Blended Inheritance As a Genetic Consequence of Unlimited Regeneration

混合遗传是无限再生的遗传结果

• 批准号: 8534198
• 负责人: Sergey V Nuzhdin
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534198
• 关键词: Adult; Affect; Animals; Back; Biological Models; Biomedical Engineering; Cell Communication; Cell Differentiation process; Cells; Communication; Communities; Conflict (Psychology); DNA Resequencing; Data; Development; Dugesia (turbellarian); Employee; Employee Strikes; Equilibrium; Escherichia coli; Evolution; Fresh Water; Future; Generations; Genetic; Genetic Identity; Genetic Models; Genetic Variation; Genome; Genomics; Germ Cells; HIV; Health; Heterogeneity; Human; Individual; Karyotype; Knowledge; Laws; Learning; Longevity; Malignant Neoplasms; Measurement; Mediating; Meiosis; Meristem; Messenger RNA; Modeling; Molecular Genetics; Mutation; Natural regeneration; Nature; Organ; Organism; Pathway interactions; Patients; Planarians; Plants; Pluripotent Stem Cells; Population; Population Genetics; Population Sizes; Process; Proliferating; RNA Sequences; Regulation; Reproduction; Research; Research Personnel; Route; Sampling; Secure; Staging; Stem cells; Subgroup; Technology; Testing; Time; Tissue Donors; To specify; Totipotent Stem Cells; Variant; Wages; Work; asexual; cancer cell; cell motility; cell type; deep sequencing; experience; fly; genetic analysis; human tissue; insight; interest; models and simulation; next generation; prevent; regenerative; reproductive; research study; stem cell differentiation; systems research; theories; tissue regeneration; transcriptome sequencing; transplantation medicine

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.

描述（由申请人提供）：解开遗传学规律和发育调节的分子本质的世纪是通过对主力模型的灵感选择而实现的：coli转化为M.阿提库斯所有这些都遵循孟德尔遗传的规则，使它们的遗传分析合乎逻辑和简单明了。由于生殖过程中的单细胞瓶颈，构成这些生物体的细胞的生殖利益是一致的。这些原则对癌细胞不起作用，癌细胞积累了促进繁殖的突变。这些细胞对以其他非癌细胞为代价进行繁殖“感兴趣”，从而伤害“宿主生物体”。这种情况说明了多玩家社区之间的典型“冲突”--无论是异质性艾滋病毒在患者体内繁殖，缩短他们的寿命，还是员工通过罢工争取更高的工资来损害公司的竞争力。Planarians是一个流行的模型，用于分析更新。在未来，再生将使人类健康取得巨大进步。必要时，再生将导致由异质细胞基因组组成的生物体。正如供体组织排斥一直是移植医学中的一个问题，当再生技术变得先进时，问题将在于细胞之间缺乏沟通和合作。传统的遗传模型不足以解释生物体内部的冲突和细胞错误通讯的规则，但真涡虫却可以。它们通常是有性生殖或孤雌生殖的--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突变废除减数分裂，它仍然可以愉快地生存。这是因为涡虫的再生能力不受限制。涡虫可以在任何轴向方向切割，所有缺失的成体解剖特征都可以完全再生。在20世纪70年代，三角洲gonocephala planarian人口是固定的减数分裂妥协突变被发现。这些种群完全通过裂变繁殖。2010年，来自这些意大利种群的额外的Planarians样本被安全地带到PI的实验室。它们仍然通过横向分裂和随后的再生进行明显的繁殖。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。它们拥有多少个体内的遗传变异？在多能细胞迁移和分化过程中，真涡虫如何解决细胞间的生殖冲突？真涡虫如何调节遗传异质细胞之间的沟通和协调问题？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用于回答这些和其他问题。摩根在遗传学上的第一个实验是在真涡虫身上进行的，但他转而用一个更简单的苍蝇模型来描述孟德尔遗传规律。现在是时候回到混合遗传模型了，在这个模型中，数十万个基因组代代相传。