RESUMO
Mitochondrial genomes exist in a nested hierarchy of populations where mitochondrial variants are subject to genetic drift and selection at each level of organization, sometimes engendering conflict between different levels of selection, and between the nuclear and mitochondrial genomes. Deletion mutants in the Caenorhabditis elegans mitochondrial genome can reach high intracellular frequencies despite strongly detrimental effects on fitness. During a mutation accumulation (MA) experiment in C. elegans, a 499 bp deletion in ctb-1 rose to 90% frequency within cells while significantly reducing fitness. During the experiment, the deletion-bearing mtDNA acquired three additional mutations in nd5, namely two single insertion frameshift mutations in a homopolymeric run, and a base substitution. Despite an additional fitness cost of these secondary mutations, all deletion-bearing molecules contained the nd5 mutations at the termination of the MA experiment. The presence of mutant mtDNA was associated with increased mtDNA copy-number. Variation in mtDNA copy-number was greater in the MA lines than in a wildtype nuclear background, including a severe reduction in copy-number at one generational timepoint. Evolutionary replay experiments using different generations of the MA experiment as starting points suggests that two of the secondary mutations contribute to the proliferation of the original ctb-1 deletion by unknown mechanisms.
Assuntos
Caenorhabditis elegans , DNA Mitocondrial , Evolução Molecular , Genoma Mitocondrial , Animais , Caenorhabditis elegans/genética , DNA Mitocondrial/genética , Acúmulo de Mutações , Mutação , Deleção de Sequência , Aptidão GenéticaRESUMO
Selfish mitochondrial DNA (mtDNA) mutations are variants that can proliferate within cells and enjoy a replication or transmission bias without fitness benefits for the host. mtDNA deletions in Caenorhabditis elegans can reach high heteroplasmic frequencies despite significantly reducing fitness, illustrating how new mtDNA variants can give rise to genetic conflict between different levels of selection and between the nuclear and mitochondrial genomes. During a mutation accumulation experiment in C. elegans, a 1,034-bp deletion originated spontaneously and reached an 81.7% frequency within an experimental evolution line. This heteroplasmic mtDNA deletion, designated as meuDf1, eliminated portions of 2 protein-coding genes (coxIII and nd4) and tRNA-thr in entirety. mtDNA copy number in meuDf1 heteroplasmic individuals was 35% higher than in individuals with wild-type mitochondria. After backcrossing into a common genetic background, the meuDf1 mitotype was associated with reduction in several fitness traits and independent competition experiments found a 40% reduction in composite fitness. Experiments that relaxed individual selection by single individual bottlenecks demonstrated that the deletion-bearing mtDNA possessed a strong transmission bias, thereby qualifying it as a novel selfish mitotype.
Assuntos
Caenorhabditis elegans , Genoma Mitocondrial , Animais , Humanos , Caenorhabditis elegans/genética , Amigos , Mitocôndrias/genética , DNA Mitocondrial/genética , MutaçãoRESUMO
Aided by new technologies, the upsurgence of research into mitochondrial genome biology during the past 15 years suggests that we have misunderstood, and perhaps dramatically underestimated, the ongoing biological and evolutionary significance of our long-time symbiotic partner. While we have begun to scratch the surface of several topics, many questions regarding the nature of mutation and selection in the mitochondrial genome, and the nature of its relationship to the nuclear genome, remain unanswered. Although best known for their contributions to studies of developmental and aging biology, Caenorhabditis nematodes are increasingly recognized as excellent model systems to advance understanding in these areas. We review recent discoveries with relevance to mitonuclear coevolution and conflict and offer several fertile areas for future work.
