Population genetic simulation: Benchmarking frameworks for non-standard models of natural selection.

Population genetic simulation has emerged as a common tool for investigating increasingly complex evolutionary and demographic models. Software capable of handling high-level model complexity has recently been developed, and the advancement of tree sequence recording now allows simulations to merge the efficiency and genealogical insight of coalescent simulations with the flexibility of forward simulations. However, frameworks utilizing these features have not yet been compared and benchmarked. Here, we evaluate various simulation workflows using the coalescent simulator msprime and the forward simulator SLiM, to assess resource efficiency and determine an optimal simulation framework. Three aspects were evaluated: (1) the burn-in, to establish an equilibrium level of neutral diversity in the population; (2) the forward simulation, in which temporally fluctuating selection is acting; and (3) the final computation of summary statistics. We provide typical memory and computation time requirements for each step. We find that the fastest framework, a combination of coalescent and forward simulation with tree sequence recording, increases simulation speed by over twenty times compared to classical forward simulations without tree sequence recording, although it does require six times more memory. Overall, using efficient simulation workflows can lead to a substantial improvement when modelling complex evolutionary scenarios-although the optimal framework ultimately depends on the available computational resources.

Allelic bias when performing in-solution enrichment of ancient human DNA.

In-solution hybridisation enrichment of genetic variation is a valuable methodology in human paleogenomics. It allows enrichment of endogenous DNA by targeting genetic markers that are comparable between sequencing libraries. Many studies have used the 1240k reagent-which enriches 1,237,207 genome-wide SNPs-since 2015, though access was restricted. In 2021, Twist Biosciences and Daicel Arbor Biosciences independently released commercial kits that enabled all researchers to perform enrichments for the same 1240 k SNPs. We used the Daicel Arbor Biosciences Prime Plus kit to enrich 132 ancient samples from three continents. We identified a systematic assay bias that increases genetic similarity between enriched samples and that cannot be explained by batch effects. We present the impact of the bias on population genetics inferences (e.g. Principal Components Analysis, ƒ-statistics) and genetic relatedness (READ). We compare the Prime Plus bias to that previously reported of the legacy 1240k enrichment assay. In ƒ-statistics, we find that all Prime-Plus-generated data exhibit artefactual excess shared drift, such that within-continent relationships cannot be correctly determined. The bias is more subtle in READ, though interpretation of the results can still be misleading in specific contexts. We expect the bias may affect analyses we have not yet tested. Our observations support previously reported concerns for the integration of different data types in paleogenomics. We also caution that technological solutions to generate 1240k data necessitate a thorough validation process before their adoption in the paleogenomic community.

The role of genetic selection and climatic factors in the dispersal of anatomically modern humans out of Africa.

The evolutionarily recent dispersal of anatomically modern humans (AMH) out of Africa (OoA) and across Eurasia provides a unique opportunity to examine the impacts of genetic selection as humans adapted to multiple new environments. Analysis of ancient Eurasian genomic datasets (~1,000 to 45,000 y old) reveals signatures of strong selection, including at least 57 hard sweeps after the initial AMH movement OoA, which have been obscured in modern populations by extensive admixture during the Holocene. The spatiotemporal patterns of these hard sweeps provide a means to reconstruct early AMH population dispersals OoA. We identify a previously unsuspected extended period of genetic adaptation lasting ~30,000 y, potentially in the Arabian Peninsula area, prior to a major Neandertal genetic introgression and subsequent rapid dispersal across Eurasia as far as Australia. Consistent functional targets of selection initiated during this period, which we term the Arabian Standstill, include loci involved in the regulation of fat storage, neural development, skin physiology, and cilia function. Similar adaptive signatures are also evident in introgressed archaic hominin loci and modern Arctic human groups, and we suggest that this signal represents selection for cold adaptation. Surprisingly, many of the candidate selected loci across these groups appear to directly interact and coordinately regulate biological processes, with a number associated with major modern diseases including the ciliopathies, metabolic syndrome, and neurodegenerative disorders. This expands the potential for ancestral human adaptation to directly impact modern diseases, providing a platform for evolutionary medicine.

Fluctuating selection and the determinants of genetic variation.

