Pointing the (zinc) finger: protein identified as factor in genetic recombination

Posted by mjs76 at Sep 07, 2010 01:15 PM |
Professor Sir Alec Jeffreys, whose work famously led to the development of genetic fingerprinting, has co-authored an important new paper on the genetic basis of human diversity.

In recent years, Sir Alec has been investigating minisatellites – short sequences of DNA which vary more, and at a faster rate, than most of the human genome – and also recombination hotspots where DNA is reshuffled during sperm and egg production. In a paper published online this week by Nature Genetics, Sir Alec and his team demonstrate that one of the major factors affecting minisatellite instability as well as these ‘hotspots’ is a protein called PR domain–containing 9 (PRDM9).

PRDM9 is 'a meiosis-specific histone H3 methyltransferase with a C-terminal tandem-repeat C2H2 zinc finger (ZnF) domain' which will mean little to the average person, but the important point is the zinc finger domain which is a portion of the protein molecule that wraps around a zinc ion. (Not to be confused with zinc fluoride, ZnF2, which is something completely different!)

Zinc finger proteins (ie. proteins with ZnF domains) are extraordinarily useful in studying genetics because they are the most common transcription factors in living organisms. They can bind directly to specific sequences in DNA and thereby control the transfer of genetic information to RNA during reproduction.

Three very recent papers provided good evidence that PRDM9 affects recombination hotspots in mice and probably humans - but this is the first time that it has been directly shown to be an important factor in human recombination (and hence, human diversity) and in DNA instability.

Jeffreys et al studied PRDM9 in semen donated by 230 men - who were found to carry various versions of the gene producing PRDM9 - and examined how this variation affected recombination in a number of different genetic hotspots. Because PRDM9 diversity is low among Europeans but relatively high in Africans, the team were careful to use both ethnic groups in their research.

Representative small-pool PCR results for minisatellite CEB1, for a PRDM9 A/A homozygote and a C/L16 heterozygote. (Don't worry if you don't understand this. The important bit is how different they look.)

The results showed a strong correlation between PRDM9 and hotspot activity but raised some curious questions around precisely how this occurs, because some PRDM9 variants (alleles) activated hotspots with which, theoretically, they should not be able to bind.

Possibly the most fascinating outcome from the research is the realisation that PRDM9, which also affects recombination activity in minisatellites, is itself encoded by a minisatellite, providing a potential explanation for the ceaseless variety of recombination in living organisms. In the Nature Genetics paper, this recursive phenomenon is summed up thus:

Could PRDM9 influence its own evolution by generating alleles that affect instability at the PRDM9 minisatellite to promote the generation of new alleles? If so, then bursts of new PRDM9 alleles could be generated whenever an interacting allele appears in a population, implying a potentially chaotic mode of hot-spot evolution.”

Or, as Sir Alec puts it, less formally:

I’ve come full circle – starting out with minisatellites to develop DNA fingerprinting, and arriving at a gene containing a minisatellite that plays a key role in driving all kinds of human DNA diversity, including variation at minisatellites. An intriguing possibility is that it is even driving its own evolution!”

The other authors, all of whom work or study in our Department of Genetics, are Dr Ingrid L Berg, Rita Neumann, Kwan-Wood G Lam, Shriparna Sarbajna, Linda Odenthal-Hesse and Dr Celia A May.

The research was funded by the Medical Research Council, the Wellcome Trust, the Boehringer Ingelheim Fonds, the Royal Society and the Louis-Jeantet Foundation. Professor Jeffreys is Royal Society Wolfson Research Professor of Genetics at Leicester.