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.

Public Health Relevance

Multicellular organisms begin as a single cell that proliferates and develops into differentiated cell types, and this shared origin and identical genomic content allows cells to communicate, cooperate, and form a functional organism. Instead, the planarian asexual form of reproduction- fission - relies on the necessity of hundreds of thousands of stem cells to regenerate lost organs after transverse splitting, directly challenging this paradigm. Knowing how obligate fission-reproducing planaria enforce cell cooperation will aid research on human tissue regeneration, stem cell differentiation, and cancer evolution.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098741-02
Application #
8322615
Study Section
Special Emphasis Panel (ZGM1-GDB-7 (EU))
Program Officer
Eckstrand, Irene A
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$328,000
Indirect Cost
$128,000
Name
University of Southern California
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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