes demonstrates that the former accumulate nucleotide substitutions much more rapidly than do the latter, and several lines of evidence are consistent with the idea that the excess substitutions are mildly deleterious. First, the average binding stability between complementary strands in the stems of mitochondrial tRNAs is less than half that in nuclear tRNAs. Second, most loop sizes in the mitochondrial tRNAs have experienced a net reduction in size over evolutionary time, and they are nearly 50 times more variable in the mitochondrial than in the nuclear genome. Third, although nearly 20% of the nucleotides in nuclear tRNA genes (particularly those involved in tertiary interactions) are invariant across all animal taxa and all tRNA species, there are no invariant sites in the mitochondrial tRNAs. These observations, as well as results from recent laboratory experiments, are consistent with the hypothesis that nonrecombining organelle genomes are subject to gradual loss of fitness due to the cumulative chance fixation of mildly deleterious mutations.

Animals↗
PubMed2003

Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the gene encoding the lysosomal exoglycohydrolase, alpha-galactosidase A (alpha-Gal A; GLA). In two unrelated classically affected males, two alpha-Gal A missense mutations were identified: R112C + D313Y (c.334C>T + c.937G>T) and C172G + D313Y (c.514T>G + c.937G>T). The D313Y lesion was previously identified in classically affected males as the single mutation [Eng et al., 1993] or in cis with another missense mutation, D313Y + G411D (c.937G>T + c.1232G>A) [Guffon et al., 1998]. To determine whether the D313Y mutation was a deleterious mutation or a coding region sequence variant, the frequency of D313Y in normal X-chromosomes, as well as its enzymatic activity and subcellular localization in COS-7 cells was determined. D313Y occurred in 0.45% of 883 normal X-chromosomes, while the R112C, C172G, and G411D missense mutations were not detected in over 500 normal X-chromosomes. Expression of D313Y in COS-7 cells resulted in approximately 60% of wild-type enzymatic activity and showed lysosomal localization, while R112C, C172G, G411D, and the double-mutated constructs had markedly reduced or no detectable activity and were all retained in the endoplasmic reticulum. The expressed D313Y enzyme was stable at lysosomal pH (pH 4.6), while at neutral pH (pH 7.4), it had decreased activity. A molecular homology model of human alpha-Gal A, based on the X-ray crystal structure of chicken alpha-galactosidase B (alpha-Gal B; alpha-N-acetylgalactosaminidase) was generated [Garman et al., 2002], which provided evidence that D313Y did not markedly disrupt the alpha-Gal A enzyme structure. Thus, D313Y is a rare exonic variant with about 60% of wild-type activity in vitro and reduced activity at neutral pH, resulting in low plasma alpha-Gal A activity.

Alleles↗
PubMed2004

Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility.

The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5'-untranslated and protein encoding regions of its gene was performed using a polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) strategy. Six polymorphisms in the coding region were identified, including two rare missense mutations (C474G or Asp158Glu, G967T or Val323Leu) and one nonsense mutation (Arg101Stop). This deleterious mutation, the most frequent (5%) in our population, presumably encodes a severely truncated protein. The influence of the nonsense mutation in lung cancer susceptibility was examined by PCR-SSCP using peripheral blood DNA from 204 cases of lung cancer and 201 controls. The CYP2A13*7 allele, which harbours the C301T mutation, was present in 2.0% of controls and 3.4% of cases. However, multivariate analysis showed an elevated risk for small cell lung cancer in subjects heterozygous for the null allele (odds ratio OR=9.9; 95% confidence interval CI=1.9-52.2). This increased risk was not linked to other histological types of lung cancer.

Aryl Hydrocarbon Hydroxylases↗
PubMed2006

Mechanisms of genetic robustness in RNA viruses.

Two key features of RNA viruses are their compacted genomes and their high mutation rate. Accordingly, deleterious mutations are common and have an enormous impact on viral fitness. In their multicellular hosts, robustness can be achieved by genomic redundancy, including gene duplication, diploidy, alternative metabolic pathways and biochemical buffering mechanisms. However, here we review evidence suggesting that during RNA virus evolution, alternative robustness mechanisms may have been selected. After briefly describing how genetic robustness can be quantified, we discuss mechanisms of intrinsic robustness arising as consequences of RNA-genome architecture, replication peculiarities and quasi-species population dynamics. These intrinsic robustness mechanisms operate efficiently at the population level, despite the mutational sensitivity shown by individual genomes. Finally, we discuss the possibility that viruses might exploit cellular buffering mechanisms for their own benefit, producing a sort of extrinsic robustness.

