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Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.

This study aimed to evaluate systematic reviews and meta-analyses that have examined the effect of exercise training on VO2max in healthy individuals at different intensities. Five databases were searched: EBSCOhost, MEDLINE/PubMed, SPORTDiscus, Web of Science, and Google Scholar. Eligibility criteria for selecting reviews included systematic reviews and meta-analyses of healthy adults that examined the effect of lower intensity training (LIT) and/or high intensity training (HIT) on VO2max. Eleven reviews met the eligibility criteria. All reviews were of moderate-to-very strong methodological quality. The included reviews reported data from 179 primary studies with an average of 23 ± 10 studies per review. All reviews included in this overview showed that exercise training robustly increased VO2max at all intensities. Three meta-analyses that compared LIT versus HIT protocols on VO2max reported small/moderate beneficial effects for HIT over LIT; however, the beneficial effects of HIT on VO2max appear to be moderated by training variables other than intensity (e.g., training impulse, interval length, training volume, and duration) and participants’ baseline characteristics (e.g., age and fitness levels). Overall, evidence from this overview suggests that the apparent differences between LIT and HIT protocols on VO2max were either small, trivial, or inconclusive, with several methodological considerations required to standardise research designs and draw definitive conclusions.

The aim of the present study was to evaluate the effect of feeding fava bean (

Quantifying and comparing the amount of adaptive evolution among different species is key to understanding how evolution works. Previous studies have shown differences in adaptive evolution across species; however, their specific causes remain elusive. Here, we use improved modeling of weakly deleterious mutations and the demographic history of the outgroup species and ancestral population and estimate that at least 20% of nonsynonymous substitutions between humans and an outgroup species were fixed by positive selection. This estimate is much higher than previous estimates, which did not correct for the sizes of the outgroup species and ancestral population. Next, we jointly estimate the proportion and selection coefficient (p+ and s+, respectively) of newly arising beneficial nonsynonymous mutations in humans, mice, and Drosophila melanogaster by examining patterns of polymorphism and divergence. We develop a novel composite likelihood framework to test whether these parameters differ across species. Overall, we reject a model with the same p+ and s+ of beneficial mutations across species and estimate that humans have a higher p+s+ compared with that of D. melanogaster and mice. We show that this result cannot be caused by biased gene conversion or hypermutable CpG sites. We discuss possible biological explanations that could generate the observed differences in the amount of adaptive evolution across species.

Secondary forests dominate some human‐modified tropical biomes, and this is expected to increase via both abandonment of marginal agricultural land as well as forest and landscape restoration programmes. A key question is whether promoting the recovery and protection of secondary tropical forests will return invertebrate functional diversity and associated functional traits. Dung beetles are ideal for assessing functional diversity as they play vital roles in several ecosystem functions, including seed dispersal, nutrient cycling and bioturbation. We examined how taxonomic and functional diversity, and the functional trait composition of native dung beetle species recovers in naturally regenerating secondary forests in comparison to both cattle pastures and primary forest in the Colombian Choco‐Andes, a global hotspot of threatened biodiversity. Using a space‐for‐time approach, we found that taxonomic and functional diversity recovered to levels comparable to primary forest within approximately 30 years of secondary forest regrowth. Functional richness and FD, measures of the diversity of traits present in a community, were similar in secondary and primary forest, but significantly lower in pasture. Rolling dung beetle species were positively associated with forest habitats, particularly primary, while dwelling species were more common in pasture. Thus, the functional trait composition of secondary forests was more similar to primary forest than to pasture. The ability of secondary forests to rapidly accumulate primary‐forest dung beetle functional diversity, and a representative suite of functional traits, provides an opportunity to protect biodiversity and ecosystem functioning, especially in regions where marginal agricultural land allows cost‐effective conservation actions.

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was surprisingly low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Available methods to control Winner’s Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.

