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From The Times, December 17, 2009
Clues to the mother and father of all genetic mysteries
By Mark Henderson, Science Editor
Genes that influence common diseases such as diabetes and breast cancer can have dramatically different effects when passed on by mothers and fathers, scientists have discovered.
Research has revealed that a genetic variation protects against type 2 diabetes when inherited from a person’s father, but increases risk of the same condition when it comes from the mother.
It is among five DNA variants with different medical effects that depend on the parent of origin which have been identified by researchers at deCODE Genetics in Iceland.
The findings highlight an entirely new source of inherited influence on common disease, which could help to explain one of the biggest puzzles in medical genetics.
While hundreds of common genetic variations that affect disease risk have been discovered in the past two years, they together explain only a small fraction of the heritable factors that are known to play a part in conditions such as diabetes, heart disease and many cancers.
At least some of this “missing heritability” could be accounted for by genes that vary in their effects with parental origin, which scientists have previously been unable to examine.
Kári Stefánsson, the chief executive of deCODE Genetics and one of the main authors of the study said: “It isn’t just the sequence that matters, it can sometimes be which parent you get the sequence from as well.
“This sort of complex inheritance may well account for a substantial part of the unexplained heritability — the dark matter of the genome that we’ve been unable to find so far.”
The research also suggests that the significance of many genetic variations for disease may have been missed by previous studies.
Several genes that differ in their effects when inherited from mothers and fathers are already known to science because of a phenomenon called imprinting that can alter the way in which DNA is switched on and off.
Where imprinting influences health, however, it has always involved major genetic mutations that cause severe but rare diseases. The best-known example is a defect on chromosome 15, which causes Prader-Willi syndrome if inherited from the father and Angelman syndrome if inherited from the mother: while each condition has different symptoms, both cause severe mental retardation but are rare.
In the new study, which is published in the journal Nature, the deCODE team used a new method of gene-hunting that allowed them to tease out effects that differ with parental origin.
The company’s database includes more than 38,000 Icelanders, who have provided detailed genealogical data as well as DNA. This enabled the scientists to trace whether particular genetic variations came from a person’s mother or father.
The team then examined almost 300,000 places in the genome for effects on several diseases, concentrating on genetic regions where imprinted genes are already known. This was done because imprinted genes often fall in clusters.
One new variation was found to increase the risk of type 2 diabetes if inherited from the mother, but to decrease it when inherited from the father. The maternal version’s effect is greater than that of all but one DNA variant previously associated with the disease.
Two other variants were found to have an effect on type 2 diabetes if inherited from one parent but not from the other. Similar effects were discovered for variants that influence breast cancer and basal cell carcinoma, a form of skin cancer.
Dr Stefansson said the effect could have emerged through natural selection. As the same gene would be able to have a negative effect in one generation and a positive effect in the next one, it may be more likely to spread than a gene that is always damaging.
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