Multiple Deeply Divergent Denisovan Ancestries in Papuans.

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.

Elevated genetic risk for multiple sclerosis emerged in steppe pastoralist populations.

Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that is most prevalent in Northern Europe. Although it is known that inherited risk for MS is located within or in close proximity to immune-related genes, it is unknown when, where and how this genetic risk originated1. Here, by using a large ancient genome dataset from the Mesolithic period to the Bronze Age2, along with new Medieval and post-Medieval genomes, we show that the genetic risk for MS rose among pastoralists from the Pontic steppe and was brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the steppe population and later in Europe, probably driven by pathogenic challenges coinciding with changes in diet, lifestyle and population density. This study highlights the critical importance of the Neolithic period and Bronze Age as determinants of modern immune responses and their subsequent effect on the risk of developing MS in a changing environment.

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.

Population genomics of the Viking world.

The maritime expansion of Scandinavian populations during the Viking Age (about AD 750-1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442 humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci-including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response-in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.

Heritability of complex traits in sub-populations experiencing bottlenecks and growth.

Populations that have experienced a bottleneck are regularly used in Genome Wide Association Studies (GWAS) to investigate variants associated with complex traits. It is generally understood that these isolated sub-populations may experience high frequency of otherwise rare variants with large effect size, and therefore provide a unique opportunity to study said trait. However, the demographic history of the population under investigation affects all SNPs that determine the complex trait genome-wide, changing its heritability and genetic architecture. We use a simulation based approach to identify the impact of the demographic processes of drift, expansion, and migration on the heritability of complex trait. We show that demography has considerable impact on complex traits. We then investigate the power to resolve heritability of complex traits in GWAS studies subjected to demographic effects. We find that demography is an important component for interpreting inference of complex traits and has a nuanced impact on the power of GWAS. We conclude that demographic histories need to be explicitly modelled to properly quantify the history of selection on a complex trait.

How admixed captive breeding populations could be rescued using local ancestry information.

This paper asks the question: can genomic information be used to recover a species that is already on the pathway to extinction due to genetic swamping from a related and more numerous population? We show that a breeding strategy in a captive breeding program can use whole genome sequencing to identify and remove segments of DNA introgressed through hybridisation. The proposed policy uses a generalized measure of kinship or heterozygosity accounting for local ancestry, that is, whether a specific genetic location was inherited from the target of conservation. We then show that optimizing these measures would minimize undesired ancestry while also controlling kinship and/or heterozygosity, in a simulated breeding population. The process is applied to real data representing the hybridized Scottish wildcat breeding population, with the result that it should be possible to breed out domestic cat ancestry. The ability to reverse introgression is a powerful tool brought about through the combination of sequencing with computational advances in ancestry estimation. Since it works best when applied early in the process, important decisions need to be made about which genetically distinct populations should benefit from it and which should be left to reform into a single population.

Genetic architecture: the shape of the genetic contribution to human traits and disease.

Genetic architecture describes the characteristics of genetic variation that are responsible for heritable phenotypic variability. It depends on the number of genetic variants affecting a trait, their frequencies in the population, the magnitude of their effects and their interactions with each other and the environment. Defining the genetic architecture of a complex trait or disease is central to the scientific and clinical goals of human genetics, which are to understand disease aetiology and aid in disease screening, diagnosis, prognosis and therapy. Recent technological advances have enabled genome-wide association studies and emerging next-generation sequencing studies to begin to decipher the nature of the heritable contribution to traits and disease. Here, we describe the types of genetic architecture that have been observed, how architecture can be measured and why an improved understanding of genetic architecture is central to future advances in the field.

VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) represents the 2019 merger of VectorBase with the EuPathDB projects. As a Bioinformatics Resource Center funded by the National Institutes of Health, with additional support from the Welllcome Trust, VEuPathDB supports >500 organisms comprising invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Designed to empower researchers with access to Omics data and bioinformatic analyses, VEuPathDB projects integrate >1700 pre-analysed datasets (and associated metadata) with advanced search capabilities, visualizations, and analysis tools in a graphic interface. Diverse data types are analysed with standardized workflows including an in-house OrthoMCL algorithm for predicting orthology. Comparisons are easily made across datasets, data types and organisms in this unique data mining platform. A new site-wide search facilitates access for both experienced and novice users. Upgraded infrastructure and workflows support numerous updates to the web interface, tools, searches and strategies, and Galaxy workspace where users can privately analyse their own data. Forthcoming upgrades include cloud-ready application architecture, expanded support for the Galaxy workspace, tools for interrogating host-pathogen interactions, and improved interactions with affiliated databases (ClinEpiDB, MicrobiomeDB) and other scientific resources, and increased interoperability with the Bacterial & Viral BRC.

