January 2004

Professor Sir Alec Jeffreys - research work and short biography

RESEARCH WORK
Human diversity

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 J Jeffreys 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. He 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. Alec J 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 Alec J Jeffreys's 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 (see figure 1), 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 (see figure 1) 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, and 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. Alec J Jeffreys has 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 (see figure 2). 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 characterizing 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, Alec J 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. 

 

Figure 1  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.

Figure 2  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 1800 children!

SHORT BIOGRAPHY

                                  

Professor Sir Alec J Jeffreys is a British citizen born in 1950. He studied biochemistry and received his PhD in 1975 at Oxford University. He then joined the laboratory of Piet Borst for a post-doctoral training at the Department of Medical Enzymology and Molecular Biology at the University of Amsterdam. In 1977, he went to the Department of Genetics at the University of Leicester where he became a professor in genetics in 1987. Sir Alec is a fellow of the Royal Society since 1986 and a Royal Society Wolfson Research Professor since 1991. He is also a member of EMBO, of Academia Europaea and of the American Academy of Forensic Sciences. He has been honoured by numerous awards and medals since 1985, notably the Davy Medal by the Royal Society in 1987, a Knighthood for services to genetics in 1994 and the Australia Prize in 1998.

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