Recent studies of cosmopolitan Drosophila populations have found hundreds to thousands of genetic loci with seasonally fluctuating allele frequencies, bringing temporally fluctuating selection to the forefront of the historical debate surrounding the maintenance of genetic variation in natural populations. Numerous mechanisms have been explored in this longstanding area of research, but these exciting empirical findings have prompted several recent theoretical and experimental studies that seek to better understand the drivers, dynamics, and genome-wide influence of fluctuating selection. In this review, we evaluate the latest evidence for multilocus fluctuating selection in Drosophila and other taxa, highlighting the role of potential genetic and ecological mechanisms in maintaining these loci and their impacts on neutral genetic variation.

Human Genetic Research in Wallacea and Sahul: Recent Findings and Future Prospects.

Genomic sequence data from worldwide human populations have provided a range of novel insights into our shared ancestry and the historical migrations that have shaped our global genetic diversity. However, a comprehensive understanding of these fundamental questions has been impeded by the lack of inclusion of many Indigenous populations in genomic surveys, including those from the Wallacean archipelago (which comprises islands of present-day Indonesia located east and west of Wallace's and Lydekker's Lines, respectively) and the former continent of Sahul (which once combined New Guinea and Australia during lower sea levels in the Pleistocene). Notably, these regions have been important areas of human evolution throughout the Late Pleistocene, as documented by diverse fossil and archaeological records which attest to the regional presence of multiple hominin species prior to the arrival of anatomically modern human (AMH) migrants. In this review, we collate and discuss key findings from the past decade of population genetic and phylogeographic literature focussed on the hominin history in Wallacea and Sahul. Specifically, we examine the evidence for the timing and direction of the ancient AMH migratory movements and subsequent hominin mixing events, emphasising several novel but consistent results that have important implications for addressing these questions. Finally, we suggest potentially lucrative directions for future genetic research in this key region of human evolution.

Admixture has obscured signals of historical hard sweeps in humans.

The role of natural selection in shaping biological diversity is an area of intense interest in modern biology. To date, studies of positive selection have primarily relied on genomic datasets from contemporary populations, which are susceptible to confounding factors associated with complex and often unknown aspects of population history. In particular, admixture between diverged populations can distort or hide prior selection events in modern genomes, though this process is not explicitly accounted for in most selection studies despite its apparent ubiquity in humans and other species. Through analyses of ancient and modern human genomes, we show that previously reported Holocene-era admixture has masked more than 50 historic hard sweeps in modern European genomes. Our results imply that this canonical mode of selection has probably been underappreciated in the evolutionary history of humans and suggest that our current understanding of the tempo and mode of selection in natural populations may be inaccurate.

Response to Comment on "A global environmental crisis 42,000 years ago".

Our study on the exact timing and the potential climatic, environmental, and evolutionary consequences of the Laschamps Geomagnetic Excursion has generated the hypothesis that geomagnetism represents an unrecognized driver in environmental and evolutionary change. It is important for this hypothesis to be tested with new data, and encouragingly, none of the studies presented by Picin et al. undermine our model.

Response to Comment on "A global environmental crisis 42,000 years ago".

Our paper about the impacts of the Laschamps Geomagnetic Excursion 42,000 years ago has provoked considerable scientific and public interest, particularly in the so-called Adams Event associated with the initial transition of the magnetic poles. Although we welcome the opportunity to discuss our new ideas, Hawks' assertions of misrepresentation are especially disappointing given his limited examination of the material.

Mitogenomes Reveal Two Major Influxes of Papuan Ancestry across Wallacea Following the Last Glacial Maximum and Austronesian Contact.

The tropical archipelago of Wallacea contains thousands of individual islands interspersed between mainland Asia and Near Oceania, and marks the location of a series of ancient oceanic voyages leading to the peopling of Sahul-i.e., the former continent that joined Australia and New Guinea at a time of lowered sea level-by 50,000 years ago. Despite the apparent deep antiquity of human presence in Wallacea, prior population history research in this region has been hampered by patchy archaeological and genetic records and is largely concentrated upon more recent history that follows the arrival of Austronesian seafarers ~3000-4000 years ago (3-4 ka). To shed light on the deeper history of Wallacea and its connections with New Guinea and Australia, we performed phylogeographic analyses on 656 whole mitogenomes from these three regions, including 186 new samples from eight Wallacean islands and three West Papuan populations. Our results point to a surprisingly dynamic population history in Wallacea, marked by two periods of extensive demographic change concentrated around the Last Glacial Maximum ~15 ka and post-Austronesian contact ~3 ka. These changes appear to have greatly diminished genetic signals informative about the original peopling of Sahul, and have important implications for our current understanding of the population history of the region.