Assuntos
Caenorhabditis , Animais , Caenorhabditis/genética , Codependência Psicológica , Evolução Biológica , GenomaRESUMO
The DNA transposon Tc1 was the first transposable element to be characterized in Caenorhabditis elegans and to date, remains the best-studied transposable element in Caenorhabditis worms. While Tc1 copy-number is regulated at approximately 30 copies in the laboratory Bristol N2 and the vast majority of C. elegans strains, the Bergerac strain and its derivatives have experienced a marked Tc1 proliferation. Given the historical importance of the Bergerac strain in the development of the C. elegans model, we implemented a modern genomic analysis of three Bergerac strains (CB4851, RW6999, and RW7000) in conjunction with multiple phenotypic assays to better elucidate the (1) genomic distribution of Tc1 and (2) phenotypic consequences of transposable element deregulation for the host organism. The median estimates of Tc1 copy-number in the Bergerac strains ranged from 451 to 748, which is both (1) greater than previously estimated and (2) likely to be an underestimate of the actual copy-numbers since coverage-based estimates and digital droplet polymerase chain reaction results both suggest higher Tc1 numbers. All three Bergerac strains had significantly reduced trait means compared with the N2 control for each of four fitness-related traits, with specific traits displaying significant differences between Bergerac strains. Tc1 proliferation was genome-wide, specific to Tc1, and particularly high on chromosomes V and X. There were fewer Tc1 insertions in highly expressed chromatin environments than expected by chance. Furthermore, Tc1 integration motifs were also less frequent in exon than noncoding sequences. The source of the proliferation of Tc1 in the Bergerac strains is specific to Tc1 and independent of other transposable elements. The Bergerac strains contain none of the alleles that have previously been found to derepress transposable element activity in C. elegans. However, the Bergerac strains had several Tc1 insertions near or within highly germline-transcribed genes which could account for the recent germline proliferation.
Assuntos
Caenorhabditis elegans , Caenorhabditis , Animais , Caenorhabditis elegans/genética , Elementos de DNA Transponíveis/genética , Caenorhabditis/genética , Fenótipo , GenômicaRESUMO
We provide a partial test of the mitonuclear sex hypothesis with the first controlled study of how male frequencies and rates of outcrossing evolve in response to mitonuclear mismatch by allowing replicate lineages of C. elegans nematodes containing either mitochondrial or nuclear mutations of electron transport chain (ETC) genes to evolve under three sexual systems: facultatively outcrossing (wildtype), obligately selfing, and obligately outcrossing. Among facultatively outcrossing lines, we found evolution of increased male frequency in at least one replicate line of all four ETC mutant backgrounds tested-nuclear isp-1, mitochondrial cox-1 and ctb-1, and an isp-1 IV; ctb-1M mitonuclear double mutant-and confirmed for a single line set (cox-1) that increased male frequency also resulted in successful outcrossing. We previously found the same result for lines evolved from another nuclear ETC mutant, gas-1. For several lines in the current experiment, however, male frequency declined to wildtype levels (near 0%) in later generations. Male frequency did not change in lines evolved from a wildtype control strain. Additional phenotypic assays of lines evolved from the mitochondrial cox-1 mutant indicated that evolution of high male frequency was accompanied by evolution of increased male sperm size and mating success with tester females, but that it did not translate into increased mating success with coevolved hermaphrodites. Rather, hermaphrodites' self-crossed reproductive fitness increased, consistent with sexually antagonistic coevolution. In accordance with evolutionary theory, males and sexual outcrossing may be most beneficial to populations evolving from a state of low ancestral fitness (gas-1, as previously reported) and less beneficial or deleterious to those evolving from a state of higher ancestral fitness (cox-1). In support of this idea, the obligately outcrossing fog-2 V; cox-1 M lines exhibited no fitness evolution compared to their ancestor, while facultatively outcrossing lines showed slight upward evolution of fitness, and all but one of the obligately selfing xol-1 X; cox-1 M lines evolved substantially increased fitness-even beyond wildtype levels. This work provides a foundation to directly test the effect of reproductive mode on the evolutionary dynamics of mitonuclear genomes, as well as whether compensatory mutations (nuclear or mitochondrial) can rescue populations from mitochondrial dysfunction.
RESUMO
DNA mismatch repair (MMR), an evolutionarily conserved repair pathway shared by prokaryotic and eukaryotic species alike, influences molecular evolution by detecting and correcting mismatches, thereby protecting genetic fidelity, reducing the mutational load, and preventing lethality. Herein we conduct the first genome-wide evaluation of the alterations to the mutation rate and spectrum under impaired activity of the MutSα homolog, msh-2, in Caenorhabditis elegans male-female fog-2(lf) lines. We performed mutation accumulation (MA) under RNAi-induced knockdown of msh-2 for up to 50 generations, followed by next-generation sequencing of 19 MA lines and the ancestral control. msh-2 impairment in the male-female background substantially increased the frequency of nuclear base substitutions (â¼23×) and small indels (â¼328×) relative to wildtype hermaphrodites. However, we observed no increase in the mutation rates of mtDNA, and copy-number changes of single-copy genes. There was a marked increase in copy-number variation of rDNA genes under MMR impairment. In C. elegans, msh-2 repairs transitions more efficiently than transversions and increases the AT mutational bias relative to wildtype. The local sequence context, including sequence complexity, G + C-content, and flanking bases influenced the mutation rate. The X chromosome exhibited lower substitution and higher indel rates than autosomes, which can either result from sex-specific mutation rates or a nonrandom distribution of mutable sites between chromosomes. Provided the observed difference in mutational pattern is mostly due to MMR impairment, our results indicate that the specificity of MMR varies between taxa, and is more efficient in detecting and repairing small indels in eukaryotes relative to prokaryotes.
