In silico modeling helps predict severity of mitochondrial disease

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In silico modeling helps predict severity of mitochondrial disease

http://www.eurekalert.org/pub_releases/2008-01/vt-ism012508.php

A team of researchers in Australia, the United Kingdom and the United

States has revealed how mitochondrial diseases are passed from the

mother to the next generation in a mouse model system. The study,

which was published on-line in Nature Genetics*, shows for the first

time how mitochondrial diseases that cause muscle weakness, diabetes,

stroke, heart failure and epilepsy are passed from mother to

offspring.

Mitochondria are the " engines " present in each cell that produce

adenosine triphosphate (ATP), the key energy currency that drives

metabolism. Mitochondria also have their own DNA (mitochondrial or

mtDNA) that encodes a small but essential number of proteins required

for energy production in cells. Mitochondria, and the mtDNA that they

contain, are inherited solely from the mother, as the paternal mtDNA

present in the sperm are destroyed after the egg is fertilized. In

almost all diseases caused by mutant mtDNA, the patient's cells will

contain a mixture of mutant and normal mtDNA. The proportion of

mutant mtDNA in most cases determines the severity of the disease.

The inheritance of these diseases does not follow the rules of

Mendelian genetics. Instead, there are large random shifts at the

mtDNA mutation level between mother and offspring. This study

explains how these large random shifts occur within the first three

weeks of embryo formation, through the combined use of computational

modeling and a mouse model system.

Dr. s, assistant professor at the Virginia Bioinformatics

Institute (VBI), commented: " The computational model used in this

investigation simulates the biological process directly and allows

scientists to examine the early stages of embryo formation and

development. Clinicians can therefore take a close look at the

replication of mitochondrial DNA and the dynamics of cell division in

mouse embryos before and after implantation in the uterus. " He

added: " Computational modeling and cutting-edge lab work were both

essential for this study. The experiments gave us new information

that we had to have to build the simulation, and the simulation was

used as a tool to analyze the data from the experiment. "

Dr. Chinnery, Wellcome Senior Fellow in Clinical Science and

professor of neurogenetics at the University of Newcastle in the

United Kingdom, remarked: " Mitochondrial disease can have devastating

effects on a family, and the chance of having affected children is a

cause of major stress. By defining the main biological mechanism, we

hope in the long term to develop counseling guidelines that will help

patients and their families make more informed decisions. "

The computational model reveals how mtDNA is divided into different

embryonic cells before and after implantation and how the replicating

mtDNA molecules are subsequently separated between the dividing germ

cells that make up the embryo. The model accounts for the marked

reduction in the number of mtDNA molecules that are transmitted from

mother to offspring, the so-called " mitochondrial genetic

bottleneck. " It is thought that this genetic bottleneck has evolved

over time to remove deleterious mitochondrial mutations from the

population. These mutations are either lost during transmission or,

if transferred, give rise to offspring with a low chance of survival.

Although the current study investigates the transmission of

mitochondrial DNA in mice, the computational model is also applicable

to human data. Mitochondrial diseases are thought to affect as many

as one person in 5000. The research offers the hope that clinicians

will be able to predict a child's risk of developing maternally

inherited mitochondrial diseases that cause muscle weakness,

diabetes, stroke, heart failure and epilepsy.

* Lynsey M Cree, C s, a Chuva de Sousa Lopes, Harsha

Karur Rajasimha, Passorn Wonnapinij, R Mann, Hans-Henrik M

Dahl, F Chinnery (2008) " A reduction of mitochondrial DNA

molecules during embryogenesis explains the rapid segregation of

genotypes, " Nature Genetics, http://dx.doi.org/10.1038/ng.2007.63.

This research is supported by the Wellcome Trust and the Thailand

Higher Education Strategic Scholarship for Frontier Research Network.