Low Genetic Quality Alters Key Dimensions of the Mutational Spectrum

Mutations affect individual health, population persistence, adaptation, diversification, and genome evolution. There is evidence that the mutation rate varies among genotypes, but the causes of this variation are poorly understood. Here, we link differences in genetic quality with variation in spontaneous mutation in a Drosophila mutation accumulation experiment. We find that chromosomes maintained in low-quality genetic backgrounds experience a higher rate of indel mutation and a lower rate of gene conversion in a manner consistent with condition-based differences in the mechanisms used to repair DNA double strand breaks. These aspects of the mutational spectrum were also associated with body mass, suggesting that the effect of genetic quality on DNA repair was mediated by overall condition, and providing a mechanistic explanation for the differences in mutational fitness decline among these genotypes. The rate and spectrum of substitutions was unaffected by genetic quality, but we find variation in the probability of substitutions and indels with respect to several aspects of local sequence context, particularly GC content, with implications for models of molecular evolution and genome scans for signs of selection. Our finding that the chances of mutation depend on genetic context and overall condition has important implications for how sequences evolve, the risk of extinction, and human health.     

Evolutionary rate variation at multiple levels of biological organization in plant mitochondrial DNA

We examined patterns of mitochondrial polymorphism and divergence in the angiosperm genus Silene and found substantial variation in evolutionary rates among species and among lineages within species. Moreover, we found corresponding differences in the amount of polymorphism within species. We argue that, along with our earlier findings of rate variation among genes, these patterns of rate heterogeneity at multiple phylogenetic scales are most likely explained by differences in underlying mutation rates. In contrast, no rate variation was detected in nuclear or chloroplast loci. We conclude that mutation rate heterogeneity is a characteristic of plant mitochondrial sequence evolution at multiple biological scales and may be a crucial determinant of how much polymorphism is maintained within species. These dramatic patterns of variation raise intriguing questions about the mechanisms driving and maintaining mutation rate heterogeneity in plant mitochondrial genomes. Additionally, they should alter our interpretation of many common phylogenetic and population genetic analyses.     

Mutation rate variation in the mammalian genome

Recent advances in the large-scale sequencing of mammalian genomes have provided a means to study divergence in not only genic sequences but also in the non-coding bulk of DNA. There is evidence of significant variation in the levels of divergence between presumably neutral regions, pointing at an underlying variation in the rate of mutation across the genome. Apparently, such variation occurs on different scales, including sequence context effects (the influence of neighboring nucleotides on the rate of mutation at individual sites), variation within chromosomes (on the scales of kilobases as well as megabases), and between chromosomes (among autosomes as well as between autosomes and sex chromosomes). An important aspect for further research in this area is to study whether there is an ultimate evolutionary explanation for mutation rate variation within mammalian genomes.     

Origins, distribution, and local co-occurrence of polyploid cytotypes in Solidago altissima (Asteraceae)

There is growing realization that intraspecific polyploidy in plants has important implications for the evolution of plant diversity and for plant and plant-herbivore community dynamics. Nonetheless, the rate at which polyploid cytotypes arise and their fate in local mixed-cytotype populations are not well understood. Although within- and especially among-population cytotype variation has been documented in many plants, particularly at the largest (continental) spatial scales, local and regional distributions of cytotypes have been well characterized only for a handful of species. Furthermore, few if any studies have addressed both local and regional patterns in the same plant species with sufficient power to detect cytotype variation on both scales. We assessed the co-occurrence and frequency distributions of diploid, tetraploid, and hexaploid cytotypes of Solidago altissima (Asteraceae) at local and regional spatial scales, sampling across a zone of presumed ploidy-form overlap in the midwestern United States. Determining ploidy by flow cytometry, we found many local populations containing two or three cytotypes, with the relative frequencies of cytotypes varying dramatically even among neighboring populations. AFLP marker data suggest that polyploid cytotypes of S. altissima likely have multiple origins from different diploid lineages. Our results are consistent with recent perspectives on polyploidization as an evolutionarily dynamic phenomenon with frequent multiple origins of higher-ploidy cytotypes.     

The role of DNA replication and isochores in generating mutation and silent substitution rate variance in mammals.

