RESUMEN
To assess the conventional treatment in evolutionary inference of alignment gaps as missing data, we propose a simple nonparametric test of the null hypothesis that the locations of alignment gaps are independent of the nucleotide substitution or amino acid replacement process. When we apply the test to 1,390 protein alignments that are informed by protein tertiary structure and use a 5% significance level, the null hypothesis of independence between amino acid replacement and gap location is rejected for â¼65% of datasets. Via simulations that include substitution and insertion-deletion, we show that the test performs well with true alignments. When we simulate according to the null hypothesis and then apply the test to optimal alignments that are inferred by each of four widely used software packages, the null hypothesis is rejected too frequently. Via further simulations and analyses, we show that the overly frequent rejections of the null hypothesis are not solely due to weaknesses of widely used software for finding optimal alignments. Instead, our evidence suggests that optimal alignments are unrepresentative of true alignments and that biased evolutionary inferences may result from relying upon individual optimal alignments.
Asunto(s)
Aminoácidos , Nucleótidos , Proteínas , Algoritmos , Sustitución de Aminoácidos , Aminoácidos/genética , Nucleótidos/genética , Proteínas/genética , Alineación de Secuencia , Programas InformáticosRESUMEN
Following a duplication, the resulting paralogs tend to diverge. While mutation and natural selection can accelerate this process, they can also slow it. Here, we quantify the paralog homogenization that is caused by point mutations and interlocus gene conversion (IGC). Among 164 duplicated teleost genes, the median percentage of postduplication codon substitutions that arise from IGC rather than point mutation is estimated to be between 7% and 8%. By differentiating between the nonsynonymous codon substitutions that homogenize the protein sequences of paralogs and the nonhomogenizing nonsynonymous substitutions, we estimate the homogenizing nonsynonymous rates to be higher for 163 of the 164 teleost data sets as well as for all 14 data sets of duplicated yeast ribosomal protein-coding genes that we consider. For all 14 yeast data sets, the estimated homogenizing nonsynonymous rates exceed the synonymous rates.
Asunto(s)
Conversión Génica , Magnoliopsida , Saccharomyces cerevisiae , Secuencia de Aminoácidos , Genes Duplicados , Selección GenéticaRESUMEN
Divergence time estimation is crucial to provide temporal signals for dating biologically important events from species divergence to viral transmissions in space and time. With the advent of high-throughput sequencing, recent Bayesian phylogenetic studies have analyzed hundreds to thousands of sequences. Such large-scale analyses challenge divergence time reconstruction by requiring inference on highly correlated internal node heights that often become computationally infeasible. To overcome this limitation, we explore a ratio transformation that maps the original $N-1$ internal node heights into a space of one height parameter and $N-2$ ratio parameters. To make the analyses scalable, we develop a collection of linear-time algorithms to compute the gradient and Jacobian-associated terms of the log-likelihood with respect to these ratios. We then apply Hamiltonian Monte Carlo sampling with the ratio transform in a Bayesian framework to learn the divergence times in 4 pathogenic viruses (West Nile virus, rabies virus, Lassa virus, and Ebola virus) and the coralline red algae. Our method both resolves a mixing issue in the West Nile virus example and improves inference efficiency by at least 5-fold for the Lassa and rabies virus examples as well as for the algae example. Our method now also makes it computationally feasible to incorporate mixed-effects molecular clock models for the Ebola virus example, confirms the findings from the original study, and reveals clearer multimodal distributions of the divergence times of some clades of interest.
Asunto(s)
Algoritmos , Filogenia , Teorema de Bayes , Factores de Tiempo , Método de MontecarloRESUMEN
Widely used approaches for extracting phylogenetic information from aligned sets of molecular sequences rely upon probabilistic models of nucleotide substitution or amino-acid replacement. The phylogenetic information that can be extracted depends on the number of columns in the sequence alignment and will be decreased when the alignment contains gaps due to insertion or deletion events. Motivated by the measurement of information loss, we suggest assessment of the effective sequence length (ESL) of an aligned data set. The ESL can differ from the actual number of columns in a sequence alignment because of the presence of alignment gaps. Furthermore, the estimation of phylogenetic information is affected by model misspecification. Inevitably, the actual process of molecular evolution differs from the probabilistic models employed to describe this process. This disparity means the amount of phylogenetic information in an actual sequence alignment will differ from the amount in a simulated data set of equal size, which motivated us to develop a new test for model adequacy. Via theory and empirical data analysis, we show how to disentangle the effects of gaps and model misspecification. By comparing the Fisher information of actual and simulated sequences, we identify which alignment sites and tree branches are most affected by gaps and model misspecification. [Fisher information; gaps; insertion; deletion; indel; model adequacy; goodness-of-fit test; sequence alignment.].
