Krausz, Csilla Gabriella

Sassone Corsi, P.

English

Florence Research

EDITORIALFlorence–Utah Symposium corner: from genetics toepigenetics of male infertilityThe etiopathogenesis of testicular failure remainsunknown in about half of the clinical cases and it isreferred to as ‘idiopathic infertility’. Since the number ofgenes involved in human spermatogenesis is possibly overthousands and only a small fraction has been identifiedand screened for mutations in infertile men (Nuti &Krausz, 2008), it is likely that a substantial proportion of‘idiopathic’ testicular failure is of genetic origin.Several new strategies are now available for searchingspermatogenesis candidate genes based both on animalmodels and on human studies, and a great selection wasshowcased at the 3rd Florence-Utah Symposium (14–16September, 2007). M.A. Handel presented data generatedin the context of the ReproGenomics Program whichdeals with genome-wide mutagenesis in the mouse fol-lowed by phenotype-driven identification of mutationsthat cause infertility (http://reproductivegenomics.jax.org).Proteomics and transcriptomics approaches also opennew horizons although their diffusion is limited by thecomplexity and the high cost of such analyses (Plattset al., 2007; Aitken & Baker, 2008; Oliva et al., 2008). Inrecent years, case ⁄ control association studies dealing withpolymorphisms have become more and more popularamong human geneticists aiming to identify genetic ‘riskfactors’. However, despite the general enthusiasm towardsgenetic variants, many in the field are often facing frus-trating situations in which initial promising data are notconfirmed in later studies (Krausz & Giachini, 2007). Arather unique example of successful replication of a previ-ously reported genetic risk factor for impaired spermato-genesis, on a substantially larger study population thanthe original one, concerns the gr ⁄ gr deletion of the AZFcregion (Repping et al., 2003; Giachini et al., 2005, 2008).The most frequently encountered biases responsible fordiscrepancies between association studies are inadequatesample size and inappropriate selection of patients andcontrols. If the purpose of a case–control associationstudy is to detect the effect of a genetic variant on sper-matogenesis, the appropriate control (‘disease-free’) groupshould be represented by normozoospermic men ratherthan men from the general population (7% are infertile)or fertile men with unknown sperm count (10% of ‘fertilemen’ are severely oligozoospermic). Patients also shouldbe properly selected because the association between agenetic risk factor and spermatogenic failure may beweakened or lost by the inclusion of patients with knowncauses of spermatogenic failure. Both the Repping et al.(2003) and the Giachini et al. (2008) studies providedstrong support to the importance of ethnic and geo-graphic matching of patients and controls (especiallyrelevant for Y chromosome variants).The best approach to minimize the effect of confound-ing factors would be the use of high-throughput geno-typing (a rapid analysis of hundreds of thousands ofSNPs) in large study populations. Unfortunately, genome-wide association studies are still lacking in the field ofandrology. There is an urgent need for this type of studiesnot only to improve our knowledge of genetic risk factorsbut also to provide a strategy that would accelerate theidentification of spermatogenesis candidate genes. Thereview article by Rodriguez-Murillo and Greenberg (2008)focuses on the strengths and weaknesses of associationstudies and provides general indications ⁄ knowledge forthis type of genetic analysis.The second review article by Carrell et al. (2008) dealswith male infertility related to sperm protamine abnor-malities. Abnormal protamine replacement may lead togenerally diminished sperm quality, impaired fertilizationability and increased DNA damage (Aoki et al., 2006).The aetiology of sperm protamine abnormalities(expressed as abnormal protamine 1 : protamine 2 ratio)is largely unknown although some recent data appear toprovide previously unappreciated clues. The sequencingof genes relevant to protamine expression in different lab-oratories did not identify clear cut cause–effect mutationsso far. On the other hand the analysis of polymorphicsites in the Contrin (YBX2) gene (a transcription factorand translation repressor) revealed the presence of a fewSNPs possibly involved in abnormal protamine expression(Hammoud et al., 2008). More studies are needed in thisspecific area of research, while it would be especially use-ful to combine analysis of multiple polymorphisms withenvironmental factors. Besides mutational screening, theauthors discuss preliminary data generated by spermmRNA profiling that show consistent variation of thesperm transcriptome between men with specific prot-amine defects and controls. Finally, they focus on the linkbetween epigenome (histone retention and DNA methyla-tion) and chromatin compaction defects. Especiallyimportant is the hypothesis related to the role of ‘pro-grammed’ histone retention in sperm chromatinwhich should ensure specific marking