Evolution, Molecular↗
PubMed2002

Enrichment and elimination of mutY mutators in Escherichia coli populations.

The kinetics of mutator sweeps was followed in two independent populations of Escherichia coli grown for up to 350 generations in glucose-limited continuous culture. A rapid elevation of mutation rates was observed in both populations within 120-150 generations, as was apparent from major increases in the proportion of the populations with unselected mutations in fhuA. The increase in mutation rates was due to sweeps by mutY mutators. In both cultures, the enrichment of mutators resulted from hitchhiking with identified beneficial mutations increasing fitness under glucose limitation; mutY hitchhiked with mgl mutations in one culture and ptsG in the other. In both cases, mutators were enriched to constitute close to 100% of the population before a periodic selection event reduced the frequency of unselected mutations and mutators in the cultures. The high proportion of mutators persisted for 150 generations in one population but began to be eliminated within 50 generations in the other. The persistence of mutator, as well as experimental data showing that mutY bacteria were as fit as near-isogenic mutY(+) bacteria in competition experiments, suggest that mutator load by deleterious mutations did not explain the rapidly diminishing proportion of mutators in the populations. The nonmutators sweeping out mutators were also unlikely to have arisen by reversion or antimutator mutations; the mutY mutations were major deletions in each case and the bacteria sweeping out mutators contained intact mutY. By following mgl allele frequencies in one population, we discovered that mutators were outcompeted by bacteria that had rare mgl mutations previously as well as additional beneficial mutation(s). The pattern of appearance of mutY, but not its elimination, conforms to current models of mutator sweeps in bacterial populations. A mutator with a narrow mutational spectrum like mutY may be lost if the requirement for beneficial mutations is for changes other than GC --> TA transversions. Alternatively, epistatic interactions between mutator mutation and beneficial mutations need to be postulated to explain mutator elimination.

DNA Glycosylases↗
PubMed2002

Rates and patterns of molecular evolution in inbred and outbred Arabidopsis.

The evolution of self-fertilization is associated with a large reduction in the effective rate of recombination and a corresponding decline in effective population size. If many spontaneous mutations are slightly deleterious, this shift in the breeding system is expected to lead to a reduced efficacy of natural selection and genome-wide changes in the rates of molecular evolution. Here, we investigate the effects of the breeding system on molecular evolution in the highly self-fertilizing plant Arabidopsis thaliana by comparing its coding and noncoding genomic regions with those of its close outcrossing relative, the self-incompatible A. lyrata. More distantly related species in the Brassicaceae are used as outgroups to polarize the substitutions along each lineage. In contrast to expectations, no significant difference in the rates of protein evolution is observed between selfing and outcrossing Arabidopsis species. Similarly, no consistent overall difference in codon bias is observed between the species, although for low-biased genes A. lyrata shows significantly higher major codon usage. There is also evidence of intron size evolution in A. thaliana, which has consistently smaller introns than its outcrossing congener, potentially reflecting directional selection on intron size. The results are discussed in the context of heterogeneity in selection coefficients across loci and the effects of life history and population structure on rates of molecular evolution. Using estimates of substitution rates in coding regions and approximate estimates of divergence and generation times, the genomic deleterious mutation rate (U) for amino acid substitutions in Arabidopsis is estimated to be approximately 0.2-0.6 per generation.

Arabidopsis↗
PubMed1998

Genetic diversity in Leavenworthia populations with different inbreeding levels.

Levels of neutral genetic diversity within and between populations were compared between outcrossing (self-incompatible) and inbreeding populations in the annual plant genus Leavenworthia. Two taxonomically independent comparisons are possible, since self-incompatibility has been lost twice in the group of species studied. Within inbred populations of L.uniflora and L.crassa, no DNA sequence variants were seen among the alleles sampled, but high diversity was seen in alleles from populations of the outcrosser L. stylosa, and in self-incompatible L. crassa populations. Diversity between populations was seen in all species. Although total diversity values were lower in the sets of inbreeding populations, between-population values were as high or higher, than those in the outcrossing taxa. Possible reasons for these diversity patterns are discussed. As the effect of inbreeding appears to be a greater than twofold reduction in diversity, we argue that some process such as selection for advantageous mutations, or against deleterious mutations, or bottlenecks occurring predominantly in the inbreeders, appears necessary to account for the findings. If selection for advantageous mutations is responsible, it appears that it must be some form of local adaptive selection, rather than substitution of alleles that are advantageous throughout the species. This is consistent with the finding of high between-population diversity in the inbreeding taxa.

