When the cloned animals breed, they pass on either an egg or a sperm. Before the clone produced these gametes, its primordial cells underwent the second round of reprogramming, as part of the normal primordial germ cell pathway. This second reprogramming stage seems to reset the epigenome properly. The gametes lose the abnormal epigenetic modifications of their cloned parent. Epigenetics explains why cloned animals have health issues, but also explains why their offspring don’t. In fact, the offspring are essentially indistinguishable from animals produced naturally.
Assisted reproductive technologies in humans (such as in vitro fertilisation) share certain technical aspects with some of the methods used in cloning. In particular, pluripotent nuclei may be transferred between cells, and cells are cultured in the laboratory before being implanted in the uterus. There is a substantial amount of controversy in the scientific journals about the abnormality rates from these procedures[93]. Some authors claim there is an increased rate of imprinting disorders in pregnancies from assisted reproductive technologies. This would imply that procedures such as culturing fertilised eggs outside the body may disrupt the delicately poised pathways that control reprogramming, especially of imprinted regions. It’s important to note, however, that there is no consensus yet on whether this really is a clinically relevant issue.
All the reprogramming of the genome in early development has multiple effects. It allows two highly differentiated cell types to fuse and form one pluripotent cell. It balances out the competing demands of the maternal and paternal genomes, and ensures that this balancing act can be re-established in every generation. Reprogramming also prevents inappropriate epigenetic modifications being passed from parent to offspring. This means that even if cells have accumulated potentially dangerous epigenetic changes, these will be removed before they are passed on.
This is why we don’t normally inherit acquired characteristics. But there are certain regions of the genome, such as IAP retrotransposons, that are relatively resistant to reprogramming. If we want to work out how certain acquired characteristics – responses to vinclozolin or responses to paternal nutrition, for example – get transmitted from parent to offspring, these IAP retrotransposons might be a good place to start looking.
Chapter 9. Generation X
The sound of a kiss is not so loud as that of a cannon, but its echo lasts a great deal longer.
At a purely biological, and especially an anatomical level, men and women are different. There are ongoing debates about whether or not certain behaviours, ranging from aggression to spatial processing, have a biological gender bias. But there are certain physical characteristics that are linked unequivocally to gender. One of the most fundamental differences is in the reproductive organs. Women have ovaries, men have testicles. Women have a vagina and a uterus, men have a penis.
There is a clear biological basis to this, and perhaps unsurprisingly, it’s all down to genes and chromosomes. Humans have 23 pairs of chromosomes in their cells, and inherited one of each pair from each parent. Twenty-two of these pairs (imaginatively named chromosomes 1 to 22) are called autosomes and each member of a specific pair of autosomes looks very similar. By ‘looks’ we mean exactly that. At a certain stage in cell division the DNA in chromosomes becomes exceptionally tightly coiled up. If we use the right techniques we can actually see chromosomes down a microscope. These chromosomes can be photographed. In pre-digital days, clinical geneticists literally used to cut out the pictures of the individual chromosomes with a pair of scissors and rearrange them in pairs to create a nice orderly picture. These days the image processing can be carried out by a computer, but in either case the result is a picture of all the chromosomes in a cell. This picture is called a karyotype.
Karyotype analysis is how scientists originally discovered that there were three copies of chromosome 21 in the cells of people with Down’s syndrome. This is known as trisomy 21.
When we produce a human karyotype from a female, there are 23 pairs of identical chromosomes. But if we create a human karyotype from a male, the picture is different, as we can see in Figure 9.1. There are 22 obvious pairs – the autosomes – but there are two chromosomes left over that don’t look like each other at all. One is very large, one exceptionally small. These are called the sex chromosomes. The large one is called X, and the small one is called Y. The notation to describe the normal chromosome constitution of human males is 46, XY. Females are described as 46, XX because they don’t have a Y chromosome, and instead have two X chromosomes.
Figure 9.1 Karyotype of all the chromosomes in a male (top) and female (bottom) somatic cell. Note that the female cell contains two X chromosomes and no Y chromosome; the male cell contains one X chromosome and one Y chromosome. Note also the substantial difference in size between the X and Y chromosomes. Photos: Wessex Reg Genetics Centre/Wellcome Images.
The Y chromosome carries very few active genes. There are only between 40 and 50 protein-coding genes on the Y chromosome, of which about half are completely male-specific. The male-specific genes only occur on the Y chromosome, so females have no copies of these. Many of these genes are required for male-specific aspects of reproduction. The most important one in terms of sex determination is a gene called SRY. SRY proteins activate a testis-determining pathway in the embryo. This leads to production of testosterone, the archetypal ‘male’ hormone, which then masculinises the embryo.
Occasionally, individuals who phenotypically appear to be girls have the male 46, XY karyotype. In these cases the SRY gene is often inactive or deleted and consequently the foetus develops down the default female pathway[94]. Sometimes, the other scenario arises. Individuals who phenotypically appear to be boys can have the typically female karyotype of 46, XX. In these cases a tiny section of the Y chromosome containing the SRY gene has often transferred onto another chromosome during formation of sperm in the father. This is enough to drive masculinisation of the foetus[95]. The region of the Y chromosome that was transferred was too small to be detected by the karyotyping process.
The X chromosome is very different. The X chromosome is extremely large and carries about 1300 genes. A disproportionate number of these genes are involved in brain function. Many are also required for various stages in formation of the ovaries or the testes, and for other aspects of fertility in both males and females[96].
So, about 1300 genes on the X chromosome. That creates an interesting problem. Females have two X chromosomes but males only have one. That means that for these 1300 genes on the X, females have two copies of each gene but males only have one. We might speculate from this that female cells would produce twice the amounts of proteins from these genes (referred to as X-linked genes) as males.
But our knowledge of disorders like Down’s syndrome makes this seem rather unlikely. Having three copies of chromosome 21 (instead of the normal two) results in Down’s syndrome, which is a major disorder in those individuals who are born with the condition. Trisomies of most other chromosomes are so severe that children are never born with these conditions, because the embryos cannot develop properly. For example, no child has ever been born who has three copies of chromosome 1 in all their cells. If the 50 per cent increase in gene expression from an autosome can cause such problems in trisomic conditions, how do we explain the X chromosome scenario? How is it possible for females to survive when they have twice as many X chromosome genes as males? Or, to put it the other way – why are males viable if they only have half as many X chromosome genes as females?
96
For a good review of this, see Graves (2010),