Systematic benchmark of ancient DNA read mapping.

The current standard practice for assembling individual genomes involves mapping millions of short DNA sequences (also known as DNA 'reads') against a pre-constructed reference genome. Mapping vast amounts of short reads in a timely manner is a computationally challenging task that inevitably produces artefacts, including biases against alleles not found in the reference genome. This reference bias and other mapping artefacts are expected to be exacerbated in ancient DNA (aDNA) studies, which rely on the analysis of low quantities of damaged and very short DNA fragments (~30-80 bp). Nevertheless, the current gold-standard mapping strategies for aDNA studies have effectively remained unchanged for nearly a decade, during which time new software has emerged. In this study, we used simulated aDNA reads from three different human populations to benchmark the performance of 30 distinct mapping strategies implemented across four different read mapping software-BWA-aln, BWA-mem, NovoAlign and Bowtie2-and quantified the impact of reference bias in downstream population genetic analyses. We show that specific NovoAlign, BWA-aln and BWA-mem parameterizations achieve high mapping precision with low levels of reference bias, particularly after filtering out reads with low mapping qualities. However, unbiased NovoAlign results required the use of an IUPAC reference genome. While relevant only to aDNA projects where reference population data are available, the benefit of using an IUPAC reference demonstrates the value of incorporating population genetic information into the aDNA mapping process, echoing recent results based on graph genome representations.

Widespread Denisovan ancestry in Island Southeast Asia but no evidence of substantial super-archaic hominin admixture.

The hominin fossil record of Island Southeast Asia (ISEA) indicates that at least two endemic 'super-archaic' species-Homo luzonensis and H. floresiensis-were present around the time anatomically modern humans arrived in the region >50,000 years ago. Intriguingly, contemporary human populations across ISEA carry distinct genomic traces of ancient interbreeding events with Denisovans-a separate hominin lineage that currently lacks a fossil record in ISEA. To query this apparent disparity between fossil and genetic evidence, we performed a comprehensive search for super-archaic introgression in >400 modern human genomes, including >200 from ISEA. Our results corroborate widespread Denisovan ancestry in ISEA populations, but fail to detect any substantial super-archaic admixture signals compatible with the endemic fossil record of ISEA. We discuss the implications of our findings for the understanding of hominin history in ISEA, including future research directions that might help to unlock more details about the prehistory of the enigmatic Denisovans.

A global environmental crisis 42,000 years ago.

Geological archives record multiple reversals of Earth's magnetic poles, but the global impacts of these events, if any, remain unclear. Uncertain radiocarbon calibration has limited investigation of the potential effects of the last major magnetic inversion, known as the Laschamps Excursion [41 to 42 thousand years ago (ka)]. We use ancient New Zealand kauri trees (Agathis australis) to develop a detailed record of atmospheric radiocarbon levels across the Laschamps Excursion. We precisely characterize the geomagnetic reversal and perform global chemistry-climate modeling and detailed radiocarbon dating of paleoenvironmental records to investigate impacts. We find that geomagnetic field minima ~42 ka, in combination with Grand Solar Minima, caused substantial changes in atmospheric ozone concentration and circulation, driving synchronous global climate shifts that caused major environmental changes, extinction events, and transformations in the archaeological record.

Additional evaluations show that specific BWA-aln settings still outperform BWA-mem for ancient DNA data alignment.

Xu et al. (2021) recently recommended a new parameterization of BWA-mem as a superior alternative to the widely-used BWA-aln algorithm to map ancient DNA sequencing data. Here, we compare the BWA-mem parameterization recommended by Xu et al. with the best-performing alignment methods determined in the recent benchmarks of Oliva and colleagues (2021), demonstrating that BWA-aln is still the gold-standard for ancient DNA read alignment .

genozip: a fast and efficient compression tool for VCF files.

