DNA fingerprinting has become an indelible part of society, helping to prove innocence or guilt in criminal cases, resolving immigration arguments and clarifying paternity. Its inventor, Professor Sir Alec Jeffreys, University of Leicester, looks back at how it began.
With highly automated and sophisticated equipment, the modern-day DNA fingerprinter can process hundreds of samples a day. Back in the late 1970s, however, molecular biology was in its infancy and was just beginning to be applied to human genetics.
"I'd been working in Amsterdam with Dick Flavell," says Professor Jeffreys. "We'd got to the point where we could detect single copies of human genes – which led to one of the first observations of introns [non-coding sections of DNA that split up genes]. But when I came to Leicester in 1977, I wanted to move away from the study of split genes, and to marry the new techniques of molecular biology with human genetics."
Professor Jeffreys's plan was to use the primitive gene detection methods of the time to look at the structures of genes and understand inherited variation – the variation between people. An early outcome of this research was one of the first descriptions of a restriction fragment length polymorphism (RFLP). (DNA-cutting enzymes target short DNA sequences, and chop the genome into pieces. Some people have a small DNA change – a single nucleotide polymorphism [SNP] – in a target site, preventing the enzymes cutting the DNA at that site.)
"We got our first SNP in 1978," says Professor Jeffreys. "Before that we knew about heritable variation in gene products, such as blood groups, but here we had examples of inherited variation in DNA, the most fundamental level of all.
While RFLPs were proof of inherited variation at the DNA level, they were difficult to find and to assay, and did not tell you much about variation between people – you either had the change or you didn't." So Professor Jeffreys started looking for pieces of DNA that would be more variable than SNPs.
A prime candidate was tandem repeat DNA – where a short sequence of DNA was repeated many times in a row. "Intuitively it seemed that regions of tandemly repeated DNA would be open to mutation processes such as duplication and recombination," says Professor Jeffreys. "They could be highly variable, informative genetic markers."
The first fingerprint
Tandem repeat DNA in the human genome remained elusive at first, and the research went down several blind routes. The answer came from a totally different project in Professor Jeffreys's lab which was searching for the human copy of the myoglobin gene, which produces the oxygen carrying protein in muscle. The group decided to look for the myoglobin gene first in grey seals (as seals produce lots of myoglobin, and have high levels of myoglobin mRNA, which makes it easy to clone a cDNA), then use the seal gene to isolate its human counterpart.
"The true story of DNA fingerprinting starts at the headquarters of the British Antarctic Survey in Cambridge," says Professor Jeffreys. "I collected a big lump of seal meat from their lock-up freezer and, to cut a long story short, we got the seal myoglobin gene, had a look at human myoglobin gene and there, inside an intron in that gene was tandem repeat DNA – a minisatellite."
This minisatellite was to prove the key to the rest of the genome, for while it was not variable itself, its sequence was similar to the very few minisatellites that had been described previously. Using the myoglobin minisatellite as a 'hook', the team could then identify more minisatellites and to their surprise discovered a core sequence - a piece of DNA that is similar in many different minisatellites. "Using the core sequence, we made a probe that should latch onto lots of these minisatellites at the same time," says Professor Jeffreys, "and, to test out the system, we hybridised the probe to a blot with DNA from several different people."
On a Monday morning in September 1984, the X-ray of the blot was developed in the Leicester University darkroom. "I took one look, thought 'what a complicated mess', then suddenly realised we had patterns," says Professor Jeffreys. "There was a level of individual specificity that was light years beyond anything that had been seen before.
"It was a 'eureka!' moment. Standing in front of this picture in the darkroom, my life took a complete turn. We could immediately see the potential for forensic investigations and paternity, and my wife pointed out that very evening that it could be used to resolve immigration disputes by clarifying family relationships."
The potential of DNA fingerprinting was clear, but could the technology be improved? Two to three months later, the grubby mess of the first fingerprint had been refined into clean patterns where DNA fingerprints, unique to an individual, could be deciphered clearly.
DNA fingerprinting was ready for prime time.
Part 2 of the DNA fingerprinting story explores its first use in immigration disputes and criminology.
Jeffreys AJ, Wilson V and Thein SL Hypervariable 'minisatellite' regions in human DNA. Nature 1985 314: 67-73. Abstract
Jeffreys AJ, Wilson V, Thein SL. Individual-specific 'fingerprints' of human DNA. Nature 1985 316(6023):76-9. Abstract