What you give, might not always be received: A fundamental process in the transm

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What you give, might not always be received

This press release is available in French.

http://www.eurekalert.org/pub_releases_ml/2008-12/aaft-q121108.php

For the English version http://www.eurekalert.org/pub_releases/2008-

12/mnia-wyg121108.php

A fundamental process in the transmission of genes from mother to

child has been identified by researchers at the Montreal Neurological

Institute, McGill University. The new study published in the December

issue of the journal Nature Genetics identifies a mechanism that

plays a key role in how mutations are transmitted from one generation

to the next, providing unprecedented insight into metabolic diseases.

DNA that is only passed on from mothers to their children is stored

in mitochondria, a compartment of cells which functions to supply

energy to the body. Mutations in mitochondrial DNA (mtDNA) are

important causes of over 40 known types of diseases and disorders

which primarily affect brain and muscle function, some of which are

severely debilitating, with symptoms including stroke, epilepsy,

deafness and blindness. One very common mutation in Quebec causes

maternally inherited blindness which has now been traced back to a

Fille du Roi sent by the king of France in the 1600s to rectify the

imbalance of gender in the newly colonized country.

MNI researchers have located a genetic bottleneck that determines the

proportion of mutated mtDNA that mothers transmit to their offspring.

This is important because there are many copies of mitochondria in

cells and their distribution in tissues has a role in the severity

and symptoms of the disease. Therefore knowing how mtDNA is

transmitted is essential for the understanding and treatment of a

range of maternally inherited diseases, and provides an opportunity

for genetic counselling and treatment.

" The proportion of mutated DNA copies shifts rapidly and

unpredictably from mother to child making it very hard to predict

what proportion of mutated DNA will be passed on. " says Dr.

Shoubridge, neuroscientist at the MNI and lead investigator in the

study. " We now understand that this is partly due to the genetic

bottleneck, in which just a small number of the original mtDNA copies

from the mother are actually transmitted to the child. This

bottleneck occurs during the development of eggs in affected females.

Only a small set of the female's mtDNA is selected to replicate

resulting in the individual producing eggs with a wide range of

proportions of mutated mtDNA. These eggs give rise to offspring with

proportions of mutated mtDNA that differ from each other and are

different from the proportion of mutated mtDNA in the mother. This

explains why the occurrence and severity of a disease from mutated

mtDNA can vary in offspring of an affected mother. The identification

and location of the genetic bottleneck in our study strengthens our

knowledge of the rules and processes of transmission and improves our

capacity for genetic counselling. "

An important application of this study is in the prevention of the

disease at the prenatal stage because therapies for sick patients are

usually ineffective, and the diseases are often fatal. The study

locates the bottleneck as occurring during the process of egg

maturation in early postnatal life of a female, supporting the

knowledge that mature oocytes or egg cells contain the full set of

copies of mtDNA. This evidence makes possible pre-implantation

genetic diagnosis, in which an oocyte is screened for harmful

mutations prior to fertilization, for in-vitro fertilization for

example. This prevents the transmission of harmful mutations and can

avoid the termination of a pregnancy in cases where an embryo is

carrying a fatal neurological disorder.

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This research was supported by the Canadian Institutes of Health

Research and the US National Institutes of Health. Shoubridge is

an International Scholar of the Institute.