Cross_species_somatic_mutation_rate_project___dog

Cancer is the result of the accumulation of mutations in the DNA of somatic tissue during the lifetime of an organism. Therefore, animals that live longer and/or have a larger number of cells should have a higher incidence of cancer. However there appears not to be no clear correlation between the longevity or body-size of a species and its rates of cancer incidence This lack of an expected correlation is known as 'Peto's paradox'. One potential explanation of this paradox is that as species increase in size or longevity there is selection for mechanisms to decrease cancer risk. One potential mechanism for this Is reducing the somatic mutation rate. However, we currently know almost nothing about the somatic mutation rate in non-human species. To address this, we plan to compare the somatic mutation rate in humans, laboratory mice and naked mole-rats. In particular, mice and naked-mole rats have a similar body size yet differ drastically in their longevity, with laboratory mice having a maximum life-span of a few years while naked-mole rats can live >32 years. By quantifying the somatic mutation rate of these species using whole-genome sequence data from monoclonal colonies derived from blood stem cells and laser-capture microdissected individual colonic crypts we will be able to compare the somatic mutation rate across these species. We will also compare the mutational signatures of these species, to learn more about the variation in the mutational processes that underlie somatic mutation across species. These results are expected to further our understanding of the evolution of the somatic mutation rate across species and may have implications for our understanding of cancer.

癌症是生物体一生中体细胞组织（somatic tissue）DNA突变累积的结果。因此，寿命更长或细胞数量更多的动物，其癌症发病率理应更高。然而，物种的寿命或体型与癌症发病率之间似乎并无明确关联，这种与预期相悖的关联缺失现象被称为佩托悖论（Peto's paradox）。
针对该悖论的一种潜在解释是：随着物种体型增大或寿命延长，自然选择会倾向于演化出降低癌症风险的机制。其中一种潜在机制是降低体细胞突变率（somatic mutation rate）。然而，目前我们对非人类物种的体细胞突变率几乎一无所知。
为解决这一问题，本研究拟比较人类、实验小鼠（laboratory mice）以及裸鼹鼠（naked mole-rats）的体细胞突变率。具体而言，实验小鼠与裸鼹鼠体型相近，但寿命差异悬殊：实验小鼠的最长寿命仅为数年，而裸鼹鼠的寿命可超过32年。本研究将利用源自血液干细胞（blood stem cells）的单克隆菌落（monoclonal colonies），以及经激光捕获显微切割（laser-capture microdissected）得到的单个结肠隐窝（colonic crypts）的全基因组测序数据（whole-genome sequence data），对这些物种的体细胞突变率进行定量分析，从而实现跨物种的体细胞突变率比较。同时，我们还将比较这些物种的突变特征（mutational signatures），以深入解析跨物种体细胞突变背后的突变过程差异。
预期本研究结果将增进我们对跨物种体细胞突变率演化的理解，并有望为癌症研究提供新的启示。