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-环境相互作用是如何在细胞水平上发生的，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，在小鼠生命早期给予低蛋白质饮食会导致整体体型缩小，这与核糖体DNA(RDNA)的活性降低有关。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的遗传序列在不同的人之间存在差异，从而影响到任何给定的人对压力环境的反应能力，例如低蛋白饮食。对高脂肪饮食的反应也发现了相关影响。我假设类似的影响也会发生在人类身上。也就是说，个体对压力条件作出反应的内在能力受到其rDNA基因组成的影响。我想鉴定这种人类rDNA变体，并了解它们是如何发挥作用的。这项拟议的工作有可能对基因-环境相互作用如何影响人类的表型和疾病结果产生新的重要见解。

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.