Genetic Variation↗
PubMed1996

Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency.

Somatic mosaicism in genetic disease generally results from a de novo deleterious mutation during embryogenesis. We now describe a somatic mosaicism due to the unusual mechanism of in vivo reversion to normal of an inherited mutation. The propositus was an adenosine deaminase-deficient (ADA-) child with progressive clinical improvement and unexpectedly mild biochemical and immunologic abnormalities. Mosaicism due to reversion was evidenced by absence of a maternally transmitted deleterious mutation in 13/15 authenticated B cell lines and in 17% of single alleles cloned from blood DNA, despite retention of a maternal 'private' ADA polymorphism linked to the mutation. Establishment of significant somatic mosaicism following reversion to normal could modify any disorder in which revertant cells have a selective advantage.

Adenosine Deaminase↗
PubMed2000

The BRCA2 genetic variant IVS7 + 2T-->G is a mutation.

Biochemical and genetic characterizations that support the conclusion that the variant BRCA2 IVS7 + 2T --> G represents a deleterious mutation are presented. RNA analysis from a breast cancer patient with BRCA2 IVS7 + 2T --> G showed that the productive message was produced from only one chromosome. A haplotype analysis confirmed that the intronic variant resides on the chromosome that does not produce the normal mRNA. Additionally, an RNA splicing product that deletes exon 7 was produced by the chromosome that carries BRCA2 IVS7 + 2T --> G. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249-287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. The experimental approach presented produces strong evidence of the presence of a deleterious mutation, because the contribution by both chromosomes to each RNA species analyzed was tracked using a coding region polymorphism as a marker. Furthermore, a single nucleotide polymorphism (SNP) haplotype analysis that confirms the location of the intronic variant and an associated family history that shows a high incidence of cancer supported these biochemical data.

5' Untranslated Regions↗
PubMed2000

Compensating for our load of mutations: freezing the meltdown of small populations.

We have investigated the reduction of fitness caused by the fixation of new deleterious mutations in small populations within the framework of Fisher's geometrical model of adaptation. In Fisher's model, a population evolves in an n-dimensional character space with an adaptive optimum at the origin. The model allows us to investigate compensatory mutations, which restore fitness losses incurred by other mutations, in a context-dependent manner. We have conducted a moment analysis of the model, supplemented by the numerical results of computer simulations. The mean reduction of fitness (i.e., expected load) scaled to one is approximately n/(n+2Ne), where Ne is the effective population size. The reciprocal relationship between the load and Ne implies that the fixation of deleterious mutations is unlikely to cause extinction when there is a broad scope for compensatory mutations, except in very small populations. Furthermore, the dependence of load on n implies that pleiotropy plays a large role in determining the extinction risk of small populations. Differences and similarities between our results and those of a previous study on the effects of Ne and n are explored. That the predictions of this model are qualitatively different from studies ignoring compensatory mutations implies that we must be cautious in predicting the evolutionary fate of small populations and that additional data on the nature of mutations is of critical importance.

Animals↗
PubMed1994

Advantages of sexual reproduction.

Despite the obvious efficiencies of many forms of asexual reproduction, sexual reproduction abounds. Asexual species, for the most part, are relatively short-lived offshoots of sexual ancestors. From the nineteenth century, it has been recognized that, since there is no obvious advantage to the individuals involved, the advantages of sexual reproduction must be evolutionary. Furthermore, the advantage must be substantial; for example, producing males entails a two-fold cost, compared to dispensing with them and reproducing by parthenogenetic females. There are a large number of plausible hypotheses. To me the most convincing of these are two. The first hypothesis, and the oldest, is that sexual reproduction offers the opportunity to produce recombinant types that can make the population better able to keep up with changes in the environment. Although the subject of a great deal of work, and despite its great plausibility, the hypothesis has been very difficult to test by critical observations or experiments. Second, species with recombination can bunch harmful mutations together and eliminate several in a single "genetic death." Asexual species, can eliminate them only in the same genotype in which they occurred. If the rate of occurrence of deleterious mutations is one or more per zygote, some mechanism for eliminating them efficiently must exist. A test of this mutation load hypothesis for sexual reproduction, then, is to find whether deleterious mutation rates in general are this high--as Drosophila data argue. Unfortunately, although molecular and evolutionary studies can give information on the total mutation rate, they cannot determine what fraction are deleterious. In addition, there are short discussions of the advantages of diploidy, anisogamy, and separate sexes.

