**5.2 Faulty repair**

#### **Structural aberrations**

Chromosomal structural aberrations such as translocations, deletions and inversions, may originate from meiotic recombination involving non-allelic repeated DNA sequences (Heyer et al., 2010). However, since about 80% of chromosomal rearrangements are reported to be of paternal origin (Buwe et al., 2005; Thomas et al., 2006) and that male and female meiosis involves similar genetic mechanisms (Gu et al., 2008; Thomas et al., 2006)**,** one can surmise that yet another process unique to male gametogenesis may be involved. We therefore hypothesize that the chromatin remodeling process in spermatids, generating transient double-strand breaks, may provide the proper context for faulty repair and induction of transgenerational polymorphism. In addition, it is tempting to speculate that, because chromatin condensation occurs, free DNA ends are brought in juxtaposition, increasing the chance of NHEJ repair involving two different chromosomes, which may lead to translocations. Interestingly, chromosomes possess their own territory within the nucleus of somatic cells and in sperm cells (Hazzouri et al., 2000; Manvelyan et al., 2008; Mudrak et al., 2005; Zalenskaya et al., 2000). Moreover, chromosomes known to have higher translocation rates have close chromosomal territories in somatic cells (Branco and Pombo, 2006; Brianna

Post-Meiotic DNA Damage and Response in Male Germ Cells 317

indels and the present review suggests chromatin remodeling of spermatids as an appropriate context for such induction of new polymorphism and possible translocations. Although the frequency of mutation may be lower in germ cells than in somatic cells (Walter et al., 1998), we hypothesize that most of the new mutations generated during spermatogenesis may be through the process of endogenous strand breaks and repair during spermiogenesis. Owing to the 1% chance for a random mutation to occur within genes due to exonic representation in the genome, most mutations are expected to be silent but, if within coding sequences, potential alteration of gene function may be transmitted. In summary, repair of the endogenous DSBs in spermatids may represent a

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**7. References** 

Caddle et al., 2007; Manoj S Gandhi and Nikiforov, 2009). Thus, chromosomes with close chromosomal territories in spermatids could be more prone to interchromosomal translocation during chromatin remodeling. In addition, the potential for the spermatidal chromatin remodeling to produce non-B DNA structure may exacerbate the propensity for spermatids to produce translocation (Hidehito Inagaki and Kurahashi, 2009; Raghavan and Lieber, 2004). Further investigation is needed on the mechanism and potential involvement of chromatin remodeling in such events.

#### **Insertions and deletions**

As outlined above, NHEJ repair pathways are known to create insertions and deletions (indels) as they use microhomology to join the two DNA ends. This type of mutations may be particularly harmful in coding sequences as it may cause codon frameshifts or alteration of mRNA splicing. Moreover, Y chromosomes microdeletions, associated with increased male infertility, may exhibit the classical signature of micro-homology based DNA repair pathways such as SSA and B-NHEJ as the deletion occurs between repetitive, often palindromic sequences (Paulo Navarro-Costa and Plancha; Yen, 1998). Although SSA is available during most of spermatogenesis, the B-NHEJ signature on the highly repetitive Y chromosome may be indicative of a faulty DNA repair in spermatids as this pathway is inhibited during meiosis.

#### **Dynamic mutations**

Several diseases with dynamic mutation, characterized by the expansion over generation of a trinucleotidic repeat (TNRs), are associated with a paternal bias of expansion, such as Huntington disease (HD), spinocerebellar ataxia type 2 and 7 (Cancel et al., 1997; Stevanin et al., 1998; Zühlke et al., 1993). TNRs are microsatellites sequences in coding or non-coding region of the genome. Their stability, which is relative to the chance of adopting a secondary structure, is dependent of the nature of the sequence and the length of the TNR (Kovtun et al.; Tóth et al., 2000). The exact mechanism of TNR expansion or contraction is still not clear. However, studies show strong evidences that TNR expansion in the huntingtin gene occurs during spermiogenesis; in a transgenic mouse model carrying the mutated human gene, an increased length of the CAG repetition was observed in mature spermatozoa but not in early haploid spermatids and other tissues. Kovtun and McMurray also demonstrated the involvement of MSH2, a protein involved in the gap repair and mismatch repair pathways, as this expansion was absent in HD mice MSH2-/- (Albin and Tagle, 1995; Kovtun and McMurray, 2001). The remodeling chromatin of spermatids may promote secondary structure formation at TNRs, providing an ideal context for such mutations.