Tropical land-use change for agricultural expansion is the primary driver of global biodiversity decline. Efforts to stem this decline often focus on protecting pristine habitats or returning farmland to forest, yet such approaches fail to protect vulnerable taxa reliant on habitats within low-intensity farmland. We assess the economic viability of carbon-based payments for ecosystem services (PES) to protect farmland trees and fallowing in Ghana, which provide vital wintering sites for imperiled Afro-palearctic migrant birds and enhance landscape-level carbon storage. We estimate the carbon breakeven prices associated with alternative agricultural management scenarios that protect existing farmland trees. Breakeven prices associated with tree protection on existing farmland were very low, ranging from US$2.49 – US$6.45 t-1 CO2. Extending and reintroducing fallow periods also carried competitive breakeven prices, US$4.67 – US$15.45 t-1 CO2, when combined with the protection of 50 trees per hectare. Accounting for leakage and economic uncertainty increased breakeven prices considerably, but scenarios protecting farmland trees and extending fallow periods remained below EU Emissions Trading Scheme (ETS) prices. Protecting low-intensity farmland habitats and associated biodiversity is cost-effective under carbon-based PES. Implementation should be combined with efforts to close yield gaps, providing greater local food security and resilience.

Significance A defining goal in genetics is linking variation in DNA sequence to trait evolution between populations and, ultimately, species. Genome sequencing efficiently captures such variation but typically in millions of tiny fragments that omit haplotype or linkage information. We present “haplotagging,” a simple, rapid linked-read sequencing technique that allows high-throughput sequencing without sacrificing haplotype information. We validated this affordable approach for whole-genome haplotyping in large populations. We used haplotagging to investigate the rise of a novel hybrid morph in parallel hybrid zones of two comimetic Heliconius butterfly species in Ecuador. Our results reveal that strikingly parallel divergences in their genomes produced coordinated shifts in haplotype frequencies across the hybrid zone, giving rise to comimetic hybrid morphs in each species., Genetic variation segregates as linked sets of variants or haplotypes. Haplotypes and linkage are central to genetics and underpin virtually all genetic and selection analysis. Yet, genomic data often omit haplotype information due to constraints in sequencing technologies. Here, we present “haplotagging,” a simple, low-cost linked-read sequencing technique that allows sequencing of hundreds of individuals while retaining linkage information. We apply haplotagging to construct megabase-size haplotypes for over 600 individual butterflies (Heliconius erato and H. melpomene), which form overlapping hybrid zones across an elevational gradient in Ecuador. Haplotagging identifies loci controlling distinctive high- and lowland wing color patterns. Divergent haplotypes are found at the same major loci in both species, while chromosome rearrangements show no parallelism. Remarkably, in both species, the geographic clines for the major wing-pattern loci are displaced by 18 km, leading to the rise of a novel hybrid morph in the center of the hybrid zone. We propose that shared warning signaling (Müllerian mimicry) may couple the cline shifts seen in both species and facilitate the parallel coemergence of a novel hybrid morph in both comimetic species. Our results show the power of efficient haplotyping methods when combined with large-scale sequencing data from natural populations.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data.

Ancient genomes anchor genealogies in directly observed historical genetic variation, and contextualise ancestral lineages with archaeological insights into their geography and lifestyles. We introduce an extension of theRelatealgorithm to incorporate ancient genomes and reconstruct the joint genealogies of 14 previously published high-coverage ancients and 278 present-day individuals of the Simons Genome Diversity Project. As the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies, we additionally present a fast and scalable method,Colate,for inferring coalescence rates between low-coverage genomes without requiring phasing or imputation. Our method leverages sharing patterns of mutations dated using a genealogy to construct a likelihood, which is maximised using an expectation-maximisation algorithm. We applyColateto 430 ancient human shotgun genomes of >0.5x mean coverage. UsingRelateandColate,we characterise dynamic population structure, such as repeated partial population replacements in Ireland, and gene-flow between early farmer and European hunter-gatherer groups. We further show that the previously reported increase in the TCC/TTC mutation rate, which is strongest in West Eurasians among present-day people, was already widespread across West Eurasia in the Late Glacial Period ~10k - 15k years ago, is strongest in Neolithic and Anatolian farmers, and is remarkably well predicted by the coalescence rates between other genomes and a 10,000-year-old Anatolian individual. This suggests that the driver of this signal originated in ancestors of ancient Anatolia >14k years ago, but was already absent by the Mesolithic and may indicate a genetic link between the Near East and European hunter-gatherer groups in the Late Paleolithic.

