Remarkably, aneuploidy also seems to occur in certain normal cells. It’s been reported that perhaps as many as 10 per cent of cells in the brains of mice and humans are aneuploid.{106} During development, the proportion is even higher, at around 30 per cent, but many of these are eliminated.{107} As far as we can tell, the remaining aneuploid cells in the brain are functionally active.{108} There is no clear understanding of why we have these brain cells with abnormal numbers of chromosomes, or the significance of similar findings of aneuploidy reported in the liver.{109}
In the situations outlined above, the aneuploidy has developed after the main bulk of the cells of the body have been produced. It occurred during cell divisions that were creating new body cells, albeit in some cases cancerous ones. The effects of these failures in chromosome segregation seem relatively mild, if any. That’s probably because there are plenty of normal cells to compensate.
But the situation is very different if the aneuploidy occurs during the formation of the eggs or sperm (gametes). If a pair of chromosomes fails to separate properly, then one of the resulting gametes will have an extra copy of the chromosome, and the other will be lacking that chromosome. Let’s say that happens in the formation of the egg, and chromosome 21 is abnormally segregated when the eggs are created. One of the eggs will have two copies of chromosome 21, the other will have none.
If the one that lacks a chromosome 21 is fertilised, the resulting embryo only has one copy of chromosome 21 and very quickly dies. But if the egg that contains two copies of chromosome 21 is fertilised, it will have three copies of this chromosome. And although such embryos are at higher than normal risk of spontaneous abortion, many do develop fully and the child is born.
Most of us have met or at least seen people with three copies of chromosome 21 (having three copies is known as a trisomy, so this condition is known as trisomy 21): this failure of chromosome segregation is the cause of Down’s Syndrome.{110} It can also occur because of a sperm with two copies of the chromosome, or through failure of chromosome separation in the first few divisions after fertilisation, but the maternal route is the most common.
Down’s Syndrome affects about one in 700 live births, and is a complex and variable disorder commonly associated with heart defects, a characteristic physical and facial appearance and a greater or lesser degree of learning disability. People with Down’s Syndrome are much more likely to reach adulthood than in the past, thanks to better medical and surgical interventions, but are at high risk of a relatively early onset of Alzheimer’s disease.{111}
The complex nature of the characteristics of Down’s Syndrome demonstrates very clearly that it’s really important that our cells contain the correct number of chromosomes. Patients with Down’s Syndrome have three copies of chromosome 21 instead of two. But this 50 per cent increase in the chromosome number, and therefore of the genes on the chromosomes, has dramatic effects on the cell and on the individual. Our cells are simply unable to deal with this excess, showing that control of gene expression must normally be tightly regulated and is so finely balanced that we are only able to compensate for changes within relatively narrow parameters.
Two other trisomies have been found in humans, both associated with much more severe conditions than Down’s Syndrome. Edward’s Syndrome is caused by trisomy of chromosome 18, and affects one in 3,000 live births. Approximately three-quarters of foetuses with trisomy 18 die in utero. Of the babies who survive to term, about 90 per cent die in the first year of birth due to cardiovascular defects. The babies grow very slowly in the womb, their birth weight is low and they have a small head, jaw and mouth plus a range of other multisystem problems including severe learning disabilities.{112}
The rarest of all these conditions is Patau’s Syndrome, trisomy 13, which affects one in 7,000 live births. The babies who survive to full term have severe developmental abnormalities and rarely survive their first year. A wide range of organ systems is involved, including the heart and kidneys. Severe malformations of the skull are common and the learning disability is extremely severe.{113}
It’s notable that having an extra chromosome from conception onwards results in obvious developmental problems. In each of these trisomies, it is very clear that the baby has a major problem from the moment they are born. Indeed, with access to prenatal scanning, most of the affected foetuses are detected during pregnancy. This tells us that having the right dose of chromosomes is vitally important for the highly coordinated process of development.
It’s tempting to wonder if there is something unusual about chromosomes 13, 18 and 21. Is there, perhaps, something different about their centromeres that makes them more susceptible to unequal segregation of the chromosomes during the formation of the egg and the sperm? Or could it be that trisomies of the other chromosomes do occur, but there’s no clinical effect so we don’t think to look for them?
This is falling into the surprisingly common trap of focusing on what we see, rather than what we don’t see. The reason that we see babies born with trisomies of chromosomes 13, 18 and 21 is because these are relatively benign, unlikely though that sounds. These are three of the smallest chromosomes and they each contain relatively few genes. Generally, the larger the chromosome, the greater the number of genes it contains. So the reason we never see trisomy of chromosome 1, for example, is because of its size. Chromosome 1 is very large and contains a lot of genes. If an egg and sperm fuse and create a zygote with three copies of this chromosome, there will be overexpression of such a large number of genes that the cell function will be disrupted catastrophically, leading to extremely early destruction of the embryo. This probably occurs before the woman is even aware she is pregnant.
For women aged between 25 and 40, the success rates for in vitro fertilisation using donated eggs are not affected by age.{114} But the likelihood of a woman becoming pregnant naturally does decline after her mid-20s. The difference between these two situations suggests that the mother’s age critically affects her eggs, rather than her uterus. We already know from Down’s Syndrome that maternal age influences the success of chromosome segregation into the eggs. So it’s not too big a leap to hypothesise that the decline in pregnancy rates after the mid-20s may be in part due to very early failures of embryo development, as a result of malfunctioning centromere activity and the creation of eggs with disastrous misallocation of large chromosomes.
7. Painting with Junk
In a twelve-month period from 2011 to 2012, 813,200 babies were born in the UK.{115} Using the rates quoted in the previous chapter, we can estimate that nearly 1,200 of these babies had Down’s Syndrome, around 270 had Edward’s Syndrome and just under 120 had Patau’s Sydrome. That’s a very small number of cots in a nursery of over three-quarters of a million babies. This is consistent with the concept that having too many copies of a chromosome is very damaging: in general we would not expect high survival rates when it occurs.
Which makes it all the more surprising to learn that about half of the babies born in that period — that’s over 400,000 children — were born with one chromosome too many. Yes, one in two of us. Even more confusingly, the extra chromosome isn’t some tiny little genetic remnant. It’s a really big chromosome. How on earth can this be, when one extra copy of a very small chromosome can cause devastating conditions such as Edward’s or Patau’s Syndromes?