DISSERTATION RESEARCH: Early social experience and epigenetic mediation of adult phenotypes

啮齿动物模型、对圈养灵长类动物的研究和来自人类的数据表明，早期生活经历对健康有长期影响，而且早期生活经历和寿命往往因社会经济地位而异。本研究利用现有的数据和存档的生物标本，从一个长期的实地研究的群居哺乳动物的社会结构，允许比较的地位阶级，以评估早期社会环境的气质和健身的影响。需要评估的早期环境影响包括产妇护理质量、同伴互动和社会地位。现有的数据和标本允许探索早期社会环境，基因表达机制，循环应激激素，个人气质和寿命之间的关系。所采用的方法包括高通量下一代DNA测序技术，生物信息学和先进的统计方法。这项工作的更广泛的影响包括更深入地了解不利压力表型的社会和分子决定因素。最终，塑造自由生活的群居哺乳动物成年压力表型的早期生活社会因素的特征将有助于将研究结果推广到其他社会物种，包括我们自己。除了支持上述科学工作外，该项目还将促进专门为密歇根州立大学非洲研究生协会成员设计的研究方法和数据分析系列讲习班。生命早期的社会经历通常通过基因的表观遗传修饰以及协调下丘脑-垂体-肾上腺轴的基因表达模式对成年气质和压力表型产生持久影响。使用来自MSU Mara Hyena项目的数据，该项目对肯尼亚自由生活的群居鬣狗进行了28年的研究，该提案将调查社会因素如何与不利的压力表型相关，并阐明这种关系在多大程度上是由DNA甲基化介导的。该项目的资金将支持两个研究目标。首先，该提案将使用简化表示亚硫酸氢盐测序（RRBS）来识别鬣狗基因组的差异甲基化区域（DMR），这些区域与成年鬣狗气质和应激激素的评估以及早期社会经验（包括母亲等级，母亲护理和与氏族伴侣的互动）的高与低应激表型相关。将通过数据增强使用计数数据的混合模型关联来识别预测成年应激表型的DMR。第二个目标是使用中介分析来评估所确定的社会诱导的、与压力相关的表观遗传途径是否介导了早期经历对长寿的影响。这项工作的发现将提高社会因素如何影响行为和生理应激表型的一个重要的新动物模型的机械理解。因为一个近似的表观遗传机制（DNA甲基化）与最终结果（适应性）相关，这项工作代表了理解表观遗传学在进化中的作用方面的一大步-这是一个基本上未被探索的概念。

Rodent models, studies of captive primates, and data from human populations indicate that early life experiences have long-lasting effects on health, and that early life experiences and longevity often vary with socioeconomic status. This study utilizes existing data and archived biospecimens from a long-term field study of a gregarious mammal with a social structure permitting comparisons among status classes to assess effects of the early social environment on temperament and fitness. Effects of the early environment to be assessed include quality of maternal care, peer interactions and social status. Available data and specimens permit exploration of relationships among the early social environment, mechanisms of gene expression, circulating stress hormones, individual temperament, and longevity. The methods employed include high-throughput next-generation DNA sequencing techniques, bioinformatics and advanced statistical methods. Broader impacts of this work include a deeper understanding of social and molecular determinants of adverse stress phenotypes. Ultimately, characterization of the early life social factors that shape adult stress phenotypes in free-living, gregarious mammals will facilitate generalization of the research findings to other social species, including our own. In addition to supporting the scientific work above, this project will facilitate a workshop series on research methods and data analysis designed specifically for members of the African Graduate Student Association at Michigan State University. Social experiences early in life have lasting effects on adult temperament and stress phenotype, often through epigenetic modification of genes, and thus patterns of gene expression, that coordinate the hypothalamic-pituitary-adrenal axis. Using data from the MSU Mara Hyena Project, a 28-year study of free-living, gregarious hyenas in Kenya, this proposal will investigate how social factors relate to adverse stress phenotypes, and elucidate the extent to which this relationship is mediated by DNA methylation. Funding from this project will support two research goals. First, this proposal will use Reduced Representation Bisulfite Sequencing (RRBS) to identify differentially methylated regions (DMRs) of the hyena genome that are associated with high vs. low stress phenotypes based on assessment of adult hyena temperament and stress hormones, as well as differences in early social experiences including maternal rank, maternal care, and interactions with clan mates. DMRs that are predictive of the adult stress phenotypes will be identified using Mixed Model Association for Count data via data Augmentation. The second goal is to use mediation analysis to assess whether the identified socially-induced, stress-related epigenetic pathways mediate the effect of early experience on longevity. Findings from this work will improve mechanistic understanding of how social factors affect behavioral and physiological stress phenotypes in an important new animal model. Because a proximate epigenetic mechanism (DNA methylation) is assessed in relation to an ultimate consequence (fitness), this work represents a large step forward in terms of understanding the role of epigenetics in evolution - a concept that has been largely unexplored.