Inference and applications of ancestral recombination graphs.

Ancestral recombination graphs (ARGs) summarize the complex genealogical relationships between individuals represented in a sample of DNA sequences. Their use is currently revolutionizing the field of population genetics and is leading to the development of powerful new methods to elucidate individual and population genetic processes, including population size history, migration, admixture, recombination, mutation and selection. In this Review, we introduce the readers to the structure of ARGs and discuss how they relate to processes such as recombination and genetic drift. We explore differences and similarities between methods of estimating ARGs and provide concrete illustrative examples of how ARGs can be used to elucidate population-level processes.

The selection landscape and genetic legacy of ancient Eurasians.

The Holocene (beginning around 12,000 years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using a dataset of more than 1,600 imputed ancient genomes1, we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer's disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

Bayesian inference of admixture graphs on Native American and Arctic populations.

Admixture graphs are mathematical structures that describe the ancestry of populations in terms of divergence and merging (admixing) of ancestral populations as a graph. An admixture graph consists of a graph topology, branch lengths, and admixture proportions. The branch lengths and admixture proportions can be estimated using numerous numerical optimization methods, but inferring the topology involves a combinatorial search for which no polynomial algorithm is known. In this paper, we present a reversible jump MCMC algorithm for sampling high-probability admixture graphs and show that this approach works well both as a heuristic search for a single best-fitting graph and for summarizing shared features extracted from posterior samples of graphs. We apply the method to 11 Native American and Siberian populations and exploit the shared structure of high-probability graphs to characterize the relationship between Saqqaq, Inuit, Koryaks, and Athabascans. Our analyses show that the Saqqaq is not a good proxy for the previously identified gene flow from Arctic people into the Na-Dene speaking Athabascans.

Fast and Accurate Estimation of Selection Coefficients and Allele Histories from Ancient and Modern DNA.

We here present CLUES2, a full-likelihood method to infer natural selection from sequence data that is an extension of the method CLUES. We make several substantial improvements to the CLUES method that greatly increases both its applicability and its speed. We add the ability to use ancestral recombination graphs on ancient data as emissions to the underlying hidden Markov model, which enables CLUES2 to use both temporal and linkage information to make estimates of selection coefficients. We also fully implement the ability to estimate distinct selection coefficients in different epochs, which allows for the analysis of changes in selective pressures through time, as well as selection with dominance. In addition, we greatly increase the computational efficiency of CLUES2 over CLUES using several approximations to the forward-backward algorithms and develop a new way to reconstruct historic allele frequencies by integrating over the uncertainty in the estimation of the selection coefficients. We illustrate the accuracy of CLUES2 through extensive simulations and validate the importance sampling framework for integrating over the uncertainty in the inference of gene trees. We also show that CLUES2 is well-calibrated by showing that under the null hypothesis, the distribution of log-likelihood ratios follows a χ2 distribution with the appropriate degrees of freedom. We run CLUES2 on a set of recently published ancient human data from Western Eurasia and test for evidence of changing selection coefficients through time. We find significant evidence of changing selective pressures in several genes correlated with the introduction of agriculture to Europe and the ensuing dietary and demographic shifts of that time. In particular, our analysis supports previous hypotheses of strong selection on lactase persistence during periods of ancient famines and attenuated selection in more modern periods.

Trait-Based Modeling of Multihost Pathogen Transmission: Plant-Pollinator Networks.

Epidemiological models for multihost pathogen systems often classify individuals taxonomically and use species-specific parameter values, but in species-rich communities that approach may require intractably many parameters. Trait-based epidemiological models offer a potential solution but have not accounted for within-species trait variation or between-species trait overlap. Here we propose and study trait-based models with host and vector communities represented as trait distributions without regard to species identity. To illustrate this approach, we develop susceptible-infectious-susceptible models for disease spread in plant-pollinator networks with continuous trait distributions. We model trait-dependent contact rates in two common scenarios: nested networks and specialized plant-pollinator interactions based on trait matching. We find that disease spread in plant-pollinator networks is impacted the most by selective pollinators, universally attractive flowers, and cospecialized plant-pollinator pairs. When extreme pollinator traits are rare, pollinators with common traits are most important for disease spread, whereas when extreme flower traits are rare, flowers with uncommon traits impact disease spread the most. Greater nestedness and specialization both typically promote disease persistence. Given recent pollinator declines caused in part by pathogens, we discuss how trait-based models could inform conservation strategies for wild and managed pollinators. Furthermore, while we have applied our model to pollinators and pathogens, its framework is general and can be transferred to any kind of species interactions in any community.

Evaluation of methods for estimating coalescence times using ancestral recombination graphs.

The ancestral recombination graph is a structure that describes the joint genealogies of sampled DNA sequences along the genome. Recent computational methods have made impressive progress toward scalably estimating whole-genome genealogies. In addition to inferring the ancestral recombination graph, some of these methods can also provide ancestral recombination graphs sampled from a defined posterior distribution. Obtaining good samples of ancestral recombination graphs is crucial for quantifying statistical uncertainty and for estimating population genetic parameters such as effective population size, mutation rate, and allele age. Here, we use standard neutral coalescent simulations to benchmark the estimates of pairwise coalescence times from 3 popular ancestral recombination graph inference programs: ARGweaver, Relate, and tsinfer+tsdate. We compare (1) the true coalescence times to the inferred times at each locus; (2) the distribution of coalescence times across all loci to the expected exponential distribution; (3) whether the sampled coalescence times have the properties expected of a valid posterior distribution. We find that inferred coalescence times at each locus are most accurate in ARGweaver, and often more accurate in Relate than in tsinfer+tsdate. However, all 3 methods tend to overestimate small coalescence times and underestimate large ones. Lastly, the posterior distribution of ARGweaver is closer to the expected posterior distribution than Relate's, but this higher accuracy comes at a substantial trade-off in scalability. The best choice of method will depend on the number and length of input sequences and on the goal of downstream analyses, and we provide guidelines for the best practices.

Maximum Likelihood Estimation of Fitness Components in Experimental Evolution.

Estimating fitness differences between allelic variants is a central goal of experimental evolution. Current methods for inferring such differences from allele frequency time series typically assume that the effects of selection can be described by a fixed selection coefficient. However, fitness is an aggregate of several components including mating success, fecundity, and viability. Distinguishing between these components could be critical in many scenarios. Here, we develop a flexible maximum likelihood framework that can disentangle different components of fitness from genotype frequency data, and estimate them individually in males and females. As a proof-of-principle, we apply our method to experimentally evolved cage populations of Drosophila melanogaster, in which we tracked the relative frequencies of a loss-of-function and wild-type allele of yellow This X-linked gene produces a recessive yellow phenotype when disrupted and is involved in male courtship ability. We find that the fitness costs of the yellow phenotype take the form of substantially reduced mating preference of wild-type females for yellow males, together with a modest reduction in the viability of yellow males and females. Our framework should be generally applicable to situations where it is important to quantify fitness components of specific genetic variants, including quantitative characterization of the population dynamics of CRISPR gene drives.