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      The AZFc region of the Y chromosome: at the crossroads between genetic diversity and male infertility

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          Abstract

          BACKGROUND

          The three azoospermia factor (AZF) regions of the Y chromosome represent genomic niches for spermatogenesis genes. Yet, the most distal region, AZFc, is a major generator of large-scale variation in the human genome. Determining to what extent this variability affects spermatogenesis is a highly contentious topic in human reproduction.

          METHODS

          In this review, an extensive characterization of the molecular mechanisms responsible for AZFc genotypical variation is undertaken. Such data are complemented with the assessment of the clinical consequences for male fertility imputable to the different AZFc variants. For this, a critical re-evaluation of 23 association studies was performed in order to extract unifying conclusions by curtailing methodological heterogeneities.

          RESULTS

          Intrachromosomal homologous recombination mechanisms, either crossover or non-crossover based, are the main drivers for AZFc genetic diversity. In particular, rearrangements affecting gene dosage are the most likely to introduce phenotypical disruptions in the spermatogenic profile. In the specific cases of partial AZFc deletions, both the actual existence and the severity of the spermatogenic defect are dependent on the evolutionary background of the Y chromosome.

          CONCLUSIONS

          AZFc is one of the most genetically dynamic regions in the human genome. This property may serve as counter against the genetic degeneracy associated with the lack of a meiotic partner. However, such strategy comes at a price: some rearrangements represent a risk factor or a de-facto causative agent of spermatogenic disruption. Interestingly, this precarious balance is modulated, among other yet unknown factors, by the evolutionary history of the Y chromosome.

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          Most cited references109

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          The origins, patterns and implications of human spontaneous mutation.

          J F Crow (2000)
          The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion-deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.
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            Gene conversion: mechanisms, evolution and human disease.

            Gene conversion, one of the two mechanisms of homologous recombination, involves the unidirectional transfer of genetic material from a 'donor' sequence to a highly homologous 'acceptor'. Considerable progress has been made in understanding the molecular mechanisms that underlie gene conversion, its formative role in human genome evolution and its implications for human inherited disease. Here we assess current thinking about how gene conversion occurs, explore the key part it has played in fashioning extant human genes, and carry out a meta-analysis of gene-conversion events that are known to have caused human genetic disease.
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              The mechanism of human nonhomologous DNA end joining.

              Double-strand breaks are common in all living cells, and there are two major pathways for their repair. In eukaryotes, homologous recombination is restricted to late S or G(2), whereas nonhomologous DNA end joining (NHEJ) can occur throughout the cell cycle and is the major pathway for the repair of double-strand breaks in multicellular eukaryotes. NHEJ is distinctive for the flexibility of the nuclease, polymerase, and ligase activities that are used. This flexibility permits NHEJ to function on the wide range of possible substrate configurations that can arise when double-strand breaks occur, particularly at sites of oxidative damage or ionizing radiation. NHEJ does not return the local DNA to its original sequence, thus accounting for the wide range of end results. Part of this heterogeneity arises from the diversity of the DNA ends, but much of it arises from the many alternative ways in which the nuclease, polymerases, and ligase can act during NHEJ. Physiologic double-strand break processes make use of the imprecision of NHEJ in generating antigen receptor diversity. Pathologically, the imprecision of NHEJ contributes to genome mutations that arise over time.
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                Author and article information

                Journal
                Hum Reprod Update
                humupd
                humupd
                Human Reproduction Update
                Oxford University Press
                1355-4786
                1460-2369
                Sep-Oct 2010
                18 March 2010
                18 March 2010
                : 16
                : 5
                : 525-542
                Affiliations
                [1 ]simpleInstituto de Medicina Molecular, Faculdade de Medicina de Lisboa , 1649-028 Lisboa, Portugal
                [2 ]simpleInstituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina de Lisboa , 1649-028 Lisboa, Portugal
                [3 ]Departamento de Genética, simpleInstituto Nacional de Saúde Dr. Ricardo Jorge , 1649-016 Lisboa, Portugal
                [4 ]simpleCEMEARE, Centro Médico de Assistência à Reprodução , 1600-922 Lisboa, Portugal
                Author notes
                [* ]Correspondence address. Tel: +351-217-999-524; E-mail: navarro-costa@ 123456fm.ul.pt
                Article
                dmq005
                10.1093/humupd/dmq005
                2918367
                20304777
                a6778307-16a3-4b6e-ab3c-45b58ed5ee3f
                © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 November 2009
                : 27 January 2010
                : 8 February 2010
                Categories
                Reviews

                Human biology
                azfc,spermatogenesis,male infertility,y chromosome,partial azfc deletions
                Human biology
                azfc, spermatogenesis, male infertility, y chromosome, partial azfc deletions

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