Mott et al. show that association between a quantitative trait and genotype can be performed using data that has been transformed by first rotating it in a high-dimensional space. The resulting..., Sharing human genotype and phenotype data is essential to discover otherwise inaccessible genetic associations, but is a challenge because of privacy concerns. Here, we present a method of homomorphic encryption that obscures individuals’ genotypes and phenotypes, and is suited to quantitative genetic association analysis. Encrypted ciphertext and unencrypted plaintext are analytically interchangeable. The encryption uses a high-dimensional random linear orthogonal transformation key that leaves the likelihood of quantitative trait data unchanged under a linear model with normally distributed errors. It also preserves linkage disequilibrium between genetic variants and associations between variants and phenotypes. It scrambles relationships between individuals: encrypted genotype dosages closely resemble Gaussian deviates, and can be replaced by quantiles from a Gaussian with negligible effects on accuracy. Likelihood-based inferences are unaffected by orthogonal encryption. These include linear mixed models to control for unequal relatedness between individuals, heritability estimation, and including covariates when testing association. Orthogonal transformations can be applied in a modular fashion for multiparty federated mega-analyses where the parties first agree to share a common set of genotype sites and covariates prior to encryption. Each then privately encrypts and shares their own ciphertext, and analyses all parties’ ciphertexts. In the absence of private variants, or knowledge of the key, we show that it is infeasible to decrypt ciphertext using existing brute-force or noise-reduction attacks. We present the method as a challenge to the community to determine its security.

Background Hospitalisation during the last weeks of life when there is no medical need or desire to be there is distressing and expensive. This study sought palliative care initiatives which may avoid or shorten hospital stay at the end of life and analysed their success in terms reducing bed days. Methods Part 1 included a search of literature in PubMed and Google Scholar between 2013 and 2018, an examination of governmental and organisational publications plus discussions with external and co-author experts regarding other sources. This initial sweep sought to identify and categorise relevant palliative care initiatives. In Part 2, we looked for publications providing data on hospital admissions and bed days for each category. Results A total of 1252 abstracts were reviewed, resulting in ten broad classes being identified. Further screening revealed 50 relevant publications describing a range of multi-component initiatives. Studies were generally small and retrospective. Most researchers claim their service delivered benefits. In descending frequency, benefits identified were support in the community, integrated care, out-of-hours telephone advice, care home education and telemedicine. Nurses and hospices were central to many initiatives. Barriers and factors underpinning success were rarely addressed. Conclusions A wide range of initiatives have been introduced to improve end-of-life experiences. Formal evidence supporting their effectiveness in reducing inappropriate/non-beneficial hospital bed days was generally limited or absent. Trial registration N/A

peer-reviewed The quality and nutritional value of dietary proteins are determined by the quantity, digestibility and bioavailability of essential amino acids (EAA), which play a critical role in human growth, longevity and metabolic health. Plant-source protein is often deficient in one or more EAAs (e.g., branched-chain amino acids, lysine, methionine and/or tryptophan) and, in its natural form, is less digestible than animal-source protein. Nevertheless, dietary intake of plant-source protein has been promoted because of its potential health benefits, lower cost of production and lower environmental impact compared to animal-source protein. Implementation of dietary strategies that improve both human and planetary health are of critical importance and subject to growing interest from researchers and consumers. Therefore, in this review we analyse current plant protein intake patterns and discuss possible countermeasures that can enhance plant protein nutrition, examples include: (1) combining different plant proteins with complementary EAA profiles; (2) identification and commercial cultivation of new and novel high-quality plant proteins; (3) industrial and domestic processing methods; and (4) genome-editing techniques.

Background: The aim of this study was to investigate the effect of whey protein supplementation on myofibrillar protein synthesis (myoPS) and muscle recovery over a 7-d period of intensified resistance training (RT). Methods: In a double-blind randomised parallel group design, 16 resistance-trained men aged 18 to 35 years completed a 7-d RT protocol, consisting of three lower-body RT sessions on non-consecutive days. Participants consumed a controlled diet (146 kJ&middot, kg&minus, 1&middot, d&minus, 1, 1.7 g&middot, 1 protein) with either a whey protein supplement or an isonitrogenous control (0.33 g&middot, 1 protein). To measure myoPS, 400 ml of deuterium oxide (D2O) (70 atom %) was ingested the day prior to starting the study and m. vastus lateralis biopsies were taken before and after RT-intervention. Myofibrillar fractional synthetic rate (myoFSR) was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography-pyrolysis-isotope ratio mass spectrometry (GC-Pyr-IRMS). Muscle recovery parameters (i.e., countermovement jump height, isometric-squat force, muscle soreness and serum creatine kinase) were assessed daily. Results: MyoFSR PRE was 1.6 (0.2) %∙d&minus, 1 (mean (SD)). Whey protein supplementation had no effect on myoFSR (p = 0.771) or any recovery parameter (p = 0.390&ndash, 0.989). Conclusions: Over an intense 7-d RT protocol, 0.33 g&middot, 1 of supplemental whey protein does not enhance day-to-day measures of myoPS or postexercise recovery in resistance-trained men.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically., Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.

