Genomic analyses inform on migration events during the peopling of Eurasia.

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

Population genetic considerations for using biobanks as international resources in the pandemic era and beyond.

The past years have seen the rise of genomic biobanks and mega-scale meta-analysis of genomic data, which promises to reveal the genetic underpinnings of health and disease. However, the over-representation of Europeans in genomic studies not only limits the global understanding of disease risk but also inhibits viable research into the genomic differences between carriers and patients. Whilst the community has agreed that more diverse samples are required, it is not enough to blindly increase diversity; the diversity must be quantified, compared and annotated to lead to insight. Genetic annotations from separate biobanks need to be comparable and computable and to operate without access to raw data due to privacy concerns. Comparability is key both for regular research and to allow international comparison in response to pandemics. Here, we evaluate the appropriateness of the most common genomic tools used to depict population structure in a standardized and comparable manner. The end goal is to reduce the effects of confounding and learn from genuine variation in genetic effects on phenotypes across populations, which will improve the value of biobanks (locally and internationally), increase the accuracy of association analyses and inform developmental efforts.

Correction to: Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

In the original article publication, there is an incorrect impression that Fig. 1 formed a formal Directed Acyclic Graph (DAG) by describing it as a causal model. However, it was not correct if interpreted in this way.

Is population structure in the genetic biobank era irrelevant, a challenge, or an opportunity?

Replicable genetic association signals have consistently been found through genome-wide association studies in recent years. The recent dramatic expansion of study sizes improves power of estimation of effect sizes, genomic prediction, causal inference, and polygenic selection, but it simultaneously increases susceptibility of these methods to bias due to subtle population structure. Standard methods using genetic principal components to correct for structure might not always be appropriate and we use a simulation study to illustrate when correction might be ineffective for avoiding biases. New methods such as trans-ethnic modeling and chromosome painting allow for a richer understanding of the relationship between traits and population structure. We illustrate the arguments using real examples (stroke and educational attainment) and provide a more nuanced understanding of population structure, which is set to be revisited as a critical aspect of future analyses in genetic epidemiology. We also make simple recommendations for how problems can be avoided in the future. Our results have particular importance for the implementation of GWAS meta-analysis, for prediction of traits, and for causal inference.

RADpainter and fineRADstructure: Population Inference from RADseq Data.

Powerful approaches to inferring recent or current population structure based on nearest neighbor haplotype "coancestry" have so far been inaccessible to users without high quality genome-wide haplotype data. With a boom in nonmodel organism genomics, there is a pressing need to bring these methods to communities without access to such data. Here, we present RADpainter, a new program designed to infer the coancestry matrix from restriction-site-associated DNA sequencing (RADseq) data. We combine this program together with a previously published MCMC clustering algorithm into fineRADstructure-a complete, easy to use, and fast population inference package for RADseq data (https://github.com/millanek/fineRADstructure; last accessed February 24, 2018). Finally, with two example data sets, we illustrate its use, benefits, and robustness to missing RAD alleles in double digest RAD sequencing.

Population identification using genetic data.

A large number of algorithms have been developed to classify individuals into discrete populations using genetic data. Recent results show that the information used by both model-based clustering methods and principal components analysis can be summarized by a matrix of pairwise similarity measures between individuals. Similarity matrices have been constructed in a number of ways, usually treating markers as independent but differing in the weighting given to polymorphisms of different frequencies. Additionally, methods are now being developed that take linkage into account. We review several such matrices and evaluate their information content. A two-stage approach for population identification is to first construct a similarity matrix and then perform clustering. We review a range of common clustering algorithms and evaluate their performance through a simulation study. The clustering step can be performed either on the matrix or by first using a dimension-reduction technique; we find that the latter approach substantially improves the performance of most algorithms. Based on these results, we describe the population structure signal contained in each similarity matrix and find that accounting for linkage leads to significant improvements for sequence data. We also perform a comparison on real data, where we find that population genetics models outperform generic clustering approaches, particularly with regard to robustness for features such as relatedness between individuals.

Inference of population structure using dense haplotype data.

