Evidence for divergent patterns of local selection driving venom variation in Mojave Rattlesnakes (\u3ci\u3eCrotalus scutulatus\u3c/i\u3e)

Snake venoms represent an enriched system for investigating the evolutionary processes that lead to complex and dynamic trophic adaptations. It has long been hypothesized that natural selection may drive geographic variation in venom composition, yet previous studies have lacked the population genetic context to examine these patterns. We leverage range-wide sampling of Mojave Rattlesnakes (Crotalus scutulatus) and use a combination of venom, morphological, phylogenetic, population genetic, and environmental data to characterize the striking dichotomy of neurotoxic (Type A) and hemorrhagic (Type B) venoms throughout the range of this species. We find that three of the four previously identified major lineages within C. scutulatus possess a combination of Type A, Type B, and a ‘mixed’ Type A + B venom phenotypes, and that fixation of the two main venom phenotypes occurs on a more fine geographic scale than previously appreciated. We also find that Type A + B individuals occur in regions of inferred introgression, and that this mixed phenotype is comparatively rare. Our results support strong directional local selection leading to fixation of alternative venom phenotypes on a fine geographic scale, and are inconsistent with balancing selection to maintain both phenotypes within a single population. Our comparisons to biotic and abiotic factors further indicate that venom phenotype correlates with fang morphology and climatic variables. We hypothesize that links to fang morphology may be indicative of co-evolution of venom and other trophic adaptations, and that climatic variables may be linked to prey distributions and/or physiology, which in turn impose selection pressures on snake venoms

Diversification and Local Adaptation in Western Fence Lizards, Sceloporus occidentalis

Thesis (Ph.D.)--University of Washington, 2019I am fascinated by intraspecific variation–by both its sources and its potential implications for how organisms interact with their environments. The importance of intraspecific variation for predicting species responses to climate change has recently become a research priority. Differences in the sources of intraspecific variation–genetic divergence, phenotypic plasticity, and drift–can have profoundly different outcomes for species responses. Variation in traits produced by heritable differences in genes will be sensitive to future selection, while variation produced by phenotypic plasticity may be buffered. Time and again, mechanistic studies of species responses have highlighted the importance of considering trait variation to predict idiosyncratic responses, and the sources of trait variation must also be considered. I studied intraspecific variation in Western Fence Lizards (Sceloporus occidentalis) at three spatial scales and three levels of organization. In Chapter 1 I investigated species-wide phylogeographic patterns and demographic scenarios throughout western North America. In Chapter 2 I characterized clinal variation in genotypes and phenotypes and gene flow along an elevation gradient in Yosemite National Park. In Chapter 3 I disentangled the genetic and plastic constituents of divergent phenotypes in a lab rearing experiment. My dissertation research provides an integrative framework for studying local adaptation in a polymorphic and well-established vertebrate system. Chapter 1 is the culmination of over two decades of research on phylogeographic structure within S. occidentalis. We sampled 108 individuals from 83 localities throughout the range in western North America. We used 4,555 SNPs from ddRADseq to characterize population structure and estimate demographic history. We found five genetically distinct populations including: one in the southwest, south of the Transverse Ranges; two west of the Sierra Nevada-Cascades cordillera, separated from north-to-south just north of San Francisco Bay; and two east of the Sierra Nevada-Cascades cordillera, separated from east-to-west in the Great Basin desert. The branching pattern of populations suggests that populations south of the Transverse Ranges and west of the Sierra Nevada-Cascades cordillera are divergent from populations east of the Sierra Nevada-Cascades cordillera. The predominant mechanism of population divergence is allopatric divergence and contemporary secondary contact, which supports Quaternary glacial cycles as drivers of intraspecific genetic divergence. Chapter 2 builds on foundational work by Leaché et al. (2010) to characterize genetic and phenotypic clines along an elevation gradient in Yosemite National Park. At high elevations lizards are larger and more melanistic, while at low elevations lizards are smaller and lighter-colored. We sampled 78 individuals from a 21 km stretch of the Grand Canyon of the Tuolumne River in northern Yosemite. The elevation gradient spanned 1321 m from N Hetch Hetchy Reservoir (37.9168 N, 119.6595 W, 1167 m) in the west to E Glen Aulin (37.9076 N, 119.4196 W, 2488 m) in the east. We used 721 SNPs from ddRADseq to characterize genetic clines and estimate demographic history of populations along the elevation gradient. We found evidence for additional population structure and genetic divergence between phenotypically divergent individuals; one genetically distinct population corresponds to low elevation individuals and another corresponds to high elevation individuals. Analyses of SNPs, maximum size (snout-vent length, SVL), and coloration (ventral patch area) confirm that genes and phenotypes vary clinally, and not discretely, along the elevation gradient. Genetically distinct populations diverged in allopatry, but contemporary gene flow between populations is asymmetric. Genes flow uphill, with five times as many migrants entering the high elevation population from low elevation than the converse. Chapter 3 delves into the underlying sources of trait divergence between low and high elevation individuals from the Grand Canyon of the Tuolumne River elevation gradient. While low and high elevation lizards mature at the same age, high elevation lizards are larger and more melanistic than low elevation lizards. We disentangled the genetic and environmental constituents of phenotypic variation by rearing hatchling lizards under controlled lab conditions. We collected five gravid females from low elevation (N Hetch Hetchy Reservoir [37.96 N, -119.78 W, ca. 1200 m]) and eight gravid females from high elevation (Glen Aulin [37.91 N, -119.42 W, ca. 2400 m]), who produced 36 and 51 hatchling lizards, respectively. We evenly distributed hatchlings from both populations among two treatments that varied in potential activity time: short activity period (6 hrs) and long activity period (12 hrs). We varied activity time by limiting access to heat-lamp-produced thermal gradients, which are necessary for thermoregulation. We found evidence that differences in size are genetically-based; high elevation hatchlings were larger than low elevation hatchlings, regardless of treatment. We found evidence that differences in color are at least partially produced by phenotypic plasticity; high elevation hatchlings were capable of plastically lightening to a color that was lighter than low elevation hatchlings. We found evidence that differences in behavior are genetically-based; high elevation hatchlings spent more time engaged in active behaviors. Overall, our findings are suggestive of local adaptation of high elevation hatchlings to restricted activity periods at high elevation

