An Epigenetic Factor Directs Meiotic Recombination

Image Courtesy of Science Photo Library C009/9397

On Grey et al., 2011 in PLoS Biology

Although the principles of inheritance as described by Gregor Mendel opened the era of Genetics, the works of another prominent scientist Thomas Hunt Morgan, helped establish the still enigmatic concepts of genetic linkage and homologous recombination (i.e. cross over). Morgan discovered that linked genes (genes that are on the same chromosome), do not always cosegregate and hypothesized the phenomenon of cross over. Although he had assumed the cross over frequency would be similar between even-spaced loci, it is later discovered that there are "recombination hotspots" where cross over frequency is higher than elsewhere on a given chromosome.

Using genome-wide linkage disequilibrium studies, about 30000 hotspots were identified in human genome. The recombinations are clustered in 1-2kb regions indicating the location of the hotspots. Although a consensus site of 7 -13 bases was shown to be present in a fraction of these regions, the biological mechanism of the hotspot formation was elusive.

As a significant step towards the elucidation of the biology of recombination hotspots, a group led by Bernard de Massy, of CNRS France discovered  a mechanistic factor behind the hotspot formation with a series of papers published in Science and in PLoS Biology. First (PLoS Biology, 2009), the group used mouse genetics to narrow down the genetic locus required for the recombination phenotype of a particular hotspot. Then they identified this as a trans-acting factor affecting cross overs genome-wide.

As recombination hotspots are associated with histone H3K4 trimethylation, PRDM9, a histone metyhltransferase expressed during meiotic prophase, was selected as a candidate gene in the locus. Next the authors correlated the variations in the PRDM9 gene with recombination phenotypes observed in mouse strains as well as in genotyped individuals. It is notable that these variations are mostly found in the DNA-binding zinc-finger domain, which is proposed to determine the location of the hotspot in the genome. In addition, they showed in vitro interactions between PRDM9 variants and the hotspot consensus sequences which supports the recruitment of the histone modification activity to the hotspot.

There is no genome-wide binding analysis for PRDM9 yet, but a next direction in this research field might involve genome-wide Chromatin IP for PRDM9, which could reveal any overlap between recombination hotspots and PRDM9 binding.

In the last paper of the series, in PloS Biology, they used the same mouse strains to confirm the role of PRDM9 in hotspot formation. PRDM9 variants in these strains contain 24 non-synonymous changes, all but one being in the DNA binding domain. By engineering the PRDM9 allele in transgenic mice they switched the recombination phenotype as scored by chromosome-wide cross-over analysis. However, they noted that the PRDM9 target sequence was also important in the recombination phenotype as changes in DNA sequence effected PRDM9 binding in vitro.

These exciting advances in meiotic recombination will have implications in the fields of population genetics, natural selection and will further prime the progress in meiosis and recombination at the molecular level.


Grey, Corinne AND Barthès, Pauline AND Chauveau-Le Friec, Gaëlle  AND Langa, Francina AND Baudat, Frédéric AND de Massy, Bernard
Mouse PRDM9 DNA-Binding Specificity Determines Sites of Histone H3 Lysine 4 Trimethylation for Initiation of Meiotic Recombination
PLoS Biol, 2011 Oct;9(10):e1001176. doi: 10.1371/journal.pbio.1001176

Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, Coop G, de Massy B.PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science, 2010 Feb 12;327(5967):836-40

Grey C, Baudat F, de Massy B. Genome-wide control of the distribution of meiotic recombination.  PLoS Biol 7(2): e1000035.doi:10.1371/journal.pbio.1000035