Genetic loads under fitness‐dependent mutation rates

Abstract Although much theory depends on the genome‐wide rate of deleterious mutations, good estimates of the mutation rate are scarce and remain controversial. Furthermore, mutation rate may not be constant, and a recent study suggests that mutation rates are higher in mildly stressful environments. If mutation rate is a function of condition, then individuals carrying more mutations will tend to be in worse condition and therefore produce more mutations. Here I examine the mean fitnesses of sexual and asexual populations evolving under such condition‐dependent mutation rates. The equilibrium mean fitness of a sexual population depends on the shape of the curve relating fitness to mutation rate. If mutation rate declines synergistically with increasing condition the mean fitness will be much lower than if mutation rate declines at a diminishing rate. In contrast, asexual populations are less affected by condition‐dependent mutation rates. The equilibrium mean fitness of an asexual population only depends on the mutation rate of the individuals in the least loaded class. Because such individuals have high fitness and therefore a low mutation rate, asexual populations experience less genetic load than sexual populations, thus increasing the twofold cost of sex.     

The rate of compensatory mutation in the DNA bacteriophage phiX174

A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage phiX174. For each deleterious mutation, we evolved 8-16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was approximately 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.     

A frequent tyrosinase gene mutation associated with type I-A (tyrosinase-negative) oculocutaneous albinism in Puerto Rico.

We have determined the mutations in the tyrosinase gene from 12 unrelated Puerto Rican individuals who have type I-A (tyrosinase-negative) oculocutaneous albinism (OCA). All but one individual are of Hispanic descent. Nine individuals were homozygous for a missense mutation (G47D) in exon I at codon 47. Two individuals were heterozygous for the G47D mutation, with one having a missense mutation at codon 373 (T373K) in the homologous allele and the other having an undetermined mutation in the homologous allele. One individual with negroid features was homozygous for a nonsense mutation (W236X). The population migration between Puerto Rico and the Canary Islands is well recognized. Analysis of three individuals with OCA from the Canary Islands showed that one was a compound heterozygote for the G47D mutation and for a novel missense mutation (L216M), one was homozygous for a missense mutation (P81L), and one was heterozygous for the missense mutation P81L. The G47D and P81L missense mutations have been previously described in extended families in the United States. Haplotypes were determined using four polymorphisms linked to the tyrosinase locus. Haplotype analysis showed that the G47D mutation occurred on a single haplotype, consistent with a common founder for all individuals having this mutation. Two different haplotypes were found associated with the P81L mutation, suggesting that this may be either a recurring mutation for the tyrosinase gene or a recombination between haplotypes.     

EVOLUTIONARY FEEDBACKS BETWEEN REPRODUCTIVE MODE AND MUTATION RATE EXACERBATE THE PARADOX OF SEX

Evolutionary theory suggests that low mutation rates should favor the persistence of asexuals. Additionally, given the observation that most nonneutral mutations are deleterious, asexuality may strengthen selection for reduced mutation rates. This reciprocal relationship raises the possibility of a positive feedback loop between sex and mutation rate. We explored the consequences of this evolutionary feedback with an individual‐based model in which a sexual population is continually challenged by the introduction of asexual clones. We found that asexuals were more likely to spread in a population when mutation rates were able to evolve relative to a model in which mutation rates were held constant. In fact, under evolving mutation rates, asexuals were able to spread to fixation even when sexuals faced no cost of sex whatsoever. The added success of asexuals was the result of their ability to evolve lower mutation rates and thereby slow the process of mutation accumulation that otherwise limited their spread. Given the existence of ample mutation rate variation in natural populations, our findings show that the evolutionary feedback between sex and mutation rate may intensify the “paradox of sex,” supporting the argument that deleterious mutation accumulation alone is likely insufficient to overcome the reproductive advantage of asexual competitors in the short term.     

The evolution of mutation rates: separating causes from consequences

Natural selection can adjust the rate of mutation in a population by acting on allelic variation affecting processes of DNA replication and repair. Because mutation is the ultimate source of the genetic variation required for adaptation, it can be appealing to suppose that the genomic mutation rate is adjusted to a level that best promotes adaptation. Most mutations with phenotypic effects are harmful, however, and thus there is relentless selection within populations for lower genomic mutation rates. Selection on beneficial mutations can counter this effect by favoring alleles that raise the mutation rate, but the effect of beneficial mutations on the genomic mutation rate is extremely sensitive to recombination and is unlikely to be important in sexual populations. In contrast, high genomic mutation rates can evolve in asexual populations under the influence of beneficial mutations, but this phenomenon is probably of limited adaptive significance and represents, at best, a temporary reprieve from the continual selection pressure to reduce mutation. The physiological cost of reducing mutation below the low level observed in most populations may be the most important factor in setting the genomic mutation rate in sexual and asexual systems, regardless of the benefits of mutation in producing new adaptive variation. Maintenance of mutation rates higher than the minimum set by this "cost of fidelity" is likely only under special circumstances.     