Asunto(s)
Evolución Molecular , Mutación INDEL , Modelos Genéticos , Modelos Estadísticos , Filogenia , Alineación de SecuenciaRESUMEN
Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur. One promising direction for increasing translational success is comparative oncology-the study of cancer across species, often involving veterinary patients that develop naturally-occurring cancers. Comparative oncology leverages the power of cross-species analyses to understand the fundamental drivers of cancer protective mechanisms, as well as factors contributing to cancer initiation and progression. Clinical trials in veterinary patients with cancer provide an opportunity to evaluate novel therapeutics in a setting that recapitulates many of the key features of human cancers, including genomic aberrations that underly tumor development, response and resistance to treatment, and the presence of comorbidities that can affect outcomes. With a concerted effort from basic scientists, human physicians and veterinarians, comparative oncology has the potential to enhance the cost-effectiveness and efficiency of pipelines for cancer drug discovery and other cancer treatments.
Asunto(s)
Descubrimiento de Drogas , Neoplasias/veterinaria , Animales , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Mutations are the raw material on which evolution acts, and knowledge of their frequency and genomic distribution is crucial for understanding how evolution operates at both long and short timescales. At present, the rate and spectrum of de novo mutations have been directly characterized in relatively few lineages. Our study provides the first direct mutation-rate estimate for a strepsirrhine (i.e., the lemurs and lorises), which comprises nearly half of the primate clade. Using high-coverage linked-read sequencing for a focal quartet of gray mouse lemurs (Microcebus murinus), we estimated the mutation rate to be among the highest calculated for a mammal at 1.52 × 10-8 (95% credible interval: 1.28 × 10-8-1.78 × 10-8) mutations/site/generation. Further, we found an unexpectedly low count of paternal mutations, and only a modest overrepresentation of mutations at CpG sites. Despite the surprising nature of these results, we found both the rate and spectrum to be robust to the manipulation of a wide range of computational filtering criteria. We also sequenced a technical replicate to estimate a false-negative and false-positive rate for our data and show that any point estimate of a de novo mutation rate should be considered with a large degree of uncertainty. For validation, we conducted an independent analysis of context-dependent substitution types for gray mouse lemur and five additional primate species for which de novo mutation rates have also been estimated. These comparisons revealed general consistency of the mutation spectrum between the pedigree-based and the substitution-rate analyses for all species compared.
Asunto(s)
Cheirogaleidae , Animales , Cheirogaleidae/genética , Genoma , Ratones , Tasa de Mutación , Linaje , FilogeniaRESUMEN
When inferring phylogenies, one important decision is whether and how nucleotide substitution parameters should be shared across different subsets or partitions of the data. One sort of partitioning error occurs when heterogeneous subsets are mistakenly lumped together and treated as if they share parameter values. The opposite kind of error is mistakenly treating homogeneous subsets as if they result from distinct sets of parameters. Lumping and splitting errors are not equally bad. Lumping errors can yield parameter estimates that do not accurately reflect any of the subsets that were combined whereas splitting errors yield estimates that did not benefit from sharing information across partitions. Phylogenetic partitioning decisions are often made by applying information criteria such as the Akaike information criterion (AIC). As with other information criteria, the AIC evaluates a model or partition scheme by combining the maximum log-likelihood value with a penalty that depends on the number of parameters being estimated. For the purpose of selecting an optimal partitioning scheme, we derive an adjustment to the AIC that we refer to as the AIC$^{(p)}$ and that is motivated by the idea that splitting errors are less serious than lumping errors. We also introduce a similar adjustment to the Bayesian information criterion (BIC) that we refer to as the BIC$^{(p)}$. Via simulation and empirical data analysis, we contrast AIC and BIC behavior to our suggested adjustments. We discuss these results and also emphasize why we expect the probability of lumping errors with the AIC$^{(p)}$ and the BIC$^{(p)}$ to be relatively robust to model parameterization.