Assuntos
Caenorhabditis elegans , Taxa de Mutação , Animais , Caenorhabditis elegans/genética , Reparo de Erro de Pareamento de DNA/genética , Feminino , Masculino , Mutação , Acúmulo de Mutações , Interferência de RNARESUMO
BACKGROUND: Transposable elements (TEs) are an almost universal constituent of eukaryotic genomes. In animals, Piwi-interacting small RNAs (piRNAs) and repressive chromatin often play crucial roles in preventing TE transcription and thus restricting TE activity. Nevertheless, TE content varies widely across eukaryotes and the dynamics of TE activity and TE silencing across evolutionary time is poorly understood. RESULTS: Here, we used experimentally evolved populations of C. elegans to study the dynamics of TE expression over 409 generations. The experimental populations were evolved at population sizes of 1, 10 and 100 individuals to manipulate the efficiency of natural selection versus genetic drift. We demonstrate increased TE expression relative to the ancestral population, with the largest increases occurring in the smallest populations. We show that the transcriptional activation of TEs within active regions of the genome is associated with failure of piRNA-mediated silencing, whilst desilenced TEs in repressed chromatin domains retain small RNAs. Additionally, we find that the sequence context of the surrounding region influences the propensity of TEs to lose silencing through failure of small RNA-mediated silencing. CONCLUSIONS: Our results show that natural selection in C. elegans is responsible for maintaining low levels of TE expression, and provide new insights into the epigenomic features responsible.
Assuntos
Caenorhabditis elegans/genética , Elementos de DNA Transponíveis/genética , Evolução Molecular , Expressão Gênica , RNA de Helmintos/genética , RNA Interferente Pequeno/genética , Animais , Seleção GenéticaRESUMO
Epigenetic regulation involves changes in gene expression independent of DNA sequence variation that are inherited through cell division. In addition to a fundamental role in cell differentiation, some epigenetic changes can also be transmitted transgenerationally through meiosis. Epigenetic alterations (epimutations) could thus contribute to heritable variation within populations and be subject to evolutionary processes such as natural selection and drift. However, the rate at which epimutations arise and their typical persistence are unknown, making it difficult to evaluate their potential for evolutionary adaptation. Here, we perform a genome-wide study of epimutations in a metazoan organism. We use experimental evolution to characterize the rate, spectrum and stability of epimutations driven by small silencing RNAs in the model nematode Caenorhabditis elegans. We show that epimutations arise spontaneously at a rate approximately 25 times greater than DNA sequence changes and typically have short half-lives of two to three generations. Nevertheless, some epimutations last at least ten generations. Epimutations mediated by small RNAs may thus contribute to evolutionary processes over a short timescale but are unlikely to bring about long-term divergence in the absence of selection.