Adaptation, Physiological↗
PubMed1998

Evolution, mutations, and human longevity: European royal and noble families.

The evolutionary theory of aging predicts that the equilibrium gene frequency for deleterious mutations should increase with age at onset of mutation action because of weaker (postponed) selection against later-acting mutations. According to this mutation accumulation hypothesis, one would expect the genetic variability for survival (additive genetic variance) to increase with age. The ratio of additive genetic variance to the observed phenotypic variance (the heritability of longevity) can be estimated most reliably as the doubled slope of the regression line for offspring life span on paternal age at death. Thus, if longevity is indeed determined by late-acting deleterious mutations, one would expect this slope to become steeper at higher paternal ages. To test this prediction of evolutionary theory of aging, we computerized and analyzed the most reliable and accurate genealogical data on longevity in European royal and noble families. Offspring longevity for each sex (8409 records for males and 3741 records for females) was considered as a dependent variable in the multiple regression model and as a function of three independent predictors: paternal age at death (for estimation of heritability of life span), paternal age at reproduction (control for parental age effects), and cohort life expectancy (control for cohort and secular trends and fluctuations). We found that the regression slope for offspring longevity as a function of paternal longevity increases with paternal longevity, as predicted by the evolutionary theory of aging and by the mutation accumulation hypothesis in particular.

Adult↗
PubMed2004

On the effects of background selection in small populations on comparisons of molecular variation.

Deleterious mutations affect genetic variation at linked neutral loci. Neutral variation can be reduced due to background selection, but in small population and with tight linkage such variation may increase due to associative overdominance. Here I report the results of computer simulations of diploid genotypes in small populations, where I look at the effect of deleterious mutations and linkage on comparisons of intra- and interspecific variation. Each chromosome consisted of 2000 loci where deleterious and neutral mutations occurred. The ratio of nonsynonymous to synonymous substitution rates (Ka/Ks) either increases with tight linkage or is unaffected, depending on the strength of selection. The ratio of the numbers of segregating mutations to the number of fixed mutations decreases under the conditions leading to background selection but can increase at tight linkage. Numbers of segregating sites (Sn) are less affected than nucleotide site diversity (pi), pi reduces more than Sn at intermediate linkage, but pi increases more than Sn when linkage is tight. Similar effects as found for Sn and pi are observed for heterozygosity and variance in allele size of tandem repeat loci.

Animals↗
PubMed1997

The Optimum Recombination Rate That Realizes the Fastest Evolution of a Novel Functional Combination of Many Genes

The effect of genetic recombination (or crossover) by sexual reproduction on the time until a novel set of genes performing a combined function appears, spreads, and becomes fixed is studied. First, we study a haploid finite population with many binary loci, in which only one sequence (called a functional gene set) is significantly advantageous over the others. The time for evolution of the function (Td) is defined as the mean number of generations until the advantageous sequence dominates in an initially random population. When the sequence diversity is initially stored sufficiently, the evolution time Td is roughly the product of the waiting time until the appearance of the advantageous sequence (creation time Tc) and the average number of appearances of the advantageous sequence from its absence until its fixation (destruction number Nd). Mutation and crossover reduce the former but enlarge the latter. If the mutation rate is low, there is an intermediate optimal rate of crossover that achieves the minimum Td. In contrast, if the mutation rate is sufficiently high, Td is smallest without crossover. Second, the breakdown of established functions by recurrent deleterious mutation in an infinite population is examined. The number of functional genes maintained decreases monotonically with the recurrent deleterious mutation rate. Thus in higher organisms having many functional sets of genes in the genome, the mutation rate must be kept very low to preserve them, and hence a high crossover rate made possible by sexual reproduction is important in accelerating the evolution of novel functional sets of genes. Implications of this long-term advantage of recombination in the maintenance of sexual reproduction in higher organisms are discussed.

Journal Article↗
PubMed2001

Recessive mutations and the maintenance of sex in structured populations.

The evolutionary maintenance of sexual reproduction remains a controversial problem. It was recently shown that recessive deleterious mutations create differences in the mutation load of sexual vs. asexual populations. Here we show that low levels of population structure or inbreeding can greatly enhance the importance of recessive deleterious mutations in the context of sexual vs. asexual populations. With population structure, the cost of sex can be substantially reduced or even eliminated for realistic levels of dominance.

Animals↗