Triple negative breast cancer: Early stages management and evolution, a two years experience at the department of breast cancer of CHSF

Breast cancer is the most common cancer in women and is a major public health problem. It is divided into several subtypes, including triple negatives. The general objective of our study is to establish the profile and the management of patients with triple negative breast cancer over a period of 2 years, operated in our department. During our study period, triple-negative breast cancers accounted for 10% of our population. The most affected age group ranges from 50 to 60. The majority of patients in our sample are pauciparous. In the group of patients who received hormone therapy, it was mainly HRT for 4 to 6 years. 96.77% of patients consulted a health worker within 3 months of the discovery of the signs. Adenopathies are frequently present at the time of diagnosis. 93.54% of the cases have an invasive ductal carcinoma. Triple negative cancers are essentially poorly differentiated. Triple-negative cancer has a high rate of cell renewal. In our study, neoadjuvant chemotherapy is mostly indicated for triple-negative breast cancers ≥ 30 mm at diagnosis and a delayed lumpectomy is then performed in 23.52% of the patients. For tumors of < 30 mm size, a lumpectomy is performed immediately in 76.47% of the patients, followed by adjuvant chemotherapy. Mastectomy was performed in 45.16% of patients; it was mainly indicated in front of a large tumor size associated with a small breast volume, then multifocal breast tumors. Breast reconstruction was performed in 21.42%. Radiation therapy is indicated in the majority of patients, postoperatively. In our population, 11 patients were proposed to have an oncogenetic survey; it was mainly indicated based on the Manchester criteria in front of a young age and a family history of cancer. There are two BRCA 1 mutations, one BRCA 2 mutation, and one case of absence of mutation. The therapeutic intake in case of a mutation is directed towards a prophylactic bilateral mastectomy and adnexectomy, proposed at the age of 40. Two patients had presented triple negative recurrences of their already treated breast cancer; first case PDL1 positive PD-L1 ≥ 1% treated with immunotherapy combined with chemotherapy (atezolizumab/abraxane) while the second and second PDL1 negative treated with chemotherapy alone. Despite their low frequency, triple negative breast cancers represent a subgroup marked by pejorative characteristics, a reserved prognosis, with limited treatment options

COVID-19 in pregnancy: Our experience at a tertiary maternity unit in France

Objectives: Our main objectives are to reveal the pregnancy and neonatal impacts of COVID-19 infection and to compare it to the results that are reported in the literature. Methods and materials: The characteristics of the admitted pregnant patients COVID-19 positive with their initial presentation, course at the hospital, and short term follow-up are exposed. Correlation of the age and gestational age with the severity of the disease was calculated. Results: Thirty five COVID-19 positive pregnant patients presented between the beginning of March and the end of April 2020. From 5 weeks till 41 weeks of gestation, all trimesters were included. The mean of age is 32 and the BMI equal 28.2. Associated comorbidities included not only diabetes and hypertension but also PCOS. The symptomatology was considered mild in most of the cases. The distribution of the symptoms included cough in 86%. 10 out of 35 delivered and cesarean was performed in 50% of the cases. The mean length of stay is 6 days. Neither maternal nor neonatal deaths occurred. There is a significant correlation between the age of the patient and the severity of the disease but this is not the case with gestational age. Conclusion: Our results were comparable to the literature in terms of initial presentation, associated comorbidities and the length of stay. Despite the fact that the cesarean rate was high, it was far below that of the literature. More data is still needed about COVID-19 in pregnancy