Assuntos
Caenorhabditis elegans , Epigênese Genética , Animais , Caenorhabditis elegans/genética , Estudo de Associação Genômica Ampla , Mutação , Seleção GenéticaRESUMO
Mitochondrial genomes can sustain mutations that are simultaneously detrimental to individual fitness and yet, can proliferate within individuals owing to a replicative advantage. We analysed the fitness effects and population dynamics of a mitochondrial genome containing a novel 499 bp deletion in the cytochrome b(1) (ctb-1) gene (Δctb-1) encoding the cytochrome b of complex III in Caenorhabditis elegans. Δctb-1 reached a high heteroplasmic frequency of 96% in one experimental line during a mutation accumulation experiment and was linked to additional spontaneous mutations in nd5 and tRNA-Asn. The Δctb-1 mutant mitotype imposed a significant fitness cost including a 65% and 52% reduction in productivity and competitive fitness, respectively, relative to individuals bearing wild-type (WT) mitochondria. Deletion-bearing worms were rapidly purged within a few generations when competed against WT mitochondrial DNA (mtDNA) bearing worms in experimental populations. By contrast, the Δctb-1 mitotype was able to persist in large populations comprising heteroplasmic individuals only, although the average intracellular frequency of Δctb-1 exhibited a slow decline owing to competition among individuals bearing different frequencies of the heteroplasmy. Within experimental lines subjected to severe population bottlenecks (n = 1), the relative intracellular frequency of Δctb-1 increased, which is a hallmark of selfish drive. A positive correlation between Δctb-1 and WT mtDNA copy-number suggests a mechanism that increases total mtDNA per se, and does not discern the Δctb-1 mitotype from the WT mtDNA. This study demonstrates the selfish nature of the Δctb-1 mitotype, given its transmission advantage and substantial fitness load for the host, and highlights the importance of population size for the population dynamics of selfish mtDNA. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
Assuntos
Caenorhabditis elegans/genética , DNA Mitocondrial/genética , Aptidão Genética , Genoma Helmíntico , Genoma Mitocondrial , Sequências Repetitivas de Ácido Nucleico/genética , Animais , Dinâmica PopulacionalRESUMO
Experimental investigations into the rates and fitness effects of spontaneous mutations are fundamental to our understanding of the evolutionary process. To gain insights into the molecular and fitness consequences of spontaneous mutations, we conducted a mutation accumulation (MA) experiment at varying population sizes in the nematode Caenorhabditis elegans, evolving 35 lines in parallel for 409 generations at three population sizes (N = 1, 10, and 100 individuals). Here, we focus on nuclear SNPs and small insertion/deletions (indels) under minimal influence of selection, as well as their accrual rates in larger populations under greater selection efficacy. The spontaneous rates of base substitutions and small indels are 1.84 (95% C.I. ± 0.14) × 10-9 substitutions and 6.84 (95% C.I. ± 0.97) × 10-10 changes/site/generation, respectively. Small indels exhibit a deletion bias with deletions exceeding insertions by threefold. Notably, there was no correlation between the frequency of base substitutions, nonsynonymous substitutions, or small indels with population size. These results contrast with our previous analysis of mitochondrial DNA mutations and nuclear copy-number changes in these MA lines, and suggest that nuclear base substitutions and small indels are under less stringent purifying selection compared to the former mutational classes. A transition bias was observed in exons as was a near universal base substitution bias toward A/T. Strongly context-dependent base substitutions, where 5'-Ts and 3'-As increase the frequency of A/T â T/A transversions, especially at the boundaries of A or T homopolymeric runs, manifest as higher mutation rates in (i) introns and intergenic regions relative to exons, (ii) chromosomal cores vs. arms and tips, and (iii) germline-expressed genes.
Assuntos
Mutação INDEL , Acúmulo de Mutações , Taxa de Mutação , Animais , Caenorhabditis elegans , Deriva Genética , Polimorfismo de Nucleotídeo Único , Seleção GenéticaRESUMO
Mutations spawn genetic variation which, in turn, fuels evolution. Hence, experimental investigations into the rate and fitness effects of spontaneous mutations are central to the study of evolution. Mutation accumulation (MA) experiments have served as a cornerstone for furthering our understanding of spontaneous mutations for four decades. In the pregenomic era, phenotypic measurements of fitness-related traits in MA lines were used to indirectly estimate key mutational parameters, such as the genomic mutation rate, new mutational variance per generation, and the average fitness effect of mutations. Rapidly emerging next-generating sequencing technology has supplanted this phenotype-dependent approach, enabling direct empirical estimates of the mutation rate and a more nuanced understanding of the relative contributions of different classes of mutations to the standing genetic variation. Whole-genome sequencing of MA lines bears immense potential to provide a unified account of the evolutionary process at multiple levels-the genetic basis of variation, and the evolutionary dynamics of mutations under the forces of selection and drift. In this review, we have attempted to synthesize key insights into the spontaneous mutation process that are rapidly emerging from the partnering of classical MA experiments with high-throughput sequencing, with particular emphasis on the spontaneous rates and molecular properties of different mutational classes in nuclear and mitochondrial genomes of diverse taxa, the contribution of mutations to the evolution of gene expression, and the rate and stability of transgenerational epigenetic modifications. Future advances in sequencing technologies will enable greater species representation to further refine our understanding of mutational parameters and their functional consequences.