It has been suggested that isochores are maintained by mutation biases, and that this leads to variation in the rate of mutation across the genome. A model of DNA replication is presented in which the probabilities of misincorporation and proofreading are affected by the composition and concentration of the free nucleotide pools. The relationship between sequence G+C content and the mutation rate is investigated. It is found that there is very little variation in the mutation rate between sequences of different G+C contents if the total concentration of the free nucleotides remains constant. However, variation in the mutation rate can be arbitrarily large if some mismatches are proofread and the total concentration of free nucleotides varies. Hence the model suggests that the maintenance of isochores by the replication of DNA in free nucleotide pools of biased composition does not lead per se to mutation rate variance. However, it is possible that changes in composition could be accompanied by changes in concentration, thus generating mutation rate variance. Furthermore, there is the possibility that germ-line selection could lead to alterations in the overall free nucleotide concentration through the cell cycle. These findings are discussed with reference to the variance in mammalian silent substitution rates.     

Characteristics, causes and evolutionary consequences of male-biased mutation

Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, alpham, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, alpham is estimated at approximately 4-6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in alpham. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex.     

Heterogeneity of the transition/transversion ratio in Drosophila and Hominidae genomes

Mutation rate varies between sites in the genome. Part of this variation can be explained by well-recognized short nucleotide contexts, but a large component of this variation remains cryptic. We used data on interspecies divergence and intraspecies polymorphism in Drosophila and Hominidae to analyze variation of the average rate of the 12 possible kinds of single-nucleotide mutations and in the transition/transversion ratio κ at single-nucleotide resolution. Both the average mutation rate and κ vary by a factor of ~3 between nucleotide sites. The characteristic scale of variation in κ is up to at least ~30 nucleotides in Drosophila and ~5 nucleotides in Hominidae. Genome segments with locally elevated mutation rates possess lower values of κ; however, a substantial fraction of variation in κ cannot be directly explained by the local mutation rates.     

The Relationship Between the Rate of Molecular Evolution and the Rate of Genome Rearrangement in Animal Mitochondrial Genomes

Evolution of mitochondrial genes is far from clock-like. The substitution rate varies considerably between species, and there are many species that have a significantly increased rate with respect to their close relatives. There is also considerable variation among species in the rate of gene order rearrangement. Using a set of 55 complete arthropod mitochondrial genomes, we estimate the evolutionary distance from the common ancestor to each species using protein sequences, tRNA sequences, and breakpoint distances (a measure of the degree of genome rearrangement). All these distance measures are correlated. We use relative rate tests to compare pairs of related species in several animal phyla. In the majority of cases, the species with the more highly rearranged genome also has a significantly higher rate of sequence evolution. Species with higher amino acid substitution rates in mitochondria also have more variable amino acid composition in response to mutation pressure. We discuss the possible causes of variation in rates of sequence evolution and gene rearrangement among species and the possible reasons for the observed correlation between the two rates. [Reviewing Editor: Dr. David Pollock]     

Genome‐based estimates of fungal rDNA copy number variation across phylogenetic scales and ecological lifestyles

Ribosomal DNA (rDNA) copy number variation (CNV) has major physiological implications for all organisms, but how it varies for fungi, an ecologically ubiquitous and important group of microorganisms, has yet to be systemically investigated. Here, we examine rDNA CNV using an in silico read depth approach for 91 fungal taxa with sequenced genomes and assess copy number conservation across phylogenetic scales and ecological lifestyles. rDNA copy number varied considerably across fungi, ranging from an estimated 14 to 1,442 copies (mean = 113, median = 82), and copy number similarity was inversely correlated with phylogenetic distance. No correlations were found between rDNA CNV and fungal trophic mode, ecological guild or genome size. Taken together, these results show that like other microorganisms, fungi exhibit substantial variation in rDNA copy number, which is linked to their phylogeny in a scale‐dependent manner.     

Importance of genetic drift during Pleistocene divergence as revealed by analyses of genomic variation

