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.

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.

100 ancient genomes show repeated population turnovers in Neolithic Denmark.

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Meeting the global protein supply requirements of a growing and ageing population.

Human dietary patterns are a major cause of environmental transformation, with agriculture occupying ~ 50% of global land space, while food production itself is responsible for ~ 30% of all greenhouse gas emissions and 70% of freshwater use. Furthermore, the global population is also growing, such that by 2050, it is estimated to exceed ~ 9 billion. While most of this expansion in population is expected to occur in developing countries, in high-income countries there are also predicted changes in demographics, with major increases in the number of older people. There is a growing consensus that older people have a greater requirement for protein. With a larger and older population, global needs for protein are set to increase. This paper summarises the conclusions from a Rank Prize funded colloquium evaluating novel strategies to meet this increasing global protein need.

A hypoenergetic diet with decreased protein intake does not reduce lean body mass in trained females.

PURPOSE: Increasing protein intake during energy restriction (ER) attenuates lean body mass (LBM) loss in trained males. However, whether this relationship exists in trained females is unknown. This study examined the impact of higher compared to lower protein intakes (35% versus 15% of energy intake) on body composition in trained females during 2 weeks of severe ER. METHODS: Eighteen well-trained females completed a 1-week energy balanced diet (HD100), followed by a 2-week hypoenergetic (40% ER) diet (HD60). During HD60, participants consumed either a high protein (HP; 35% protein, 15% fat) or lower protein (CON; 15% protein, 35% fat) diet. Body composition, peak power, leg strength, sprint time, and anaerobic endurance were assessed at baseline, pre-HD60, and post-HD60. RESULTS: Absolute protein intake was reduced during HD60 in the CON group (from 1.6 to 0.9 g·d·kgBM-1) and maintained in the HP group (~ 1.7 g·d·kgBM-1). CON and HP groups decreased body mass equally during HD60 (- 1.0 ± 1.1 kg; p = 0.026 and - 1.1 ± 0.7 kg; p = 0.002, respectively) and maintained LBM. There were no interactions between time point and dietary condition on exercise performance. CONCLUSION: The preservation of LBM during HD60, irrespective of whether absolute protein intake is maintained or reduced, contrasts with findings in trained males. In trained females, the relationship between absolute protein intake and LBM change during ER warrants further investigation. Future recommendations for protein intake during ER should be expressed relative to body mass, not total energy intake, in trained females.

The impact of dietary protein supplementation on recovery from resistance exercise-induced muscle damage: A systematic review with meta-analysis.

BACKGROUND: It is unknown whether dietary protein consumption can attenuate resistance exercise-induced muscle damage (EIMD). Managing EIMD may accelerate muscle recovery and allow frequent, high-quality exercise to promote muscle adaptations. This systematic review and meta-analysis examined the impact of peri-exercise protein supplementation on resistance EIMD. METHODS: A literature search was conducted on PubMed, SPORTDiscus, and Web of Science up to March 2021 for relevant articles. PEDro criteria were used to assess bias within included studies. A Hedges' g effect size (ES) was calculated for indirect markers of EIMD at h post-exercise. Weighted ESs were included in a random effects model to determine overall ESs over time. RESULTS: Twenty-nine studies were included in the systematic review and 40 trials were included in ≥1 meta-analyses (16 total). There were significant overall effects of protein for preserving isometric maximal voluntary contraction (MVC) at 96 h (0.563 [0.232, 0.894]) and isokinetic MVC at 24 h (0.639 [0.116, 1.162]), 48 h (0.447 [0.104, 0.790]), and 72 h (0.569 [0.136, 1.002]). Overall ESs were large in favour of protein for attenuating creatine kinase concentration at 48 h (0.836 [-0.001, 1.673]) and 72 h (1.335 [0.294, 2.376]). Protein supplementation had no effect on muscle soreness compared with the control. CONCLUSION: Peri-exercise protein consumption could help maintain maximal strength and lower creatine kinase concentration following resistance exercise but not reduce muscle soreness. Conflicting data may be due to methodological divergencies between studies. Standardised methods and data reporting for EIMD research are needed.

