Perhaps as a consequence, repeats are a bigger cause of problems in rodents than in humans. If repeats replicate in the genome, they may insert into or near functional protein-coding genes and interfere with their normal roles. In some cases they may prevent the correct protein from being expressed. In others, they may drive increased expression of the protein. In mice, insertion of repeats into novel regions of the genome is 60 times more likely to be the cause of a new genetic condition than is the case in human cells. In mice, these account for 10 per cent of all new genetic mutations, whereas the figure is one in 600 for humans. We seem to have our genomes under tighter control than our rodent cousins.
Perhaps this is just as well, when we look at some of the consequences of this kind of mutation mechanism in rodents. There’s a mouse strain in which such a mutation results in no tail. This in itself might not be too problematical, but the kidneys also fail to develop, and that’s a very bad thing indeed.{29} This is because the insertion leads to over-expression of a nearby gene. In a different strain, the insertion switches off an important gene in the central nervous system. This results in mice that spasm if they are handled, and have a lifespan of just two weeks.{30}
We can also draw a similar conclusion about the potential impact of such repeats from the opposite phenomenon, i.e. by looking at regions of the genome where these repeats hardly ever occur.
There is group of genes called the HOX cluster, which is very important in driving the correct development of complex cellular organisms. The genes in the cluster are switched on in a specific order during development, and expressed at highly regulated levels. If anything goes wrong with this order, the effects can be very profound. The importance of the HOX cluster was first shown in fruit flies. Flies with mutations in these genes developed some extraordinary characteristics. In the most famous example, the flies didn’t have antennae on their heads. Instead, their heads had a pair of legs on them.{31}
Just like flies, mammals also rely on the appropriate expression patterns of HOX genes for the development of the correct body patterns. Mutations at the HOX cluster are rare in humans, probably because these genes are so important. But it has been shown that a mutation in at least one HOX gene results in defects in the ends of the limbs.{32}
The HOX cluster is one of the few places in the human genome that is almost completely clear of interspersed repetitive elements. This suggests that even relatively benign genetic interlopers have the potential to affect gene expression, and that there are some regions of the genome where evolution has ensured that they are kept at bay. This repeat-free aspect of the HOX cluster is also found in other primates and in rodents.
The presence of interspersed repeats in the genome can have unexpected consequences. There’s an unusual class of repeats caused ERVs. ERV stands for endogenous retrovirus. The human immunodeficiency virus (HIV, the causative agent of AIDS) is an example of a retrovirus. Such viruses are characterised by the genetic material being made of RNA, not DNA. The viral RNA is copied to form DNA, which can then integrate into the host genome. The host treats the DNA like its own, producing new viral components and ultimately new viruses.
Long ago in our evolutionary history, some retroviruses became fully established in our genomes. Many are now genomic fossils. Certain parts of the retroviral sequences have been lost, and so they can never again produce viral particles. But some still contain all the components required to make new viruses. These are normally kept under very tight control by the cell.{33} Scientists have also discovered that the immune system doesn’t just fight off viruses that infect us from the outside world; it also plays a role in keeping these endogenous viruses under control. Genetically engineered mice which lack certain components of the normal immune system suffer problems through the reactivation of these viruses lurking in their own genomes.{34}
This control of endogenous retroviruses is a potential issue in one approach to tackling a problematic area of human health. Every year, thousands of people die on waiting lists for organ transplants because there aren’t enough donors. For example, approximately one in three of the people whose lives could potentially be saved by a heart transplant dies while still on the waiting list.{35}
One potential way around this would be if we could use hearts from animals as replacement organs. This is known as xenotrans-plantation (‘xeno’ is derived from the Greek for ‘foreign’). For cardiac transplants, the animal of choice is the pig. Its heart is about the same size and strength as the human organ.
There are a number of technical hurdles to overcome (in addition to ethical issues around the use of pigs that matter to certain religious groups).{36} Some of these are being addressed by the creation of genetically modified pigs that don’t provoke the very aggressive immune response that is a problem when introducing pig cells into the human cardiovascular system. But there may be another issue. The pig genome contains endogenous retroviruses, just as the human genome does. But the ones in pigs are different from the ones in humans. Work at the end of the 20th century showed that some of these pig retroviruses can infect human cells, given the right conditions.{37}
There’s a possible scenario that has worried some scientists. Anyone who receives a pig heart will inevitably be receiving immunosuppressive drugs to prevent rejection of the foreign organ. Reactivation of endogenous retroviruses is more likely when individuals are immunosuppressed. Human systems have evolved in part to control the endogenous retroviruses that have been in our genome since we evolved. But they may not be as efficient at controlling the ones hiding in the pig genome. This theoretically could mean that the endogenous retroviruses could escape from the pig heart and attack and enter other cells in the human recipient. From there, they might even escape into the wider population.
More recent data have suggested that the risk of this happening has perhaps been overstated in the past,{38} but it’s certainly an area of junk DNA that will require close scrutiny if xenotransplantation is to become a reality.
Other repeated sequences in the genome can cause health problems more directly. There are some parts of the genome where large sections, sometimes hundreds of thousands of base pairs in length, were duplicated relatively recently during human evolution. The ‘original’ and the ‘duplicate’ may end up in very different parts of the genome, even on different chromosomes from one another.
These regions can cause problems when eggs or sperm are being formed. During this formation, there is a very important stage where chromosomes undergo a process called crossing-over. A chromosome inherited from your mother pairs up with the equivalent chromosome inherited from your father, and they swap bits of DNA between the two. It’s a way of increasing the amount of variation in the gene pool, by mixing up combinations of genes. If there are two parts of the genome that look very similar because of repeat sequences but which are not actually a matching pair of chromosomes, this crossing-over may occur between regions of the genome that aren’t meant to swap material. The consequence may be that eggs or sperm are produced that have extra sections of DNA, or are missing critical regions.{39}