title: Variability in gene expression underlies incomplete penetrance.
abstract: The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.
authors.affiliation: Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raj
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rifkin
authors.forename: Erik
authors.initials: E
authors.lastname: Andersen
authors.forename: Alexander
authors.initials: A
authors.lastname: van Oudenaarden
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050980:GATA Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000196:embryology; D008957:Models, Genetic; D019683:Penetrance; D018510:RNA, Helminth / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D013269:Stochastic Processes; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C094134:ELT-2 protein, C elegans; C109211:END-1 protein, C elegans; D050980:GATA Transcription Factors; D018510:RNA, Helminth; D012333:RNA, Messenger; D014157:Transcription Factors; C073702:skn-1 protein, C elegans