This post is an archive from the old blog, originally written in 2007.
I’ve been discussing in the “Sunday syndrome” column various disorders caused by genetic aberrations, but I haven’t really explained how such aberrations occur. There are several different types of aberration that occur, and several different mechanisms that cause them. In the Thursday paper, I’ll look at one of the mechanisms, and another will be discussed in a few weeks; for now I will just name and categorise the aberrations that occur.
In eukaryotes, genes are laid out on DNA molecules, which are organised into specific structures, chromosomes, by associating with proteins. In humans, the normal compliment of these is 22 pairs of “autosomes” and two sex-determining chromosomes (the X and Y). The fact that the chromosomes are in pairs is important, as it means that there are two copies of most genes (except on the sex chromosomes, and in a few special cases which will be discussed in a later Sunday syndrome post). Genetic aberrations can be classified in a system which indicates the type of change, and roughly indicates the amount of material involved. “Chromosomal aberrations” are those aberrations that involve so much genetic material that the difference can be seen with a microscope (an arbitrary benchmark in terms of the science). Numerical chromosomal aberrations, or “aneuplodies”, involve the loss of one or more whole chromosomes, to create an “monoploid” condition; or one or more extra copy of one or more chromosome, to create a “triploid” condition. Structural chromosomal aberrations include the loss, or gain, of part of a chromosome: a partial deletion, ranging in size from a few genes, to an entire arm of a chromosome; a partial duplication, with the extra section being tagged onto the same, or another chromosome; or part of the chromosome breaking off and being attached to the wrong chromosome. Alongside chromosomal aberrations, beyond the reach of the microscope, are the micro-mutations — the staple of evolution and individual variation, and the source of our more subtle syndromes.
Why loss of material should be detrimental is obvious: the cell is missing genes and therefore looses some functionality. It is less obvious why we should have any problem tolerating addition of material, such that we have three copies of genes that we would otherwise have two copies off; or why we should have any problem loosing just one of the two copies of a gene. The main reason, which I’ll discuss in more depth in a future Sunday syndrome post, is that quantity and concentration is important in determining a gene’s activity. Some genes have a continuum of slightly modified activity along their concentration gradient; others have a threshold, beyond which their activity suddenly and radically shifts. Another reason why loosing one of a pair of chromosomes is harmful is that it allows the expression of harmful mutants: part of the advantage of having two copies of every gene, is that these harmful genes are masked by their normal (“wild-type”) alleles (that is, they are “recessive” to the “dominant” wild-types).
There are many syndromes caused by partial deletions and partial duplications of chromosomes. The deletions we see are those that affect fewer genes, and genes which do not have critical roles in development. Large scale deletions simply don’t survive to term: only one true monosomy is ever seen in live births, and that is because it is a special case. In Turner’s syndrome, only one X chromosome, and no Y chromosome is present. The reason Turner’s is a viable genotype is that the X chromosome is only ever present in a single dose: males have an X and Y, while females switch off one of their two X chromosomes in every cell (“Lyonisation”) as “dosage compensation”, bringing them in line with the males. All except a handful of genes, that is: because there are a handful of active genes on the Y chromosome, a corresponding handful of genes on the inactive X are exempt from Lyonisation . Turner’s, therefore, is not exempt from symptoms, which include short stature, webbing of the neck, abnormal hands and feet, lack of maturation of the genitalia, and predisposition to heart disease and renal malfunction. Miscarriage also remains common.
Duplication of material is generally more tolerated: the difference in gene proportions is one third, not a half, and harmful recessive alleles are not unleashed. An extra Y chromosome has little effect, except to boost height, and individuals have been reported with more than two Y chromosomes. Around one in every thousand females is thought to have three X chromosomes (“triple X syndrome”), a condition that has no serious symptoms (because Lyonisation switched off all but one X), but which may be correlated with increased height, early onset of puberty, and very mild learning difficulties. The presence of more than three X chromosomes has been observed in live births. Males with two X chromosomes, alongside their Y, have Klinefelter’s syndrome, and usually have under-developed testicles, and correspondingly lower production of testosterone, shifting their pattern of hormone expression towards that of the female. The consequences of this vary, but infertility, effeminate facial features and body shape, and breast development are common; frequency of breast cancer and osteoporosis, which are hormone-dependent diseases, are also higher in Klinefelter’s than in other males. Many with Klinefelter’s still manage to go through life undiagnosed, however, and many others are only discovered during fertility treatment. As in the case of chromosome deletions, the effect of duplications on the autosomes are more severe. Only three of the 22 potential autosomal trisomies survive to term in a significant proportion of cases, and even in these, the majority still miscarry. The most common of these istrisomy 21 — the chromosome with the smallest number of genes — which causes Down’s syndrome, with obvious mental and physical effects. Trisomy 18 causes Edwards’ syndrome, while trisomy 14 causes Patau’s syndrome. Both chromosomes contain relatively few genes, and both syndromes are characterised by severe mental and physical abnormalities, and predisposition to diseases.
The smaller the amount of material deleted or duplicated, and the less important that material in development, the better tolerated the aberration, in terms of disability, disease development, fertility, and so on. Partial aneuplodies may result in similar syndromes to full aneuplodies, depending on the parts of the chromosome affected. Partial trisomy of chromosome 21, if it occurs in the “Down’s syndrome critical region” of around 20-40 genes (a tenth of the whole chromosome), will cause Down’s syndrome. Below the level of structural aberrations we get to the micro-mutations. These include small scale deletions or duplications of one or two genes, as well as deletion, insertion and substitutions within genes. These mutations may knock out a gene altogether, upset the balance of gene concentrations, or merely alter a gene’s function subtly. These are far more common, but far less drastic in their effects. The effects depend, of course, on the gene’s normal role in development: is it a pivotal player in a handful of developmental programs, or a mostly redundant component of a system that is not even active in early years? At the level of micro-mutations it becomes difficult to determine the difference between “syndrome” and “normal variation”: mutations of this kind are a normal part of evolution, and every one of us carries many “abnormal” (or at least, “rare”) gene variants, but would not classify ourselves as suffering from a disorder because of them; this will be the subject of another future Sunday syndrome.
That there is such a diverse range of genetic abnormalities that can lead to developmental abnormalities (and I’ve only scratched the surface of this detail), alongside a diverse range of environmental variables involved, reflects the complexity of developmental processes. The fact that we see such extensive deletions as Down’s, Edwards’ and Patau’s syndromes in live births is an amazing illustration of the ability of these developmental processes to tolerate harmful genetic aberrations.