Large reservoir of mitochondrial DNA mutations identified in humans

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Large reservoir of mitochondrial DNA mutations identified in humans

http://www.eurekalert.org/pub_releases/2008-08/vt-lro081108.php

Researchers at the University of Newcastle, England, and the Virginia

Bioinformatics Institute at Virginia Tech in the United States have

revealed a large reservoir of mitochondrial DNA mutations present in

the general population. Clinical analysis of blood samples from

almost 3,000 infants born in north Cumbria, England, showed that at

least 1 in 200 individuals in the general public harbor mitochondrial

DNA mutations that may lead to disease. The findings, which highlight

the need to develop new approaches to prevent the transmission of

mitochondrial diseases, were published in The American Journal of

Human Genetics.*

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

adenosine triphosphate, are passed from mother to offspring.

Mutations in mitochondrial DNA inherited from the mother may cause

mitochondrial diseases that include muscle weakness, diabetes,

stroke, heart failure, or epilepsy. In almost all mitochondrial

diseases caused by mutant mitochondrial DNA, the patient's cells will

contain a mixture of mutant and normal mitochondrial DNA. The

proportion of mutant mitochondrial DNA in most cases determines the

severity of disease.

Previous estimates from epidemiological studies suggested that

mitochondrial diseases affect as many as one person in 5,000.

However, the incidence of new mitochondrial mutations and the

prevalence of those carrying these mutations were never fully

established due to limitations in the methods used. Most of the

earlier estimates of the frequency of mitochondrial DNA mutations in

the general population, for example, have depended on identification

of clinically affected patients and subsequent retracing of

inheritance on the maternal side of the family. This approach fails

to detect the gradual accumulation of mutations in some members of

the population, including those individuals who harbor mitochondrial

DNA mutations but who otherwise do not show the symptoms of disease.

Dr. s, Assistant Professor at the Virginia Bioinformatics

Institute and an author on this study, commented: " We know from many

clinical studies of patients and their families that our cells can

tolerate a rather large amount of mutant mitochondrial DNA with no

significant loss of function. From that observation we have suspected

that there may be a large number of people in the general population

who carry pathogenic mitochondrial DNA mutations, but who are not

obviously ill with a mitochondrial disease. This study gives us, for

the first time, a measurement of the number of these carriers of

pathogenic mitochondrial DNA mutations in the general population. One

in every 200 individuals is a lot of people – around 1.5 million

people in the United States alone. "

The scientists looked at 10 mitochondrial DNA mutations (arising from

single nucleotide replacements) often found in patients with

mitochondrial disease. By taking advantage of a high-throughput

genotyping system that uses mass spectrometry measurements, the

researchers were able to detect mutated mitochondrial DNA at high

sensitivity. In each positive case, DNA cloning and sequencing were

used to confirm the findings. By looking at differences in tissue

samples from mother and child, the researchers were also able to

estimate the rate at which new DNA mutations had arisen in the

population. The incidence of new mutations was close to 100 for every

100, 000 live births.

Dr. s commented: " These new clinical measurements have given

direct evidence for the widespread incidence of pathogenic

mitochondrial DNA mutations in the human population. These findings

emphasize the pressing need to develop effective ways to interrupt

the transmission of these mutations to the next generation. "