Joshua G. Schraiber

A High-Coverage Genome Sequence from an Archaic Denisovan Individual

Ancient Genomics The Denisovans were archaic humans closely related to Neandertals, whose populations overlapped with the ancestors of modern-day humans. Using a single-stranded library preparation method, Meyer et al. (p. 222, published online 30 August) provide a detailed analysis of a high-quality Denisovan genome. The genomic sequence provides evidence for very low rates of heterozygosity in the Denisova, probably not because of recent inbreeding, but instead because of a small population size. The genome sequence also illuminates the relationships between humans and archaics, including Neandertals, and establishes a catalog of genetic changes within the human lineage. A close-up look provides clues to the relationships between modern humans, Denisovans, and Neandertals. We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals

Denisovan DNA retained in Melanesians Modern humans carry remnants of DNA from interbreeding events with archaic lineages, such as Neandertals. However, people from Oceania also retain genes from a second ancient lineage, the Denisovans. Vernot et al. surveyed archaic genomic sequences in a worldwide sample of modern humans, including 35 individuals from the Melanesian Islands. All non-African genomes surveyed contained Neandertal DNA, but a significant Denisovan component was found only in the Melanesians. Reconstruction of this genetic history suggests that Neandertals bred with modern humans multiple times, but Denosivans only once, in ancestors of modern-day Melanesians. Science, this issue p. 235 Neandertal and Denisovan DNA live on in modern day Melanesians. Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.

Genome sequencing reveals fine scale diversification and reticulation history during speciation in Sus

BackgroundElucidating the process of speciation requires an in-depth understanding of the evolutionary history of the species in question. Studies that rely upon a limited number of genetic loci do not always reveal actual evolutionary history, and often confuse inferences related to phylogeny and speciation. Whole-genome data, however, can overcome this issue by providing a nearly unbiased window into the patterns and processes of speciation. In order to reveal the complexity of the speciation process, we sequenced and analyzed the genomes of 10 wild pigs, representing morphologically or geographically well-defined species and subspecies of the genus Sus from insular and mainland Southeast Asia, and one African common warthog.ResultsOur data highlight the importance of past cyclical climatic fluctuations in facilitating the dispersal and isolation of populations, thus leading to the diversification of suids in one of the most species-rich regions of the world. Moreover, admixture analyses revealed extensive, intra- and inter-specific gene-flow that explains previous conflicting results obtained from a limited number of loci. We show that these multiple episodes of gene-flow resulted from both natural and human-mediated dispersal.ConclusionsOur results demonstrate the importance of past climatic fluctuations and human mediated translocations in driving and complicating the process of speciation in island Southeast Asia. This case study demonstrates that genomics is a powerful tool to decipher the evolutionary history of a genus, and reveals the complexity of the process of speciation.

Phylogenetic Analysis Using Lévy Processes: Finding Jumps in the Evolution of Continuous Traits

Gaussian processes, a class of stochastic processes including Brownian motion and the Ornstein-Uhlenbeck process, are widely used to model continuous trait evolution in statistical phylogenetics. Under such processes, observations at the tips of a phylogenetic tree have a multivariate Gaussian distribution, which may lead to suboptimal model specification under certain evolutionary conditions, as supposed in models of punctuated equilibrium or adaptive radiation. To consider non-normally distributed continuous trait evolution, we introduce a method to compute posterior probabilities when modeling continuous trait evolution as a Lévy process. Through data simulation and model testing, we establish that single-rate Brownian motion (BM) and Lévy processes with jumps generate distinct patterns in comparative data. We then analyzed body mass and endocranial volume measurements for 126 primates. We rejected single-rate BM in favor of a Lévy process with jumps for each trait, with the lineage leading to most recent common ancestor of great apes showing particularly strong evidence against single-rate BM.

Methods and models for unravelling human evolutionary history.

The genomes of contemporary humans contain considerable information about the history of our species. Although the general contours of human evolutionary history have been defined with increasing resolution throughout the past several decades, the continuing deluge of massively large sequencing data sets presents new opportunities and challenges for understanding human evolutionary history. Here, we review the signatures that demographic history imparts on patterns of DNA sequence variation, statistical methods that have been developed to leverage information contained in genome-scale data sets and insights gleaned from these studies. We also discuss the importance of using exploratory analyses to assess data quality, the strengths and limitations of commonly used population genomics methods, and factors that confound population genomics inferences.