基于功率谱分析的基因编码序列单碱基突变研究

针对DNA序列单碱基的不同类型突变,利用数字信号处理方法,研究了单碱基替换突变、删除突变、插入突变对DNA序列三周期功率谱的影响。研究结果表明:对于不同长度的编码序列,替换突变对序列功率谱的影响较小,删除突变和插入突变对序列功率谱的影响较大;随着序列编码区长度的减小,替换、删除、插入突变对序列编码区的功率谱影响会越来越大。对于中等长度外显子,插入突变对序列三周期功率谱影响最大,对于短外显子,删除突变对序列三周期功率谱的影响最大。研究结果可为含突变基因编码区的识别与检测提供参考。     

A novel mtDNA C11777A mutation in Leigh syndrome

A novel mitochondrial DNA point mutation, a C-to-A mutation at nucleotide position (np) 11,777, was identified in two unrelated patients out of 100 with Leigh syndrome. This mutation converted a highly evolutionary conserved arginine to a serine at codon 340 in ND4 gene. This codon was also converted by a G-to-A mutation at np 11,778, the most common mutation associated with Leber's hereditary optic neuropathy (LHON), but the amino acid replacement was different (R340S vs. R340H). Cybrid study revealed that the percentage of heteroplasmy was correlated with complex I function and that the novel mutation caused a much more deleterious effect than the np 11,778 LHON mutation in complex I activity.     

Interactions between mutations affecting ribosome synthesis in Escherichia coli

RNA synthesis was followed during amino acid starvation of strains of Escherichia coli that contained both the relaxed (relA) mutation and a mutation affecting ribosome assembly that results in oversynthesis of RNA. The ribosome mutation did not by itself lead to relaxedness. The relaxed mutation could be expressed in organisms that contained the ribosome mutation.     

Mutation analysis of Korean patients with citrullinemia

Citrullinemia is an autosomal recessive disease due to the mutations in the argininosuccinate synthetase (ASS) gene. Mutation analysis was performed on three Korean patients with citrullinemia. All of the three patients had the splicing mutation previously reported as IVS6-2A>G mutation. Two had Gly324Ser mutation and the other patient had a 67-bp insertion mutation in exon 15. The IVS6-2A>G mutation was reported to be found frequently in Japanese patients with citrullinemia, but Caucasian patients showed the extreme mutational heterogeneity. Although a limited number of Korean patients were studied, the IVS6-2A>G mutation appears to be one of the most frequent mutant alleles in Korean patients with citrullinemia. The Gly324Ser mutation identified in two patients also suggests the possible high frequency of this mutation in Korean patients as well.     

Epistasis and frequency dependence influence the fitness of an adaptive mutation in a diversifying lineage

The opportunity for a mutation to invade a population can dramatically vary depending on the context in which this mutation occurs. Such context dependence is difficult to document as it requires the ability to measure how a mutation affects phenotypes and fitness and to manipulate the context in which the mutation occurs. We identified a mutation in a gene encoding a global regulator in one of two ecotypes that diverged from a common ancestor during 1200 generations of experimental evolution. We replaced the ancestral allele by the mutant allele, and vice versa, in several clones isolated during the time course of the evolution experiment, and compared the phenotype and fitness of clones isogenic except for the focal mutation. We show that the fitness and phenotype of the mutation are strongly affected by epistatic interactions between genes in the same genome, as well as by frequency dependent selection resulting from biotic interactions between individuals in the same population. We conclude that amongst the replicate population in which it spread, the mutation we identified is only adaptive when occurring in specific genomes and competing with specific individuals. This study thus demonstrates that the opportunity for an adaptive mutation to spread in an evolutionary lineage can only be understood in the light of its genomic and competitive environments.     

Recurrent mutation in the human phenylalanine hydroxylase gene.

We report the identification of a missense mutation of Glu280 to Lys280 in the phenylalanine hydroxylase (PAH) gene of a phenylketonuria (PKU) patient in Denmark. The mutation is associated with haplotype 1 of the PAH gene in this population. This mutation has previously been found in North Africa, where it is in linkage disequilibrium with haplotype 38. While it is conceivable that this mutation could have been transferred from one haplotype background to another by a double crossover or gene conversion event, the fact that the mutation is exclusively associated with the two different haplotypes in the two distinct populations supports the hypothesis that these two PKU alleles are the result of recurrent mutations in the human PAH gene. Furthermore, since the site of mutation involves a CpG dinucleotide, they may represent hot spots for mutation in the human PAH locus.     

