Nature throws curve ball in complex chromosome research

In the 1860s an Austrian monk, Brother Gregor Johann Mendel, first figured out the principles of inheritance we now call Mendel’s Laws. He published his findings in an obscure scientific journal, where they remained buried until the same principles were again discovered by another researcher. The second researcher publicized the “laws” but Mendel gets the honor of having his name memorialized.

Mendel’s Laws have been very useful in tracking genetic disorders, genetic counseling, establishing parentage, and so on, but now we find nature can throw us a baffling curve ball. There are cases where Mendel’s Laws simply don’t work. In 1980 a Swiss geneticist, Eric Engel, proposed an explanation for some of the discrepancies, but the tools he needed to investigate his theories, the DNA probes, were tools of the future. It remained for Arthur Beaudet, a microbiologist working in genetics at Baylor University in Houston, to discover the first human case that fitted Engel’s theory.

In 1988, Beaudet’s goal was to find the gene responsible for causing the disease cystic fibrosis. He was comparing genes from as many cystic fibrosis patients and their families as he could find, especially patients with other congenital disorders. At a scientific meeting he was told of a woman with CF in upstate New York who was abnormally short. Beaudet arranged to have blood samples sent to him from this patient, and, since CF occurs only when both parents carry the CF trait, he also had samples sent from her family members.

Using the DNA probes Engel lacked, Beaudet was investigating the No. 7 pair of chromosomes, the chromosomes thought to harbor the gene or genes involved in CF. He found that neither of the No. 7 chromosomes had come from the father. The father was not a carrier of the CF trait. At first he suspected the patient’s real father was someone other than her mother’s husband. He checked other chromosomes though and decided the evidence from the DNA probes of the other chromosomes proved the man she thought was her father really was. But how could this be? Then he checked the No. 7 pair of chromosomes further and found that, as far as he could tell, they were identical. Both units of the paired No. 7 chromosomes had come from the mother. This was the first recorded human case of what Engel had called uni-parental disomy, both sides of a paired chromosome coming from the same parent.

Perhaps we shouldn’t have been so surprised that uni-parental disomy occurs. Most cells in the body of each of us have 46 chromosomes, 23 pairs. The exception is the reproductive cells, the sperm and egg cells. Each reproductive cell has only 23 unpaired chromosomes, so that when fertilization occurs, the resulting fertilized ovum will have the required 46 chromosomes, 23 pairs, half from each parent. We’ve known for 30 years that sometimes an egg cell or a sperm cell can have an extra chromosome, two instead of one. When one of these reproductive cells with an extra chromosome is involved in a fertilization, the resulting fetus has an extra chromosome too, 47 instead of 46. One of the chromosomes has to be tripled instead of paired, a condition called trisomy. Trisomy simply means three (chromo)somes. The best known of the trisomies is a tripling of chromosome 21, called trisomy 21, which is Down’s syndrome. It used to be called Mongolian Idiocy.

There are also children born missing one chromosome out of a pair, or a part of a chromosome missing. These are called deletions. Engel guessed that during the development of either an egg cell or sperm cell, one or the other could have a chromosome doubled, while the other had a deletion of the same chromosome. If that sperm fertilized that egg, the resulting fetus would have both sides of that chromosome pair from the same parent. That’s the origin of the term “uni-parental disomy.”

These gross abnormalities of chromosomes, the trisomies and monosomies, will be picked up easily by automatic chromosome sorters. Normal cells are disomies, two chromosomes in pairs. Automatic sorters can’t tell whether each pair came from one parent or both, so prenatal screening of cells obtained by amniocentesis will miss the uni-parental disomies. Uni-parental disomies are so extremely rare though I expect the much more difficult and expensive DNA-probing of chromosomes prenatally will be done only when there is a strong possibility of a congenital defect.

Engel thought that in some cases children born with uni-parental disomy might be perfectly normal. Others are not so sure. Based on mouse studies and the few cases of uni-parental disomies discovered so far in humans, they think these patients will be of short stature and have some sort of learning disability.

We may be hearing a lot more about uni-parental disomy in the future, and I bet they’ll shorten it to UPD. It’s the only way we can explain cases like that of the French boy with true hemophilia. Normally, hemophilia is caused by a defect in the X chromosome, which is contributed only by the mother in male offspring. It causes the disease only when paired with a Y chromosome. So hemophilia is a disease that afflicts only males but it is inherited only through their mothers. The boy’s father was hemophiliac but his mother was not a carrier, so he shouldn’t have been at risk at all. Yet he also was born with hemophilia, an impossibility under Mendelian Laws. The only way this could happen would be if he had inherited both his X and Y chromosomes from his father by uni-parental disomy.

Robert A. Graves, M.D. is a retired physician who lives in Orono. His column appears biweekly.