Genetics and Imprinting

Excerpts from:
Tug of War Pits Genes of Parents in the Fetus

By NICHOLAS WADE

Published: September 13, 2010

NY Times
 
Under Mendel’s laws of inheritance, you could thank mom and dad equally for all the outstanding qualities you inherited.


But there’s long been some fine print suggesting that a mother’s and father’s genes do not play exactly equal roles. Research published last month now suggests the asymmetry could be far more substantial than supposed. The asymmetry, based on a genetic mechanism called imprinting, could account for some of the differences between male and female brains and for differences in a mother’s and father’s contributions to social behavior.

A person gets one set of genes from each parent. Apart from the sex chromosomes, the two sets are equivalent, and in principle it should not matter if a gene comes from mother or father. The first sign that this is not always true came from experiments in which mouse embryos were engineered to carry two male genomes, or two female genomes. The double male and double female mice all died in the womb. Nature evidently requires one genome from each parent.

Biologists then made the embryos viable by mixing in some normal cells. The surprising outcome was that mice with two male genomes had large bodies and small brains. With the double female genome mice, it was the other way around. Evidently the maternal and paternal genomes have opposite effects on the size of the brain.

The root of the asymmetry is a procedure called imprinting in which either the mother’s or the father’s copy of a particular gene is inactivated. The best worked out example concerns a gene called insulinlike growth factor-2, which promotes the growth of the fetus. The IGF-2 gene is active in the paternal genome but imprinted or inactivated in the genome the fetus receives from its mother.

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Until last month only a hundred imprinted genes were known, and the mechanism seemed just an interesting deviation from Mendelian genetics. Research led by Christopher Gregg and Catherine Dulac of Harvard has shown that imprinting is far more common and more intricate than supposed.


Working in mice, the Harvard team showed that around 1,300 genes are imprinted. Dr. Dulac said that she expects a substantial, though lesser, proportion to be imprinted in people — maybe some 1 percent of the genome — because humans are more monogamous than mice and so the parents’ interests are more closely aligned.

Dr. Dulac was able to detect so many new imprinted genes by taking advantage of the ease with which genes can now be decoded. She cross-bred two very different strains of mice, thus ensuring that the maternal and paternal versions of each gene would have recognizably different sequences of DNA.

When a gene is activated, the cell transcribes it into RNA, DNA’s close chemical cousin. By decoding all the RNA transcripts in the mouse’s cells, Dr. Dulac could pick out those genes in which the paternal version was being transcribed much more than maternal version, and vice versa.

Besides finding far more imprinted genes than expected, Dr. Dulac’s team also picked up unexpected patterns in the way the genes were expressed. Maternal genes were more active in the embryo’s brain, but paternal genes became more active in the adult.

In another novel pattern, she found sex differences in imprinted genes in different region of the brain, particularly those concerned with feeding and with mating behavior. A gene called interleukin-18 is activated from the mother’s version in two important regions of the brain. This asymmetry is of interest because the gene in people has been linked with multiple sclerosis, a disease that predominates in women.

Altogether Dr. Dulac found 347 genes where either the mother’s or the father’s copy was more actively expressed in certain regions of the brain. Sex differences in the brain are usually attributed to the influence of hormones, but sex-based differences in imprinting may be another mechanism by which nature spins male and female brains out of the same genome.

“In your brain, your mom and your dad keep telling you what to do — I keep laughing when I think about it,” Dr. Dulac said.

In the cortex of the brain, Dr. Dulac discovered another unexpected asymmetry. Women have two X chromosomes, one from the mother and one from the father. The usual rule is that in each cell either the mother’s or the father’s copy is chosen at random to be switched off. But in the neurons of the cortex, there is a much greater chance that the paternal X chromosome will be switched off. “So again, it’s the conflict between mom and dad — each tries to use different chromosomes to influence you,” Dr. Dulac said.


For complete NYT article go to link: http://www.nytimes.com/2010/09/14/health/14gene.html?th&emc=th