peer-reviewed The effects of nutrition on exercise metabolism and performance remain an important topic among sports scientists, clinical, and athletic populations. Recently, fasted exercise has garnered interest as a beneficial stimulus which induces superior metabolic adaptations to fed exercise in key peripheral tissues. Conversely, pre‐exercise feeding augments exercise performance compared with fasting conditions. Given these seemingly divergent effects on performance and metabolism, an appraisal of the literature is warranted. This review determined the effects of fasting vs pre‐exercise feeding on continuous aerobic and anaerobic or intermittent exercise performance, and post‐exercise metabolic adaptations. A search was performed using the MEDLINE and PubMed search engines. The literature search identified 46 studies meeting the relevant inclusion criteria. The Delphi list was used to assess study quality. A meta‐analysis and meta‐regression were performed where appropriate. Findings indicated that pre‐exercise feeding enhanced prolonged (P = .012), but not shorter duration aerobic exercise performance (P = .687). Fasted exercise increased post‐exercise circulating FFAs (P = .023) compared to fed exercise. It is evidenced that pre‐exercise feeding blunted signaling in skeletal muscle and adipose tissue implicated in regulating components of metabolism, including mitochondrial adaptation and substrate utilization. This review's findings support the hypothesis that the fasted and fed conditions can divergently influence exercise metabolism and performance. Pre‐exercise feeding bolsters prolonged aerobic performance, while seminal evidence highlights potential beneficial metabolic adaptations that fasted exercise may induce in peripheral tissues. However, further research is required to fully elucidate the acute and chronic physiological adaptations to fasted vs fed exercise.

Quantifying and comparing the amount of adaptive evolution among different species is key to understanding how evolution works. Previous studies have shown differences in adaptive evolution across species; however, their specific causes remain elusive. Here, we use improved modeling of weakly deleterious mutations and the demographic history of the outgroup species and ancestral population and estimate that at least 20% of nonsynonymous substitutions between humans and an outgroup species were fixed by positive selection. This estimate is much higher than previous estimates, which did not correct for the sizes of the outgroup species and ancestral population. Next, we jointly estimate the proportion and selection coefficient (p(+) and s(+), respectively) of newly arising beneficial nonsynonymous mutations in humans, mice, and Drosophila melanogaster by examining patterns of polymorphism and divergence. We develop a novel composite likelihood framework to test whether these parameters differ across species. Overall, we reject a model with the same p(+) and s(+) of beneficial mutations across species and estimate that humans have a higher p(+)s(+) compared with that of D. melanogaster and mice. We show that this result cannot be caused by biased gene conversion or hypermutable CpG sites. We discuss possible biological explanations that could generate the observed differences in the amount of adaptive evolution across species.

Meeting rising demand for oil palm whilst minimizing the loss of tropical biodiversity and associated ecosystem functions is a core conservation challenge. One potential solution is focusing the expansion of high-yielding crops on presently low-yielding farmlands alongside protecting nearby tropical forests that can enhance provision of ecosystem functions. A key question is how this solution would impact invertebrate functional diversity. We focus on oil palm in the Colombian Llanos, where plantations are replacing improved cattle pastures and forest fragments, and on dung beetles, which play key functional roles in nutrient cycling and secondary seed dispersal. We show that functional richness and functional diversity of dung beetles is greater in oil palm than in cattle pasture, and that functional metrics did not differ between oil palm and remnant forest. The abundance-size class profile of dung beetles in oil palm was more similar to forest than to pasture, which had lower abundances of the smallest and largest dung beetles. The abundance of tunneling and rolling dung beetles did not differ between oil palm and forest, while higher forest cover increased the abundance of diurnal and generalist-feeding beetles in oil palm landscapes. This suggests that prioritizing agricultural development on low-yielding cattle pasture will have positive effects on functional diversity and highlights the need for forest protection to maintain ecosystem functioning within agricultural landscapes.