MOTIVATION: genozip is a new lossless compression tool for Variant Call Format (VCF) files. By applying field-specific algorithms and fully utilizing the available computational hardware, genozip achieves the highest compression ratios amongst existing lossless compression tools known to the authors, at speeds comparable with the fastest multi-threaded compressors. AVAILABILITY AND IMPLEMENTATION: genozip is freely available to non-commercial users. It can be installed via conda-forge, Docker Hub, or downloaded from github.com/divonlan/genozip. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Genetic redundancy fuels polygenic adaptation in Drosophila.

The genetic architecture of adaptive traits is of key importance to predict evolutionary responses. Most adaptive traits are polygenic-i.e., result from selection on a large number of genetic loci-but most molecularly characterized traits have a simple genetic basis. This discrepancy is best explained by the difficulty in detecting small allele frequency changes (AFCs) across many contributing loci. To resolve this, we use laboratory natural selection to detect signatures for selective sweeps and polygenic adaptation. We exposed 10 replicates of a Drosophila simulans population to a new temperature regime and uncovered a polygenic architecture of an adaptive trait with high genetic redundancy among beneficial alleles. We observed convergent responses for several phenotypes-e.g., fitness, metabolic rate, and fat content-and a strong polygenic response (99 selected alleles; mean s = 0.059). However, each of these selected alleles increased in frequency only in a subset of the evolving replicates. We discerned different evolutionary paradigms based on the heterogeneous genomic patterns among replicates. Redundancy and quantitative trait (QT) paradigms fitted the experimental data better than simulations assuming independent selective sweeps. Our results show that natural D. simulans populations harbor a vast reservoir of adaptive variation facilitating rapid evolutionary responses using multiple alternative genetic pathways converging at a new phenotypic optimum. This key property of beneficial alleles requires the modification of testing strategies in natural populations beyond the search for convergence on the molecular level.

Drosophila simulans: A Species with Improved Resolution in Evolve and Resequence Studies.

The combination of experimental evolution with high-throughput sequencing of pooled individuals-i.e., evolve and resequence (E&R)-is a powerful approach to study adaptation from standing genetic variation under controlled, replicated conditions. Nevertheless, E&R studies in Drosophila melanogaster have frequently resulted in inordinate numbers of candidate SNPs, particularly for complex traits. Here, we contrast the genomic signature of adaptation following ∼60 generations in a novel hot environment for D. melanogaster and D. simulans For D. simulans, the regions carrying putatively selected loci were far more distinct, and thus harbored fewer false positives, than those in D. melanogaster We propose that species without segregating inversions and higher recombination rates, such as D. simulans, are better suited for E&R studies that aim to characterize the genetic variants underlying the adaptive response.

Sequencing pools of individuals - mining genome-wide polymorphism data without big funding.

The analysis of polymorphism data is becoming increasingly important as a complementary tool to classical genetic analyses. Nevertheless, despite plunging sequencing costs, genomic sequencing of individuals at the population scale is still restricted to a few model species. Whole-genome sequencing of pools of individuals (Pool-seq) provides a cost-effective alternative to sequencing individuals separately. With the availability of custom-tailored software tools, Pool-seq is being increasingly used for population genomic research on both model and non-model organisms. In this Review, we not only demonstrate the breadth of questions that are being addressed by Pool-seq but also discuss its limitations and provide guidelines for users.

A genome-wide, fine-scale map of natural pigmentation variation in Drosophila melanogaster.

Various approaches can be applied to uncover the genetic basis of natural phenotypic variation, each with their specific strengths and limitations. Here, we use a replicated genome-wide association approach (Pool-GWAS) to fine-scale map genomic regions contributing to natural variation in female abdominal pigmentation in Drosophila melanogaster, a trait that is highly variable in natural populations and highly heritable in the laboratory. We examined abdominal pigmentation phenotypes in approximately 8000 female European D. melanogaster, isolating 1000 individuals with extreme phenotypes. We then used whole-genome Illumina sequencing to identify single nucleotide polymorphisms (SNPs) segregating in our sample, and tested these for associations with pigmentation by contrasting allele frequencies between replicate pools of light and dark individuals. We identify two small regions near the pigmentation genes tan and bric-à-brac 1, both corresponding to known cis-regulatory regions, which contain SNPs showing significant associations with pigmentation variation. While the Pool-GWAS approach suffers some limitations, its cost advantage facilitates replication and it can be applied to any non-model system with an available reference genome.