Hunter-gatherer vs. agriculturalist growth and immune system functional genomics

 描述（由申请人提供） 我们提出了一个功能基因组学研究的差异免疫系统和生长激素的反应，使用一种新的比较人口的方法与自然的人类模型。大约12，000年前开始的向农业的文化转型促使人类地方性传染病的负担发生了重大转变。绝大多数现代人现在生活在以农业为基础的社会中，其进化史部分是由这些相对较新的传染病特征变化所塑造的。迄今为止，大多数疾病的遗传关联研究--或相关的功能性基因组对疾病的反应--都只关注农业人口。然而，直接比较农业人口和狩猎采集人口将提供重要的，新的见解，如何对农业转型的进化反应影响了人类的生理。这对于现代人类的疾病反应和其他生物特征都是如此，这些生物特征在农学家和狩猎采集者之间存在差异，例如身体大小。在拟议的研究中，我们将使用强大的体外系统研究农业和狩猎采集者群体之间的差异免疫系统和生长激素反应，其中来自每个群体的50-89个个体的细胞将受到生长激素和模拟病毒和细菌感染的配体的挑战，然后通过RNA-seq来确定调节反应中的全基因组群体差异。然后将这些结果与全基因组SNP基因型和靶向重测序数据进行比较，以鉴定和表征对群体间免疫应答和体型差异具有潜在功能和进化意义的遗传基因座。这些综合分析将有助于我们了解人类生长和发育的功能基因组途径，并揭示人类免疫系统如何受到农业文化转型的影响，从而促进我们对现代人类疾病反应和医疗结果的理解。

 DESCRIPTION (provided by applicant) We propose a functional genomics investigation of differential immune system and growth hormone responses, using a novel comparative population approach with a natural human model. The cultural transition to agriculture that began ~12,000 years ago precipitated a major shift in the burden of human endemic infectious diseases. The vast majority of modern humans now live in agriculture-based societies, with an evolutionary history shaped in part by these relatively recent infectious disease profile changes. Most genetic association studies of disease - or of the related functional genomic response to disease - that have been conducted to date have focused exclusively on agriculture-based populations. Yet direct comparisons between agriculturalist and hunter-gatherer populations would provide important, novel insights into how evolutionary responses to the agricultural transition have influenced human physiology. This is true for both the modern human disease response and other biological traits that differ between agriculturalists and hunter-gatherers, such as body size. In the proposed study we will investigate the differential immune system and growth hormone responses between an agriculturalist and hunter-gatherer population using a powerful in vitro system in which the cells of 50-89 individuals from each population will be challenged with growth hormones and ligands that mimic viral and bacterial infections, followed by RNA-seq to identify genome-wide population differences in the regulatory responses. These results will then be compared to genome-wide SNP genotype and targeted resequencing data to identify and characterize genetic loci with potential functional and evolutionary significance for inter- population immune response and body size differences. These integrated analyses will contribute to our understanding of human growth and development functional genomic pathways and also shed light on how the human immune system has been affected by the cultural transition to agriculture, thereby advancing our understanding of the modern human disease response and medical outcomes.