A new type of mutation in the human genome

In the July issue of The American Journal of Human Genetics, researchers from Indiana University reveal a new mechanism for mutation in the human genome by providing evidence that duplicated regions of DNA can be located at chromosomal regions distant to each other. Duplications of DNA in humans have long been known to occur, but they are generally found as two side-by-side copies of the duplicated region, either in tandem or in inverse orientations. Now, Dr. Marion Hodes and colleagues have identified two families afflicted with Pelizaeus-Merzbacher disease and have discovered that the disease in both families results from the insertion of a duplicated region of DNA at a distant site to the original copy, resulting in a noncontiguous duplication of genetic sequences. The duplicated region includes the gene for the proteolipid protein, the gene associated with Pelizaeus-Merzbacher, a neurologic disease that leads to psychomotor developmental delay and abnormal muscle tone. Pelizaeus-Merzbacher is one of several genetic syndromes that arise when a gene within a duplicated region of DNA has a dose-sensitive effect. That is, the presence of more copies of the gene, and therefore of more gene product, is deleterious.

This new form of genetic duplication implies that the human genome has more ways of rearranging itself than were previously appreciated. While contiguous duplications arise from recombination between stretches of similar, repeated DNA, noncontiguous duplications must arise through a new mechanism that involves excision of the duplicated portion of DNA and at least three breaks to the DNA.

As the chromosomes containing these duplications appear normal, and as duplications don't necessarily lead to disease, the prevalence of noncontiguous duplications is unknown at this point. Although the complete process by which these duplications arise is not clear, their identification gives researchers insight into the plasticity of the human genome.

For the full text of this article, entitled "Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arising by separate integration into the X chromosome",see the "July 2000"section in the electronic edition of The American Journal of Human Genetics at http://www.ajhg.org.

Contributed by Dr. Kate Beauregard, The American Journal of Human Genetics
Tel: 404-712-9985. Email: kbeaure@emory.edu