Research articles

By Dr. Jian M Chen , Dr. David N Cooper , Dr. Claude Férec
Corresponding Author Dr. Jian M Chen
INSERM U1078 and EFS-Bretagne, - France 29218
Submitting Author Dr. Jian-min Chen
Other Authors Dr. David N Cooper
Institute of Medical Genetics, Cardiff University , n - United Kingdom

Dr. Claude Férec
INSERM U1078 and EFS-bretagne, - France


PRDM9-binding motif, Homologous recombination hotspot, FUT2, Gene conversion, Nonallelic homologous recombination, NAHR

Chen JM, Cooper DN, Férec C. Identification of a Putative PRDM9-Binding Motif within the Homologous Recombination Hotspot in the SEC1 and FUT2 Genes. WebmedCentral BLOOD TRANSFUSION 2012;3(3):WMC003202
doi: 10.9754/journal.wmc.2012.003202

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submitted on: 28 Mar 2012 08:31:19 PM GMT
Published on: 29 Mar 2012 03:59:06 PM GMT


The FUT2 gene (OMIM #182100) encodes ?(1,2)fucosyltransferase which regulates the expression of the ABO and Lewis histo-blood group antigens via the synthesis of H antigen on epithelial cells. FUT2 and its homologous pseudogene, SEC1, are separated by 23 kb on chromosome 19q13.3. To date, two alleles derived from homologous recombination between these two genes have been reported: whereas the Sefus allele was generated by nonallelic homologous recombination (NAHR),[1] the SEC1-FUT2-SEC1 allele originated via interlocus gene conversion.[2] The highly unusual overlap between the crossover region of the NAHR event and the maximal converted tract (MaxCT[3]) of the interlocus gene event[4] could be held to imply the existence of a novel homologous recombination hotspot in the human genome.

It has been increasingly appreciated that local DNA sequence features contribute to the formation of recombination hotspots.[5] In particular, PRDM9, a meiosis-specific histone H3 methyltransferase, has recently been identified as a major determinant of meiotic recombination hotspots in humans and mice.[6-14] PRDM9 activates recombination hotspots via chromatin remodeling by binding to a degenerate 13-mer motif, CCNCCNTNNCCNC.[15] We wondered whether PRDM9 might also drive the SEC1/FUT2 homologous recombination hotspot and we therefore searched the hotspot region and its flanking 1-kb sequences on both sides for the possible presence of the 13-mer motif.

Results and Discussion

Having allowed for one mismatch,[16] we identified a single putative PRDM9-binding site (termed motif A): it is located not only within the aforementioned overlapping region (of only 158-bp) but also only 2-bp 5´ to our previously identified non-B DNA-forming motif (termed motif B) (Illustration 1). In the Figure, the SEC1 sequence was used for illustration because SEC1 represents the “acceptor” in the interlocus gene conversion event involving SEC1 and FUT2.[2] This means that the double-strand break that initiated the interlocus gene conversion event must have occurred within the SEC1 sequence. Nonetheless, both motif A and motif B are present within the overlapping region (indicated by two downward pointing arrows) that are shared by the crossover region (delimited by vertical bars) of the NAHR event[1] and the MaxCT of the interlocus gene conversion event;[2] no paralogous sequence variants exist in this region between the two genes. In other words, use of either SEC1 sequence or FUT2 sequence for illustration does not affect our observation.

The co-localization of this putative PRDM9-binding site and the non-B DNA-forming motif prompted us to speculate that the two distinct motifs could have interacted synergistically to initiate homologous recombination between the SEC1 and FUT2 loci in the following way: the binding of PRDM9 to motif A (i) would serve to modify the local chromatin structure, thereby facilitating the formation (ii) of a non-B DNA structure (motif B) which is susceptible to double-strand breaks (iii) which then initiate homologous recombination (iv).

To the best of our knowledge, this is the first time that the co-localization of a putative PRDM9-binding motif and a non-B DNA-forming motif has been explicitly invoked to explain the activity of a homologous recombination hotspot. Our finding may however find wide application as additional NAHR and interlocus gene conversion hotspots are characterized at the nucleotide sequence level.


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