The same – and yet entirely different

18. December 2007

Up to now - with a few exceptions - the rule applied: If two have the same gene equipment, the environment determines the development of each person. Geneticists at Harvard University have discovered new soil, just how the cell produces its inimitability. Mono-allelic expression or "rolling the dice while reading".

Immunoglobulins, receptors for identification of odors and interleukins – messengers of the immune system. The few genes for that were considered exotics so far. They had to produce varied different patterns of their proteins. Apparently that is why they also draw on an exotic process of mono-allelic gene expression. Geneticists believe that coincidence determines whether the cell reads the maternal or the paternal or both alleles. A few weeks ago, the work of Alexander Gimelbrant and his colleagues published in "Science" showed that this lottery of the cell does not only apply for exotics.

More than 1,000 possibilities for a potential combination

The human geneticists at Harvard Medical School in Boston used DNA-chips for an explanation to study RNA and DNA of genes displaying a "single-nucleotid"- polymorphism in their sequence. They used lymphoblastoid B-cell lines as source material, which pass on their method of gene expression to direct clone descendants as well as their polymorphisms. This way, the Harvard team was able to study about 4,000 genes regarding their gene expression because both alleles vary in the sequence of their direct transcript. And here came the surprise: Instead of the few expected samples, about ten percent of the genes showed a sample taken at random where the cell read only one out of two alleles. The examination of various cell clones showed that evolution keeps an even more ample room for combinations. Because just one fifth of the more than 300 genes displayed a stringent mono-allelic gene expression. Depending on the cell respectively its descendants, they sometimes used both sister chromosomes for RNA production. Projected on the entire genome there would be more than 1,000 genes with random selection during reading.

Different from the "Genetic Imprinting", mother and father are equally relevant for this method of inactivation of an allel. The use of one of the two alleles does not depend on the DNA strand of a chromosome either, as it is the case in the inactivation of the redundant X-chromosome in women. Because the genes found by Gimelbrant and colleagues are distributed evenly across the entire genome. Rolf Ohlsson of the Schwedish University at Uppsala writes in his accompanying comment in "Science": "Especially genes for receptors on the cell surface are over-represented in this group." According to Ohlson, the consequence is an enormous potential of regulation of cell-to-cell contacts and thus of "diversity and destiny of cells".

Same genes – different risks for diseases

Researchers found among the genes with mono-allelic expression for example the "Amyloid Precurser Protein APP" which plays a role in the development of Alzheimer. Ralf Sudbrak of the Max-Planck-Institute for Molecular Genetics in Berlin showed during an interview with DocCheck just what the potential consequences in the medical field could look like: "In monozygotic twins, a copy of a risk gene for a disease could be inactive. By mono-allelic gene expression, the second copy might fail as well". The result: different development of diseases in the twins despite their identical DNA code.

Several years ago, when the human genome was sequenced, researchers asked themselves why a man compared to a fly manages with just about double of the genes. Perhaps the publication of Gimelbrant provides a potential answer. Because by combination of random mono-allelic and bi-allelic expression, an abundance of new variations made from the same basic material is possible. Alongside the "why", many work groups will start working on clarifying the secrets of the surprising discovery with data. Just how does the cell inactivate its genes when rolling the "expression"-dice? Which genes are mainly affected and how many? Read the next chapter of this enthralling story in "Science", "Nature" or "Cell".

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