More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4 ) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.

SummaryFibroblast growth factor 21 (FGF21) is a hormone that has insulin-sensitizing properties. Some trials of FGF21 analogs show weight loss and lipid-lowering effects. Recent studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed, but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study, aiming to use the human allele to inform potential adverse and beneficial effects of targeting FGF21. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with higher blood pressure and waist-hip ratio, despite an association with lower total body-fat percentage, than it is with BMI or type 2 diabetes. These human phenotypes of variation in the FGF21 gene will inform research into FGF21’s mechanisms and therapeutic potential.

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Over 100,000 genetic variants are classified as disease-causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and may be over-estimated by clinical ascertainment. As more people undergo genome sequencing there is an increasing need to assess the true penetrance of alleles. Until recently, this was not possible in a population-based setting. Here, we use data from 388,714 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants.Although rare variants are harder to genotype accurately than common variants, we were able to classify 1,244 of 4,585 (27%) putatively clinically relevant rare variants genotyped on the UKB microarray as high-quality. We defined "rare" as variants with a minor allele frequency of <0.01, and "clinically relevant" as variants that were either classified as pathogenic/likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases in which we have some expertise: Maturity-Onset Diabetes of the Young (MODY) and severe developmental disorders (DD). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically-relevant traits available in UKB.We identified 27 putatively clinically relevant rare variants associated with a UKB trait but that exhibited reduced penetrance or variable expressivity compared with their associated disease. For example, the P415A PER3 variant that has been reported to cause familial advanced sleep phase syndrome is present at 0.5% frequency in the population and associated with an odds ratio of 1.38 for being a morning person (P=2x10 -18 ). We also observed novel associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g. heterozygous carriers of the R799W ERCC4 variant that causes Xeroderma pigmentosum were more susceptible to sunburn (one extra sunburn episode reported, P=2x10 -8 ). Within our two disease subsets, we were able to refine the penetrance estimate for the R114W HNF4A variant in diabetes (only ~10% by age 40yrs) and refute the previous disease-association of RNF135 in developmental disorders.In conclusion, this study shows that very large population-based studies will help refine the penetrance estimates of rare variants. This information will be important for anyone receiving information about their health based on putatively pathogenic variants.

Nest predation impacts duck production and recruitment in many areas of North America. Yet little research has been conducted to evaluate beliefs of waterfowl managers about predation of duck nests or predation management strategies. We surveyed 176 waterfowl managers employed by the United States Fish and Wildlife Service (USFWS) and state wildlife agencies to determine their beliefs about the impact of nest predation on duck populations and evaluate their use and perceptions of different predation management techniques. The overall survey response rate was 85% for USFWS and 92% for state managers. Managers believed predation was having a significant impact on duck‐nest success. Over 64% of respondents reported that rates of nest success on their management units averaged <30% between 1996–2000. Concomitantly, most managers (93%) reported implementing >1 technique on their management area to reduce nest predation, but most techniques were rated as only somewhat effective. Habitat management (e.g., establishment of dense nesting cover), nesting structures, and lethal control (e.g., trapping) of predators were perceived as being the most effective methods to reduce nest predation. To successfully manage nest predation in the future, managers believed more information is needed about the impact of control techniques on nontarget species and some technical aspects of technique implementation.

word summaryFibroblast Growth Factor 21 (FGF21) is a hormone that induces weight loss in model organisms. These findings have led to trials in humans of FGF21 analogues with some showing weight loss and lipid lowering effects. Recent genetic studies have shown that a common allele in the FGF21 gene alters the balance of macronutrients consumed but there was little evidence of an effect on metabolic traits. We studied a common FGF21 allele (A:rs838133) in 451,099 people from the UK Biobank study. We replicated the association between the A allele and higher percentage carbohydrate intake. We then showed that this allele is more strongly associated with body fat distribution, with less fat in the lower body, and higher blood pressure, than it is with BMI, where there is only nominal evidence of an effect. These human phenotypes of naturally occurring variation in the FGF21 gene will inform decisions about FGF21's therapeutic potential. IntroductionFGF21 is a hormone secreted primarily by the liver whose multiple functions include signalling to the paraventricular nucleus of the hypothalamus to suppress sugar and alcohol intake [1,2], stimulating insulin-independent glucose uptake by adipocytes [3] and acting as an insulin sensitizer [4]. These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7]. A recent study suggested that FGF21 analogues may alter not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/214700 doi: bioRxiv preprint first posted online Nov. 6, 2017; blood pressure in humans [8], although changes in blood pressure were not observed in a previous trial [9]. Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].Recent studies have shown that FGF21 affects the balance of macronutrients consumed. Studies in mice and non human primates show that genetically and pharmacologically raising FGF21 levels suppresses sugar and alcohol intake [1,2]. Three human genetic studies have shown that the minor A allele at rs838133 (A/G, Minor Allele Frequency=44.7%), which results in a synonymous change to the first exon of FGF21, is associated with higher carbohydrate and lower...