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations.

Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data.

During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations and deep-sequencing 119 offspring, we detect thousands of crossover and non-crossover events genome-wide with unprecedented power and spatial resolution. We find that both crossovers and non-crossovers are strongly depleted at DSB hotspots where the DSB-positioning protein PRDM9 fails to bind to the unbroken homologous chromosome, revealing that PRDM9 also functions to promote homologue-templated repair. Our results show that complex non-crossovers are much rarer in mice than humans, consistent with complex events arising from accumulated non-programmed DNA damage. Unexpectedly, we also find that GC-biased gene conversion is restricted to non-crossover tracts containing only one mismatch. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9-related hybrid infertility., During meiotic recombination, genetic information is transferred or exchanged between parental chromosome copies. Using a large hybrid mouse pedigree, the authors generated high-resolution maps of these transfer/exchange events and discovered new properties governing their processing and resolution.

Quantifying and comparing the amount of adaptive evolution among different species is key to understanding evolutionary processes. Previous studies have shown differences in adaptive evolution across species; however, their specific causes remain elusive. Here, we use improved modeling of weakly deleterious mutations and the demographic history of the outgroup species and ancestral population and estimate that at least 20% of nonsynonymous substitutions between humans and an outgroup species were fixed by positive selection. This estimate is much higher than previous estimates, which did not correct for the sizes of the outgroup species and ancestral population. Next, we directly estimate the proportion and selection coefficients (p+ands+, respectively) of newly arising beneficial nonsynonymous mutations in humans, mice, andDrosophila melanogasterby examining patterns of polymorphism and divergence. We develop a novel composite likelihood framework to test whether these parameters differ across species. Overall, we reject a model with the samep+ands+of beneficial mutations across species, and estimate that humans have a higherp+s+compared toD. melanogasterand mice. We demonstrate that this result cannot be caused by biased gene conversion or hypermutable CpG sites. In summary, we find the proportion of beneficial mutations to be higher in humans than inD. melanogasteror mice, suggesting that organismal complexity, which increases the number of steps required in adaptive walks, may be a key predictor of the amount of adaptive evolution within a species.

peer-reviewed Twenty‐three resistance trained men 18‐35 years (23 [3] years, 1.8 [0.1] m, 81 [10] kg body mass, 2.3 [1.1] years resistance training experience; mean [SD]) performed repeated maximal voluntary isometric squats (ISQ) and countermovement jumps (CMJ) pre‐ and +30 minutes post a unilateral microbiopsy of m. vastus lateralis. ISQ and CMJ were simultaneously measured by two force plates sampling ipsilateral (biopsied) and contralateral (non‐biopsied) limb force. Bilateral limb force (ipsilateral + contralateral) and imbalance (ipsilateral/bilateral) data are reported as % change from pre‐biopsy (mean [95% CI]). A post‐biopsy reduction in bilateral ISQ peak force (−17 [−23, −11] %; P < 0.001), ISQ rate of force development (RFD; −28 [−41, −15] %, P = 0.002) and CMJ peak take‐off force (−7 [−13, −1]%, P = 0.019) occurred. Imbalance was observed for ISQ peak force (3.2 [2.1, 4.3] %, P < 0.001), RFD (2.8 [1.6, 4.0] %, P < 0.001) and CMJ landing (3.3 [1.0, 5.6] %, P = 0.009), resultant of a force transfer from the ipsilateral (biopsied) to the contralateral (non‐biopsied) limb. These data suggest that in young, resistance trained men a modulatory influence on maximal voluntary static and dynamic lower‐body contractile function is evoked acutely (+30 minutes) following a microbiopsy of m. vastus lateralis.

Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain

Recent national interest in golden eagle (Aquila chrysaetos) conservation and wind energy development prompted us to investigate golden eagle home range and resource use in the Columbia Plateau Ecoregion (CPE) in Washington and Oregon. From 2004 to 2013, we deployed satellite transmitters on adult eagles (n = 17) and monitored their movements for up to 7 years. We used the Brownian bridge movement model (BBMM) to estimate range characteristics from global position system (GPS) fixes and flight paths of 10 eagles, and modeled resource selection probability functions (RSPFs). Multi-year home ranges of resident eagles were large (99% volume contour; , SD = 370.2 km2) but were one-third the size (, SD = 94.6 km2) and contained half as many contours when defined by 95% isopleths. Annual ranges accounted for 66% of multi-year range size. During the breeding season (16 Jan–15 Aug), eagles occupied ranges that were less fragmented, about half as large, and largely contained within ranges they used outside the breeding season ( overlap = 82.5%, SD = 19.0). Eagles selected upper slopes, rugged terrain, and ridge tops that appear to reflect underlying influences of prey, deflective wind currents, and proximity to nests. Fix distribution predicted by our resource selection model and that of 4 eagles monitored independently in the CPE were highly correlated (rs = 0.992). Our findings suggest conservative landscape management strategies addressing development in lower-elevation montane and shrub-steppe/grassland ecosystems can best define golden eagle ranges using exclusive 12.8-km buffers around nests. Less conservative strategies based on 9.6-km buffers must include identification and management of upper slopes, ridge-tops, and areas of varied terrain defined by predictive models or GPS telemetry. For both strategies, high, year-round intensity of eagle flight and perch use within 50% volume contours (average 3.2 km from nests) due to nest centricity may dramatically increase the probability of eagle conflict with wind turbines in core areas as evidenced by eagle turbine strikes that studies have documented within and beyond this zone. © 2014 The Wildlife Society.

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Background— Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. Methods and Results— We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes–based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p discovery =3.3×10 −7 , p replication =5.3×10 −4 p combined =1.12×10 −9 ). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used ( P =4.1×10 −10 versus 3.2×10 −7 ), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self–cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. Conclusions— We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.

Background— Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) at multiple loci that are significantly associated with coronary artery disease (CAD) risk. In this study, we sought to determine and compare the predictive capabilities of 9p21.3 alone and a panel of SNPs identified and replicated through GWAS for CAD. Methods and Results— We used the Ottawa Heart Genomics Study (OHGS) (3323 cases, 2319 control subjects) and the Wellcome Trust Case Control Consortium (WTCCC) (1926 cases, 2938 control subjects) data sets. We compared the ability of allele counting, logistic regression, and support vector machines. Two sets of SNPs, 9p21.3 alone and a set of 12 SNPs identified by GWAS and through a model-fitting procedure, were considered. Performance was assessed by measuring area under the curve (AUC) for OHGS using 10-fold cross-validation and WTCCC as a replication set. AUC for logistic regression using OHGS increased significantly from 0.555 to 0.608 ( P =3.59×10 −14 ) for 9p21.3 versus the 12 SNPs, respectively. This difference remained when traditional risk factors were considered in a subgroup of OHGS (1388 cases, 2038 control subjects), with AUC increasing from 0.804 to 0.809 ( P =0.037). The added predictive value over and above the traditional risk factors was not significant for 9p21.3 (AUC 0.801 versus 0.804, P =0.097) but was for the 12 SNPs (AUC 0.801 versus 0.809, P =0.0073). Performance was similar between OHGS and WTCCC. Logistic regression outperformed both support vector machines and allele counting. Conclusions— Using the collective of 12 SNPs confers significantly greater predictive capabilities for CAD than 9p21.3, whether traditional risks are or are not considered. More accurate models probably will evolve as additional CAD-associated SNPs are identified.

Background: Serum protein profiling patterns can reflect the pathological state of a patient and therefore may be useful for clinical diagnostics. Here, we present results from a pilot study of proteomic expression patterns in hemodialysis patients designed to evaluate the range of serum proteomic alterations in this population. Methods: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was used to analyze serum obtained from patients on periodic hemodialysis treatment and healthy controls. Serum samples from patients and controls were first fractionated into six eluants on a strong anion exchange column, followed by application to four array chemistries representing cation exchange, anion exchange, metal affinity and hydrophobic surfaces. A total of 144 SELDI-TOF-MS spectra were obtained from each serum sample. Results: The overall profiles of the patient and control samples were consistent and reproducible. However, 30 well-defined protein differences were observed; 15 proteins were elevated and 15 were decreased in patients compared to controls. Serum from 1 patient exhibited novel protein peaks suggesting possible additional changes due to a secondary disease process. Conclusion: SELDI-TOF-MS demonstrated consistent serum protein profile differences between patients and controls. Similarity in protein profiles among dialysis patients suggests that patient physiological responses to end-stage renal disease and/or dialysis therapy have a major effect on serum protein profiles.