Asunto(s)
Biología Computacional/métodos , Filogenia , Teorema de Bayes , Modelos Biológicos , Modelos GenéticosRESUMEN
Interlocus gene conversion (IGC) homogenizes repeats. While genomes can be repeat-rich, the evolutionary importance of IGC is poorly understood. Additional statistical tools for characterizing it are needed. We propose a composite likelihood strategy for incorporating IGC into widely-used probabilistic models for sequence changes that originate with point mutation. We estimated the percentage of nucleotide substitutions that originate with an IGC event rather than a point mutation in 14 groups of yeast ribosomal protein-coding genes, and found values ranging from 20% to 38%. We designed and applied a procedure to determine whether these percentages are inflated due to artifacts arising from model misspecification. The results of this procedure are consistent with IGC having had an important role in the evolution of each of these 14 gene families. We further investigate the properties of our IGC approach via simulation. In contrast to usual practice, our findings suggest that the IGC should and can be considered when multigene family evolution is investigated.
Asunto(s)
Conversión Génica , Familia de Multigenes , Levaduras/genética , Secuencia de Bases/genética , Evolución Biológica , Evolución Molecular , Modelos Genéticos , Nucleótidos/genética , Filogenia , Mutación Puntual , Saccharomyces cerevisiae , Análisis de Secuencia de ADN/métodosRESUMEN
Rates of molecular evolution can vary over time. Diverse statistical techniques for divergence time estimation have been developed to accommodate this variation. These typically require that all sequence (or codon) positions at a locus change independently of one another. They also generally assume that the rates of different types of nucleotide substitutions vary across a phylogeny in the same way. This permits divergence time estimation procedures to employ an instantaneous rate matrix with relative rates that do not differ among branches. However, previous studies have suggested that some substitution types (e.g., CpG to TpG changes in mammals) are more clock-like than others. As has been previously noted, this is biologically plausible given the mutational mechanism of CpG to TpG changes. Through stochastic mapping of sequence histories from context-independent substitution models, our approach allows for context-dependent nucleotide substitutions to change their relative rates over time. We apply our approach to the analysis of a 0.15 Mb intergenic region from eight primates. In accord with previous findings, we find comparatively little rate variation over time for CpG to TpG substitutions but we find more for other substitution types. We conclude by discussing the limitations and prospects of our approach.
Asunto(s)
Relojes Biológicos/fisiología , Islas de CpG/fisiología , ADN Intergénico/genética , Evolución Molecular , Modelos Biológicos , Animales , HumanosRESUMEN
Phytophthora infestans is one of the most destructive plant pathogens of potato and tomato globally. The pathogen is closely related to four other Phytophthora species in the 1c clade including P. phaseoli, P. ipomoeae, P. mirabilis and P. andina that are important pathogens of other wild and domesticated hosts. P. andina is an interspecific hybrid between P. infestans and an unknown Phytophthora species. We have sequenced mitochondrial genomes of the sister species of P. infestans and examined the evolutionary relationships within the clade. Phylogenetic analysis indicates that the P. phaseoli mitochondrial lineage is basal within the clade. P. mirabilis and P. ipomoeae are sister lineages and share a common ancestor with the Ic mitochondrial lineage of P. andina. These lineages in turn are sister to the P. infestans and P. andina Ia mitochondrial lineages. The P. andina Ic lineage diverged much earlier than the P. andina Ia mitochondrial lineage and P. infestans. The presence of two mitochondrial lineages in P. andina supports the hybrid nature of this species. The ancestral state of the P. andina Ic lineage in the tree and its occurrence only in the Andean regions of Ecuador, Colombia and Peru suggests that the origin of this species hybrid in nature may occur there.