Assuntos
Genética/tendências , Genoma , Acúmulo de Mutações , Taxa de Mutação , Sequenciamento Completo do Genoma , Animais , Epigênese Genética , Humanos , Transcrição GênicaRESUMO
Gene duplication and deletion are pivotal processes shaping the structural and functional repertoire of genomes, with implications for disease, adaptation, and evolution. We employed a mutation accumulation (MA) framework partnered with high-throughput genomics to assess the molecular and transcriptional characteristics of newly arisen gene copy-number variants (CNVs) in Caenorhabditis elegans populations subjected to varying intensity of selection. Here, we report a direct spontaneous genome-wide rate of gene duplication of 2.9 × 10-5/gene per generation in C. elegans, the highest for any species to date. The rate of gene deletion is sixfold lower (5 × 10-6/gene per generation). Deletions of highly expressed genes are particularly deleterious, given their paucity in even the N = 1 lines with minimal efficacy of selection. The increase in average transcript abundance of new duplicates arising under minimal selection is significantly greater than twofold compared with single copies of the same gene, suggesting that genes in segmental duplications are frequently overactive at inception. The average increase in transcriptional activity of gene duplicates is greater in the N = 1 MA lines than in MA lines with larger population bottlenecks. There is an inverse relationship between the ancestral transcription levels of new gene duplicates and population size, with duplicate copies of highly expressed genes less likely to accumulate in larger populations. Our results demonstrate a fitness cost of increased transcription following duplication, which results in purifying selection against new gene duplicates. However, on average, duplications also provide a significant increase in gene expression that can facilitate adaptation to novel environmental challenges.
Assuntos
Adaptação Fisiológica/genética , Caenorhabditis elegans , Deleção de Genes , Dosagem de Genes , Duplicação Gênica , Transcrição Gênica , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Estudo de Associação Genômica AmplaRESUMO
The consequences of mutations for population fitness depends on their individual selection coefficients and the effective population size. An earlier study of Caenorhabditis elegans spontaneous mutation accumulation lines evolved for 409 generations at three population sizes found that Ne = 1 populations declined significantly in fitness whereas the fitness of larger populations (Ne = 5, 50) was indistinguishable from the ancestral control under benign conditions. To test if larger MA populations harbor a load of cryptic deleterious mutations that are obscured under benign laboratory conditions, we measured fitness under osmotic stress via exposure to hypersaline conditions. The fitness of Ne = 1 lines exhibited a further decline under osmotic stress compared to benign conditions. However, the fitness of larger populations remained indistinguishable from that of the ancestral control. The average effects of deleterious mutations in Ne = 1 lines were estimated to be 22% for productivity and 14% for survivorship, exceeding values previously detected under benign conditions. Our results suggest that fitness decline is due to large effect mutations that are rapidly removed via selection even in small populations, with implications for conservation practices. Genetic stochasticity may not be as potent and immediate a threat to the persistence of small populations as other demographic and environmental stochastic factors.
Assuntos
Evolução Biológica , Caenorhabditis elegans/genética , Aptidão Genética , Mutação , Pressão Osmótica/fisiologia , Animais , Caenorhabditis elegans/fisiologia , Densidade DemográficaRESUMO
Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial mutations in small populations in the absence and presence of selection, we evolved mutation accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/CâA/T mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication.
Assuntos
Genoma Mitocondrial/genética , Seleção Genética/genética , Animais , Evolução Biológica , Caenorhabditis elegans/genética , DNA Mitocondrial/genética , Evolução Molecular , Mitocôndrias/genética , Mutação , Acúmulo de Mutações , Taxa de Mutação , Filogenia , Filogeografia , Densidade Demográfica , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND: Gene copy-number variation (CNVs), which provides the raw material for the evolution of novel genes, is widespread in natural populations. We investigated whether CNVs constitute a common mechanism of genetic change during adaptation in experimental Caenorhabditis elegans populations. Outcrossing C. elegans populations with low fitness were evolved for >200 generations. The frequencies of CNVs in these populations were analyzed by oligonucleotide array comparative genome hybridization, quantitative PCR, PCR, DNA sequencing across breakpoints, and single-worm PCR. RESULTS: Multiple duplications and deletions rose to intermediate or high frequencies in independent populations. Several lines of evidence suggest that these changes were adaptive: (i) copy-number changes reached high frequency or were fixed in a short time, (ii) many independent populations harbored CNVs spanning the same genes, and (iii) larger average size of CNVs in adapting populations relative to spontaneous CNVs. The latter is expected if larger CNVs are more likely to encompass genes under selection for a change in gene dosage. Several convergent CNVs originated in populations descended from different low fitness ancestors as well as high fitness controls. CONCLUSIONS: We show that gene copy-number changes are a common class of adaptive genetic change. Due to the high rates of origin of spontaneous duplications and deletions, copy-number changes containing the same genes arose readily in independent populations. Duplications that reached high frequencies in these adapting populations were significantly larger in span. Many convergent CNVs may be general adaptations to laboratory conditions. These results demonstrate the great potential borne by CNVs for evolutionary adaptation.