Milk protein ingestion does not enhance recovery from muscle-damaging resistance exercise in untrained males and females: a randomized controlled trial.

Milk-based proteins are a common choice of post-exercise nutrition to enhance exercise recovery and adaptation. Peri-exercise milk protein ingestion may attenuate exercise-induced muscle damage (EIMD), which is a particular risk to untrained individuals. However, most research has been conducted with males, and due to potential sex differences in EIMD, research with both sexes is required. This parallel-group randomized controlled trial examined the impact of milk protein ingestion on recovery from EIMD. Untrained males and females performed a single bout of leg-based resistance exercise and consumed a milk protein (MILK-PRO: n = 4 males, n = 8 females) or isoenergetic control (CON: n = 4 males, n = 8 females) supplement over 4 days post-exercise (17 doses total). Maximum strength was assessed ≥3 wk pre- and 72 and 168 h post-exercise, and measures of leg circumference, range of motion, muscle soreness, pressure-pain threshold (PPT), and serum creatine kinase concentration ([CK]) were conducted pre-, immediately post-, and 24, 48, 72, and 168 h post-exercise. Resistance exercise induced mild muscle damage that was not attenuated with MILK-PRO relative to CON. Peak increases in [CK] and reductions in PPT were greater in males compared with females. Changes in other markers were comparable between sexes. We conclude that moderate resistance exercise in naïve individuals induces muscle damage without compromising muscle strength. We support sex differences in EIMD and emphasize the need for further research with both sexes. Milk protein ingestion was not beneficial for recovery from EIMD, thus alternative management strategies should be investigated. This trial was prospectively registered at ClinicalTrials.gov PRS (protocol ID: 290580A).

The impact of COVID-19 on the assessment and management of ectopic pregnancies.

Lay Summary: During the COVID-19 pandemic, the public delayed seeking medical help, which may have affected the impact of having an ectopic pregnancy. An ectopic pregnancy is when pregnancy tissue grows outside its normal position in the womb, and it can be life-threatening. It can be treated by non-surgical or surgical options, and any delay in seeking help can reduce the options for treatment and increase the need for more urgent management. We wanted to assess whether there were differences in the presentation and management of ectopic pregnancies in a major teaching hospital between 2019 (pre-COVID-19) and 2021 (COVID-19 period). We found that the pandemic did not cause a delay in seeking medical help or cause worse outcomes. In fact, immediate surgical treatment and time in the hospital were less during COVID-19, perhaps because of a desire to avoid admission to hospital. One outcome of COVID-19 is reassurance that we can safely use more non-surgical treatments for ectopic pregnancies.

Expanding the stdpopsim species catalog, and lessons learned for realistic genome simulations.

Simulation is a key tool in population genetics for both methods development and empirical research, but producing simulations that recapitulate the main features of genomic datasets remains a major obstacle. Today, more realistic simulations are possible thanks to large increases in the quantity and quality of available genetic data, and the sophistication of inference and simulation software. However, implementing these simulations still requires substantial time and specialized knowledge. These challenges are especially pronounced for simulating genomes for species that are not well-studied, since it is not always clear what information is required to produce simulations with a level of realism sufficient to confidently answer a given question. The community-developed framework stdpopsim seeks to lower this barrier by facilitating the simulation of complex population genetic models using up-to-date information. The initial version of stdpopsim focused on establishing this framework using six well-characterized model species (Adrion et al., 2020). Here, we report on major improvements made in the new release of stdpopsim (version 0.2), which includes a significant expansion of the species catalog and substantial additions to simulation capabilities. Features added to improve the realism of the simulated genomes include non-crossover recombination and provision of species-specific genomic annotations. Through community-driven efforts, we expanded the number of species in the catalog more than threefold and broadened coverage across the tree of life. During the process of expanding the catalog, we have identified common sticking points and developed the best practices for setting up genome-scale simulations. We describe the input data required for generating a realistic simulation, suggest good practices for obtaining the relevant information from the literature, and discuss common pitfalls and major considerations. These improvements to stdpopsim aim to further promote the use of realistic whole-genome population genetic simulations, especially in non-model organisms, making them available, transparent, and accessible to everyone.

