Identification and functional characterisation of environmentally responsive rDNA variants in the human genome

哺乳动物的表型受遗传和环境相互作用的影响。因此，了解这些基因-环境相互作用如何在细胞水平上发生，对于阐明哺乳动物表型的起源至关重要。最近，我的团队发现，在生命早期为小鼠提供减少蛋白质饮食会导致整体体型缩小，这与核糖体DNA（rDNA）活性降低有关。rDNA是基因组的重要组成部分，编码蛋白质合成所需的分子，从而允许细胞生长。我们研究中最令人惊讶的发现是，rDNA的遗传序列在个体之间存在差异，从而影响任何特定个体对低蛋白饮食等应激环境的反应能力。在高脂肪饮食中也发现了相关的影响。我假设类似的效应也发生在人类身上。也就是说，一个人对压力条件做出反应的内在能力受到其rDNA遗传组成的影响。我想识别这些人类rDNA变异并了解它们的功能。拟议的工作有可能产生新的和重要的见解如何基因-环境相互作用影响人类的表型和疾病的结果。

Mammalian phenotypes are influenced by the interaction between genetics and environment. Understanding how these gene-environment interactions occur at the level of the cell is therefore crucial for elucidating the origins of mammalian phenotypes. Recently, my team found that providing mice with a reduced protein diet during early life results in reduced overall body size which is correlated with reduced activity of the ribosomal DNA (rDNA). The rDNA is an important part of the genome that codes for molecules required for protein synthesis, thereby permitting cell growth. The most surprising finding of our study was that the genetic sequence of the rDNA varied amongst individuals, thereby influencing any given individual's capacity to respond to stressful environments such as low protein diet. Related effects were also found in response to a high-fat diet. I hypothesize that similar effects occur in humans. That is, an individual's inherent capacity to respond to conditions of stress is influenced by the genetic make up of their rDNA. I would like to identify such human rDNA variants and understand how they function. The proposed work has the potential to yield new and important insights into how gene-environment interactions influence phenotypic and disease outcomes in humans.