The advent of genome-wide dense variation data provides an opportunity to investigate ancestry in unprecedented detail, but presents new statistical challenges. We propose a novel inference framework that aims to efficiently capture information on population structure provided by patterns of haplotype similarity. Each individual in a sample is considered in turn as a recipient, whose chromosomes are reconstructed using chunks of DNA donated by the other individuals. Results of this "chromosome painting" can be summarized as a "coancestry matrix," which directly reveals key information about ancestral relationships among individuals. If markers are viewed as independent, we show that this matrix almost completely captures the information used by both standard Principal Components Analysis (PCA) and model-based approaches such as STRUCTURE in a unified manner. Furthermore, when markers are in linkage disequilibrium, the matrix combines information across successive markers to increase the ability to discern fine-scale population structure using PCA. In parallel, we have developed an efficient model-based approach to identify discrete populations using this matrix, which offers advantages over PCA in terms of interpretability and over existing clustering algorithms in terms of speed, number of separable populations, and sensitivity to subtle population structure. We analyse Human Genome Diversity Panel data for 938 individuals and 641,000 markers, and we identify 226 populations reflecting differences on continental, regional, local, and family scales. We present multiple lines of evidence that, while many methods capture similar information among strongly differentiated groups, more subtle population structure in human populations is consistently present at a much finer level than currently available geographic labels and is only captured by the haplotype-based approach. The software used for this article, ChromoPainter and fineSTRUCTURE, is available from http://www.paintmychromosomes.com/.

HTRX: an R package for learning non-contiguous haplotypes associated with a phenotype.

Summary: Haplotype Trend Regression with eXtra flexibility (HTRX) is an R package to learn sets of interacting features that explain variance in a phenotype. Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) associated with complex traits and diseases, but finding the true causal signal from a high linkage disequilibrium block is challenging. We focus on the simpler task of quantifying the total variance explainable not just with main effects but also interactions and tagging, using haplotype-based associations. HTRX identifies haplotypes composed of non-contiguous SNPs associated with a phenotype and can naturally be performed on regions with a GWAS hit before or after fine-mapping. To reduce the space and computational complexity when investigating many features, we constrain the search by growing good feature sets using 'Cumulative HTRX', and limit the maximum complexity of a feature set. As the computational time scales linearly with the number of SNPs, HTRX has the potential to be applied to large chromosome regions. Availability and implementation: HTRX is implemented in R and is available under GPL-3 licence from CRAN (https://cran.r-project.org/web/packages/HTRX/readme/README.html). The development version is maintained on GitHub (https://github.com/YaolingYang/HTRX). Contact: yaoling.yang@bristol.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Genetic drift from the out-of-Africa bottleneck leads to biased estimation of genetic architecture and selection.

Most complex traits evolved in the ancestors of all modern humans and have been under negative or balancing selection to maintain the distribution of phenotypes observed today. Yet all large studies mapping genomes to complex traits occur in populations that have experienced the Out-of-Africa bottleneck. Does this bottleneck affect the way we characterise complex traits? We demonstrate using the 1000 Genomes dataset and hypothetical complex traits that genetic drift can strongly affect the joint distribution of effect size and SNP frequency, and that the bias can be positive or negative depending on subtle details. Characterisations that rely on this distribution therefore conflate genetic drift and selection. We provide a model to identify the underlying selection parameter in the presence of drift, and demonstrate that a simple sensitivity analysis may be enough to validate existing characterisations. We conclude that biobanks characterising more worldwide diversity would benefit studies of complex traits.

A Chromosome-Painting-Based Pipeline to Infer Local Ancestry under Limited Source Availability.

Contemporary individuals are the combination of genetic fragments inherited from ancestors belonging to multiple populations, as the result of migration and admixture. Isolating and characterizing these layers are crucial to the understanding of the genetic history of a given population. Ancestry deconvolution approaches make use of a large amount of source individuals, therefore constraining the performance of Local Ancestry Inferences when only few genomes are available from a given population. Here we present WINC, a local ancestry framework derived from the combination of ChromoPainter and NNLS approaches, as a method to retrieve local genetic assignments when only a few reference individuals are available. The framework is aided by a score assignment based on source differentiation to maximize the amount of sequences retrieved and is capable of retrieving accurate ancestry assignments when only two individuals for source populations are used.

Differences in local population history at the finest level: the case of the Estonian population.

