Introduction

---

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 Se^fus 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.

References

---

1. Koda Y, Soejima M, Liu Y, Kimura H. Molecular basis for secretor type ?(1,2)-fucosyltransferase gene deficiency in a Japanese population: a fusion gene generated by unequal crossover responsible for the enzyme deficiency. Am J Hum Genet 1996;59:343-50.
2. Soejima M, Fujihara J, Takeshita H, Koda Y. Sec1-FUT2-Sec1 hybrid allele generated by interlocus gene conversion. Transfusion 2008;48:488-92.
3. Chen JM, Cooper DN, Chuzhanova N, Férec C, Patrinos GP. Gene conversion: mechanisms, evolution and human disease. Nat Rev Genet 2007;8:762-75.
4. Chen JM, Férec C. Role of non-B DNA conformations in initiating the nonallelic homologous recombination-derived Sefus allele and the interlocus gene conversion-derived Sec1-FUT2-Sec1 hybrid allele. Transfusion 2008;48:1522-3.
5. Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM. On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 2011;32:1075-99.
6. 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;327:836-40.
7. Berg IL, Neumann R, Lam KW, Sarbajna S, Odenthal-Hesse L, May CA, Jeffreys AJ. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat Genet 2010;42:859-63.
8. Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 2010;327:876-9.
9. Parvanov ED, Petkov PM, Paigen K. Prdm9 controls activation of mammalian recombination hotspots. Science 2010;327:835.
10. Kong A, Thorleifsson G, Gudbjartsson DF, Masson G, Sigurdsson A, Jonasdottir A, Walters GB, Jonasdottir A, Gylfason A, Kristinsson KT, Gudjonsson SA, Frigge ML, Helgason A, Thorsteinsdottir U, Stefansson K. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 2010;467:1099-103.
11. Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Boerwinkle E, Cai Q, Caporaso N, Casey G, Cupples LA, Deming SL, Diver WR, Divers J, Fornage M, Gillanders EM, Glessner J, Harris CC, Hu JJ, Ingles SA, Isaacs W, John EM, Kao WH, Keating B, Kittles RA, Kolonel LN, Larkin E, Le Marchand L, McNeill LH, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, Nyante S, Papanicolaou GJ, Press MF, Psaty BM, Reiner AP, Rich SS, Rodriguez-Gil JL, Rotter JI, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Thun MJ, Tucker MA, Wang Z, Wiencke JK, Witte JS, Wrensch M, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Zhu X, Redline S, Hirschhorn JN, Henderson BE, Taylor HA Jr, Price AL, Hakonarson H, Chanock SJ, Haiman CA, Wilson JG, Reich D, Myers SR. The landscape of recombination in African Americans. Nature 2011;476:170-5.
12. Berg IL, Neumann R, Sarbajna S, Odenthal-Hesse L, Butler NJ, Jeffreys AJ. Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations. Proc Natl Acad Sci USA 2011;108:12378-83.
13. Grey C, Barthès P, Chauveau-Le Friec G, Langa F, Baudat F, de Massy B. Mouse PRDM9 DNA-binding specificity determines sites of histone H3 lysine 4 trimethylation for initiation of meiotic recombination. PLoS Biol 2011;9:e1001176.
14. Ségurel L, Leffler EM, Przeworski M. The case of the fickle fingers: how the PRDM9 zinc finger protein specifies meiotic recombination hotspots in humans. PLoS Biol 2011;9:e1001211.
15. Myers S, Freeman C, Auton A, Donnelly P, McVean G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet 2008;40:1124-9.
16. Sarbajna S, Denniff M, Jeffreys AJ, Neumann R, Soler Artigas M, Veselis A, May CA. A major recombination hotspot in the XqYq pseudoautosomal region gives new insight into processing of human gene conversion events. Hum Mol Genet 2012 Feb 8. [Epub ahead of print]

Source(s) of Funding

---

none

Competing Interests

---

none

Disclaimer

---

This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.