This can lead to disease in individuals who inherit these genomic defects. One example is Charcot-Marie-Tooth disease, where there are defects in the nerves that transmit sensation and control motor functions.{40} Another is Williams-Beuren syndrome, a condition characterised by developmental delay, relative shortness, a range of unusual behavioural traits combined with mild learning disability, and long-sightedness.{41}
The duplicated regions in the genome that give rise to the problems during crossing-over often contain multiple protein-coding genes. It’s probably not surprising that the symptoms in patients affected by abnormal crossing-over are often quite complex. It’s likely that more than one pathway is affected by the change in the number of multiple genes.
It might seem odd that these duplicated regions have been retained during human evolution, if they can give rise to such problems. But in reality, most of the time the cells that form eggs and sperm perform crossing-over really well, and don’t mix up the wrong parts of chromosomes. The duplications have also acted as a way that the human genome has been able to increase the numbers of certain genes quite rapidly, in evolutionary terms. This can be useful. The ‘spare’ copy may act as the raw material for evolutionary adaptation. A few changes to the protein-coding gene sequence can create a protein with a related but discrete function from the original. This may be how the large family of genes that allows mammals to detect a huge range of different smells evolved.{42} It’s another example of the parsimony with which the human genome has evolved, adapting existing genes and proteins, rather than starting from scratch. A genomic two-for-one offer.
Most of the junk repetitive DNA that we have considered so far in this chapter is formed of quite large units. These tend to be at least 100 base pairs in length and are frequently much longer. That’s partly why they account for so much of the genome. But there are other junk repetitive units that are much smaller, based on repeats of just a few base pairs. These are called simple sequence repeats. We already met a few examples of these in the exploration of Fragile X syndrome, Friedreich’s ataxia and myotonic dystrophy. In each of these cases, three-base-pair sequences were repeated a number of times, and reached their maximum in patients with the disorders.
Repeats of short motifs account for about 3 per cent of the human genome. They are very variable between individuals. Let’s consider an arbitrary repeat of two base pairs, say GT, at a particular position on chromosome 6. I may have inherited eight copies (sequence would be GTGTGTGTGTGTGTGT) on chromosome 6 from my mother and seven copies on chromosome 6 from my father. You, on the other hand, may have inherited ten copies from your mother and four from your father.
These simple sequence repeats have proved to have great usefulness because they are found all over the genome, vary a lot between individuals at each position where they occur in the genome and are easy to detect using cheap, sensitive methods.
Because of these characteristics, such repeats are now used for DNA fingerprinting. This is the process by which blood or tissue samples can be unequivocally associated with a specific individual. This has facilitated paternity testing and revolutionised forensic science. Its applications in the latter have included identification of victims of massacres, convictions of the guilty and exonerations of the innocent, including cases where the wrong person has been in jail for decades. Over 300 people in the United States have been freed after DNA testing established their innocence, nearly 20 of whom had been on death row at some point during their incarceration.{43} Additionally, in about half of these cases, DNA evidence was able to determine the real guilty party.
Not bad for a bit of junk.
5. Everything Shrinks When We Get Old
The movie Trading Places, starring Dan Aykroyd, Eddie Murphy and Jamie Lee Curtis, was a huge hit in 1983, grossing over $90 million at the US box office.{44} It’s a convoluted comedy but the premise behind it is the exploration of genes versus environment. Is a successful man successful because of intrinsic merit or because of the environment in which he is placed? The movie comes out firmly on the side of the latter.
A similar phenomenon can happen in our genomes. An individual gene may perform a relatively innocuous role, helping a cell keep on keeping on, so to speak. The gene produces protein at just the right rate to do this job. A major factor in controlling the amount of protein that is produced is the position of the gene on the chromosome.
Now let’s imagine that the gene is transported to a new neighbourhood, like Dan Aykroyd’s character ending up in the slums or Eddie Murphy’s character finding himself transported to a mansion. In this neighbourhood, our transported gene is surrounded by new genomic information, which instructs it to make much higher amounts of protein. The high levels of the protein whip the cell forwards, pushing it to grow and divide much faster than usual. This can be one of the steps that leads to cancer. There’s nothing bad about the gene itself, it’s just in the wrong place at the wrong time.
This process is caused when two chromosomes break in a cell at the same time. When a chromosome breaks, a repair machinery immediately targets the break and joins the two bits up again. This is usually a pretty slick process. But if two (or more) chromosomes break at the same time, there can be problems. The ends of the chromosomes may become joined up incorrectly, as shown in Figure 5.1. This is how a ‘good’ gene may end up in a ‘bad’ neighbourhood, and begin causing problems. This is particularly an issue because the rearranged chromosomes will be passed on to all daughter cells every time cell division takes place. Probably the most famous example of this mechanism is in a human blood cancer called Burkitt’s lymphoma, where there is a rearrangement between chromosomes 8 and 14. This results in very strong over-expression of a gene[2] that encourages cells to proliferate aggressively.{45}
Figure 5.1 In the upper panel a single chromosome breaks and is repaired by the cell. In the lower panel two chromosomes break simultaneously. The cell machinery may be unable to work out which break occurred on which chromosome. The chromosomes may be joined together inappropriately, creating hybrid structures.
Luckily, it’s probably quite rare that two chromosomes break at exactly the same time. More frequently there will be a time difference. So, the machinery that repairs DNA has evolved to act really quickly. After all, the faster it repairs a break, the lower the chance that there will be multiple breaks present at the same time in an individual cell. The DNA repair machinery starts to operate as soon as the cell detects that there is a broken piece of DNA. It does this by having mechanisms to detect the end of the break.
But this creates a whole new set of problems. Our cells contain 46 chromosomes, each of which is linear. In other words, our cells always have 92 chromosome ends, one at each end of a chromosome. The DNA damage machinery has to have a way of distinguishing the perfectly normal ends of chromosomes from the abnormal ends caused by breakages.
The way that cells have solved this is to have special structures on the normal ends of the chromosomes. Are you wearing shoes with laces? If so, have a quick look at those laces. At either end there is a little cap made from metal or plastic. This is called the aglet, and it stops the lace from unravelling and fraying. Our chromosomes have their own aglets, and these are extremely important for maintaining the integrity of our genome.