Periodic vegetation disturbance is an important yet controversial tool for waterfowl managers. Some have reported livestock grazing removes residual vegetation and thus is detrimental to nesting ducks, and others argue that such disturbance is necessary to maintain grassland health. We evaluated the impact of winter livestock grazing on duck nesting at Bear River Migratory Bird Refuge, Utah. During winter 1999, 6 experimental plots were grazed by cattle and 6 were ungrazed; in winter 2000, 8 plots were grazed and 8 were ungrazed. All grazing treatments were conducted during 15 November-15 March and averaged a stocking rate of 9.5 animal unit months/ha. During the following spring nesting season, we measured visual obstruction readings (VOR) on grazed and ungrazed sites. Although VOR on ungrazed sites were greater than those on grazed sites, this difference became less important as the nesting season progressed. Winter grazing impacted the nesting habitat of early-nesting ducks such as mallards (Anas platyrhynchos), but not that of late-nesting species such as cinnamon teal (Anas cyanoptera) and gadwall (Anas strepera). When using livestock grazing to manage grasslands, waterfowl managers should consider their management goals, the species composition of breeding duck populations, and environmental conditions. ResumenEl disturbio perió dico de la vegetació n es una herramienta importante, pero controversial, para los manejadores de las á reas de há bitat de aves acuá ticas. Algunos han reportado que el apacentamiento del ganado remueve la vegetació n residual y que es prejudicial para el anidamiento de los patos, mientras que otros argumentan que tal disturbio es necesario para mantener la salud del pastizal. Evaluamos el impacto del apacentamiento del ganado en invierno sobre el anidamiento de los patos en el Refugio de Aves Migratorias Bear River, Utah. Durante el invierno de 1999, 6 parcelas experimentales fueron apacentadas por ganado y otras 6 no recibieron apacentamiento; en el invierno del 2000, 8 parcelas se apacentaron y otras 8 no; todos los tratamientos de apacentamiento se condujeron del 15 de Noviembre al 15 de Marzo con una carga promedio de 9.5 Unidades Animal Mes ha À1 . Durante la época de anidamiento en la siguiente primavera tomamos lecturas de la obstrucció n visual (OVR) en los sitios apacentados y sin apacentar. Aunque las VOR de los sitios sin apacentar fueron mayores que las de los sitios apacentados, esta diferencia vino a ser menos importante conforme la estació n de anidamiento progresó . El apacentamiento invernal impacto el há bitat de anidamiento de los patos que anidan temprano, como los ''Mallard'' (Anas platyrhynchos), pero no el de las especies que anidan má s tarde, como el ''Cinnamon teal'' (Anas cyanoptera) y el ''Gadwall'' (Anas strepera). Cuando se utiliza el apacentamiento del ganado para manejar el pastizal, los manejadores de las á reas de anidamiento de aves acuá ticas deben considerar en sus metas de manejo la composició n de especies de las poblaciones de patos...

Periodic vegetation disturbance is an important yet controversial tool for waterfowl managers. Some have reported livestock grazing removes residual vegetation and thus is detrimental to nesting ducks, and others argue that such disturbance is necessary to maintain grassland health. We evaluated the impact of winter livestock grazing on duck nesting at Bear River Migratory Bird Refuge, Utah. During winter 1999, 6 experimental plots were grazed by cattle and 6 were ungrazed; in winter 2000, 8 plots were grazed and 8 were ungrazed. All grazing treatments were conducted during 15 November-15 March and averaged a stocking rate of 9.5 animal unit months/ha. During the following spring nesting season, we measured visual obstruction readings (VOR) on grazed and ungrazed sites. Although VOR on ungrazed sites were greater than those on grazed sites, this difference became less important as the nesting season progressed. Winter grazing impacted the nesting habitat of early-nesting ducks such as mallards (Anas platyrhynchos), but not that of late-nesting species such as cinnamon teal (Anas cyanoptera) and gadwall (Anas strepera). When using livestock grazing to manage grasslands, waterfowl managers should consider their management goals, the species composition of breeding duck populations, and environmental conditions. ResumenEl disturbio perió dico de la vegetació n es una herramienta importante, pero controversial, para los manejadores de las á reas de há bitat de aves acuá ticas. Algunos han reportado que el apacentamiento del ganado remueve la vegetació n residual y que es prejudicial para el anidamiento de los patos, mientras que otros argumentan que tal disturbio es necesario para mantener la salud del pastizal. Evaluamos el impacto del apacentamiento del ganado en invierno sobre el anidamiento de los patos en el Refugio de Aves Migratorias Bear River, Utah. Durante el invierno de 1999, 6 parcelas experimentales fueron apacentadas por ganado y otras 6 no recibieron apacentamiento; en el invierno del 2000, 8 parcelas se apacentaron y otras 8 no; todos los tratamientos de apacentamiento se condujeron del 15 de Noviembre al 15 de Marzo con una carga promedio de 9.5 Unidades Animal Mes ha À1 . Durante la época de anidamiento en la siguiente primavera tomamos lecturas de la obstrucció n visual (OVR) en los sitios apacentados y sin apacentar. Aunque las VOR de los sitios sin apacentar fueron mayores que las de los sitios apacentados, esta diferencia vino a ser menos importante conforme la estació n de anidamiento progresó . El apacentamiento invernal impacto el há bitat de anidamiento de los patos que anidan temprano, como los ''Mallard'' (Anas platyrhynchos), pero no el de las especies que anidan má s tarde, como el ''Cinnamon teal'' (Anas cyanoptera) y el ''Gadwall'' (Anas strepera). Cuando se utiliza el apacentamiento del ganado para manejar el pastizal, los manejadores de las á reas de anidamiento de aves acuá ticas deben considerar en sus metas de manejo la composició n de especies de las poblaciones de patos en repro...