Asunto(s)
Genoma Mitocondrial , Mitocondrias/genética , Filogenia , Phytophthora infestans/genética , Phytophthora/genética , Evolución Biológica , Quimera/microbiología , Colombia , ADN Mitocondrial/genética , Ecuador , Solanum lycopersicum/microbiología , Perú , Filogeografía , Phytophthora/clasificación , Phytophthora infestans/clasificación , Enfermedades de las Plantas/microbiología , Análisis de Secuencia de ADN , Solanum tuberosum/microbiologíaRESUMEN
Although most of the important evolutionary events in the history of biology can only be studied via interspecific comparisons, it is challenging to apply the rich body of population genetic theory to the study of interspecific genetic variation. Probabilistic modeling of the substitution process would ideally be derived from first principles of population genetics, allowing a quantitative connection to be made between the parameters describing mutation, selection, drift, and the patterns of interspecific variation. There has been progress in reconciling population genetics and interspecific evolution for the case where mutation rates are sufficiently low, but when mutation rates are higher, reconciliation has been hampered due to complications from how the loss or fixation of new mutations can be influenced by linked nonneutral polymorphisms (i.e., the Hill-Robertson effect). To investigate the generation of interspecific genetic variation when concurrent fitness-affecting polymorphisms are common and the Hill-Robertson effect is thereby potentially strong, we used the Wright-Fisher model of population genetics to simulate very many generations of mutation, natural selection, and genetic drift. This was done so that the chronological history of advantageous, deleterious, and neutral substitutions could be traced over time along the ancestral lineage. Our simulations show that the process by which a nonrecombining sequence changes over time can markedly deviate from the Markov assumption that is ubiquitous in molecular phylogenetics. In particular, we find tendencies for advantageous substitutions to be followed by deleterious ones and for deleterious substitutions to be followed by advantageous ones. Such non-Markovian patterns reflect the fact that the fate of the ancestral lineage depends not only on its current allelic state but also on gene copies not belonging to the ancestral lineage. Although our simulations describe nonrecombining sequences, we conclude by discussing how non-Markovian behavior of the ancestral lineage is plausible even when recombination rates are not low. As a result, we believe that increased attention needs to be devoted to the robustness of evolutionary inference procedures that rely upon the Markov assumption.
Asunto(s)
Evolución Molecular , Cadenas de Markov , Modelos Genéticos , Simulación por Computador , Aptitud Genética , Variación Genética , Polimorfismo Genético , Selección GenéticaRESUMEN
By modeling the homoeologous gene losses that occurred in 50 genomes deriving from ten distinct polyploidy events, we show that the evolutionary forces acting on polyploids are remarkably similar, regardless of whether they occur in flowering plants, ciliates, fishes, or yeasts. We show that many of the events show a relative rate of duplicate gene loss before the first postpolyploidy speciation that is significantly higher than in later phases of their evolution. The relatively weak selective constraint experienced by the single-copy genes these losses produced leads us to suggest that most of the purely selectively neutral duplicate gene losses occur in the immediate postpolyploid period. Nearly all of the events show strong evidence of biases in the duplicate losses, consistent with them being allopolyploidies, with 2 distinct progenitors contributing to the modern species. We also find ongoing and extensive reciprocal gene losses (alternative losses of duplicated ancestral genes) between these genomes. With the exception of a handful of closely related taxa, all of these polyploid organisms are separated from each other by tens to thousands of reciprocal gene losses. As a result, it is very unlikely that viable diploid hybrid species could form between these taxa, since matings between such hybrids would tend to produce offspring lacking essential genes. It is, therefore, possible that the relatively high frequency of recurrent polyploidies in some lineages may be due to the ability of new polyploidies to bypass reciprocal gene loss barriers.
Asunto(s)
Eucariontes , Evolución Molecular , Diploidia , Humanos , Filogenia , PoliploidíaRESUMEN
Background and objectives: Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers in this group is unknown. Characterizing the genetic changes associated with hepatocellular carcinoma in prosimians may point to possible causes, treatments and methods of prevention, aiding conservation efforts that are particularly crucial to the survival of endangered lemurs. Although genomic studies of cancer in non-human primates have been hampered by a lack of tools, recent studies have demonstrated the efficacy of using human exome capture reagents across primates. Methodology: In this proof-of-principle study, we applied human exome capture reagents to tumor-normal pairs from five lemurs with hepatocellular carcinoma to characterize the mutational landscape of this disease in lemurs. Results: Several genes implicated in human hepatocellular carcinoma, including ARID1A, TP53 and CTNNB1, were mutated in multiple lemurs, and analysis of cancer driver genes mutated in these samples identified enrichment of genes involved with TP53 degradation and regulation. In addition to these similarities with human hepatocellular carcinoma, we also noted unique features, including six genes that contain mutations in all five lemurs. Interestingly, these genes are infrequently mutated in human hepatocellular carcinoma, suggesting potential differences in the etiology and/or progression of this cancer in lemurs and humans. Conclusions and implications: Collectively, this pilot study suggests that human exome capture reagents are a promising tool for genomic studies of cancer in lemurs and other non-human primates. Lay Summary: Hepatocellular carcinoma occurs frequently in prosimians, but the cause of these liver cancers is unknown. In this proof-of-principle study, we applied human DNA sequencing tools to tumor-normal pairs from five lemurs with hepatocellular carcinoma and compared the lemur mutation profiles to those of human hepatocellular carcinomas.
