Dnmt3L haploinsufficent retrotransposition leads to genetic hypermutation

最近的人类和哺乳动物遗传学研究得出了一个意想不到的发现，即我们基因组中的多态性程度，高达3.7%的基因组显示拷贝数变异（CNV）。出现的问题包括：新生CNV发生的频率以及CNV引起疾病的频率？如果导致CNVs的减数分裂突变如此频繁，那么有丝分裂突变也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（在生命中）<br />的时间点

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.