Determining what factors affect the structuring of genetic variation is key to deciphering the relative roles of different evolutionary processes in species differentiation. Such information is especially critical to understanding how the frequent shifts and fragmentation of species distributions during the Pleistocene translates into species differences, and why the effect of such rapid climate change on patterns of species diversity varies among taxa. Studies of mitochondrial DNA (mtDNA) have detected significant population structure in many species, including those directly impacted by the glacial cycles. Yet, understanding the ultimate consequence of such structure, as it relates to how species divergence occurs, requires demonstration that such patterns are also shared with genomic patterns of differentiation. Here we present analyses of amplified fragment length polymorphisms (AFLPs) in the montane grasshopper Melanoplus oregonensis to assess the evolutionary significance of past demographic events and associated drift-induced divergence as inferred from mtDNA. As an inhabitant of the sky islands of the northern Rocky Mountains, this species was subject to repeated and frequent shifts in species distribution in response to the many glacial cycles. Nevertheless, significant genetic structuring of M. oregonensis is evident at two different geographic and temporal scales: recent divergence associated with the recolonization of the montane meadows in individual sky islands, as well as older divergence associated with displacements into regional glacial refugia. The genomic analyses indicate that drift-induced divergence, despite the lack of long-standing geographic barriers, has significantly contributed to species divergence during the Pleistocene. Moreover, the finding that divergence associated with past demographic events involves the repartitioning of ancestral variation without significant reductions of genomic diversity has intriguing implications - namely, the further amplification of drift-induced divergence by selection.     

A genome-wide view of mutation rate co-variation using multivariate analyses

Background  

While the abundance of available sequenced genomes has led to many studies of regional heterogeneity in mutation rates, the co-variation among rates of different mutation types remains largely unexplored, hindering a deeper understanding of mutagenesis and genome dynamics. Here, utilizing primate and rodent genomic alignments, we apply two multivariate analysis techniques (principal components and canonical correlations) to investigate the structure of rate co-variation for four mutation types and simultaneously explore the associations with multiple genomic features at different genomic scales and phylogenetic distances.     

Variation in routine metabolism of juvenile muskellunge: evidence for seasonal metabolic compensation in fishes

Metabolic rate of age 0 muskellunge Esox masquinongy ranged from 0·10 at 5° C to 0·24 mg O₂ g^-1 h^-1 at 25° C and was significantly higher in spring and autumn than during winter months at comparable water temperatures. Reduced metabolic rate in winter was consistent with the metabolic compensation hypothesis, implying that metabolism of muskellunge varies independently of acclimation temperature and gonadogenesis. Moreover, seasonal variation in metabolic rate has important implications for energy budget studies. Single-season estimates of esocid metabolism may be inadequate to describe annual energy requirements; the magnitude of errors will depend on the time of year metabolic rate was measured. As a result, it is suggested that seasonal variation in metabolic rate be incorporated into energy budget determinations for fishes.     

The ecology of individuals: incidence and implications of individual specialization

Most empirical and theoretical studies of resource use and population dynamics treat conspecific individuals as ecologically equivalent. This simplification is only justified if interindividual niche variation is rare, weak, or has a trivial effect on ecological processes. This article reviews the incidence, degree, causes, and implications of individual-level niche variation to challenge these simplifications. Evidence for individual specialization is available for 93 species distributed across a broad range of taxonomic groups. Although few studies have quantified the degree to which individuals are specialized relative to their population, between-individual variation can sometimes comprise the majority of the population's niche width. The degree of individual specialization varies widely among species and among populations, reflecting a diverse array of physiological, behavioral, and ecological mechanisms that can generate intrapopulation variation. Finally, individual specialization has potentially important ecological, evolutionary, and conservation implications. Theory suggests that niche variation facilitates frequency-dependent interactions that can profoundly affect the population's stability, the amount of intraspecific competition, fitness-function shapes, and the population's capacity to diversify and speciate rapidly. Our collection of case studies suggests that individual specialization is a widespread but underappreciated phenomenon that poses many important but unanswered questions.     

Individual variation in microsatellite mutation rate in barn swallows

The hypermutable nature of some microsatellite loci implies realistic possibilities for the large-scale detection of germline mutations by pedigree analysis. We have developed a model system for mutation analysis by the characterisation of patterns of mutation at three hypervariable microsatellites (two tetranucleotide and one pentanucleotide repeat loci) in barn swallows, all three markers having mutation rates at the percentage level. Here, we study how the mutation rate varies between individual birds of a Spanish population of barn swallows. A total of 53 mutations were identified from 2920 germline transmissions in 90 families with a total of 694 offspring. Mutations were not randomly distributed among individuals (P = 0.020). Attempts to correlate mutation rate with allele size, degree of inbreeding, immunocompetence and male age only revealed a strong effect of allele size. The mean mutation rate differed between colonies of breeding swallows which was probably due to a corresponding variation in allele size between colonies. There was no difference in the mean mutation rate between the Spanish and an Italian population. These results corroborate earlier findings, at the population level, of an allele size effect on the microsatellite mutation rate.     