Relationships Between Anthropometric Measures and Body Composition With Individual ACFT Event Performance Among Army Reserve Officers' Training Corps Cadets.

ABSTRACT: Thompson, MB, Lawson, DJ, Orr, RM, Lockie, RG, and Dawes, JJ. Relationships between anthropometric measures and body composition with individual ACFT event performance among army reserve officers' training corps cadets. J Strength Cond Res 38(4): 749-754, 2024-The U.S. military commonly uses body composition as an indicator of a soldier's potential to meet the physical demands required of their occupation. The purpose of this study was to determine whether significant relationships existed between select body composition variables and Army Combat Fitness Test (ACFT) performance among a cohort of university Army Reserve Officers' Training Corps (ROTC) cadets. Twenty-six male (20.4 ± 1.6 years, 81.8 ± 8.5 kg, 178.3 ± 7.8 cm) and 12 female (19.9 ± 1.4 years, 64.2 ± 6.7 kg, 161.9 ± 4.9 cm) cadets voluntarily participated in this study. Body composition was measured using bioelectrical impedance analysis, and ACFT event scores were recorded by the cadre using the U.S. Army standard protocol and provided to the investigators. Pearson's correlations were used to identify relationships between body composition variables and ACFT event performance with an alpha level of p ≤ 0.05. Moderate to strong relationships were observed between total body water, dry lean mass, lean body mass, skeletal muscle mass, body fat mass (FM), and body fat percentage and all event scores for the sample as a whole. Body mass index showed weak to moderate significant positive relationships with hand-release push-up and maximum hexagonal bar deadlift in the sample as a whole. No relationships were observed in the men of this sample. All body composition variables showed moderate, nonsignificant relationships with at least 1 ACFT event within the women of this sample. Considering the findings of this study, a multitude of variables could be useful to assess ROTC cadets as predictors for ACFT performance. Reserve Officers' Training Corps programs should emphasize attaining and maintaining functional lean mass, whereas reducing nonfunctional body mass (i.e., excess FM) among cadets to enhance health and performance across the occupational life span.

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.

The genome of the stable fly, Stomoxys calcitrans, reveals potential mechanisms underlying reproduction, host interactions, and novel targets for pest control.

BACKGROUND: The stable fly, Stomoxys calcitrans, is a major blood-feeding pest of livestock that has near worldwide distribution, causing an annual cost of over $2 billion for control and product loss in the USA alone. Control of these flies has been limited to increased sanitary management practices and insecticide application for suppressing larval stages. Few genetic and molecular resources are available to help in developing novel methods for controlling stable flies. RESULTS: This study examines stable fly biology by utilizing a combination of high-quality genome sequencing and RNA-Seq analyses targeting multiple developmental stages and tissues. In conjunction, 1600 genes were manually curated to characterize genetic features related to stable fly reproduction, vector host interactions, host-microbe dynamics, and putative targets for control. Most notable was characterization of genes associated with reproduction and identification of expanded gene families with functional associations to vision, chemosensation, immunity, and metabolic detoxification pathways. CONCLUSIONS: The combined sequencing, assembly, and curation of the male stable fly genome followed by RNA-Seq and downstream analyses provide insights necessary to understand the biology of this important pest. These resources and new data will provide the groundwork for expanding the tools available to control stable fly infestations. The close relationship of Stomoxys to other blood-feeding (horn flies and Glossina) and non-blood-feeding flies (house flies, medflies, Drosophila) will facilitate understanding of the evolutionary processes associated with development of blood feeding among the Cyclorrhapha.

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.

On the use of genome-wide data to model and date the time of anthropogenic hybridisation: An example from the Scottish wildcat.

While hybridisation has long been recognised as an important natural phenomenon in evolution, the conservation of taxa subject to introgressive hybridisation from domesticated forms is a subject of intense debate. Hybridisation of Scottish wildcats and domestic cats is a good example in this regard. Here, we developed a modelling framework to determine the timescale of introgression using approximate Bayesian computation (ABC). Applying the model to ddRAD-seq data from 129 individuals, genotyped at 6546 loci, we show that a population of wildcats genetically distant from domestic cats is still present in Scotland. These individuals were found almost exclusively within the captive breeding programme. Most wild-living cats sampled were introgressed to some extent. The demographic model predicts high levels of gene-flow between domestic cats and Scottish wildcats (13% migrants per generation) over a short timeframe, the posterior mean for the onset of hybridisation (T1 ) was 3.3 generations (~10 years) before present. Although the model had limited power to detect signals of ancient admixture, we found evidence that significant recent hybridisation may have occurred subsequent to the founding of the captive breeding population (T2 ). The model consistently predicts T1 after T2 , estimated here to be 19.3 generations (~60 years) ago, highlighting the importance of this population as a resource for conservation management. Additionally, we evaluate the effectiveness of current methods to classify hybrids. We show that an optimised 35 SNP panel is a better predictor of the ddRAD-based hybrid score in comparison with a morphological method.

