Patterns of Recent Natural Selection on Genetic Loci Associated with Sexually Differentiated Human Body Size and Shape Phenotypes

Levels of sex differences for human body size and shape phenotypes are hypothesized to have adaptively reduced following the agricultural transition as part of an evolutionary response to relatively more equal divisions of labor and new technology adoption. In this study, we tested this hypothesis by studying genetic variants associated with five sexually differentiated human phenotypes: height, body mass, hip circumference, body fat percentage, and waist circumference. We first analyzed genome-wide association (GWAS) results for UK Biobank individuals (~194,000 females and ~167,000 males) to identify a total of 114,199 single nucleotide polymorphisms (SNPs) significantly associated with at least one of the studied phenotypes in females, males, or both sexes (P \u3c 5x10-8). From these loci we then identified 3,016 SNPs (2.6%) with significant differences in the strength of association between the female- and male-specific GWAS results at a low false-discovery rate (FDR \u3c 0.001). Genes with known roles in sexual differentiation are significantly enriched for co-localization with one or more of these SNPs versus SNPs associated with the phenotypes generally but not with sex differences (2.73-fold enrichment; permutation test; P = 0.0041). We also confirmed that the identified variants are disproportionately associated with greater phenotype effect sizes in the sex with the stronger association value. We then used the singleton density score statistic, which quantifies recent (within the last ~3,000 years; post-agriculture adoption in Britain) changes in the frequencies of alleles underlying polygenic traits, to identify a signature of recent positive selection on alleles associated with greater body fat percentage in females (permutation test; P = 0.0038; FDR = 0.0380), directionally opposite to that predicted by the sex differences reduction hypothesis. Otherwise, we found no evidence of positive selection for sex difference-associated alleles for any other trait. Overall, our results challenge the longstanding hypothesis that sex differences adaptively decreased following subsistence transitions from hunting and gathering to agriculture

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Making evolution stick: using sticky notes to teach the mechanisms of evolutionary change

Abstract Evolution and its mechanisms of action are concepts that unite all aspects of biology, but remain some of the most difficult for students to understand. To address this challenge, we designed a hands-on activity that introduces fundamental mechanisms of evolutionary change: natural selection, genetic drift, and gene flow. In small groups, students use a population of sticky notes to reveal the consequences of each mechanism on phenotype frequency. In a follow-up homework assignment, students then explore how changes in phenotype frequency reflect changes in allele frequency in the population. This activity is suitable for anyone learning the basics of evolution, from high-school through the undergraduate level. We have provided detailed instructions, in-class worksheets, follow-up homework, and extensions that allow the activity to be simplified or made more complex as needed. In our own classrooms, we have observed that the concrete and collaborative nature of this activity enables students to deepen their understanding of the mechanisms through which evolution occurs. We have designed this study such that, in completing this activity, we hope to offer students the opportunity to confront potential misconceptions about evolution and gain a solid foundation for future explorations in the discipline

Behavioural bioassays on captive ring-tailed lemurs (Lemur catta)

Results of behavioural bioassays conducted in October 2016 at the Duke Lemur Center in Durham, North Carolina. All animals were captive born adults, housed socially in single or mixed-sex social groups. All bioassays were videotaped and animal behaviour recorded using a published ethogram (see manuscript Supplementary Material). Each bioassay is represented by two data lines (one for each dowel used in each trial)

Data from: Costs of injury for scent signalling in a strepsirrhine primate

Honesty is crucial in animal communication when signallers are conveying information about their condition. Condition dependence implies a cost to signal production; yet, evidence of such cost is scarce. We examined the effects of naturally occurring injury on the quality and salience of olfactory signals in ring-tailed lemurs (Lemur catta). Over a decade, we collected genital secretions from 23 (13 male, 10 female) adults across 34 unique injuries, owing primarily to intra-group fights. Using gas chromatography-mass spectrometry, we tested for differences in the chemical composition of secretions across pre-injury, injury, and recovery, in animals that did and did not receive antibiotics. Lemur genital secretions were significantly dampened and altered during injury, with patterns of change varying by sex, season, and antibiotics. Using behavioural bioassays (excluding odorants from antibiotic-treated animals), we showed that male ‘recipients’ discriminated injury status based on scent alone, directing more competitive counter marking towards odorants from injured vs. uninjured male ‘signallers.’ That injured animals could not maintain their normal signatures provides rare evidence of the energetic cost to signal production. That conspecifics detected olfactory-encoded ‘weakness’ suggests added behavioural costs: By influencing the likelihood of intra- or inter-sexual conflict, condition-dependent signals could have important implications for socio-reproductive behaviour

Genetic variation at MHC class II loci influences both olfactory signals and scent discrimination in ring-tailed lemurs

