Epigenetic phenomena, and in particular heritable epigenetic changes, or transgenerational effects, are the subject of much discussion in the current literature. This article presents a model of ...transgenerational epigenetic inheritance and explores the effect of epigenetic inheritance on the risk and recurrence risk of a complex disease. The model assumes that epigenetic modifications of the genome are gained and lost at specified rates and that each modification contributes multiplicatively to disease risk. The potentially high rate of loss of epigenetic modifications causes the probability of identity in state in close relatives to be smaller than is implied by their relatedness. As a consequence, the recurrence risk to close relatives is reduced. Although epigenetic modifications may contribute substantially to average risk, they will not contribute much to recurrence risk and heritability unless they persist on average for many generations. If they do persist for long times, they are equivalent to mutations and hence are likely to be in linkage disequilibrium with SNPs surveyed in genomewide association studies. Thus epigenetic modifications are a potential solution to the problem of missing causality of complex diseases but not to the problem of missing heritability. The model highlights the need for empirical estimates of the persistence times of heritable epialleles.
Ancient DNA and human history Slatkin, Montgomery; Racimo, Fernando
Proceedings of the National Academy of Sciences - PNAS,
06/2016, Letnik:
113, Številka:
23
Journal Article
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We review studies of genomic data obtained by sequencing hominin fossils with particular emphasis on the unique information that ancient DNA (aDNA) can provide about the demographic history of humans ...and our closest relatives. We concentrate on nuclear genomic sequences that have been published in the past few years. In many cases, particularly in the Arctic, the Americas, and Europe, aDNA has revealed historical demographic patterns in a way that could not be resolved by analyzing present-day genomes alone. Ancient DNA from archaic hominins has revealed a rich history of admixture between early modern humans, Neanderthals, and Denisovans, and has allowed us to disentangle complex selective processes. Information from aDNA studies is nowhere near saturation, and we believe that future aDNA sequences will continue to change our understanding of hominin history.
Range expansions cause a series of founder events. We show that, in a one-dimensional habitat, these founder events are the spatial analog of genetic drift in a randomly mating population. The ...spatial series of allele frequencies created by successive founder events is equivalent to the time series of allele frequencies in a population of effective size ke, the effective number of founders. We derive an expression for ke in a discrete-population model that allows for local population growth and migration among established populations. If there is selection, the net effect is determined approximately by the product of the selection coefficients and the number of generations between successive founding events. We use the model of a single population to compute analytically several quantities for an allele present in the source population: (i) the probability that it survives the series of colonization events, (ii) the probability that it reaches a specified threshold frequency in the last population, and (iii) the mean and variance of the frequencies in each population. We show that the analytic theory provides a good approximation to simulation results. A consequence of our approximation is that the average heterozygosity of neutral alleles decreases by a factor of 1-1/(2ke) in each new population. Therefore, the population genetic consequences of surfing can be predicted approximately by the effective number of founders and the effective selection coefficients, even in the presence of migration among populations. We also show that our analytic results are applicable to a model of range expansion in a continuously distributed population.
Woolly mammoths (Mammuthus primigenius) populated Siberia, Beringia, and North America during the Pleistocene and early Holocene. Recent breakthroughs in ancient DNA sequencing have allowed for ...complete genome sequencing for two specimens of woolly mammoths (Palkopoulou et al. 2015). One mammoth specimen is from a mainland population 45,000 years ago when mammoths were plentiful. The second, a 4300 yr old specimen, is derived from an isolated population on Wrangel island where mammoths subsisted with small effective population size more than 43-fold lower than previous populations. These extreme differences in effective population size offer a rare opportunity to test nearly neutral models of genome architecture evolution within a single species. Using these previously published mammoth sequences, we identify deletions, retrogenes, and non-functionalizing point mutations. In the Wrangel island mammoth, we identify a greater number of deletions, a larger proportion of deletions affecting gene sequences, a greater number of candidate retrogenes, and an increased number of premature stop codons. This accumulation of detrimental mutations is consistent with genomic meltdown in response to low effective population sizes in the dwindling mammoth population on Wrangel island. In addition, we observe high rates of loss of olfactory receptors and urinary proteins, either because these loci are non-essential or because they were favored by divergent selective pressures in island environments. Finally, at the locus of FOXQ1 we observe two independent loss-of-function mutations, which would confer a satin coat phenotype in this island woolly mammoth.