The fine-scale genetic structure of the British population.

Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.

The UK10K project identifies rare variants in health and disease.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

Evolutionary superscaffolding and chromosome anchoring to improve Anopheles genome assemblies.

BACKGROUND: New sequencing technologies have lowered financial barriers to whole genome sequencing, but resulting assemblies are often fragmented and far from 'finished'. Updating multi-scaffold drafts to chromosome-level status can be achieved through experimental mapping or re-sequencing efforts. Avoiding the costs associated with such approaches, comparative genomic analysis of gene order conservation (synteny) to predict scaffold neighbours (adjacencies) offers a potentially useful complementary method for improving draft assemblies. RESULTS: We evaluated and employed 3 gene synteny-based methods applied to 21 Anopheles mosquito assemblies to produce consensus sets of scaffold adjacencies. For subsets of the assemblies, we integrated these with additional supporting data to confirm and complement the synteny-based adjacencies: 6 with physical mapping data that anchor scaffolds to chromosome locations, 13 with paired-end RNA sequencing (RNAseq) data, and 3 with new assemblies based on re-scaffolding or long-read data. Our combined analyses produced 20 new superscaffolded assemblies with improved contiguities: 7 for which assignments of non-anchored scaffolds to chromosome arms span more than 75% of the assemblies, and a further 7 with chromosome anchoring including an 88% anchored Anopheles arabiensis assembly and, respectively, 73% and 84% anchored assemblies with comprehensively updated cytogenetic photomaps for Anopheles funestus and Anopheles stephensi. CONCLUSIONS: Experimental data from probe mapping, RNAseq, or long-read technologies, where available, all contribute to successful upgrading of draft assemblies. Our evaluations show that gene synteny-based computational methods represent a valuable alternative or complementary approach. Our improved Anopheles reference assemblies highlight the utility of applying comparative genomics approaches to improve community genomic resources.

Crystal Structure and Solid-State Packing of 4-Chloro-5H-1,2,3-dithiazol-5-one and 4-Chloro-5H-1,2,3-dithiazole-5-thione.

The crystal structure and solid-state packing of 4-chloro-5H-1,2,3-dithiazol-5-one and two polymorphs of 4-chloro-5H-1,2,3-dithiazole-5-thione were analyzed and compared to structural data of similar systems. These five-membered S,N-rich heterocycles are planar with considerable bond localization. All three structures demonstrate tight solid-state packing without voids which is attributed to a rich network of short intermolecular electrostatic contacts. These include Sδ+…Nδ-, Sδ+…Oδ-, Sδ+…Clδ- and Sδ+…Sδ- interactions that are well within the sum of their van der Waals radii (∑VDW). B3LYP, BLYP, M06, mPW1PW, PBE and MP2 were employed to calculate their intramolecular geometrical parameters, the Fukui condensed functions to probe their reactivity, the bond order, Bird Index and NICS(1) to establish their aromaticity.

Transcriptional variation of sensory-related genes in natural populations of Aedes albopictus.

BACKGROUND: The Asian tiger mosquito, Aedes albopictus, is a highly dangerous invasive vector of numerous medically important arboviruses including dengue, chikungunya and Zika. In four decades it has spread from tropical Southeast Asia to many parts of the world in both tropical and temperate climes. The rapid invasion process of this mosquito is supported by its high ecological and genetic plasticity across different life history traits. Our aim was to investigate whether wild populations, both native and adventive, also display transcriptional genetic variability for functions that may impact their biology, behaviour and ability to transmit arboviruses, such as sensory perception. RESULTS: Antennal transcriptome data were derived from mosquitoes from a native population from Ban Rai, Thailand and from three adventive Mediterranean populations: Athens, Greece and Arco and Trento from Italy. Clear inter-population differential transcriptional activity was observed in different gene categories related to sound perception, olfaction and viral infection. The greatest differences were detected between the native Thai and the Mediterranean populations. The two Italian populations were the most similar. Nearly one million quality filtered SNP loci were identified. CONCLUSION: The ability to express this great inter-population transcriptional variability highlights, at the functional level, the remarkable genetic flexibility of this mosquito species. We can hypothesize that the differential expression of genes, including those involved in sensory perception, in different populations may enable Ae. albopictus to exploit different environments and hosts, thus contributing to its status as a global vector of arboviruses of public health importance. The large number of SNP loci present in these transcripts represents a useful addition to the arsenal of high-resolution molecular markers and a resource that can be used to detect selective pressure and adaptive changes that may have occurred during the colonization process.

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.