Genetic architecture influences when and how hybridization contributes to colonization

The role of genetic architecture in adaptation to novel environments has received considerable attention when the source of adaptive variation is de novo mutation. Relatively less is known when the source of adaptive variation is inter- or intraspecific hybridization. We model hybridization between divergent source populations and subsequent colonization of an unoccupied novel environment using individual-based simulations to understand the influence of genetic architecture on the timing of colonization and the mode of adaptation. We find that two distinct categories of genetic architecture facilitate rapid colonization but that they do so in qualitatively different ways. For few and/or tightly linked loci, the mode of adaptation is via the recovery of adaptive parental genotypes. With many unlinked loci, the mode of adaptation is via the generation of novel hybrid genotypes. The first category results in the shortest colonization lag phases across the widest range of parameter space, but further adaptation is mutation limited. The second category takes longer and is more sensitive to genetic variance and dispersal rate, but can facilitate adaptation to environmental conditions that exceed the tolerance of parental populations. These findings have implications for understanding the origins of biological invasions and the success of hybrid populations.     

Factors that contribute to variation in evolutionary rate among Arabidopsis genes

Surprisingly, few studies have described evolutionary rate variation among plant nuclear genes, with little investigation of the causes of rate variation. Here, we describe evolutionary rates for 11,492 ortholog pairs between Arabidopsis thaliana and A. lyrata and investigate possible contributors to rate variation among these genes. Rates of evolution at synonymous sites vary along chromosomes, suggesting that mutation rates vary on genomic scales, perhaps as a function of recombination rate. Rates of evolution at nonsynonymous sites correlate most strongly with expression patterns, but they also vary as to whether a gene is duplicated and retained after a whole-genome duplication (WGD) event. WGD genes evolve more slowly, on average, than nonduplicated genes and non-WGD duplicates. We hypothesize that levels and patterns of expression are not only the major determinants that explain nonsynonymous rate variation among genes but also a critical determinant of gene retention after duplication.     

Recombination rate variation in mice from an isolated island

Recombination rate is a heritable trait that varies among individuals. Despite the major impact of recombination rate on patterns of genetic diversity and the efficacy of selection, natural variation in this phenotype remains poorly characterized. We present a comparison of genetic maps, sampling 1212 meioses, from a unique population of wild house mice (Mus musculus domesticus) that recently colonized remote Gough Island. Crosses to a mainland reference strain (WSB/EiJ) reveal pervasive variation in recombination rate among Gough Island mice, including subchromosomal intervals spanning up to 28% of the genome. In spite of this high level of polymorphism, the genomewide recombination rate does not significantly vary. In general, we find that recombination rate varies more when measured in smaller genomic intervals. Using the current standard genetic map of the laboratory mouse to polarize intervals with divergent recombination rates, we infer that the majority of evolutionary change occurred in one of the two tested lines of Gough Island mice. Our results confirm that natural populations harbour a high level of recombination rate polymorphism and highlight the disparities in recombination rate evolution across genomic scales.     

Evidence for heterozygote instability in microsatellite loci in house wrens

Microsatellite loci have high mutation rates and high levels of allelic variation, but the factors influencing their mutation rate are not well understood. The proposal that heterozygosity may increase mutation rates has profound implications for understanding the evolution of microsatellite loci, but currently has limited empirical support. We examined 20 microsatellite mutations identified in an analysis of 12 260 meiotic events across three loci in two populations of a songbird, the house wren (Troglodytes aedon). We found that for an allele of a given length, mutation was significantly more likely when there was a relatively large difference in size between the allele and its homologue (i.e. a large ‘allele span’). Our results support the proposal of heterozygote instability at microsatellite loci.     

Implications of genetic heterogeneity in cancer

DNA sequencing studies have established that many cancers contain tens of thousands of clonal mutations throughout their genomes, which is difficult to reconcile with the very low rate of mutation in normal human cells. This observation provides strong evidence for the mutator phenotype hypothesis, which proposes that a genome-wide elevation in the spontaneous mutation rate is an early step in carcinogenesis. An elevated mutation rate implies that cancers undergo continuous evolution, generating multiple subpopulations of cells that differ from one another in DNA sequence. The extensive heterogeneity in DNA sequence and continual tumor evolution that would occur in the context of a mutator phenotype have important implications for cancer diagnosis and therapy.