Sex differences in the impact of resistance exercise load on muscle damage: A protocol for a randomised parallel group trial.

INTRODUCTION: Resistance training can induce skeletal muscle hypertrophy and strength gains, but is also associated with acute muscle damage, characterised by muscle soreness, impaired muscle function, and structural damage to muscle cell membranes and its components. These consequences can be detrimental to future exercise performance and dampen long-term training adaptations. Previous research has considered resistance exercise intensity as a factor in exercise-induced muscle damage (EIMD), though a clear direction of the findings has not yet been established. Further, female populations are heavily underrepresented in this field of study. Therefore, we here propose a study protocol designed to examine sex differences in the muscle damage response to resistance exercise performed with low or high loads in a population of untrained, young adults. METHODS: This study will employ a randomised parallel group design. Twenty-four males and 24 females will perform an acute leg-based resistance exercise session at either 30% (low-load) or 80% (high-load) of their pre-determined one-repetition maximum (1RM). Maximal leg strength will be determined by a 1RM test 3 wk before and 72 and 168 h after the exercise bout. Additionally, muscle damage will be assessed immediately before the exercise bout and immediately, 24, 48, 72, and 168 h after the exercise bout through measures of muscle soreness, limb circumference, range of motion, and serum concentrations of creatine kinase and interleukin-6. The outcomes of this trial could inform sex-specific resistance training recommendations and help bridge the sex data gap in sport and exercise science research.

Unearthing Neanderthal population history using nuclear and mitochondrial DNA from cave sediments.

Bones and teeth are important sources of Pleistocene hominin DNA, but are rarely recovered at archaeological sites. Mitochondrial DNA (mtDNA) has been retrieved from cave sediments but provides limited value for studying population relationships. We therefore developed methods for the enrichment and analysis of nuclear DNA from sediments and applied them to cave deposits in western Europe and southern Siberia dated to between 200,000 and 50,000 years ago. We detected a population replacement in northern Spain about 100,000 years ago, which was accompanied by a turnover of mtDNA. We also identified two radiation events in Neanderthal history during the early part of the Late Pleistocene. Our work lays the ground for studying the population history of ancient hominins from trace amounts of nuclear DNA in sediments.

Opioid crisis in primary care? An audit of high-dose opioid prescribing at Bangholm GP Practice.

BACKGROUND: Opioids are effective analgesics for acute and palliative pain, but there is no evidence base for long-term pain relief. They also carry considerable risks such as overdose and dependence. Despite this, they are increasingly prescribed for chronic pain. In the UK, opioid prescribing more than doubled between 1998 and 2018. AIM: An audit at Bangholm GP Practice to understand the scale of high-strength opioid prescribing. The aim of the audit was to find out if indications, length of prescription, discussion, and documentation at initial consultation and review process were consistent with best-practice guidelines. METHOD: A search on Scottish Therapeutics Utility for patients prescribed an average daily dose of opioid equivalent ≥50 mg morphine between 1 July 2019 and 1 October 2019, excluding methadone, cancer pain, or palliative prescriptions. The Faculty of Pain Medicine's best-practice guidelines were used. RESULTS: Demographics: 60 patients (37 females), average age 62, 28% registered with repeat opioid prescription, 38% comorbid depression. Length of prescription: average 6 years, 57% >5 years, 22% >10 years. Opioid: 52% tramadol, 23% on two opioids. INDICATIONS: back pain (42%), osteoarthritis (12%), fibromyalgia (10%). Initial consultation: 7% agreed outcomes, 35% follow-up documented. REVIEW: 56% 4-week, 70% past year. CONCLUSION: Opioid prescribing guidelines are not followed. The significant issues are: long-term prescriptions for chronic pain, especially back pain; new patients registering with repeat prescriptions; and no outcomes of treatment agreed, a crucial message is the goal is pain management rather than relief. Changes have been introduced at the practice: a patient information sheet, compulsory 1-month review for new patients on opioids, and in-surgery pain referrals.