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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.

The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such "hypobaric hypoxia" may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help understanding of hypoxic adaptive processes. Here, we seek evidence of such positive selection using five Ethiopian populations, three of which are from high-altitude areas in Ethiopia. As these populations may have been recipients of Eurasian gene flow, we correct for this admixture. Using single-nucleotide polymorphism genotype data from multiple populations, we find the strongest signal of selection in BHLHE41 (also known as DEC2 or SHARP1). Remarkably, a major role of this gene is regulation of the same hypoxia response pathway on which selection has most strikingly been observed in both Tibetan and Andean populations. Because it is also an important player in the circadian rhythm pathway, BHLHE41 might also provide insights into the mechanisms underlying the recognized impacts of hypoxia on the circadian clock. These results support the view that Ethiopian, Andean, and Tibetan populations living at high altitude have adapted to hypoxia differently, with convergent evolution affecting different genes from the same pathway.

Abstract Background The HapMap project is a publicly available catalogue of common genetic variants that occur in humans, currently including several million SNPs across 1115 individuals spanning 11 different populations. This important database does not provide any programmatic access to the dataset, furthermore no standard relational database interface is provided. Results interPopula is a Python API to access the HapMap dataset. interPopula provides integration facilities with both the Python ecology of software (e.g. Biopython and matplotlib) and other relevant human population datasets (e.g. Ensembl gene annotation and UCSC Known Genes). A set of guidelines and code examples to address possible inconsistencies across heterogeneous data sources is also provided. Conclusions interPopula is a straightforward and flexible Python API that facilitates the construction of scripts and applications that require access to the HapMap dataset.

Abstract Background Anti-malarial drugs are constantly exposed to the threat of evolving drug resistance so good stewardship of existing therapy is an essential component of public health policy. However, the widespread availability of numerous different drugs through informal providers could undermine official drug deployment policies. A policy of multiple first-line therapy (MFT) is compared with the conventional policy of sequential drug deployment, i.e., where one drug is used until resistance evolves and then replaced by the next drug in the sequence. Methods Population genetic models of drug resistance are used to make the comparison; this methodology explicitly tracks the genetics of drug resistance (including, importantly, recombination in the sexual stage, intrahost dynamics, and direction of linkage disequilibrium). Results A policy of MFT outlasts sequential application providing drug usages are low to moderate, and appears not to drive widespread multi-drug resistance. Inadequate dosing is an even more potent driver of drug resistance than the MFT/sequential policy decision. Conclusions The provision of MFT as a deliberate policy can be encouraged provided overall treatment rates are low or moderate (less than around half of malaria infections are treated) and the ad hoc provision of MFT through the private sector may be tolerated. This must be fully supported by education to ensure people take adequate doses of each of the drugs.

Abstract Background Testing for selection is becoming one of the most important steps in the analysis of multilocus population genetics data sets. Existing applications are difficult to use, leaving many non-trivial, error-prone tasks to the user. Results Here we present LOSITAN, a selection detection workbench based on a well evaluated Fst-outlier detection method. LOSITAN greatly facilitates correct approximation of model parameters (e.g., genome-wide average, neutral Fst), provides data import and export functions, iterative contour smoothing and generation of graphics in a easy to use graphical user interface. LOSITAN is able to use modern multi-core processor architectures by locally parallelizing fdist, reducing computation time by half in current dual core machines and with almost linear performance gains in machines with more cores. Conclusion LOSITAN makes selection detection feasible to a much wider range of users, even for large population genomic datasets, by both providing an easy to use interface and essential functionality to complete the whole selection detection process.

Estimating the effective population size and effective number of breeders per year (Nb) can facilitate early detection of population declines. We used computer simulations to quantify bias and precision of the one‐sample LDNe estimator of Nb in age‐structured populations using a range of published species life history types, sample sizes, and DNA markers. Nb estimates were biased by ~5%–10% when using SNPs or microsatellites in species ranging from fishes to mosquitoes, frogs, and seaweed. The bias (high or low) was similar for different life history types within a species suggesting that life history variation in populations will not influence Nb estimation. Precision was higher for 100 SNPs (H ≈ 0.30) than for 15 microsatellites (H ≈ 0.70). Confidence intervals (CIs) were occasionally too narrow, and biased high when Nb was small (Nb < 50); however, the magnitude of bias would unlikely influence management decisions. The CIs (from LDNe) were sufficiently narrow to achieve high statistical power (≥0.80) to reject the null hypothesis that Nb = 50 when the true Nb = 30 and when sampling 50 individuals and 200 SNPs. Similarly, CIs were sufficiently narrow to reject Nb = 500 when the true Nb = 400 and when sampling 200 individuals and 5,000 loci. Finally, we present a linear regression method that provides high power to detect a decline in Nb when sampling at least five consecutive cohorts. This study provides guidelines and tools to simulate and estimate Nb for age structured populations (https://github.com/popgengui/agestrucnb/), which should help biologists develop sensitive monitoring programmes for early detection of changes in Nb and population declines. [ABSTRACT FROM AUTHOR]