RESUMEN
There have been substantial improvements in statistical tools for assessing the evolutionary roles of mutation and natural selection from interspecific sequence data. The importance of having the rate at which a point mutation occurs depend on the DNA sequence at sites surrounding the mutation is now better appreciated and can be accommodated in probabilistic models of protein evolution. To quantify the evolutionary impact of some aspect of phenotype, one promising strategy is to develop a system for predicting phenotype from the DNA sequence and to then infer how the evolutionary rates of sequence change are affected by the predicted phenotypic consequences of the changes. Although statistical tools for characterizing protein evolution are improving, the list of candidate phenomena that can affect rates of protein evolution is long and the relative contributions of these phenomena are only beginning to be disentangled.
Asunto(s)
Evolución Molecular , Modelos Moleculares , Proteínas/química , Proteínas/genética , Pliegue de ProteínaRESUMEN
Evolutionary models of proteins are widely used for statistical sequence alignment and inference of homology and phylogeny. However, the vast majority of these models rely on an unrealistic assumption of independent evolution between sites. Here we focus on the related problem of protein structure alignment, a classic tool of computational biology that is widely used to identify structural and functional similarity and to infer homology among proteins. A site-independent statistical model for protein structural evolution has previously been introduced and shown to significantly improve alignments and phylogenetic inferences compared with approaches that utilize only amino acid sequence information. Here we extend this model to account for correlated evolutionary drift among neighboring amino acid positions. The result is a spatiotemporal model of protein structure evolution, described by a multivariate diffusion process convolved with a spatial birth-death process. This extended site-dependent model (SDM) comes with little additional computational cost or analytical complexity compared with the site-independent model (SIM). We demonstrate that this SDM yields a significant reduction of bias in estimated evolutionary distances and helps further improve phylogenetic tree reconstruction. We also develop a simple model of site-dependent sequence evolution, which we use to demonstrate the bias resulting from the application of standard site-independent sequence evolution models.
Asunto(s)
Biología Computacional/métodos , Proteínas/química , Proteínas/metabolismo , Evolución Molecular , Modelos Estadísticos , Alineación de Secuencia , Análisis de Secuencia de Proteína , Homología Estructural de ProteínaRESUMEN
Identifying causes of genetic divergence is a central goal in evolutionary biology. Although rates of nucleotide substitution vary among taxa and among genes, the causes of this variation tend to be poorly understood. In the present study, we examined the rate and pattern of molecular evolution for five DNA regions over a phylogeny of Cornus, the single genus of Cornaceae. To identify evolutionary mechanisms underlying the molecular variation, we employed Bayesian methods to estimate divergence times and to infer how absolute rates of synonymous and nonsynonymous substitutions and their ratios change over time. We found that the rates vary among genes, lineages, and through time, and differences in mutation rates, selection type and intensity, and possibly genetic drift all contributed to the variation of substitution rates observed among the major lineages of Cornus. We applied independent contrast analysis to explore whether speciation rates are linked to rates of molecular evolution. The results showed no relationships for individual genes, but suggested a possible localized link between species richness and rate of nonsynonymous nucleotide substitution for the combined cpDNA regions. Furthermore, we detected a positive correlation between rates of molecular evolution and morphological change in Cornus. This was particularly pronounced in the dwarf dogwood lineage, in which genome-wide acceleration in both molecular and morphological evolution has likely occurred.
Asunto(s)
Cornus/clasificación , Cornus/genética , Evolución Molecular , Especiación Genética , Teorema de Bayes , Cloroplastos/genética , Cornus/anatomía & histología , ADN de Cloroplastos/genética , ADN de Plantas/genética , Fósiles , Genes de Plantas , Genoma del Cloroplasto , Modelos Genéticos , Nucleótidos/genética , Filogenia , Análisis de Secuencia de ADNRESUMEN
Different types of nucleotide substitutions experience different patterns of rate change over time. We propose clustering context-dependent (or context-independent) nucleotide substitution types according to how their rates change and then using the grouping for divergence time estimation. With our models, relative rates among types that are in the same group are fixed, whereas absolute rates of the types within a group change over time according to a shared relaxed molecular clock. We illustrate our procedure by analysing a 0.15 Mb intergenic region to infer divergence times relating eight primates. The different groupings of substitution types that we explore have little effect on the posterior means of divergence times, but the widths of the credibility intervals decrease as the number of groups increases.This article is part of the themed issue 'Dating species divergences using rocks and clocks'.