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 homogenous environments vary, suggesting that randomness in developmental processes such as gene expression may also generate diversity. In order to examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the roundworm 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, while 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 thresholded to produce 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.

Rare copy number variation in cerebral palsy

“…45 Eleven of the 14 CNVs that we identified were inherited from an unaffected parent and were considered to be of potential relevance to CP. Reasons for discordance between parent and child could include variable expressivity, 46 incomplete penetrance, 47 and epigenetic modification of gene expression. 47 Expression of a clinical phenotype in the child but not in the parent could also be explained by the 'two hit' hypothesis, 20,23 which postulates the additive effects of two or more de novo or inherited genetic abnormalities in the affected individual, with fewer such abnormalities in the unaffected parent.…”

“…Reasons for discordance between parent and child could include variable expressivity, 46 incomplete penetrance, 47 and epigenetic modification of gene expression. 47 Expression of a clinical phenotype in the child but not in the parent could also be explained by the 'two hit' hypothesis, 20,23 which postulates the additive effects of two or more de novo or inherited genetic abnormalities in the affected individual, with fewer such abnormalities in the unaffected parent. Other mechanisms include the presence of a point mutation on the other allele in the affected children, not identified by the CNV profiling, 48 and various combinations of CNVs and point mutations affecting different genes.…”

Optic tectum morphogenesis: A step‐by‐step model based on the temporal–spatial organization of the cell proliferation. Significance of deterministic and stochastic components subsumed in the spatial organization

“…This study also presents a biomathematical approach that could provide a conceptual framework to analyze a recurrent and controversial point in developmental biology: the problem about ''determinism'' and ''stochasticity'' and their possible role in developing organisms (Bronk et al, 1968;Saunders et al, 2002;Meng et al, 2004;Song et al, 2006;Raj et al, 2010;Zernicka-Goetz and Huang, 2010;Wu et al, 2011).…”

On the impact of discreteness and abstractions on modelling noise in gene regulatory networks

“…In particular, we showed that certain parameter combinations are responsible for bursty temporal patterns. While there is strong experimental evidence supporting transcriptional bursts both in prokaryotes (Golding et al, 2005) and (especially) in eukaryotes (Raj et al, 2006), the underlying biological mechanism still remains unclear. Even though many complex mechanisms, involving the biochemical machinery of DNA transcription, seem to contribute to pulsatile transcription (as suggested in Golding et al (2005)), our study supports the fact that gene regulation mechanisms themselves (and the relative speed of the different reactions involved) play an important role in determining this pattern of transcription.…”

“…Thus, it is becoming clear that noise and stochasticity underlie critical events in cell's life such as differentiation and decision making (Balázsi et al, 2011). Moreover, some authors suggest that random phenotypic switching can represent an efficient mechanism for adapting to fluctuating environments (see, e.g., Balázsi et al, 2011;Raj et al, 2010). These findings have raised new interest in analysing the role of noise in gene expression.…”