Highlights d Blood cell traits differ by ancestry and are subject to selective pressure d We assessed 15 blood cell traits in 746,667 participants from 5 global populations d We identified more than 5,500 associations, including 100 associations not found in Europeans d These analyses improved risk prediction and identified potential causal variants

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BackgroundGoat populations that are characterized within the AdaptMap project cover a large part of the worldwide distribution of this species and provide the opportunity to assess their diversity at a global scale. We analysed genome-wide 50 K single nucleotide polymorphism (SNP) data from 144 populations to describe the global patterns of molecular variation, compare them to those observed in other livestock species, and identify the drivers that led to the current distribution of goats.ResultsA high degree of genetic variability exists among the goat populations studied. Our results highlight a strong partitioning of molecular diversity between and within continents. Three major gene pools correspond to goats from Europe, Africa and West Asia. Dissection of sub-structures disclosed regional gene pools, which reflect the main post-domestication migration routes. We also identified several exchanges, mainly in African populations, and which often involve admixed and cosmopolitan breeds. Extensive gene flow has taken place within specific areas (e.g., south Europe, Morocco and Mali-Burkina Faso-Nigeria), whereas elsewhere isolation due to geographical barriers (e.g., seas or mountains) or human management has decreased local gene flows.ConclusionsAfter domestication in the Fertile Crescent in the early Neolithic era (ca. 12,000 YBP), domestic goats that already carried differentiated gene pools spread to Europe, Africa and Asia. The spread of these populations determined the major genomic background of the continental populations, which currently have a more marked subdivision than that observed in other ruminant livestock species. Subsequently, further diversification occurred at the regional level due to geographical and reproductive isolation, which was accompanied by additional migrations and/or importations, the traces of which are still detectable today. The effects of breed formation were clearly detected, particularly in Central and North Europe. Overall, our results highlight a remarkable diversity that occurs at the global scale and is locally partitioned and often affected by introgression from cosmopolitan breeds. These findings support the importance of long-term preservation of goat diversity, and provide a useful framework for investigating adaptive introgression, directing genetic improvement and choosing breeding targets.Electronic supplementary materialThe online version of this article (10.1186/s12711-018-0422-x) contains supplementary material, which is available to authorized users.

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls who were frequency-matched on age, gender and smoking status. All subjects were non-Hispanic whites. Two XPD polymorphisms (C22541A and A35931C) were typed using the restriction enzymes TfiI and PstI, respectively. Multivariate logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). In the controls, the frequencies of the variant 22541A and 35931C alleles were 44.7% and 33.8%, respectively. The frequency of the 22541A homozygous genotype (22541AA) was lower in cases (15.9%) than in controls (20.4%) but was not associated with risk (adjusted OR = 0.90; 95% CI = 0.52-1. 56) for SCCHN. The frequency of the 35931C homozygous genotype (35931CC) was higher in cases (16.4%) than in controls (11.5%) and associated with a borderline increased risk (adjusted OR = 1.55; 95% CI = 0.96-2.52) for SCCHN. The risk was higher in older subjects (OR = 2.22; 95% CI = 1.03-4.80), current smokers (OR = 1.83; 95% CI = 0.79-4.27) and current drinkers (OR = 2.59; 95% CI = 1.25-5.34) in the stratification analysis. These results suggest a gene-environment interaction, but this did not reach statistical significance. The findings are limited due to the relatively small numbers in the subgroups and need to be verified by further investigations.

An immune response must be tightly controlled so that it will be commensurate with the level of response needed to protect the organism without damaging normal tissue. The roles of cytokines and chemokines in orchestrating these processes are well known, but although stress has long been thought to also affect immune responses, the underlying mechanisms were not as well understood. Recently, the role of nerves and, specifically, the sympathetic nervous system, in regulating immune responses is being revealed. Generally, an acute stress response is beneficial but chronic stress is detrimental because it suppresses the activities of effector immune cells while increasing the activities of immunosuppressive cells. In this review, we first discuss the underlying biology of adrenergic signaling in cells of both the innate and adaptive immune system. We then focus on the effects of chronic adrenergic stress in promoting tumor growth, giving examples of effects on tumor cells and immune cells, explaining the methods commonly used to induce stress in preclinical mouse models. We highlight how this relates to our observations that mandated housing conditions impose baseline chronic stress on mouse models, which is sufficient to cause chronic immunosuppression. This problem is not commonly recognized, but it has been shown to impact conclusions of several studies of mouse physiology and mouse models of disease. Moreover, the fact that preclinical mouse models are chronically immunosuppressed has critical ramifications for analysis of any experiments with an immune component. Our group has found that reducing adrenergic stress by housing mice at thermoneutrality or treating mice housed at cooler temperatures with β-blockers reverses immunosuppression and significantly improves responses to checkpoint inhibitor immunotherapy. These observations are clinically relevant because there are numerous retrospective epidemiological studies concluding that cancer patients who were taking β-blockers have better outcomes. Clinical trials testing whether β-blockers can be repurposed to improve the efficacy of traditional and immunotherapies in patients are on the horizon.