Clonal competition in stem cells as a driver of paternal age effect diseases

描述（由申请人提供）：各种疾病，包括自闭症，精神分裂症，软骨发育不全，Apert综合征和一些癌症在年长父亲所生的孩子中更常见。这种关联被称为父亲年龄效应（PAE）。高通量、低成本的DNA测序技术最近在这些疾病中的一些中产生了非常大量的候选从头等位基因（例如，自闭症和精神分裂症）。人类睾丸中突变精原干细胞（SSC）的阳性选择可能使异常精子能够将这种从头突变等位基因贡献给下一代，导致观察到的病理学。我们正在解决这一假设，操纵成人精原干细胞在文化中，结合移植在体内，以提供直接的，实验证据的假定机制的PAEs。该项目的目标是解决特定疾病相关突变的机制，并开发一种发现和快速验证新突变的方案。为了设计策略来防止 或治疗遗传性疾病，了解它们的分子起源将是非常有价值的。本文所述的实验将支持PAE的共同机制，并且将显示PAE疾病可以被认为是原型干细胞疾病。突变等位基因发现的体外建模方法最终可以克服鉴定与多基因PAE疾病相关的遗传病变的一些技术障碍（例如，自闭症），否则需要大量的人类数据集。通过提高我们对PAE疾病发病机制的细胞基础和离散突变的作用的理解，SSC的实验操作可以直接为患者带来新的治疗策略。

DESCRIPTION (provided by applicant): A variety of disorders, including autism, schizophrenia, achondroplasia, Apert Syndrome, and some cancers are more common in those born to older fathers. This association has been referred to as the paternal age effect (PAE). High-throughput, low-cost DNA sequencing techniques have recently yielded very large numbers of candidate de novo alleles in some of these diseases (e.g., autism and schizophrenia). Positive selection of mutant spermatogonial stem cells (SSCs) in the human testis may enable aberrant sperm to contribute such de novo mutant alleles to the next generation, resulting in the observed pathology. We are addressing this hypothesis by manipulating adult SSCs in culture, in conjunction with transplantation in vivo, in order to provide direct, experimental evidence for a putative mechanism of PAEs. The goals of the project are to address the mechanisms of specific disease-associated mutations and develop a protocol to discover and rapidly validate novel mutations. In order to design strategies to prevent or treat inherited disorders, an understanding of their molecular origins will be extremely valuable. The experiments described herein would support a common mechanism for PAEs and would show that PAE diseases could be considered prototypical stem cell-based diseases. An in vitro modeling approach to mutant allele discovery could eventually overcome some of the technical barriers to identification of genetic lesions associated with multigenic PAE diseases (e.g., autism), which otherwise requires large human data sets. By improving our understanding of the cellular basis for PAE disease pathogenesis and the roles of discrete mutations, experimental manipulation of SSCs could lead directly to novel therapeutic strategies for patients.