International audience; Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts1,2,3,4. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

Common intronic SNPs in the human fat mass and obesity associated (FTO) gene are strongly associated with body mass index (BMI). In mouse models, inactivation of the Fto gene results in a lean phenotype, whereas overexpression of Fto leads to increased food intake and obesity. The latter finding suggests that copy number variants at the FTO locus might be associated with extremes of adiposity. To address this question, we searched for rare, private or de novo copy number variation in a cohort of 985 obese and 869 lean subjects of European ancestry drawn from the extremes of the BMI distribution, genotyped on Affymetrix 6.0 arrays. A ∼680 kb duplication, confirmed by real-time PCR and G-to-FISH analyses, was observed between ∼rs11859825 and rs9932411 in a 68-year-old male with severe obesity. The duplicated region on chromosome 16 spans the entire genome-wide association studies risk locus for obesity, and further encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene. Affected family members exhibit a unique obesity phenotype, characterized by increased fat distribution in the shoulders and neck with a significantly increased neck circumference. This phenotype was accompanied by increased peripheral blood expression of RBL2 with no alteration in expression of FTO or other genes in the region. No other duplications or deletions in this region were identified in the cohort of obese and lean individuals or in a further survey of 4778 individuals, suggesting that large rare copy number variants surrounding the FTO gene are not a frequent cause of obesity.

Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.

Aims Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an important cause of morbidity and mortality. A genetic mutation in the NPPA gene, which encodes the atrial natriuretic peptide, has been identified as the putative causative factor in a family with an autosomal dominant pattern of inheritance for AF. Two common single nucleotide polymorphisms (SNPs) in NPPA , rs5063 and rs5065, result in amino acid changes of the primary peptide and have been previously implicated in conditions associated with AF, including stroke and hypertension. Recently, the rs5063 SNP has been reported to confer an increased risk of AF development in a Chinese population. We sought to examine the associations of both rs5063 and rs5065 with AF in two separate North American cohorts of European ancestry. Methods and results Patients with early-onset AF, along with healthy controls, were recruited at the University of Ottawa Heart Institute (UOHI) and the Massachusetts General Hospital (MGH). Study participants were genotyped for rs5063 and rs5065 using a combination of restriction fragment length polymorphism analysis and DNA microarrays. The study genotyped a total of 620 AF cases and 2446 healthy controls. The UOHI arm of the study identified an odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.42–1.24] for rs5063, whereas an OR of 1.33 (95% CI: 0.80–2.21) was observed in the MGH arm. The combined OR approximated unity (OR 0.99; 95% CI: 0.54–1.80). Analysis of rs5065 revealed an OR of 1.12 (95% CI: 0.84–1.48) in UOHI, 1.08 (95% CI 0.80–1.45) in MGH, and 1.10 (95% CI 0.90–1.35) when combined. Conclusion Common non-synonymous genetic variants within NPPA in these two large North American cohorts of European ancestry are not associated with the development of AF.

Introduction Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism. Methods Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2 , KCNQ1 , KCNE1 , KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison. Results Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93ms versus 376±40ms, P=0.048) and T peak to T end (T p -T e ) intervals (147±25ms versus 94±25ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in T p -T e intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant. Conclusions TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The T p -T e interval at baseline, in AV block and pre-TdP may predict a genetic mutation or polymorphism compromising repolarization reserve. Patients with TdP in the setting of AV block represent a phenotypic manifestation of latent congenital long QT syndrome.

The role of surface-generated mixing in determining the seasonal variation of the ocean thermal structure is investigated using a one-dimensional numerical model. The model contains vertical eddy diffusion with a constant coefficient KH = 0.5 cm2 s−1, an instantaneous convective adjustment mechanism as commonly used in oceanic general circulation models, and a simple parameterization of surface-generated wind and convective mixing based on recent mixed-layer theories. Forcing on the seasonal time scale is accomplished by prescribing the atmospheric solar radiation, longwave radiation, wind speed, temperature and dew point to vary sinusoidally with the annual period. Results of model integrations show that surface-generated wind and convective mixing are responsible for producing many features which are observed in the real ocean including the occurrence of two sea surface temperature maxima—one in summer and another in early fall.