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Knowledge of genome-wide genealogies for thousands of individuals would simplify most evolutionary analyses for humans and other species, but has remained computationally infeasible. We developed a method, Relate, scaling to > 10,000 sequences while simultaneously estimating branch lengths, mutational ages, and variable historical population sizes, as well as allowing for data errors. Application to 1000 Genomes Project haplotypes produces joint genealogical histories for 26 human populations. Highly diverged lineages are present in all groups, but most frequent in Africa. Outside Africa, these mainly reflect ancient introgression from groups related to Neanderthals and Denisovans, while African signals instead reflect unknown events, unique to that continent. Our approach allows more powerful inferences of natural selection than previously possible. We identify multiple novel regions under strong positive selection, and multi-allelic traits including hair colour, BMI, and blood pressure, showing strong evidence of directional selection, varying among human groups.Large-scale genetic variation datasets are now available for a variety of species, including tens of thousands of humans. In principle, all information about a sample's genetic history is captured by their underlying genealogical history, which records the historical coalescence, recombination, and mutation events that produced the observed variation patterns. In practice, several key existing approaches (e.g., Refs. [1,2]) leverage an underlying coalescent model, because this provides a flexible modelling framework and is the limiting behaviour of a variety of finite-population models 3,4 . However, inference under the coalescent is complicated by the structure of the model, uncertainty over the correct genealogy conditional on observed data, and the large resulting space of possible sample histories 5 . Other approaches 6-11 use more heuristic approximations to the coalescent, sometimes reducing accuracy: regardless, all published existing methods scale to tens or a few hundred samples at most.As a result of these issues, the use of direct genealogy-based inference to detect recombination events, date mutations, and reveal evidence of positive selection has been limited to smaller datasets 1,2 , while for larger datasets approaches based on data summaries 12-14 or downsampling 15,16 have predominated. A diverse set of tools have detected genetic structure that is in good agreement with geopolitical separation over generations 17 .Admixtures of ancient populations have been identified and dated 18 . Other applications have found bottlenecks in population sizes that are consistent with anthropological evidence of initial human migration from the African continent 15,19-21 and evidence of subsequent introgression with archaic humans, such as Neanderthals 22 .We have developed a scalable method, Relate, to estimate genome-wide genealogies (see Figure 1; Methods;URLs for implementation). Relate separates two steps; firstly identifying a genealogical fra...

The grey wolf (Canis lupus) was the first species to give rise to a domestic population, and they remained widespread throughout the last Ice Age when many other large mammal species went extinct. Little is known, however, about the history and possible extinction of past wolf populations or when and where the wolf progenitors of the present-day dog lineage (Canis familiaris) lived1–8. Here we analysed 72 ancient wolf genomes spanning the last 100,000 years from Europe, Siberia and North America. We found that wolf populations were highly connected throughout the Late Pleistocene, with levels of differentiation an order of magnitude lower than they are today. This population connectivity allowed us to detect natural selection across the time series, including rapid fixation of mutations in the gene IFT88 40,000–30,000 years ago. We show that dogs are overall more closely related to ancient wolves from eastern Eurasia than to those from western Eurasia, suggesting a domestication process in the east. However, we also found that dogs in the Near East and Africa derive up to half of their ancestry from a distinct population related to modern southwest Eurasian wolves, reflecting either an independent domestication process or admixture from local wolves. None of the analysed ancient wolf genomes is a direct match for either of these dog ancestries, meaning that the exact progenitor populations remain to be located.

We present a full-likelihood method to estimate and quantify polygenic adaptation from contemporary DNA sequence data. The method combines population genetic DNA sequence data and GWAS summary statistics from up to thousands of nucleotide sites in a joint likelihood function to estimate the strength of transient directional selection acting on a polygenic trait. Through population genetic simulations of polygenic trait architectures and GWAS, we show that the method substantially improves power over current methods. We examine the robustness of the method under uncorrected GWAS stratification, uncertainty and ascertainment bias in the GWAS estimates of SNP effects, uncertainty in the identification of causal SNPs, allelic heterogeneity, negative selection, and low GWAS sample size. The method can quantify selection acting on correlated traits, fully controlling for pleiotropy even among traits with strong genetic correlation (|rg| = 80%; c.f. schizophrenia and bipolar disorder) while retaining high power to attribute selection to the causal trait. We apply the method to study 56 human polygenic traits for signs of recent adaptation. We find signals of directional selection on pigmentation (tanning, sunburn, hair, P=5.5e-15, 1.1e-11, 2.2e-6, respectively), life history traits (age at first birth, EduYears, P=2.5e-4, 2.6e-4, respectively), glycated hemoglobin (HbA1c, P=1.2e-3), bone mineral density (P=1.1e-3), and neuroticism (P=5.5e-3). We also conduct joint testing of 137 pairs of genetically correlated traits. We find evidence of widespread correlated response acting on these traits (2.6-fold enrichment over the null expectation, P=1.5e-7). We find that for several traits previously reported as adaptive, such as educational attainment and hair color, a significant proportion of the signal of selection on these traits can be attributed to correlated response, vs direct selection (P=2.9e-6, 1.7e-4, respectively). Lastly, our joint test uncovers antagonistic selection that has acted to increase type 2 diabetes (T2D) risk and decrease HbA1c (P=1.5e-5).

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualise ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of &gt; 0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ∼10k-15k years ago, but is not observed in samples &gt;30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localises the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species.

Random walks are basic diffusion processes on networks and have applications in, for example, searching, navigation, ranking, and community detection. Recent recognition of the importance of temporal aspects on networks spurred studies of random walks on temporal networks. Here we theoretically study two types of event-driven random walks on a stochastic temporal network model that produces arbitrary distributions of interevent times. In the so-called active random walk, the interevent time is reinitialized on all links upon each movement of the walker. In the so-called passive random walk, the interevent time is reinitialized only on the link that has been used the last time, and it is a type of correlated random walk. We find that the steady state is always the uniform density for the passive random walk. In contrast, for the active random walk, it increases or decreases with the node's degree depending on the distribution of interevent times. The mean recurrence time of a node is inversely proportional to the degree for both active and passive random walks. Furthermore, the mean recurrence time does or does not depend on the distribution of interevent times for the active and passive random walks, respectively.