The early C. elegans embryo is a powerful model to study the global genetic architecture underlying development. During the current funding period we have (1) identified most of the genes required for all visible processes during early embryonic development using large-scale RNAi followed by analysis of time-lapse recordings;(2) built a global view of the molecular complexes required for early embryogenesis by integrating high-resolution phenotypes with other functional genomic data;and (3) explored the properties of the map by studying the function of several new proteins. For example, we have found that MEL-28 plays an essential role coordinating nuclear envelope and kinetochore functions in the early embryo. In the current proposal we aim to extend these studies to identify the role of proteins beyond the essential ones and to identify how the essential complexes are coordinated and functionally linked with one other. We have developed a high-throughput system for genome-wide RNAi to identify suppressor and enhancer interactions using existing conditional alleles. Using ~30 alleles of representative genes from diverse processes in the early embryo, we aim to apply this approach to build a global scaffold of suppressor and enhancer interactions in the early embryo. We expect that the identification and analysis of these genetic interactions will extend dramatically our view of the genes working in the early embryo and how they interact to coordinate biological processes. Elucidating these mechanisms will help further our understanding of complex phenotypes underlying human disease. 1 7. Narrative A fundamental question, now that the human genome sequence has been elucidated, is to understand how it directs complex biological and development programs in both normal and disease states. Over the last few years we have made progress in deciphering the single gene requirements in many basic developmental processes but we have a very limited view of how multi-gene interactions affect these programs. Since most human diseases arise from complex effects of multiple interacting components it is imperative that we gain insights into these mechanisms. We will conduct genome-wide analyses to uncover genetic interactions required during the early developmental programs in the genetic model C. elegans. The resulting map will help us understand complex genetic networks underlying development and disease in humans. 1

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046236-09
Application #
8197020
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Coulombe, James N
Project Start
2003-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$537,303
Indirect Cost
$185,094
Name
New York University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
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Fernandez, Anita G; Mis, Emily K; Lai, Allison et al. (2014) Uncovering buffered pleiotropy: a genome-scale screen for mel-28 genetic interactors in Caenorhabditis elegans. G3 (Bethesda) 4:185-96
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Fernandez, Anita G; Mis, Emily K; Bargmann, Bastiaan O R et al. (2010) Automated sorting of live C. elegans using laFACS. Nat Methods 7:417-8

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