Assuntos
Caenorhabditis elegans/genética , Variações do Número de Cópias de DNA , Evolução Molecular , Dosagem de Genes , Adaptação Biológica/genética , Animais , Cruzamentos Genéticos , Deleção de Genes , Duplicação Gênica , Aptidão Genética , Variação Genética , Genética Populacional , Mutação , Sequências Repetitivas de Ácido NucleicoRESUMO
BACKGROUND: Human gene duplicates have been the focus of intense research since the development of array-based and targeted next-generation sequencing approaches in the last decade. These studies have primarily concentrated on determining the extant copy-number variation from a population-genomic perspective but lack a robust evolutionary framework to elucidate the early structural and genomic characteristics of gene duplicates at emergence and their subsequent evolution with increasing age. RESULTS: We analyzed 184 gene duplicate pairs comprising small gene families in the draft human genome with 10% or less synonymous sequence divergence. Human gene duplicates primarily originate from DNA-mediated events, taking up genomic residence as intrachromosomal copies in direct or inverse orientation. The distribution of paralogs on autosomes follows random expectations in contrast to their significant enrichment on the sex chromosomes. Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions. Surprisingly, despite the large average length of human genes, the majority of extant duplicates (83%) are complete duplicates, wherein the entire ORF of the ancestral copy was duplicated. The preponderance of complete duplicates is in accord with an extremely large median duplication span of 36 kb, which enhances the probability of capturing ancestral ORFs in their entirety. With increasing evolutionary age, human paralogs exhibit declines in (i) the frequency of intrachromosomal paralogs, and (ii) the proportion of complete duplicates. These changes may reflect lower survival rates of certain classes of duplicates and/or the role of purifying selection. Duplications arising from RNA-mediated events comprise a small fraction (11.4%) of all human paralogs and are more numerous in older evolutionary cohorts of duplicates. CONCLUSIONS: The degree of structural resemblance, genomic location and duplication span appear to influence the long-term maintenance of paralogs in the human genome. The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric). The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.
Assuntos
Genes Duplicados , Mapeamento Cromossômico , Cromossomos Humanos , Evolução Molecular , HumanosRESUMO
The rate and fitness effects of new mutations have been investigated by mutation accumulation (MA) experiments in which organisms are maintained at a constant minimal population size to facilitate the accumulation of mutations with minimal efficacy of selection. We evolved 35 MA lines of Caenorhabditis elegans in parallel for 409 generations at three population sizes (N = 1, 10, and 100), representing the first spontaneous long-term MA experiment at varying population sizes with corresponding differences in the efficacy of selection. Productivity and survivorship in the N = 1 lines declined by 44% and 12%, respectively. The average effects of deleterious mutations in N = 1 lines are estimated to be 16.4% for productivity and 11.8% for survivorship. Larger populations (N = 10 and 100) did not suffer a significant decline in fitness traits despite a lengthy and sustained regime of consecutive bottlenecks exceeding 400 generations. Together, these results suggest that fitness decline in very small populations is dominated by mutations with large deleterious effects. It is possible that the MA lines at larger population sizes contain a load of cryptic deleterious mutations of small to moderate effects that would be revealed in more challenging environments.
