Domestic animals are excellent models for genetic studies of phenotypic evolution. They have evolved genetic adaptations to a new environment, the farm, and have been subjected to strong human-driven selection leading to remarkable phenotypic changes in morphology, physiology and behaviour. Identifying the genetic changes underlying these developments provides new insight into general mechanisms by which genetic variation shapes phenotypic diversity. Here we describe the use of massively parallel sequencing to identify selective sweeps of favourable alleles and candidate mutations that have had a prominent role in the domestication of chickens (Gallus gallus domesticus) and their subsequent specialization into broiler (meat-producing) and layer (egg-producing) chickens. We have generated 44.5-fold coverage of the chicken genome using pools of genomic DNA representing eight different populations of domestic chickens as well as red jungle fowl (Gallus gallus), the major wild ancestor. We report more than 7,000,000 single nucleotide polymorphisms, almost 1,300 deletions and a number of putative selective sweeps. One of the most striking selective sweeps found in all domestic chickens occurred at the locus for thyroid stimulating hormone receptor (TSHR), which has a pivotal role in metabolic regulation and photoperiod control of reproduction in vertebrates. Several of the selective sweeps detected in broilers overlapped genes associated with growth, appetite and metabolic regulation. We found little evidence that selection for loss-of-function mutations had a prominent role in chicken domestication, but we detected two deletions in coding sequences that we suggest are functionally important. This study has direct application to animal breeding and enhances the importance of the domestic chicken as a model organism for biomedical research.

Yellow skin is an abundant phenotype among domestic chickens and is caused by a recessive allele (W*Y) that allows deposition of yellow carotenoids in the skin. Here we show that yellow skin is caused by one or more cis-acting and tissue-specific regulatory mutation(s) that inhibit expression of BCDO2 (beta-carotene dioxygenase 2) in skin. Our data imply that carotenoids are taken up from the circulation in both genotypes but are degraded by BCDO2 in skin from animals carrying the white skin allele (W*W). Surprisingly, our results demonstrate that yellow skin does not originate from the red junglefowl (Gallus gallus), the presumed sole wild ancestor of the domestic chicken, but most likely from the closely related grey junglefowl (Gallus sonneratii). This is the first conclusive evidence for a hybrid origin of the domestic chicken, and it has important implications for our views of the domestication process.

ObjectiveTo compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA).MethodsPatients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003–2005/2006–2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy).ResultsDuring 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006–2009 than 2003–2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003–2005 vs 2006–2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001).ConclusionsDiscontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.

Bonobos are large, highly mobile primates living in the relatively undisturbed, contiguous forest south of the Congo River. Accordingly, gene flow among populations is assumed to be extensive, but may be impeded by large, impassable rivers. We examined mitochondrial DNA control region sequence variation in individuals from five distinct localities separated by rivers in order to estimate relative levels of genetic diversity and assess the extent and pattern of population genetic structure in the bonobo. Diversity estimates for the bonobo exceed those for humans, but are less than those found for the chimpanzee. All regions sampled are significantly differentiated from one another, according to genetic distances estimated as pairwise FSTs, with the greatest differentiation existing between region East and each of the two Northern populations (N and NE) and the least differentiation between regions Central and South. The distribution of nucleotide diversity shows a clear signal of population structure, with some 30% of the variance occurring among geographical regions. However, a geographical patterning of the population structure is not obvious. Namely, mitochondrial haplotypes were shared among all regions excepting the most eastern locality and the phylogenetic analysis revealed a tree in which haplotypes were intermixed with little regard to geographical origin, with the notable exception of the close relationships among the haplotypes found in the east. Nonetheless, genetic distances correlated with geographical distances when the intervening distances were measured around rivers presenting effective current-day barriers, but not when straight-line distances were used, suggesting that rivers are indeed a hindrance to gene flow in this species.

Objective. To estimate the nationwide incidence of rheumatoid arthritis (RA) in Sweden, including its variation across age, sex, geography, and demography, and to describe the sensitivity of register-based incidence estimates to different RA case definitions. Conclusion.The overall nationwide register-based incidence of RA was robust across different case definitions. In a country with universal access to care, RA displayed demographic and socioeconomic, but no geographic, variations in incidence, and peaks at an older age than most commonly reported, with no difference in peak age at RA onset between sexes.

Background: The effectiveness of commercial weight-loss programs consisting of very-low-calorie diets (VLCDs) and low-calorie diets (LCDs) is unclear.Objective: The aim of the study was to quantify weight loss and dropout during a commercial weight-loss program in Sweden (Itrim; cost: $1300/€1000; all participants paid their own fee).Design: This observational cohort study linked commercial weight-loss data with National Health Care Registers. Weight loss was induced with a 500-kcal liquid-formula VLCD [n = 3773; BMI (in kg/m2): 34 ± 5 (mean ± SD); 80% women; 45 ± 12 y of age (mean ± SD)], a 1200–1500-kcal formula and food-combination LCD (n = 4588; BMI: 30 ± 4; 86% women; 50 ± 11 y of age), and a 1500–1800-kcal/d restricted normal-food diet (n = 676; BMI: 29 ± 5; 81% women; 51 ± 12 y of age). Maintenance strategies included exercise and a calorie-restricted diet. Weight loss was analyzed by using an intention-to-treat analysis (baseline substitution).Results: After 1 y, mean (±SD) weight changes were −11.4 ± 9.1 kg with the VLCD (18% dropout), −6.8 ± 6.4 kg with the LCD (23% dropout), and −5.1 ± 5.9 kg with the restricted normal-food diet (26% dropout). In an adjusted analysis, the VLCD group lost 2.8 kg (95% CI: 2.5, 3.2) and 3.8 kg (95% CI: 3.2, 4.5) more than did the LCD and restricted normal-food groups, respectively. A high baseline BMI and rapid initial weight loss were both independently associated with greater 1-y weight loss (P < 0.001). Younger age and low initial weight loss predicted an increased dropout rate (P < 0.001). Treatment of depression (OR: 1.4; 95% CI: 1.1, 1.9) and psychosis (OR: 2.6; 95% CI: 1.1, 6.3) were associated with an increased dropout rate in the VLCD group.Conclusion: A commercial weight-loss program, particularly one using a VLCD, was effective at reducing body weight in self-selected, self-paying adults.

Dispersal is a rare event that is difficult to observe in slowly maturing, long-lived wild animal species such as the bonobo. In this study we used sex-linked (mitochondrial DNA sequence and Y-chromosome microsatellite) markers from the same set of individuals to estimate the magnitude of difference in effective dispersal between the sexes and to investigate the long-term demographic history of bonobos. We sampled 34 males from four distinct geographical areas across the bonobo distribution range. As predicted for a female-dispersing species, we found much higher levels of differentiation among local bonobo populations based upon Y-chromosomal than mtDNA genetic variation. Specifically, almost all of the Y-chromosomal variation distinguished populations, while nearly all of the mtDNA variation was shared between populations. Furthermore, genetic distance correlated with geographical distance for mtDNA but not for the Y chromosome. Female bonobos have a much higher migration rate and/or effective population size as compared to males, and the estimate for the mitochondrial TMRCA (time to most recent common ancestor) was approximately 10 times greater than the estimate for the Y chromosome (410,000 vs. 40,000-45,000). For humans the difference is merely a factor of two, suggesting a more stable demographic history in bonobos in comparison to humans.

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