ScienceDaily (Feb. 18, 2010) — For years, biologists have wondered how it is possible that not every person who carries a mutated gene expresses the trait or condition associated with the mutation. This common but poorly understood phenomenon, known as incomplete penetrance, exists in a wide range of organisms, including humans.
Now, a team of MIT biophysicists has demonstrated that some cases of incomplete penetrance are controlled by random fluctuations in gene expression.
"It's not just nature or nurture," says Alexander van Oudenaarden, leader of the research team and a professor of physics and biology at MIT. "There is a random component to this. Molecules bounce around and find each other probabilistically. It doesn't work like clockwork."
In a study of intestinal development of C. elegans, a small worm, the team was able to pinpoint specific fluctuations that appear to determine whether the mutant trait is expressed or not.
The work, published in Nature on Feb. 18, may also be relevant to human diseases that display incomplete penetrance, such as Parkinson's disease and Type 1 diabetes, says van Oudenaarden. For example, knowing the specific points in cellular pathways that are most important in controlling a cell's response to mutation could give drug designers better targets for new therapies.
"It's not just nature or nurture," says Alexander van Oudenaarden, leader of the research team and a professor of physics and biology at MIT. "There is a random component to this. Molecules bounce around and find each other probabilistically. It doesn't work like clockwork."
In a study of intestinal development of C. elegans, a small worm, the team was able to pinpoint specific fluctuations that appear to determine whether the mutant trait is expressed or not.
The work, published in Nature on Feb. 18, may also be relevant to human diseases that display incomplete penetrance, such as Parkinson's disease and Type 1 diabetes, says van Oudenaarden. For example, knowing the specific points in cellular pathways that are most important in controlling a cell's response to mutation could give drug designers better targets for new therapies.
...
Read more here/Leia mais aqui: Science Daily
+++++
Arjun Raj1,2,4,5, Scott A. Rifkin1,2,4,5, Erik Andersen2,3 & Alexander van Oudenaarden1,2
1. Department of Physics,
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA
3. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA
These authors contributed equally to this work.
Present addresses: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA (A.R.). Section of Ecology, Behavior, and Evolution, Division of Biology, University of California, San Diego 92093, USA (S.A.R.).
Correspondence to: Alexander van Oudenaarden1,2 Correspondence and requests for materials should be addressed to A.v.O. (Email: avano@mit.edu).
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.
1. Department of Physics,
2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
3. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA
These authors contributed equally to this work.
Present addresses: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA (A.R.). Section of Ecology, Behavior, and Evolution, Division of Biology, University of California, San Diego 92093, USA (S.A.R.).
Correspondence to: Alexander van Oudenaarden1,2 Correspondence and requests for materials should be addressed to A.v.O. (Email: avano@mit.edu).
Correspondence to: Alexander van Oudenaarden1,2 Correspondence and requests for materials should be addressed to A.v.O. (Email: avano@mit.edu).
+++++
Professores, pesquisadores e alunos de universidade públicas e privadas com acesso ao site CAPES/Periódicos podem ler gratuitamente este artigo da Nature e de mais 22.440 publicações científicas.
