We are currently in the midst of an era of rapidly advancing technologies that are exponentially increasing our ability to identify genetic variants responsible for complex diseases, such as male infertility [Heard et al. Citation2010]. Understanding the genetic basis of male infertility is necessary to provide appropriate diagnostic and therapeutic options to infertile couples, to assess the risk of transmission of genetic anomalies to offspring, and to better prevent and treat infertility by improved understanding of the role and risks of environmental exposures on fertility. The 4th Utah/Florence International Symposium on the Genetics of Male Infertility was held in the winter of 2010 in Park City, Utah and provided a forum for interaction between clinicians and basic scientists involved in the study of male infertility. This issue of Systems Biology in Reproductive Medicine contains reviews and reports from some of the esteemed participants of the symposium.
Studies on genetic causes of male infertility, like genetic studies of other complex diseases, have been hampered by the relative inability of medical resequencing studies and genomewide association studies (GWAS) to identify disease causing genetic variants. Although some novel variants have been identified through these studies, conflicting data abound in the literature and overall the variants associated with infertility account for a low percentage of the disease [Heard et al. Citation2010; Matzuk and Lamb Citation2008]. Therefore, much excitement and emphasis is currently being placed in new technologies that allow the possibility of genomewide sequencing to identify uncommon (<1%) variants, and the analysis of structural variations in the genome, such as copy number variations (CNVs) [Ciulli and Goldstein 2010; Stankiewicz and Lupski Citation2010; Zhao and Grant Citation2010]. In the first manuscript of this issue, James Lupski, an expert in CNV analysis, and colleagues provide an elegant description of the state of art of CNV analysis and its potential to assist in the study of complex diseases. Additionally, Douglas Carrell and Kenneth Aston report on the status of gene re-sequencing studies and the results of the first GWAS study to evaluate variants linked to azoospermia and oligozoospermia [Aston and Carrell Citation2009; Aston et al. Citation2010]. They also discuss the first genomewide studies for CNVs and epigenetics in regards to male infertility [Carrell and Hammoud Citation2010; Hammoud et al. Citation2009]. Chris Lau et al. provide an elegant analysis of one gene involved in spermatogenesis, the gonadoblastoma gene, and recent data from their laboratory on the function of this gene. Lastly, John Parrington et al. provide a glimpse to the future with a review of potential treatment of genetic disorders through gene therapy techniques relevant to male infertility.
Sperm undergo extensive chromatin remodeling following meiosis, resulting in the replacement of most histones with sperm-specific nuclear proteins termed protamines [Carrell et al. Citation2007]. In addition to protein replacement, sperm chromatin is marked with specific epigenetic marks that are associated with gene activation or silencing [Dhawan and Mishra Citation2010; Hammoud et al. Citation2009]. These changes include DNA methylation and chemical modifications to the histones. Abnormal epigenetic marks are not only potential causes of disease, but are also important because of their potential as a mechanism of conveyance of environmental causes of disease [Bell and Beck Citation2010]. Two manuscripts, Michael Ortega et al. and Sophie Rousseaux et al., beautifully review the post-meiotic changes that sperm undergo and subsequent epigenetic modifications. Epigenetics is an area of study that is rapidly growing and new tools for the study of epigenetics are key to further growth. Additionally, Graham Johnson et al. show that an interspecies tiling array is a practical and useful tool in the study of transgenic mice developed to study proteins involved in chromatin structure and function. Lastly, Christopher Somers provides an exciting review of data demonstrating the role of environmental factors, in this case air pollution, on epigenetic marks in sperm.
The next section of this issue deals with clinical aspects of male infertility. Robert Oates provides a concise and valuable model for clinicians to follow in the initial evaluation of male infertility, with practical, evidence-based suggestions. One aspect of evaluating an infertile male that has been particularly relevant and controversial in recent years is the clinical implementation of sperm DNA damage testing [Barratt et al. Citation2010]. Armand Zini provides a critical analysis of the literature regarding DNA damage testing and fertility treatments. At a time in which much variation in DNA damage testing protocols exists, Zini's careful and methodical analysis is a useful tool in aiding clinicians and focusing attention of future areas of study. Similarly, Lars Björndahl and Ulrik Kvist report on the role of zinc as a factor in chromatin stability, and the ramifications for the analysis of the mechanisms of sperm DNA damage. Recently sperm chromosome aneuploidy testing has undergone significant advancements, and as described by Helen Tempest, is another useful tool for clinicians to use in the analysis of male infertility.
A highlight of the symposium was the keynote address by Ryuzo Yanagimachi, held in a ski lodge halfway up the ski resort mountain and reached by an evening chairlift journey. Dr. Yanagimachi has been a renowned researcher in the study of male reproduction for many years, and provides a unique perspective to the study of male reproduction. His accomplishments are numerous, including sentinel studies of molecular mechanisms of fertilization, karyotyping of sperm, and breakthrough studies in animal cloning [Yanagimachi Citation1969; Yanagimachi et al. Citation1976; Rudak et al. Citation1978; Wakayama et al. Citation1998]. Dr. Yanagimachi provides a provocative and creative review of both the past and future of genetic analysis of male reproduction that elegantly points researchers and clinicians alike to possible future technologies and techniques in the study and treatment of male infertility.
The challenges facing us in the elucidation of genetic causes of male infertility are complex and serious. They include the lack of large cooperative study groups with tissue banked from clearly defined phenotypes, and the paucity of funding for such undertaking. Additionally, the amazing quantity of data derived from studies of the genome and epigenome must not only be rigorously analyzed via complex bioinformatic and statistical techniques, but must ultimately be integrated and analyzed in tandem and in conjunction with environmental data [Chari et al. Citation2010; Hawkins et al. Citation2010].. Lastly, we are only beginning to understand the possible significance of new areas of study, such as understanding the significance of previously ignored large regions of non-coding DNA [Alexander et al. Citation2010]. However, the technological breakthroughs in genetic research continue to exceed expectations, and with the continued collaboration of researchers and clinicians the future for meaningful progress in understanding and treating male infertility is bright.
Guest Editor, Special Issue: Invited Papers from the 4th Utah-Florence Symposium on the Genetics of Male Infertility Systems Biology in Reproductive Medicine
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