Several recent studies detected fine-scale genetic structure in human populations. Hence, groups conventionally treated as single populations harbour significant variation in terms of allele frequencies and patterns of haplotype sharing. It has been shown that these findings should be considered when performing studies of genetic associations and natural selection, especially when dealing with polygenic phenotypes. However, there is little understanding of the practical effects of such genetic structure on demography reconstructions and selection scans when focusing on recent population history. Here we tested the impact of population structure on such inferences using high-coverage (~30×) genome sequences of 2305 Estonians. We show that different regions of Estonia differ in both effective population size dynamics and signatures of natural selection. By analyzing identity-by-descent segments we also reveal that some Estonian regions exhibit evidence of a bottleneck 10-15 generations ago reflecting sequential episodes of wars, plague and famine, although this signal is virtually undetected when treating Estonia as a single population. Besides that, we provide a framework for relating effective population size estimated from genetic data to actual census size and validate it on the Estonian population. This approach may be widely used both to cross-check estimates based on historical sources as well as to get insight into times and/or regions with no other information available. Our results suggest that the history of human populations within the last few millennia can be highly region specific and cannot be properly studied without taking local genetic structure into account.

The role of weak selection and high mutation rates in nearly neutral evolution.

Neutral dynamics occur in evolution if all types are 'effectively equal' in their reproductive success, where the definition of 'effectively equal' depends on the population size and the details of mutations. Empirically observed neutral genetic evolution in extremely large clonal populations can only be explained under current models if selection is completely absent. Such models typically consider the case where population dynamics occurs on a different timescale to evolution. However, this assumption is invalid when mutations are not rare in a whole population. We show that this has important consequences for the occurrence of neutral evolution in clonal populations. In highly connected type spaces, neutral dynamics can occur for all population sizes despite significant selective differences, via the forming of effectively neutral networks connecting rare neutral types. Biological implications include an explanation for the high diversity of rare types that survive in large clonal populations, and a theoretical justification for the use of neutral null models.

Tracing Genetic Exchange and Biogeography of Cryptococcus neoformans var. grubii at the Global Population Level.

Cryptococcus neoformans var. grubii is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically human immunodeficiency virus/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterize the major subdivisions, their relative diversity, and the level of genetic exchange between them. While most isolates of C. neoformans var. grubii belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of C. neoformans var. grubii (serotype AA) and of hybrids with C. neoformans var. neoformans (serotype AD) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil reveal that the previously "African" VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions; demonstrating the highly dispersive nature of this pathogen.

Apparent strength conceals instability in a model for the collapse of historical states.

An explanation for the political processes leading to the sudden collapse of empires and states would be useful for understanding both historical and contemporary political events. We examine political disintegration across eras, cultures and geographical scale to form a simple hypothesis that can be expressed verbally yet formulated mathematically. Factions within a state make choices described by game-theory about whether to accept the political status quo, or to attempt to better their circumstances through costly rebellion. In lieu of precise data we verify our model using sensitivity analysis. We find that a small amount of dissatisfaction is typically harmless to the state, but can trigger sudden collapse when there is a sufficient buildup of political inequality. Contrary to intuition, a state is predicted to be least stable when its leadership is at the height of its political power and thus most able to exert its influence through external warfare, lavish expense or autocratic decree.

Understanding clustering in type space using field theoretic techniques.

The birth/death process with mutation describes the evolution of a population, and displays rich dynamics including clustering and fluctuations. We discuss an analytical 'field-theoretical' approach to the birth/death process, using a simple dimensional analysis argument to describe evolution as a 'super-Brownian motion' in the infinite population limit. The field theory technique provides corrections to this for large but finite population, and an exact description at arbitrary population size. This allows a characterisation of the difference between the evolution of a phenotype, for which strong local clustering is observed, and a genotype for which distributions are more dispersed. We describe the approach with sufficient detail for non-specialists.

Neutral evolution in a biological population as diffusion in phenotype space: reproduction with local mutation but without selection.

The process of "evolutionary diffusion," i.e., reproduction with local mutation but without selection in a biological population, resembles standard diffusion in many ways. However, evolutionary diffusion allows the formation of localized peaks that undergo drift, even in the infinite population limit. We relate a microscopic evolution model to a stochastic model which we solve fully. This allows us to understand the large population limit, relates evolution to diffusion, and shows that independent local mutations act as a diffusion of interacting particles taking larger steps.