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.

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.

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 XX(X): 000-000, 2023-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.

Limited historical admixture between European wildcats and domestic cats.

Domestic cats were derived from the Near Eastern wildcat (Felis lybica), after which they dispersed with people into Europe. As they did so, it is possible that they interbred with the indigenous population of European wildcats (Felis silvestris). Gene flow between incoming domestic animals and closely related indigenous wild species has been previously demonstrated in other taxa, including pigs, sheep, goats, bees, chickens, and cattle. In the case of cats, a lack of nuclear, genome-wide data, particularly from Near Eastern wildcats, has made it difficult to either detect or quantify this possibility. To address these issues, we generated 75 ancient mitochondrial genomes, 14 ancient nuclear genomes, and 31 modern nuclear genomes from European and Near Eastern wildcats. Our results demonstrate that despite cohabitating for at least 2,000 years on the European mainland and in Britain, most modern domestic cats possessed less than 10% of their ancestry from European wildcats, and ancient European wildcats possessed little to no ancestry from domestic cats. The antiquity and strength of this reproductive isolation between introduced domestic cats and local wildcats was likely the result of behavioral and ecological differences. Intriguingly, this long-lasting reproductive isolation is currently being eroded in parts of the species' distribution as a result of anthropogenic activities.

Genetic swamping of the critically endangered Scottish wildcat was recent and accelerated by disease.

The European wildcat population in Scotland is considered critically endangered as a result of hybridization with introduced domestic cats,1,2 though the time frame over which this gene flow has taken place is unknown. Here, using genome data from modern, museum, and ancient samples, we reconstructed the trajectory and dated the decline of the local wildcat population from viable to severely hybridized. We demonstrate that although domestic cats have been present in Britain for over 2,000 years,3 the onset of hybridization was only within the last 70 years. Our analyses reveal that the domestic ancestry present in modern wildcats is markedly over-represented in many parts of the genome, including the major histocompatibility complex (MHC). We hypothesize that introgression provides wildcats with protection against diseases harbored and introduced by domestic cats, and that this selection contributes to maladaptive genetic swamping through linkage drag. Using the case of the Scottish wildcat, we demonstrate the importance of local ancestry estimates to both understand the impacts of hybridization in wild populations and support conservation efforts to mitigate the consequences of anthropogenic and environmental change.

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.

Deciphering the ground state of a C3-symmetrical Blatter-type triradical by CW and pulse EPR spectroscopy.

3,3',3''-(Benzene-1,3,5-triyl)tris(1-phenyl-1H-benzo[e][1,2,4]triazin-4-yl) (1) is a C3-symmetrical triradical comprised of three Blatter radical units connected at the 1, 3, 5 positions of a central trimethylenebenzene core. This triradical has an excellent air, moisture, and thermal stability. Single-crystal XRD indicates that triradical 1 adopts a propeller-like geometry with the benzotriazinyl moieties twisted by 174.1(2)° and packs in 1D chains along the c axis to form an extensive network of weak intermolecular interactions. Frozen solution continuous wave (CW) EPR spectra and variable-temperature field-sweep echo-detected (FSED) spectra revealed an intramolecular ferromagnetic exchange within the spin system, supporting a quartet S = 3/2 ground state. DFT calculations further supported these experimental findings.

Beyond Mechanical Tension: A Review of Resistance Exercise-Induced Lactate Responses & Muscle Hypertrophy.

The present review aims to explore and discuss recent research relating to the lactate response to resistance training and the potential mechanisms by which lactate may contribute to skeletal muscle hypertrophy or help to prevent muscle atrophy. First, we will discuss foundational information pertaining to lactate including metabolism, measurement, shuttling, and potential (although seemingly elusive) mechanisms for hypertrophy. We will then provide a brief analysis of resistance training protocols and the associated lactate response. Lastly, we will discuss potential shortcomings, resistance training considerations, and future research directions regarding lactate's role as a potential anabolic agent for skeletal muscle hypertrophy.

Relationships between Lower-body Power, Sprint and Change of Direction Speed among Collegiate Basketball Players by Sex.

The purpose of this study was to determine if significant relationships exist between absolute and relative lower-body power and selected measures of speed among male and female collegiate basketball players. Archived performance testing data from 29 (male = 14; female = 15) NCAA division II collegiate basketball players were used for this analysis. These measures included lane agility, 10-yard sprint, and shuttle run time (sec). A Pearson's correlation coefficient was used to determine if significant relationships existed between measures of lower-body power and linear sprint time, change of direction speed (CODS), and shuttle performance. Statistical significance was set a priori at p ≤ 0.05. A significant large correlation was found between absolute power and lane agility (r = 0.54, p = 0.05) among male players. No significant correlations were found between absolute or relative power for 10-yard sprint times, lane agility, or shuttle run performance (p > 0.05). Females showed no significant correlations between relative power and lane agility (r = -0.25, p = 0.37) or 10-yard sprint (r = -0.47, p = 0.08), but did show a significant large correlation (r = -0.64, p = 0.01) between relative power and shuttle run performance. Generating high amounts of relative power is vital in intermittent team sports such as basketball. In particular, this study provided evidence that relative power in female collegiate basketball players is significantly related to shuttle run ability.

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.

CLARITY: comparing heterogeneous data using dissimilarity.

Integrating datasets from different disciplines is hard because the data are often qualitatively different in meaning, scale and reliability. When two datasets describe the same entities, many scientific questions can be phrased around whether the (dis)similarities between entities are conserved across such different data. Our method, CLARITY, quantifies consistency across datasets, identifies where inconsistencies arise and aids in their interpretation. We illustrate this using three diverse comparisons: gene methylation versus expression, evolution of language sounds versus word use, and country-level economic metrics versus cultural beliefs. The non-parametric approach is robust to noise and differences in scaling, and makes only weak assumptions about how the data were generated. It operates by decomposing similarities into two components: a 'structural' component analogous to a clustering, and an underlying 'relationship' between those structures. This allows a 'structural comparison' between two similarity matrices using their predictability from 'structure'. Significance is assessed with the help of re-sampling appropriate for each dataset. The software, CLARITY, is available as an R package from github.com/danjlawson/CLARITY.

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.

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.

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.

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.

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.