Random fluctuations give rise to odd genetic phenomenon

February 17, 2010

CAMBRIDGE, Mass. -- 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.

Many mutations in genes that are linked to diseases, including Parkinson's disease and Type 1 diabetes, are incompletely penetrant. Some of this variation may be due to environmental factors and the influence of other genes, but not all: It has been shown that genetically identical organisms living in the same environment can show variability in some incompletely penetrant traits.

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.

How they did it: The team studied the embryonic development of the digestive tract of C. elegans. The tract starts out as a single cell and eventually becomes 20 cells in the adult worm. That process is initiated by a gene called skn-1, which activates a series of other genes. Most of those genes code for transcription factors, which bind to DNA and turn on additional genes.

The team first characterized normal progression of intestine development, using a probe the team members developed that binds to messenger RNA inside cells, allowing them to count the number of copies of a particular messenger RNA sequence. (Messenger RNA carries DNA's instructions to the cell's protein-building machinery.)

They then studied worms with a mutation in skn-1, and found that some of the worms developed normal digestive tracts while others failed to develop a digestive tract. It appears that the controlling factor is the number of copies of mRNA produced by a gene called end-1, one of the genes activated by skn-1. The number of end-1 mRNA strands varied greatly in embryos with the mutation: In those with a number above a certain threshold, development proceeded normally; if the number was below the threshold, no digestive tract developed.

It appears that evolution has produced networks of genes that smooth out the effects of those fluctuations, which are revealed only when there is a mutation in the pathway, says van Oudenaarden.

Next steps: Van Oudenaarden plans to use the same technique to study mammalian colon stem cells, in hopes of figuring out whether random fluctuations in gene expression influence the mutations that can cause cancer. If he can show that random fluctuations in a particular gene appear to be subject to the same threshold effect that he saw in C. elegans embryonic development, it could give drug designers new targets.
Source: "Variability in gene expression underlies incomplete penetrance in multicellular development," Arjun Raj, Scott Rifkin, Erik Andersen, Alexander van Oudenaarden. Nature, February 18, 2010.

Massachusetts Institute of Technology

Related Diabetes Articles from Brightsurf:

New diabetes medication reduced heart event risk in those with diabetes and kidney disease
Sotagliflozin - a type of medication known as an SGLT2 inhibitor primarily prescribed for Type 2 diabetes - reduces the risk of adverse cardiovascular events for patients with diabetes and kidney disease.

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.