Estimating the effective population size and effective number of breeders per year (Nb) can facilitate early detection of population declines. We used computer simulations to quantify bias and precision of the one‐sample LDNe estimator of Nb in age‐structured populations using a range of published species life history types, sample sizes, and DNA markers. Nb estimates were biased by ~5%–10% when using SNPs or microsatellites in species ranging from fishes to mosquitoes, frogs, and seaweed. The bias (high or low) was similar for different life history types within a species suggesting that life history variation in populations will not influence Nb estimation. Precision was higher for 100 SNPs (H ≈ 0.30) than for 15 microsatellites (H ≈ 0.70). Confidence intervals (CIs) were occasionally too narrow, and biased high when Nb was small (Nb < 50); however, the magnitude of bias would unlikely influence management decisions. The CIs (from LDNe) were sufficiently narrow to achieve high statistical power (≥0.80) to reject the null hypothesis that Nb = 50 when the true Nb = 30 and when sampling 50 individuals and 200 SNPs. Similarly, CIs were sufficiently narrow to reject Nb = 500 when the true Nb = 400 and when sampling 200 individuals and 5,000 loci. Finally, we present a linear regression method that provides high power to detect a decline in Nb when sampling at least five consecutive cohorts. This study provides guidelines and tools to simulate and estimate Nb for age structured populations (https://github.com/popgengui/agestrucnb/), which should help biologists develop sensitive monitoring programmes for early detection of changes in Nb and population declines. [ABSTRACT FROM AUTHOR]

Estimation of the effective number of breeders per reproductive event (N b) using single sample DNA-marker-based methods has rapidly grown in recent years. However, estimating N b is difficult in age-structured populations because the performance of estimators is influenced by the N b / N e ratio, which varies among species with different life histories. We provide a computer program, AgeStrucNb , to simulate age-structured populations (including life history) and also estimate N b. The AgeStrucNb program is composed of 4 major components to simulate, subsample, estimate, and then visualize N b time series data. AgeStrucNb allows users to also quantify the precision and accuracy of any set of loci or sample size to estimate N b for many species and populations. AgeStrucNb allows users to conduct power analysis to evaluate sensitivity to detect changes in N b or the power to detect a correlation between trends in N b and environmental variables (e.g. temperature, habitat quality, predator or pathogen abundance) that could be driving changes in N b. The software provides N b estimates for empirical data sets using the LDNe (linkage disequilibrium) method, includes publication-quality output graphs, and outputs genotype files in Genepop format for use in other programs. AgeStrucNb will help advance the application of genetic markers for monitoring N b, which will help biologists to detect population declines and growth, which is crucial for research and conservation of natural and managed populations. [ABSTRACT FROM AUTHOR]

Estimation of the effective number of breeders per reproductive event (N b) using single sample DNA-marker-based methods has rapidly grown in recent years. However, estimating N b is difficult in age-structured populations because the performance of estimators is influenced by the N b / N e ratio, which varies among species with different life histories. We provide a computer program, AgeStrucNb , to simulate age-structured populations (including life history) and also estimate N b. The AgeStrucNb program is composed of 4 major components to simulate, subsample, estimate, and then visualize N b time series data. AgeStrucNb allows users to also quantify the precision and accuracy of any set of loci or sample size to estimate N b for many species and populations. AgeStrucNb allows users to conduct power analysis to evaluate sensitivity to detect changes in N b or the power to detect a correlation between trends in N b and environmental variables (e.g. temperature, habitat quality, predator or pathogen abundance) that could be driving changes in N b. The software provides N b estimates for empirical data sets using the LDNe (linkage disequilibrium) method, includes publication-quality output graphs, and outputs genotype files in Genepop format for use in other programs. AgeStrucNb will help advance the application of genetic markers for monitoring N b, which will help biologists to detect population declines and growth, which is crucial for research and conservation of natural and managed populations. [ABSTRACT FROM AUTHOR]

In iteroparous species, it is easier to estimate Nb (effective number of breeders in one reproductive cycle) than Ne (effective population size per generation). Nb can be used as a proxy for Ne and also can provide crucial insights into eco-evolutionary processes that occur during reproduction. We used analytical and numerical methods to evaluate effects of intermittent breeding and litter/clutch size on inbreeding Nb and Ne. Fixed or random litter sizes ≥ 3 have little effect on either effective-size parameter; however, in species (e.g., many large mammals) in which females can produce only one offspring per cycle, female Nb = ∞ and overall Nb = 4 Nb( male). Intermittent breeding reduces the pool of female breeders, which reduces both female and overall Nb; reductions are larger in high-fecundity species with high juvenile mortality and increase when multiple reproductive cycles are skipped. Simulated data for six model species showed that both intermittent breeding and litter-size constraints increase Ne, but only slightly. We show how to quantitatively account for these effects, which are important to consider when (1) using Nb to estimate Ne, or (2) drawing inferences about male reproductive success based on estimates of female Nb. [ABSTRACT FROM AUTHOR]

In iteroparous species, it is easier to estimate Nb (effective number of breeders in one reproductive cycle) than Ne (effective population size per generation). Nb can be used as a proxy for Ne and also can provide crucial insights into eco-evolutionary processes that occur during reproduction. We used analytical and numerical methods to evaluate effects of intermittent breeding and litter/clutch size on inbreeding Nb and Ne. Fixed or random litter sizes ≥ 3 have little effect on either effective-size parameter; however, in species (e.g., many large mammals) in which females can produce only one offspring per cycle, female Nb = ∞ and overall Nb = 4 Nb( male). Intermittent breeding reduces the pool of female breeders, which reduces both female and overall Nb; reductions are larger in high-fecundity species with high juvenile mortality and increase when multiple reproductive cycles are skipped. Simulated data for six model species showed that both intermittent breeding and litter-size constraints increase Ne, but only slightly. We show how to quantitatively account for these effects, which are important to consider when (1) using Nb to estimate Ne, or (2) drawing inferences about male reproductive success based on estimates of female Nb. [ABSTRACT FROM AUTHOR]