食药用菌诱变育种研究进展

诱变育种是一项借助诱变剂人为的诱导突变,创造出杂交育种中无法创制的新性状的育种技术。自然界中的突变只有0.1%,而诱变育种可以提高到3%左右,比自然突变高100倍以上。诱变技术已经在食药用菌育种中广为利用,本文针对诱变育种的原理、方法、在食药用菌中的应用情况进行了阐述,最后为食药用菌诱变育种的进一步发展进行了探讨和展望,这为利用诱变技术进行食药用菌品种的选育提供了理论依据和参考。     

Joint Frequencies of Alleles Determined by Separate Formulations for the Mating and Mutation Systems

A method to calculate joint gene frequencies, which are the probabilities that two neutral genes taken at random from a population have certain allelic states, is developed taking into account the effects of the mating system and the mutation scheme. We assume that the mutation rates are constant in the population and that the mating system does not depend on allelic states. Under either--the condition that mutation rates are symmetric or that the mating unit is large and the mutation rate is small--the general formula is represented by two terms, one for the mating system and the other for the mutation scheme. The term for the mating system is expressed using the coancestry coefficient in the infinite allele model, and the term for the mutation scheme is a function of the eigenvalues and the eigenvectors of the mutation matrix. Several examples are presented as applications of the method, including homozygosity in a stepping-stone model with a symmetric mutation scheme.     

The coupon collector and the suppressor mutation: estimating the number of compensatory mutations by maximum likelihood

Compensatory mutation occurs when a loss of fitness caused by a deleterious mutation is restored by its epistatic interaction with a second mutation at a different site in the genome. How many different compensatory mutations can act on a given deleterious mutation? Although this quantity is fundamentally important to understanding the evolutionary consequence of mutation and the genetic complexity of adaptation, it remains poorly understood. To determine the shape of the statistical distribution for the number of compensatory mutations per deleterious mutation, we have performed a maximum-likelihood analysis of experimental data collected from the suppressor mutation literature. Suppressor mutations are used widely to assess protein interactions and are under certain conditions equivalent to compensatory mutations. By comparing the maximum likelihood of a variety of candidate distribution functions, we established that an L-shaped gamma distribution (alpha=0.564, theta=21.01) is the most successful at explaining the collected data. This distribution predicts an average of 11.8 compensatory mutations per deleterious mutation. Furthermore, the success of the L-shaped gamma distribution is robust to variation in mutation rates among sites. We have detected significant differences among viral, prokaryotic, and eukaryotic data subsets in the number of compensatory mutations and also in the proportion of compensatory mutations that are intragenic. This is the first attempt to characterize the overall diversity of compensatory mutations, identifying a consistent and accurate prior distribution of compensatory mutation diversity for theoretical evolutionary models.     

Clinical evaluation and sequence analysis of the complete mitochondrial genome of three Chinese patients with hearing impairment associated with the 12S rRNA T1095C mutation

Mutations in mitochondrial DNA (mtDNA), particularly those in the 12S rRNA gene, have been shown to be associated with sensorineural hearing loss. Here we report the clinical and sequence analysis of the entire mitochondrial genome in three Chinese subjects with aminoglycoside-induced and non-syndromic hearing impairment. Clinical evaluation showed a variable phenotype of hearing impairment including the age of onset and audiometric configuration in these subjects. Sequence analysis of the complete mitochondrial genomes in three subjects showed the distinct sets of mtDNA polymorphism, in addition to the identical mitochondrial 12S rRNA T1095C mutation. This mutation was previously identified to be associated with hearing impairment in three families from different genetic backgrounds. The T1095C mutation was absent in 364 Chinese control. In fact, the occurrence of the T1095C mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. Among other nucleotide changes, the A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 exhibited a high evolutionary conservation. These data suggest that the T1095C mutation may be associated with aminoglycoside-induced and non-syndromic hearing impairments and A2238G and T2885C mutations in the 16S rRNA, the I175V mutation in the CO2, the F16L mutation in the A6 and the V112M mutation in the ND6 may contribute to the phenotypic expression of the T1095C mutation in these subjects.     

