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

 描述(由申请人提供) 我们建议对差异免疫系统和生长激素反应进行功能基因组学研究，使用一种新的比较种群方法和自然人类模型。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，其进化史在一定程度上受到这些相对较新的传染病概况变化的影响。迄今进行的大多数疾病遗传关联研究--或对疾病的相关功能基因组反应--仅侧重于以农业为基础的人口。然而，农学家和狩猎采集人口之间的直接比较将为农业转型的进化反应如何影响人类生理提供重要的、新颖的见解。现代人类对疾病的反应以及农学家和狩猎采集者之间不同的其他生物学特征都是如此，比如体型。在拟议的研究中，我们将使用一个强大的体外系统来研究农学家和狩猎采集群体之间的差异免疫系统和生长激素反应，在该系统中，来自每个群体的50-89个人的细胞将受到模拟病毒和细菌感染的生长激素和配体的挑战，随后是RNA-SEQ，以确定全基因组群体在调控反应中的差异。然后将这些结果与全基因组SNP基因型和目标重测序数据进行比较，以识别和表征对种群间免疫反应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理解人类生长发育的功能基因组途径，也有助于阐明人类免疫系统如何受到向农业的文化转型的影响，从而促进我们对现代人类疾病反应和医学结果的理解。

 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.