Assuntos
Caenorhabditis elegans/genética , Evolução Molecular , Aptidão Genética , Taxa de Mutação , Animais , Mutação , População/genéticaRESUMO
Gene copy-number differences due to gene duplications and deletions are rampant in natural populations and play a crucial role in the evolution of genome complexity. Per-locus analyses of gene duplication rates in the pre-genomic era revealed that gene duplication rates are much higher than the per nucleotide substitution rate. Analyses of gene duplication and deletion rates in mutation accumulation lines of model organisms have revealed that these high rates of copy-number mutations occur at a genome-wide scale. Furthermore, comparisons of the spontaneous duplication and deletion rates to copy-number polymorphism data and bioinformatic-based estimates of duplication rates from sequenced genomes suggest that the vast majority of gene duplications are detrimental and removed by natural selection. The rate at which new gene copies appear in populations greatly influences their evolutionary dynamics and standing gene copy-number variation in populations. The opportunity for mutations that result in the maintenance of duplicate copies, either through neofunctionalization or subfunctionalization, also depends on the equilibrium frequency of additional gene copies in the population, and hence on the spontaneous gene duplication (and loss) rate. The duplication rate may therefore have profound effects on the role of adaptation in the evolution of duplicated genes as well as important consequences for the evolutionary potential of organisms. We further discuss the broad ramifications of this standing gene copy-number variation on fitness and adaptive potential from a population-genetic and genome-wide perspective.
RESUMO
BACKGROUND: Gene duplicates often exhibit asymmetric rates of molecular evolution in their early evolutionary existence. This asymmetry in rates is thought to signify the maintenance of the ancestral function by one copy and the removal of functional constraint on the other copy, enabling it to embark on a novel evolutionary trajectory. Here I focused on a large population of evolutionarily young gene duplicates (KS ≤ 0.14) in the Caenorhabditis elegans genome in order to conduct the first combined analysis of four predictors (evolutionary age, chromosomal location, structural resemblance between duplicates, and duplication span) which may be implicated in the asymmetric sequence divergence of paralogs at the nucleotide and amino acid level. In addition, I investigate if either paralog is equally likely to embark on a trajectory of accelerated sequence evolution or whether the derived paralog is more likely to exhibit faster sequence evolution. RESULTS: Three predictors (evolutionary age of duplicates, chromosomal location and duplication span) serve as major determinants of sequence asymmetry between C. elegans paralogs. Paralogs diverge asymmetrically in sequence with increasing evolutionary age, the relocation of one copy to a different chromosome and attenuated duplication spans that likely fail to capture the entire ancestral repertoire of coding sequence and regulatory elements. Furthermore, for paralogs residing on the same chromosome, opposite transcriptional orientation and increased genomic distance do not increase sequence asymmetry between paralogs. For a subset of duplicate pairs wherein the ancestral versus derived paralog could be distinguished, the derived paralogs are more likely to evolve at accelerated rates. CONCLUSIONS: This genome-wide study of evolutionarily young duplicates stemming primarily from DNA-mediated small-scale duplication events demonstrates that genomic relocation to a new chromosome has important consequences for asymmetric divergence of paralogs, akin to paralogs arising from RNA-mediated duplication events. Additionally, the duplication span is negatively correlated with sequence rate asymmetry among paralogs, suggesting that attenuated duplication spans stemming from incomplete duplication of the ORF and/or ancestral regulatory elements further accelerate sequence divergence between paralogs. Cumulatively, derived copies exhibit accelerated rates of sequence evolution suggesting that they are primed for a divergent evolutionary trajectory by changes in structure and genomic context at inception.
Assuntos
Caenorhabditis elegans/genética , Caenorhabditis/classificação , Caenorhabditis/genética , Evolução Molecular , Duplicação Gênica , Animais , Genoma Helmíntico , Estudo de Associação Genômica AmplaRESUMO
The gene duplication process has exhibited far greater promiscuity in the creation of paralogs with novel exon-intron structures than anticipated even by Ohno. In this paper I explore the history of the field, from the neo-Darwinian synthesis through Ohno's formulation of the canonical model for the evolution of gene duplicates and culminating in the present genomic era. I delineate the major tenets of Ohno's model and discuss its failure to encapsulate the full complexity of the duplication process as revealed in the era of genomics. I discuss the diverse classes of paralogs originating from both DNA- and RNA-mediated duplication events and their evolutionary potential for assuming radically altered functions, as well as the degree to which they can function unconstrained from the pressure of gene conversion. Lastly, I explore theoretical population-genetic considerations of how the effective population size (N(e)) of a species may influence the probability of emergence of genes with radically altered functions.