Blended Inheritance As a Genetic Consequence of Unlimited Regeneration

描述（由申请人提供）：一个世纪的遗传学规律和发育调节的分子本质是由灵感选择的主力模型：从大肠杆菌到家养m.s。它们都遵循孟德尔遗传法则，使基因分析合乎逻辑且简单明了。由于繁殖过程中的单细胞瓶颈，构成这些生物体的细胞的繁殖利益是一致的。这些原理并不适用于癌细胞，癌细胞已经积累了促进繁殖的突变。这些细胞“有兴趣”以牺牲其他非癌细胞为代价进行繁殖，从而损害“宿主生物”。这种情况说明了多玩家社区之间的典型“冲突”——可能是异质HIV病毒在患者体内繁殖，缩短了患者的寿命，或者是员工通过罢工要求更高的工资而损害了公司的竞争能力。涡虫是一种流行的再生分析模型。在未来，再生将使人类健康取得巨大进步。在必要的情况下，再生将产生一个由异质基因组细胞组成的有机体。就像供体组织排斥一直是移植医学的一个问题一样，当再生技术变得先进时，细胞之间缺乏沟通和合作将成为一个问题。传统的遗传模型不足以解释生物内部冲突和细胞错误沟通的规则，但涡虫是。它们要么是有性繁殖，要么是孤雌繁殖——这两个过程都涉及减数分裂和基因组瓶颈。然而，当一个涡虫谱系遇到一个消除减数分裂的突变时，它仍然可以快乐地生存。这是由于涡虫无限制的再生能力。涡虫可以在任何轴向切割，完全再生所有缺失的成人解剖特征发生。在20世纪70年代，发现了因减数分裂妥协突变而固定的gonocephala涡虫种群。这些种群完全通过裂变繁殖。2010年，从这些意大利种群中获得的更多涡虫样本被带到PI的实验室。它们仍然通过横向裂变和随后的再生来明确地繁殖。它们必须代表“基因组被子”，其中个体由多种遗传异质性细胞群体类型组成。他们拥有多少个体内部遗传变异？涡虫在多能性细胞迁移和分化过程中如何解决细胞间的生殖冲突？涡虫如何介导基因异质细胞之间的通讯和协调问题？个体基因组的深度测序，分化过程中个体多能细胞的mRNA测序，以及近似贝叶斯计算将被用来回答这些问题。摩根在《遗传学》上的第一个实验是用涡虫做的，但他转而用一个更简单的苍蝇模型来描述孟德尔遗传定律。现在是回到混合遗传模式的时候了，在这种模式下，成千上万的基因组一代一代地传递。

DESCRIPTION (provided by applicant): The Century of untangling the laws of Genetics, and molecular nature of developmental regulation was enabled by inspired choice of workhorse models: from E. coli to M. domesticus. All of them abide to the rules of Mendelian inheritance, making the genetic analyses in them logical and straightforward. The reproductive interests of cells constituting these organisms are aligned due to a single cell bottleneck during reproduction. These principles do not work for cancer cells, which have accumulated mutations promoting reproduction. These cells are 'interested' in reproducing at the expense of other non-cancer cells, thereby harming the 'host organism'. This scenario illustrates a typical 'conflict' between multi-player communities - be it heterogeneous HIV viruses multiplying within a patient, shortening their lifespan, or employees hurting the competitive ability of a company by striking for a greater salary. Planarians are a popular model for the analyses of regeneration. Regeneration will, in the future, enable dramatic advances in human health. By necessity, regeneration will result in an organism consisting of heterogeneous genomes of cells. Just as donor-tissue rejection has been a problem in transplant medicine, when regeneration technologies become advanced, a problem will be in the lack of communication and cooperation between cells. Traditional genetic models are inadequate for deciphering the rules of intraorganismal conflicts and cell mis-communication, but planarians are. They are typically either sexual or parthenogenetic - both processes involving meiosis and a genome bottleneck. However, when a planarian lineage encounters a mutation abolishing meiosis, it can still happily survive. This is due to the planarian unrestricted regenerative ability. Planarians can be cut in any axial orientation and complete regeneration of all absent adult anatomical features occurs. In the 1970s, Dugesia gonocephala planarian populations that are fixed for meiosis-compromising mutations were discovered. These populations reproduce exclusively by fission. Additional samples of planarians from these Italian populations were secured and brought to the PI's lab in 2010. They still reproduce explicitly by transverse fission with subsequent regeneration. They must represent 'genomic quilts', where individuals are made of multiple genetically heterogeneous cell population types. How much intraindividual genetic variation do they possess? How do planarians resolve reproductive conflicts among cells in the process of pluripotent cell migration and differentiation? How do planarians mediate communication and coordination problems between genetically heterogeneous cells? Deep sequencing of individuals genomes, mRNA sequencing of individual pluripotent cells in the process of differentiation, and approximate Bayesian computations will be used to answer these and other questions. Morgan's first experiments in Genetics were with planarians, but he switched to a simpler fly model to describe the laws of Mendelian inheritance. It is time now to come back to the model of blended inheritance, in which hundreds of thousands of genomes are transmitted from generation to generation.