The science behind genetic fingerprinting
We are all genetically unique, thanks to the many sites of inherited variation within the 3,000,000,000 bases or chemical letters in our DNA that make up the human 'book of life'.
In 1978, Alec Jeffreys (not yet a Professor or Sir) was one of the first to apply the emerging science of genomics to the study of inherited variation in human DNA, discovering a type of variation, termed RFLPs, that result from alterations in single bases in our DNA. He showed that these are abundant - we now know that there are about 10,000,000 different sites at which people can vary in their DNA sequence.
Professor Jeffreys went on to show that some regions of human DNA are far more variable than these sites of single base variation. These regions, termed minisatellites, show the curious property of being stuttered, with variation resulting from individual differences in the number of stutters. This work led, almost accidentally, to the development in 1984 of DNA fingerprinting.
Professor Jeffreys demonstrated that a single test could in principle distinguish everyone on the face of the planet (except for identical twins). The subsequent impact that DNA fingerprinting has had on individual identification in criminal investigations and in legal medicine has been dramatic and remains as one of the most well known applications of human molecular genetics. The origin of all this inherited variation in human DNA remains the focus of Jeffreys' research.
Variation ultimately arises from two processes. The first is mutation, which can create heritable changes in our DNA. There are many ways by which DNA can mutate and any can produce either benign differences between individuals or pathological changes that can cause inherited disease. The second process is crossover, also known as recombination, whereby maternal and paternal copies of a given region of DNA pair up and exchange information during the formation of spermatozoa and eggs. Sometimes crossover can go wrong, leading to DNA rearrangements that can cause inherited disorders.
Mutation and crossover are fundamentally important processes. An analogy can be drawn with a deck of playing cards: without mutation, all the cards will be identical; without crossover, there is no shuffling between games. Both are needed to play the game of human evolution. However, both processes are very difficult to study in humans.
The traditional approach is to compare children with their parents to look for mutations or places of crossover. For both processes, this is tough: 10,000 children would have to be surveyed to detect just one mutation or one crossover in a typical gene. Professor Jeffreys solved this problem imposed by small families by developing alternative approaches that detect these events, not in children but instead by screening thousands or even millions of sperm.
He has already used this approach to reveal the complex way by which minisatellites mutate - by abnormal recombination, as it turns out - and is now characterising the basic rules that govern how crossovers occur along human DNA and how these affect patterns of genetic diversity in human populations. In the longer term, Professor Jeffreys will attempt to extend this research to other modes of human mutation, including jumping DNA and mutations in single bases in DNA.
This is fundamental research that will illuminate the dynamics of human DNA evolution and the factors that influence the integrity of our DNA as it is transmitted from generation to generation. It will also help throw new light on the nature of human genetic diversity and of the origin of our species, of populations and of pathological changes in our DNA.
Our turbulent genome
Some of the varied ways by which mutation, as well as recombination between paternal (black) and maternal (red) regions of DNA, can change the DNA sequence, numbers of genes (filled boxes) and lengths of stuttered DNA (lined boxes). An additional process is transposition which creates new copies of jumping DNA sequences (shaded boxes). Some changes will be harmless, while others might have devastating consequences.
Detecting minisatellite mutations in families and sperm
The family shows two different versions of the minisatellite per person, with each child inheriting one copy from the mother (circle) and one from the father (square). The last child in the family shows a paternal mutation (arrow). Spermatozoa were analysed in batches of 100, amplifying individual DNA molecules containing this minisatellite and analysing them for mutation. Many mutant molecules can be seen, as well as unchanged molecules. To obtain this number of mutants in a family would have required the man to have had 1,800 children!