Although they no doubt appeared in one form or another very early on in the evolution of life on Earth, human chromosomes (from the Greek for “colored bodies”) were first seen in the cell nucleus, under the microscope, at the end of the 19th Century. Their journey through the scientific realm proved difficult, as it was only in 1956 that their number, 46 in human cells, was correctly established, three years after the elucidation of the molecular structure of DNA.

Chromosomes are full-fledged entities with their own internal lives, as each of their units, or genes, spells out the synthesis of chemicals crucial to individual cell function. They also attend to their own duplication and continuity, and that of our reproductive cells, ensuring the future of our descendants. And they have a mind of their own!

Once their exact number in the human cell was discovered, it came as a surprise to learn that that number could deviate from the norm. Such deviations were observed in diverse congenital disorders, beginning with Down’s syndrome, the expression of a trisomy or condition in which a small extra chromosome, the so-called chromosome number 21, is present in all the cell nuclei of the body. (A normal chromosome pair is called a disomy.) It was then discovered that other numerical abnormalities exist, from either the addition or subtraction of a chromosome in each cell, which can result in viable life but most often causes early spontaneous fetal abortions. Geneticists then were amazed to learn of the high frequency with which such mishaps occur.

It is useful to recall that chromosomes are best observed during cell division and that, except for sex chromosomes XX or XY, the pairs are attributed numbers from 1 to 22 according to their size, from largest to smallest. The principle behind a chromosomal error is simple: each genitor or parent contributes a normal reproductive cell, either an egg or a sperm, to an offspring. Those two cells contain only half of each parent’s full chromosome set, i.e. one member of each chromosomal pair, for a total at fertilization of 2 x 23 chromosomes. That in essence is what normally happens at the onset of the development of a new being. Alas, as mentioned, all too often the conceptus, the embryo during the very early stages of development, falls victim to the loss or surplus of a member of a chromosomal pair, a condition that is always harmful.

But setting aside such mismatched cases, let’s consider the case at fertilization where the male or female parental germ cell possesses a surplus chromosome that, by sheer coincidence and luck, happens to be the very chromosome missing from the other parent’s germ cell (a reasonable possibility given the high frequency of chromosomally abnormal germ cells). All is well as a quantitative and qualitative balance seems achieved. Under the microscope, a sampling of such cells will not divulge that at fertilization both members of one of the 23 pairs of chromosomes originated from just one parent rather than from both. So in these cases two identical members exist – a disomy that originates from one parent instead of both, termed uniparental.

Just a few decades ago when uniparental disomy (UPD) was first identified, using molecular markers that were able to unveil the parental source of each chromosome through minuscule chemical differences, it caused quite a commotion in the field of genetics, not least because the concept goes against the classical, accepted Mendelian laws of inheritance. It further appeared that, depending on the particular chromosome, the chromosomal substitution could be inconsequential and inconspicuous or, on the contrary, detrimental and even catastrophic. Such a discrepancy needed explanation.

In some chromosome pairs, in situations where both members of the pair are received from only one parent rather than from both (and are thus uniparental), a pathological situation develops that is stereotypical in that the condition has been shown to be specific for the chromosome member involved and its parental source. This is the case for UPD involving chromosomes 6, 7, 11, 14, 15 and 20. For instance, UPD for chromosome 15 of maternal origin is responsible for a characteristic disorder that causes obesity, a voracious appetite, mental retardation, compulsive behavior and particular facial features among other anomalies, named Prader-Labhardt-Willi Syndrome, after the two Swiss and Belgian pediatricians who first identified it. This same UPD, from the duplication of chromosome 15 but of paternal origin, results in severe mental retardation and microcephaly, accompanied by seizures, specific facial features, repetitive gestures, spasmodic laughter and the quasi-total absence of verbal communication, a condition described by British pediatrician Harry Angelman and thus called Angelman syndrome. Its cause seems clear: in the case of chromosome 15, the normal paternal chromosome cannot assume the genetic function of the maternal chromosome it replaces, just as in the opposite case the normal maternal chromosome cannot behave as the fair substitute for the paternal counterpart. The genetic expression of chromosome 15 passed down by the mother is not the same as that transmitted by the father and vice versa.

Today we know that the altered genetic expression of two normal and theoretically alike chromosomes as described above results for some chromosomes from the erasure of various genes, depending on whether the germ cell transmitted originated in the egg or sperm. The phenomenon by which certain genes are repressed in a parent-of-origin-specific manner constitutes genomic imprinting. The rare atypical pattern of UPD transmission, hypothesized in 1980 (American Journal of Medical Genetics, vol. 6) and proven for the first time in the clinical field in 1988 (American Journal of Human Genetics, vol. 42), offers its clearest manifestation.

Such pathological conditions as those mentioned here and their related suffering for both the patients and their families serve to highlight the importance of genomic imprinting as a major process in the physiology of our genome or genetic makeup. In the long run and eventually as an approach to therapy, if applied early, pharmacologic attempts at freeing normal genes wrongly locked in cell nuclei because of the mistaken origin of one of the chromosomes in a pair might temper the effects of this error in the development of an affected child. Such efforts have a long way to go before reaching their goal but appear plausible. Therapy could perhaps also be fostered by the fact that “acquired UPD,” the exclusive doubling of an initially single, unmatched chromosome member in an erratic cancer cell clone, has now been observed among the intricate and pathogenic chromosome changes that occur in malignant tissues such as leukemias. We have also learned that a large number of UPD cases perceived in the human results from a trisomy’s very early reduction to disomy (in an attempt at rescue?), owing to the spontaneous loss of an extra chromosome. Indeed, our genome is more eruptive than we could ever have imagined and we should remember that, in health as in disease, genetics is in its broadest sense the study of variation!

Eric Engel, MD

This article, translated from the French, first appeared in the Journal de Genève et Gazette de Lausanne (No. 14) on 19 November 2009. Copyright © 2010 by Eric Engel. All rights reserved.