Abstract Background Diversity at the Major Histocompatibility Complex (MHC) is critical to health and fitness, such that MHC genotype may predict an individual’s quality or compatibility as a competitor, ally, or mate. Moreover, because MHC products can influence the components of bodily secretions, an individual’s body odors may signal its MHC composition and influence partner identification or mate choice. Here, we investigated MHC-based signaling and recipient sensitivity by testing for odor-gene covariance and behavioral discrimination of MHC diversity and pairwise dissimilarity in a strepsirrhine primate, the ring-tailed lemur (Lemur catta). Methods First, we coupled genotyping of the MHC class II gene, DRB, with gas chromatography-mass spectrometry of genital gland secretions to investigate if functional genetic diversity is signaled by the chemical diversity of lemur scent secretions. We also assessed if the chemical similarity between individuals correlated with their MHC-DRB similarity. Next, we assessed if lemurs discriminated this chemically encoded, genetic information in opposite-sex conspecifics. Results We found that both sexes signaled overall MHC-DRB diversity and pairwise MHC-DRB similarity via genital secretions, but in a sex- and season-dependent manner. Additionally, the sexes discriminated absolute and relative MHC-DRB diversity in the genital odors of opposite-sex conspecifics, suggesting that lemur genital odors function to advertise genetic quality. Conclusions In summary, genital odors of ring-tailed lemurs provide honest information about an individual’s absolute and relative MHC quality. Complementing evidence in humans and Old World monkeys, we suggest that reliance on scent signals to communicate MHC quality may be important across the primate lineage

Data from: Genetic wealth, population health: major histocompatibility complex variation in captive and wild ring-tailed lemurs (Lemur catta)

Across species, diversity at the major histocompatibility complex (MHC) is critical to individual disease resistance and, hence, to population health; however, MHC diversity can be reduced in small, fragmented, or isolated populations. Given the need for comparative studies of functional genetic diversity, we investigated whether MHC diversity differs between populations which are open, that is experiencing gene flow, versus populations which are closed, that is isolated from other populations. Using the endangered ring-tailed lemur (Lemur catta) as a model, we compared two populations under long-term study: a relatively “open,” wild population (n = 180) derived from Bezà Mahafaly Special Reserve, Madagascar (2003–2013) and a “closed,” captive population (n = 121) derived from the Duke Lemur Center (DLC, 1980–2013) and from the Indianapolis and Cincinnati Zoos (2012). For all animals, we assessed MHC-DRB diversity and, across populations, we compared the number of unique MHC-DRB alleles and their distributions. Wild individuals possessed more MHC-DRB alleles than did captive individuals, and overall, the wild population had more unique MHC-DRB alleles that were more evenly distributed than did the captive population. Despite management efforts to maintain or increase genetic diversity in the DLC population, MHC diversity remained static from 1980 to 2010. Since 2010, however, captive-breeding efforts resulted in the MHC diversity of offspring increasing to a level commensurate with that found in wild individuals. Therefore, loss of genetic diversity in lemurs, owing to small founder populations or reduced gene flow, can be mitigated by managed breeding efforts. Quantifying MHC diversity within individuals and between populations is the necessary first step to identifying potential improvements to captive management and conservation plans

Whole-body Computed Tomography Versus Dual Energy X‑ray Absorptiometry for Assessing Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder that leads to heterotopic ossification (HO), resulting in progressive restriction of physical function. In this study, low-dose, whole-body computed tomography (WBCT) and dual energy X-ray absorptiometry (DXA) were evaluated to determine the preferred method for assessing total body burden of HO in patients with FOP. This was a non-interventional, two-part natural history study in patients with FOP (NCT02322255; date of registration: December 2014). In Part A (described here), WBCT and DXA scans were individually assessed for HO presence and severity across 15 anatomical regions. All images were independently reviewed by an expert imaging panel. Ten adult patients were enrolled across four sites. The sensitivity to HO presence and severity varied considerably between the two imaging modalities, with WBCT demonstrating HO in more body regions than DXA (76/138 [55%] versus 47/113 [42%]) evaluable regions). Inability to evaluate HO presence, due to overlapping body regions (positional ambiguity), occurred less frequently by WBCT than by DXA (mean number of non-evaluable regions per scan 1.2 [standard deviation: 1.5] versus 2.4 [1.4]). Based on the increased sensitivity and decreased positional ambiguity of low-dose WBCT versus DXA in measuring HO in patients with FOP, low-dose WBCT was chosen as the preferred imaging for measuring HO. Therefore, low-dose WBCT was carried forward to Part B of the natural history study, which evaluated disease progression over 36&nbsp;months in a larger population of patients with FOP

Academic leaders must support inclusive scientific communities during COVID-19

CITATION: Maas, B. et al. 2020. Academic leaders must support inclusive scientific communities during COVID-19. Nature Ecology and Evolution, doi:10.1038/s41559-020-1233-3.The original publication is available at https://www.nature.comThe COVID-19 pandemic poses major challenges for all sectors of society, including scientists faced with abrupt disruptions and redirections of research and higher education1. The consequences of this crisis will disproportionately impact early-career scientists; especially those from communities historically underrepresented, disadvantaged and/or discriminated in the fields of environmental sciences, including women, researchers from the Global South and persons with disabilities2. We call for a collective effort by the entire scientific community, especially those in leadership positions, to respond to the short- and long-term challenges of this crisis and to protect decades of efforts to build an inclusive scientific community3.https://www.nature.com/articles/s41559-020-1233-3Publisher's versio