of genes to beinternational journal of andrology ISSN 0105-6263ª 2008 The AuthorsJournal compilation ª 2008 European Academy of Andrology • International Journal of Andrology 31, 535–536 535preferentially activated in early embryo development.Abnormal protamine replacement could therefore affectnot only gene expression in mature sperm but also inearly embryo and ultimately affect embryo implantationcapacity.These studies are in keeping with the notion that thetranscriptional machinery who governs the differentiationprogramme of male germ cells is highly specializedand intimately connected to unique epigenetic control(Kimmins & Sassone-Corsi, 2005). The epigenetic pro-gramme of male germ cells involves the generation ofhighly specific histone variants, the histone-to-protaminereplacement process and the activation of distinct histonemodifications that are uncommon in somatic cells. Inaddition, recent evidence indicates that the microRNApathway plays a critical role in the timing of post-meioticRNA translation. The chromatoid body of spermatids,a unique organelle with remarkable structural and func-tional features, seems to operate as a ‘nerve-centre’ forthe RNA metabolic pathway, in a fashion that is reminis-cent of the P-bodies of somatic cells (Kotaja & Sassone-Corsi, 2007).The multiple fascinating facets of germ cell develop-ment make it unique for biologists and clinicians. Thechallenge of future studies lies on linking the interplay ofall molecular mechanisms to the various pathologies, spe-cifically in the understanding of how genetic regulationand epigenetic control operate in concert to insure thefidelity and efficacy of the differentiation programme.C. Krausz* and P. Sassone-Corsi*Andrology Unit, Department of Clinical Physiopathology,Faculty of Medicine, University of Florence, Viale Pieraccini,Italy, and Department of Pharmacology, 2115 GillespieNeuroscience, University of California, Irvine, CA, USAE-mail: c.krausz@dfc.unifi.itReferencesAitken, R. J. & Baker, M. A. (2008) The role of proteomics inunderstanding sperm cell biology. International Journal ofAndrology 31, 295–302.Aoki, V. W., Liu, L., Jones, K. P., Hatasaka, H. H., Gibson,M., Peterson, C. M. & Carrell, D. T. (2006) Sperm prot-amine 1 ⁄ protamine 2 ratios are related to in vitro fertiliza-tion pregnancy rates and predictive of fertilization ability.Fertility and Sterility 86, 1408–1415.Carrell, D. T., Emery, B. R. & Hammoud, S. (2008) The aetiol-ogy of sperm protamine abnormalities and their potentialimpact on the sperm epigenome. International Journal ofAndrology 31, 537–545.Giachini, C., Guarducci, E., Longepied, G., Degl’Innocenti, S.,Becherini, L., Forti, G., Mitchell, M. J. & Krausz, C. (2005)The gr ⁄ gr deletion(s): a new genetic test in male infertility?Journal of Medical Genetics 42, 497–502.Giachini, C., Laface, I., Guarducci, E., Balercia, G., Forti, G. &Krausz, C. (2008) Partial AZFc deletions and duplications:clinical correlates in the Italian population. Human Genetics,doi: 10.1007/s00439-008-0561-1.Hammoud, S., Emery, B. R., Dunn, D., Weiss, R. B. & Carrell,D. T. (2008) Sequence alterations in the YBX2 gene areassociated with male factor infertility. Fertility and Sterility,doi: 10.1016/j.fertnstert.2008.01.009.Kimmins, S. & Sassone-Corsi, P. (2005) Chromatin remodel-ling and epigenetic features of germ cells. Nature 434, 583–589.Kotaja, N. & Sassone-Corsi, P. (2007) The chromatoid body: agerm-cell-specific RNA-processing centre. Nature ReviewsMolecular Cell Biology 8, 85–90.Krausz, C. & Giachini, C. (2007) Genetic risk factors in maleinfertility. Archives of Andrology 53, 125–133.Nuti, F. & Krausz, C. (2008) Gene polymorphisms ⁄mutationsrelevant to abnormal spermatogenesis. Reproductive Biomedi-cine 16, 504–513.Oliva, R., Martı´nez-Heredia, J. & Estanyol, J. M. (2008) Prote-omics in the study of the sperm cell composition, differenti-ation and function. Systems Biology in Reproductive Medicine54, 23–36.Platts, A. E., Dix, D. J., Chemes, H. E., Thompson, K. E.,Goodrich, R., Rockett, J. C. et al. (2007) Success and failurein human spermatogenesis as revealed by teratozoospermicRNAs. Human Molecular Genetics 16, 763–773.Repping, S., Skaletsky, H., Brown, L., van Daalen, S. K., Kor-ver, C. M., Pyntikova, T. et al. (2003) Polymorphism for a1.6-Mb deletion of the human Y chromosome persiststhrough balance between recurrent mutation and haploidselection. Nature Genetics 35, 247–251.Rodriguez-Murillo, L. & Greenberg, D. A. (2008) Genetic asso-ciation analysis: a primer on how it works, its strengths andits weaknesses. International Journal of Andrology 31, 546–556.doi: 10.1111/j.1365-2605.2008.00935.xFrom genetics to epigenetics of male infertility C. Krausz and P. Sassone-Corsi536ª 2008 The AuthorsJournal compilation ª 2008 European Academy of Andrology • International Journal of Andrology 31, 535–536

Florence-Utah Symposium corner: from genetics toepigenetics of male infertility

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Florence-Utah Symposium corner: from genetics toepigenetics of male infertility

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