The man who invented DNA fingerprinting has now identified a key gene driving human genetic variation.

Although humans share 99.5 per cent of their DNA with each other, the remaining unshared half a per cent is what makes us all genetically and physically different.

Some of the differences arise from mutations in DNA, in which a single DNA unit is replaced with another. Other differences arise from recombination, where whole chunks of parental DNA are swapped around when sperm and eggs form.

Shuffling the deck

“Mutations are like spots on playing cards, and without them all our genetic cards would be identical,” says Alec Jeffreys of the University of Leicester, UK, who led the team that made the discovery. He pioneered DNA fingerprinting in 1984.


“Recombination is like shuffling the genetic pack,” says Jeffreys. “So without mutation and recombination, we would all be clones and genetically identical.”

Now Jeffreys and his colleagues have found that a particular gene plays a major role in how DNA is recombined, and where in the genome this happens.

Called Prdm9, short for “PR domain-containing 9”, the gene makes an enzyme that latches onto DNA and reshuffles it when sperm eggs develop from germ cells. The enzyme mostly targets recombination “hotspots” where this re-juggling is already known to occur.

Vive la différence

Working with sperm donated by 74 men of African ancestry and 156 of white European descent, Jeffreys and his colleagues show that there’s also huge variation in the Prdm9 gene itself, leading to heavy recombination in some individuals and only light reshuffling in others. Jeffreys found five previously known variants of Prdm9, plus 24 new ones, in the men he studied, with variation particularly rich among Africans.

In experiments, the researchers demonstrated that the enzyme made by Prdm9 worked at a dozen or so “hotspot” regions that they had chosen to test. But the amount of recombination varied depending on which Prdm9 variant had been inherited.

Another surprise was a connection between Prdm9 and minisatellites, the repeating sequences of DNA that Jeffreys discovered in 1984. These pepper the genomes of every person, but vary so enormously between individuals that they allow DNA fingerprinting.

Now, Jeffreys and his colleagues have demonstrated that the Prdm9 gene itself contains a minisatellite, and that this is probably what makes the gene vary so much between individuals.

And because minisatellites themselves often occur at recombination “hotspots” in the genome, it now looks likely that they drive their own evolution through interaction with the minisatellite in Prdm9.

Loop back

“For me, that’s absolutely fantastic,” says Jeffreys. “Because I originally isolated these minisatellites, my career seems to have gone in a huge 25-year loop right back to them.”

Other groups of researchers had already predicted from mouse studies and analyses of human gene sequences that Prdm9 would interact with recombination hotspots. “Jeffreys’s paper helps to confirm and considerably extend our findings,” says Graham Coop of the University of California, Davis, a key member of one of the teams that identified Prdm9 as a major evolutionary player.

Although recombination is vital for evolution and variation, it can cause disease when it goes awry. For example, Jeffrey’s team notes that faulty recombination is to blame for Charcot-Marie-Tooth syndrome, which results in muscle wastage and loss of nerve sensitivity, and hereditary neuropathy with liability to pressure palsies (HNPP), in which physical pressure damages nerves.

Andrew Clark of Cornell University in Ithaca, New York, calls Prdm9 a “master regulator of recombination and genome rearrangement”. He says that Jeffreys and colleagues have provided “extraordinary direct evidence” that Prdm9 plays a major role in directing recombination rates in 10 distinct hotspots.

Journal reference: Nature Genetics, DOI: 10.1038/ng.658