Dnmt3L haploinsufficent retrotransposition leads to genetic hypermutation

最近人类和哺乳动物遗传学研究的一个意外发现是我们基因组内的多态性程度，高达3.7%的基因组显示拷贝数变异（CNV）。由此产生的问题包括：新生CNV发生的频率和CNV引起疾病的频率？如果引起CNVs的减数分裂突变如此频繁，那么有丝分裂突变也很可能比以前认为的更常见。这些突变可能导致许多疾病，这取决于受影响的细胞类型和（生命期间）<br /> 发生有丝分裂突变。CNV是由各种突变机制产生的，包括减数分裂重组、同源定向和非同源修复双链断裂以及复制错误1。我们认为，表观遗传学，DNA甲基化和逆转录转座因子（RTE）是基因组稳定性和不稳定性的关键因素，包括逆转录转座突变和CNV的产生。由于减数分裂对哺乳动物基因组的强烈选择压力，以及多代后代的适应性，RTE已经塑造了基因组的进化，并将继续这样做。由于表观遗传失调如DNA甲基化已被证明具有跨代效应，这可能取决于起源的亲本，因此基因组稳定性可能存在差异，这取决于失调发生的时间（哪代）和地点（哪代亲本）。如果发生在生殖细胞中的表观遗传失调在受精后传递给子细胞，那么体细胞突变可能会增加，这可能是特定细胞区室所特有的，正如最近对神经祖细胞的研究所暗示的那样。我们使用一个小鼠模型，<br /> 通过使用下一代测序（NGS），将RTEs的甲基化去调节，以寻找生殖系和体细胞突变，包括CNV。这项研究将在生育力，遗传和先天性缺陷，疾病发展和基因组进化等领域产生影响。

An unexpected finding resulting from recent human and mammalian genetics studies has been the extent of polymorphism within our genome, with up to 3.7% of it showing copy number variation (CNV). Questions arising include: how often does de novo CNV occur and how often do CNVs cause disease? If meiotic mutation causing CNVs can be so frequent, it is also likely that mitotic mutation is more common that previously thought. These mutations may contribute to numerous diseases, depending on the cell type affected and the time point at which (during life)<br /> mitotic mutation occurs. CNVs are generated by various mutational mechanisms including meiotic recombination, homology-directed and non-homologous repair of double-strand breaks, and errors in replication1. We believe that epigenetics, DNA methylation and RetroTransposable Elements (RTE) are key contributors to genome stability and instability, including mutation by retrotransposition and generation of CNV. With the intense selective pressure on mammalian genomes due to meiosis, and the fitness of offspring over multiple generations, RTEs have shaped the evolution of the genome, and continue to do so. Because epigenetic deregulation such as DNA methylation has been shown to have transgenerational effects which may depend on the parent of origin, there is the potential that there are differences in genome stability depending on when (which generation) and where (which parent (s)) the deregulation occurred. If the epigenetic deregulation that occurs in germcells is passed on to daughter cells after fertilization, there may be an increase in somatic mutation, which may be particular to a specific cellular compartment, as implied by a recent study in neural progenitor cells. We use a mouse model in which DNA<br /> methylation of RTEs is deregulated, to look for both germline and somatic mutation, including CNV, using Next Generation Sequencing (NGS). This study will have implications in the fields of fertility, genetic and congenital defects, development of disease, and genome evolution.