Variation and inheritance of retrotransposon epigenotype in the mouse

人们通常认为，人类和其他哺乳动物的特征主要是DNA序列编码信息的产物，环境也有一定影响。然而，有明确的证据表明，即使在环境差异可以忽略不计的情况下，具有完全相同DNA的个体（如同卵双胞胎）的特征也可能存在很大差异。这种变异可以由表观遗传因素产生，化学变化或蛋白质与DNA的结合改变了基因的使用方式。表观遗传因素可以像DNA本身一样从一代传递到下一代，这使得很难知道一个特征是在DNA本身中编码还是表观遗传。我们发现小鼠的一些表观遗传性状是由反转录转座子引起的，这是一种寄生在基因内和基因之间的元素，可以自我繁殖，但没有任何已知的功能（人类基因组近一半是由反转录转座子组成的）。反转录转座子通常由于表观遗传因素而保持沉默，但有时也会变得活跃；当它们这样做时，它们可能会扰乱正常的基因活动模式，导致性状变化甚至疾病。因此，人类的许多变异可能是由于逆转录转座子的表观遗传状态（表观遗传型）的变异。我们建议研究小鼠表观基因型的变异和遗传，重点关注反转录转座子。我们将使用简单的方法来比较基因相同的小鼠中一些反转录转座子的表观基因型，我们将询问我们发现的任何差异是否可遗传。我们还将研究表观遗传型的重置，即表观遗传因素被清除和重置的发育点。我们怀疑这种情况发生在发育早期。这些研究可能揭示了一个与孟德尔发现的规则完全不同的变异和遗传系统，它可能对特征有广泛的影响，包括人类的散发性疾病。

It is often assumed that traits in humans and other mammals are a product primarily of information encoded in the sequence of DNA, with some contribution from the environment. However, there is clear evidence that traits may vary widely between individuals with precisely the same DNA, such as identical twins, even in circumstances where environmental differences are negligible. This variation can be produced by epigenetic factors chemical changes or protein binding to DNA that alter the way genes are used. Epigenetic factors can be passed from one generation to the next like the DNA itself, and this can make it difficult to know if a trait is encoded in the DNA itself or is epigenetic. We have found that some epigenetic traits in mice are caused by retrotransposons, which are parasitic elements that reside in and among genes, and can reproduce themselves, but do not have any known function (nearly half the human genome is made up of retrotransposons). Retrotransposons are generally kept silent by epigenetic factors, but may sometimes become active; when they do they may disturb normal patterns of gene activity and cause changes in traits and even disease. Much variation in humans may thus be due to variation in the epigenetic state (epigenotype) of retrotransposons. We propose to investigate variation and inheritance of epigenotype in mice, focussing on retrotransposons. We will use simple methods to compare epigenotype of a number of retrotransposons in genetically identical mice, and we will ask if any differences we find are heritable. We will also investigate the resetting of epigenotype the point in development when epigenetic factors are cleared and reset. We suspect that this occurs in early development. These studies may reveal a system of variation and inheritance with rules completely different from those found by Mendel, which may have a pervasive influence on traits, including sporadic diseases in humans.