The study of mitochondrial A3243G mutation in different samples

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is the most frequent syndromic manifestation of A3243G mutation in mitochondrial DNA. Detection of A3243G mutation in blood is less helpful for the diagnosis of MELAS and the carriers, and the mutation ratio in blood correlates only in a limited extent with the severity of the disease. Here we compared the ratio of A3243G mutation in four easily available samples (blood, urine, hair follicle and saliva) in patients with MELAS carrying A3243G mutation as well as their maternal relatives from 32 families, to find out the samples appropriate for the detection of the patients and carriers and useful for the evaluation of clinical severity from their mutation ratio. In MELAS patients and the carriers with minor symptoms or normal phenotype, A3243G mutation ratio was significantly higher in urine than in blood. A close correlation between A3243G mutation ratio in blood and that in urine, hair follicles and saliva was found in the probands and their relatives. Clinical features closely correlated with the mutation ratio in urine. Measurement of A3243G mutation ratio in urine is a non-invasive, convenient and rapid method with its diagnostic meaning superior to blood testing.     

A new codon 31 (-C) mutant resulting in beta zero-thalassemia.

A new beta zero-thalassemia mutation, a frameshift mutation with deletion of a single cytosine nucleotide in codon 31, is described. The propositus, which is compound heterozygous for this mutation and the 17 beta A-T beta zero-thalassemia mutation, has the phenotype of severe beta-thalassemia major.     

Interaction between two regulatory proteins in osmoregulatory expression of ompF and ompC genes in Escherichia coli: a novel ompR mutation suppresses pleiotropic defects caused by an envZ mutation.

The ompR and envZ genes, which together constitute the ompB operon, are involved in osmoregulatory expression of the OmpF and OmpC proteins, major outer membrane proteins of Escherichia coli. The envZ11 mutation results in the OmpF- OmpC-constitutive phenotype. A mutant which suppressed defects caused by the envZ11 mutation was isolated. The suppressor mutation also suppressed the LamB- PhoA- phenotype caused by the envZ11 mutation. The mutation occurred in the ompR gene and hence was termed ompR77. The ompR77 mutation alone produced no obvious phenotype. Functioning of the ompR77 allele remained envZ gene dependent. Although the ompR77 mutation suppressed the envZ11 mutation, it did not suppress a mutation that occurred in another position within the envZ gene (envZ160). These results indicate that OmpR and EnvZ, two regulatory proteins, functionally interact with each other.     

Hyper-mutation caused by the reml mutation in yeast is not dependent on error-prone or excision repair

The reml mutations of Saccharomyces cerevisiae confer a semi-dominant hyper-recombination/hyper-mutation phenotype. Neither reml mutant allele has any apparent meiotic affect. We have examined spontaneous mutation in reml-2 strains and demonstrate that the reml-2 mutation, like reml-1, confers an average 10-fold increase in reversion and forward mutation rates. Unlike certain yeast rad mutations with phenotypes similar to reml, strains containing reml are resistant to MMS and only slightly UV sensitive at very high doses. To understand the mutator phenotype of reml, we have used a double-mutant approach, combining the reml mutation with radiation-sensitive mutations affecting DNA repair. Double mutants of reml-2 and a mutation in the yeast error-prone repair group (rad6-1) or a mutation in excision repair (rad1-2 or rad4) maintain the hyper-mutation phenotype. Since mutation rates remain elevated in these double-mutant strains, it appears as if the mutations which occur in the presence of reml resemble spontaneous mutation since they do not require the action of a repair system.     

Natural selection fails to optimize mutation rates for long-term adaptation on rugged fitness landscapes

The rate of mutation is central to evolution. Mutations are required for adaptation, yet most mutations with phenotypic effects are deleterious. As a consequence, the mutation rate that maximizes adaptation will be some intermediate value. Here, we used digital organisms to investigate the ability of natural selection to adjust and optimize mutation rates. We assessed the optimal mutation rate by empirically determining what mutation rate produced the highest rate of adaptation. Then, we allowed mutation rates to evolve, and we evaluated the proximity to the optimum. Although we chose conditions favorable for mutation rate optimization, the evolved rates were invariably far below the optimum across a wide range of experimental parameter settings. We hypothesized that the reason that mutation rates evolved to be suboptimal was the ruggedness of fitness landscapes. To test this hypothesis, we created a simplified landscape without any fitness valleys and found that, in such conditions, populations evolved near-optimal mutation rates. In contrast, when fitness valleys were added to this simple landscape, the ability of evolving populations to find the optimal mutation rate was lost. We conclude that rugged fitness landscapes can prevent the evolution of mutation rates that are optimal for long-term adaptation. This finding has important implications for applied evolutionary research in both biological and computational realms.