Constraints on the use of lifespan-shortening Wolbachia to control dengue fever

Dengue fever, a viral disease spread by the mosquito Aedes aegypti, affects 50-100 million people a year in many tropical countries. Because the virus must incubate within mosquito hosts for two weeks before being able to transmit the infection, shortening the lifespan of mosquitoes may curtail dengue transmission. We developed a continuous time reaction-diffusion model of the spatial spread of Wolbachia through a population of A. aegypti. This model incorporates the lifespan-shortening effects of Wolbachia on infected A. aegypti and the fitness advantage to infected females due to cytoplasmic incompatibility (CI). We found that local establishment of the Wolbachia infection can occur if the fitness advantage due to CI exceeds the fitness reduction due to lifespan-shortening effects, in accordance with earlier results concerning fecundity reduction. However, spatial spread is possible only if the fitness advantage due to CI is twice as great as the fitness reduction due to lifespan shortening effects. Moreover, lifespan-shortening and fecundity-reduction can have different effects on the speed of wave-retreat. Using data from the literature, we estimated all demographic parameters for infected and uninfected mosquitoes and computed the velocities of spread of infection. Our most optimistic estimates suggest that the spatial spread of lifespan-shortening Wolbachia may be so slow that efficient spatial spread would require a prohibitively large number of point releases. However, as these estimates of demographic parameters may not accurately reflect natural conditions, further research is necessary to corroborate these predictions.

Emergence of a Homo sapiens- specific gene family and chromosome 16p11.2 CNV susceptibility

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage—a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11.2 rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

Bayesian Inference of Natural Selection from Allele Frequency Time Series

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.

Approximation to the distribution of fitness effects across functional categories in human segregating polymorphisms.

Quantifying the proportion of polymorphic mutations that are deleterious or neutral is of fundamental importance to our understanding of evolution, disease genetics and the maintenance of variation genome-wide. Here, we develop an approximation to the distribution of fitness effects (DFE) of segregating single-nucleotide mutations in humans. Unlike previous methods, we do not assume that synonymous mutations are neutral or not strongly selected, and we do not rely on fitting the DFE of all new nonsynonymous mutations to a single probability distribution, which is poorly motivated on a biological level. We rely on a previously developed method that utilizes a variety of published annotations (including conservation scores, protein deleteriousness estimates and regulatory data) to score all mutations in the human genome based on how likely they are to be affected by negative selection, controlling for mutation rate. We map this and other conservation scores to a scale of fitness coefficients via maximum likelihood using diffusion theory and a Poisson random field model on SNP data. Our method serves to approximate the deleterious DFE of mutations that are segregating, regardless of their genomic consequence. We can then compare the proportion of mutations that are negatively selected or neutral across various categories, including different types of regulatory sites. We observe that the distribution of intergenic polymorphisms is highly peaked at neutrality, while the distribution of nonsynonymous polymorphisms has a second peak at . Other types of polymorphisms have shapes that fall roughly in between these two. We find that transcriptional start sites, strong CTCF-enriched elements and enhancers are the regulatory categories with the largest proportion of deleterious polymorphisms.

Evolution of a membrane protein regulon in Saccharomyces

Expression variation is widespread between species. The ability to distinguish regulatory change driven by natural selection from the consequences of neutral drift remains a major challenge in comparative genomics. In this work, we used observations of mRNA expression and promoter sequence to analyze signatures of selection on groups of functionally related genes in Saccharomycete yeasts. In a survey of gene regulons with expression divergence between Saccharomyces cerevisiae and S. paradoxus, we found that most were subject to variation in trans-regulatory factors that provided no evidence against a neutral model. However, we identified one regulon of membrane protein genes controlled by unlinked cis- and trans-acting determinants with coherent effects on gene expression, consistent with a history of directional, nonneutral evolution. For this membrane protein group, S. paradoxus alleles at regulatory loci were associated with elevated expression and altered stress responsiveness relative to other yeasts. In a phylogenetic comparison of promoter sequences of the membrane protein genes between species, the S. paradoxus lineage was distinguished by a short branch length, indicative of strong selective constraint. Likewise, sequence variants within the S. paradoxus population, but not across strains of other yeasts, were skewed toward low frequencies in promoters of genes in the membrane protein regulon, again reflecting strong purifying selection. Our results support a model in which a distinct expression program for the membrane protein genes in S. paradoxus has been preferentially maintained by negative selection as the result of an increased importance to organismal fitness. These findings illustrate the power of integrating expression- and sequence-based tests of natural selection in the study of evolutionary forces that underlie regulatory change.