169 research outputs found
Interpreting the dependence of mutation rates on age and time
Mutations can arise from the chance misincorporation of nucleotides during
DNA replication or from DNA lesions that are not repaired correctly. We
introduce a model that relates the source of mutations to their accumulation
with cell divisions, providing a framework for understanding how mutation rates
depend on sex, age and absolute time. We show that the accrual of mutations
should track cell divisions not only when mutations are replicative in origin
but also when they are non-replicative and repaired efficiently. One
implication is that the higher incidence of cancer in rapidly renewing tissues,
an observation ascribed to replication errors, could instead reflect exogenous
or endogenous mutagens. We further find that only mutations that arise from
inefficiently repaired lesions will accrue according to absolute time; thus, in
the absence of selection on mutation rates, the phylogenetic "molecular clock"
should not be expected to run steadily across species.Comment: 5 figures, 2 table
Inferring the Demographic History and Rate of Adaptive Substitution in Drosophila
An important goal of population genetics is to determine the forces that have shaped the pattern of genetic variation in natural populations. We developed a maximum likelihood method that allows us to infer demographic changes and detect recent positive selection (selective sweeps) in populations of varying size from DNA polymorphism data. Applying this approach to single nucleotide polymorphism data at more than 250 noncoding loci on the X chromosome of Drosophila melanogaster from an (ancestral) African population and a (derived) European, we found that the African population expanded about 60,000 y ago and that the European population split off from the African lineage about 15,800 y ago, thereby suffering a severe population size bottleneck. We estimated that about 160 beneficial mutations (with selection coefficients s between 0.05% and 0.5%) were fixed in the euchromatic portion of the X in the African population since population size expansion, and about 60 mutations (with s around 0.5%) in the diverging European lineage
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The Case of the Fickle Fingers: How the PRDM9 Zinc Finger Protein Specifies Meiotic Recombination Hotspots in Humans
During mammalian meiosis, double-strand breaks are deliberately made throughout the genome and then repaired, leading to the exchange of genetic material between copies of chromosomes. How the locations of breaks are specified was largely unknown until a fortuitous confluence of statistical genetics and molecular biology uncovered the role of PRDM9, a DNA binding protein. Many properties of this protein remain mysterious, however, including how it binds to DNA, how it contributes to male infertility—both in humans, and in hybrid mice—and why, in spite of its fundamental function in meiosis, its binding domain varies extensively among humans and across mammals. We present a brief summary of what has recently been learned about PRDM9 in different fields, focusing on the puzzles yet to be resolved.</p
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Pervasive Natural Selection in the <i>Drosophila</i> Genome?
Over the past four decades, the predominant view of molecular evolution saw little connection between natural selection and genome evolution, assuming that the functionally constrained fraction of the genome is relatively small and that adaptation is sufficiently infrequent to play little role in shaping patterns of variation within and even between species. Recent evidence from Drosophila, reviewed here, suggests that this view may be invalid. Analyses of genetic variation within and between species reveal that much of the Drosophila genome is under purifying selection, and thus of functional importance, and that a large fraction of coding and noncoding differences between species are adaptive. The findings further indicate that, in Drosophila, adaptations may be both common and strong enough that the fate of neutral mutations depends on their chance linkage to adaptive mutations as much as on the vagaries of genetic drift. The emerging evidence has implications for a wide variety of fields, from conservation genetics to bioinformatics, and presents challenges to modelers and experimentalists alike.</p
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A Population Genetics-Phylogenetics Approach to Inferring Natural Selection in Coding Sequences
Through an analysis of polymorphism within and divergence between species, we can hope to learn about the distribution of selective effects of mutations in the genome, changes in the fitness landscape that occur over time, and the location of sites involved in key adaptations that distinguish modern-day species. We introduce a novel method for the analysis of variation in selection pressures within and between species, spatially along the genome and temporally between lineages. We model codon evolution explicitly using a joint population genetics-phylogenetics approach that we developed for the construction of multiallelic models with mutation, selection, and drift. Our approach has the advantage of performing direct inference on coding sequences, inferring ancestral states probabilistically, utilizing allele frequency information, and generalizing to multiple species. We use a Bayesian sliding window model for intragenic variation in selection coefficients that efficiently combines information across sites and captures spatial clustering within the genome. To demonstrate the utility of the method, we infer selective pressures acting in Drosophila melanogaster and D. simulans from polymorphism and divergence data for 100 X-linked coding regions.</p
Variation in the molecular clock of primates
Events in primate evolution are often dated by assuming a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life history traits, suggesting it should also be found among primates. Motivated by these considerations, we analyze whole genomes from 10 primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs), and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are up to 64% higher in lineages leading from the hominoid–NWM ancestor to NWMs than to apes. Within apes, rates are ∼2% higher in chimpanzees and ∼7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however; in particular, transitions at CpG sites exhibit a more clocklike behavior than do other types, presumably because of their nonreplicative origin. Thus, not only the total rate, but also the mutational spectrum, varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate the human and chimpanzee divergence time is 12.1 million years, and the human and gorilla divergence time is 15.1 million years.United States. National Institutes of Health (F32 GM115006-01
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Genetic Structure of Chimpanzee Populations
Little is known about the history and population structure of our closest living relatives, the chimpanzees, in part because of an extremely poor fossil record. To address this, we report the largest genetic study of the chimpanzees to date, examining 310 microsatellites in 84 common chimpanzees and bonobos. We infer three common chimpanzee populations, which correspond to the previously defined labels of “western,” “central,” and “eastern,” and find little evidence of gene flow between them. There is tentative evidence for structure within western chimpanzees, but we do not detect distinct additional populations. The data also provide historical insights, demonstrating that the western chimpanzee population diverged first, and that the eastern and central populations are more closely related in time.</p
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