One enduring question in evolutionary biology is the extent of archaic admixture in the genomes of present-day populations. In this paper, we present a test for ancient admixture that exploits the ...asymmetry in the frequencies of the two nonconcordant gene trees in a three-population tree. This test was first applied to detect interbreeding between Neandertals and modern humans. We derive the analytic expectation of a test statistic, called the D statistic, which is sensitive to asymmetry under alternative demographic scenarios. We show that the D statistic is insensitive to some demographic assumptions such as ancestral population sizes and requires only the assumption that the ancestral populations were randomly mating. An important aspect of D statistics is that they can be used to detect archaic admixture even when no archaic sample is available. We explore the effect of sequencing error on the false-positive rate of the test for admixture, and we show how to estimate the proportion of archaic ancestry in the genomes of present-day populations. We also investigate a model of subdivision in ancestral populations that can result in D statistics that indicate recent admixture.
The advent of accessible ancient DNA technology now allows the direct ascertainment of allele frequencies in ancestral populations, thereby enabling the use of allele frequency time series to detect ...and estimate natural selection. Such direct observations of allele frequency dynamics are expected to be more powerful than inferences made using patterns of linked neutral variation obtained from modern individuals. We developed a Bayesian method to make use of allele frequency time series data and infer the parameters of general diploid selection, along with allele age, in nonequilibrium populations. We introduce a novel path augmentation approach, in which we use Markov chain Monte Carlo to integrate over the space of allele frequency trajectories consistent with the observed data. Using simulations, we show that this approach has good power to estimate selection coefficients and allele age. Moreover, when applying our approach to data on horse coat color, we find that ignoring a relevant demographic history can significantly bias the results of inference. Our approach is made available in a C++ software package.
Linkage disequilibrium--the nonrandom association of alleles at different loci--is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of ...methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.
In 2004, the term ‘ghost population’ was introduced to summarize the effect of unsampled subpopulations that exchange migrants with other subpopulations that have been sampled. Estimated long‐term ...migration rates among populations sampled will be affected by ghost populations. Although it would be convenient to be able to define an apparent migration matrix among sampled populations that incorporate the exchange of migrants with ghost populations, no such matrix can be defined in a way that predicts all features of the coalescent process for the true migration matrix. This paper shows that if the underlying migration matrix is symmetric, it is possible to define an apparent migration matrix among sampled subpopulations that predicts the same within‐population and between‐population homozygosities among sampled populations as is predicted by the true migration matrix. Application of this method shows that there is no simple relationship between true and apparent migration rates, nor is there a way to place an upper bound on the effect of ghost populations. In general, ghost populations can create the appearance of migration between subpopulations that do not actually exchange migrants. Comparison with published results from the application of the program, migrate, shows that the apparent migration rates inferred with that program in a three‐subpopulation model differ from those based on pairwise homozygosities. The apparent migration matrix determined by the method described in this paper probably represents the upper bound on the effect of ghost populations.
The increasing abundance of DNA sequences obtained from fossils calls for new population genetics theory that takes account of both the temporal and spatial separation of samples. Here, we exploit ...the relationship between Wright's F
and average coalescence times to develop an analytic theory describing how F
depends on both the distance and time separating pairs of sampled genomes. We apply this theory to several simple models of population history. If there is a time series of samples, partial population replacement creates a discontinuity in pairwise F
values. The magnitude of the discontinuity depends on the extent of replacement. In stepping-stone models, pairwise F
values between archaic and present-day samples reflect both the spatial and temporal separation. At long distances, an isolation by distance pattern dominates. At short distances, the time separation dominates. Analytic predictions fit patterns generated by simulations. We illustrate our results with applications to archaic samples from European human populations. We compare present-day samples with a pair of archaic samples taken before and after a replacement event.
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