Doctoral Dissertation Research: Ancient Genomics and the Molecular Mechanisms of Human Tolerance to Arsenic

砷会对人类造成严重的毒理学影响，但一些人类群体已经进化到对这种元素的耐受。今天，一些地区的人们可能携带着一种关键酶的保护性突变，该酶在肝脏中代谢砷。然而，关于砷耐受的进化史和遗传基础，有几个方面仍然不清楚。因此，这项博士论文研究项目研究了古代和现代暴露于砷的人群的DNA样本的遗传史、生存模式和基因调控机制。这些发现可以扩大我们对生物文化过程的理解，通过这些过程，人类能够适应他们的环境。该项目还支持本科生和研究生的学生指导和培训机会，国际研究合作机会，以及通过会议和社交媒体传播科学。该项目的核心是了解生活在砷丰富地区的古代和现代人口的文化和生物多样性。具体地说，讨论了三个主要问题：(1)古代和现代人口之间的遗传史和关系是什么？(2)向农业的过渡对饮食和口腔健康有何影响？以及(3)与砷耐受相关的突变在AS3MT基因的表达中扮演什么角色/功能？研究人员利用古代DNA和现代基因组数据重建了该地区的基因史前。此外，来自古代牙石的口腔微生物组数据被用来描述史前饮食、口腔健康和农业前和农业人口的环境暴露。第三，携带保护性突变的基因序列被用于实验评估它们是否在体外改变/调节AS3MT基因的表达。这一裁决反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Arsenic causes severe toxicological effects in humans, yet some human populations have evolved to tolerate this element. Today, people in some regions may carry protective mutations in a key enzyme that metabolizes arsenic in the liver. However, several aspects remain unclear about the evolutionary history and genetic basis of arsenic tolerance. This doctoral dissertation research project therefore examines the genetic history, modes of subsistence, and gene regulatory mechanisms in ancient and modern DNA samples from populations exposed to arsenic. The findings can expand our understanding of biocultural processes through which humans are able to adapt to their environment. The project also supports student mentorship and training opportunities for undergraduate and graduate students, opportunities for international research collaborations, and science dissemination through conferences and social media.This project is centered on the understanding of the cultural and biological diversity of ancient and modern populations living in an arsenic rich region. Specifically, three main questions are addressed: (1) what are the genetic history and relationships among ancient and modern populations? (2) how did the transition to agriculture impact diet and oral health? and (3) what role/function do the mutations associated with arsenic tolerance play in the expression of the AS3MT gene? The researcher reconstructs the genetic prehistory of the region using ancient DNA and modern genomic data. In addition, oral microbiome data from ancient dental calculus are used to characterize the prehistoric diet, oral health and environmental exposures among pre-agricultural and agricultural populations. Third, genetic sequences carrying protective mutations are used to assess experimentally whether they alter/regulate the expression of the AS3MT gene in vitro.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.