Abstract
Structural reorganization carriers usually present compromised fertility accompanied by an increased risk of producing gametes with chromosomal abnormalities that can be transmitted to the offspring. In part these imbalances are ascribed to result from the occurrence of meiotic disturbances produced by the rearrangements in the proper segregation of other chromosome pairs. This phenomenon of interference has been called interchromosomal effect (ICE). Several studies have been performed to assess the occurrence of ICE in structural reorganization carriers by analyzing the frequencies of numerical abnormalities in the gametes. Nevertheless, the occurrence and distribution of these disturbing events still is a controversial issue. In this work we present compiled data from 130 sperm fluorescent in situ hybridization (FISH) studies performed in carriers of the most frequent structural rearrangements in humans: 44 Robertsonian translocations, 66 reciprocal translocations and 13 inversions. Data from 7 complex/multiple rearrangements will be considered in a separate group.
Significant increases of gametes with numerical abnormalities have been detected in all types of reorganization carriers. Among the groups of non-complex/multiple rearrangements, Robertsonian translocations appear to be the most prone to produce such interference (54.5%) closely followed by reciprocal translocations (43.9%). In contrast, ICE's were only detected in 7.7% of the inversion carriers analyzed. The presence of complex/multiple rearrangements seems to be an important factor for promoting ICE, as 71.4% of these carriers presented increased rates of gametes with numerical abnormalities. Altogether, almost half of the structural reorganization carriers (45.4%) present a higher reproductive risk of producing aneuploid/diploid spermatozoa compared to the general population. This high incidence has been obtained by analyzing a small set of chromosomes, suggesting that underlying meiotic disorders could be present in these individuals.
Further ICE studies in structural reorganization carriers will help to clarify the still unknown predisposing cytogenetic features that promote this phenomenon.
Introduction
Around 2% of infertile males are carriers of structural chromosome abnormalities [Mau-Holzmann Citation2005], a percentage which is six times higher than that observed in the general population. The most frequent structural variants are Robertsonian translocations (0.7%; [Mau-Holzmann Citation2005]), reciprocal translocations (0.6%; [Mau-Holzmann Citation2005]), and inversions (0.2%; [Mau-Holzmann Citation2005]).
Effects of structural chromosome reorganizations in human fertility
Chromosomal reorganization may affect the proper progression of gametogenesis in the affected carriers. Meiosis is a highly regulated process that involves a first stage (prophase I) where homologous recognition between chromosome pairs is required to allow their complete pairing (homosynapsis). The presence of chromosomal variants hinders both the recognition of homology and the subsequent distribution of crossovers [Joyce and McKim Citation2010; Citation2011]. This can compromise the fertility of the individuals in two fundamental aspects:
Abnormal progression of meiosis: To achieve homosynapsis during Prophase I, the rearranged chromosomes adopt complex pairing geometries which can promote the appearance of asynaptic regions, usually near to the breakpoints [Oliver-Bonet et al. Citation2005]. These anomalies can be detected at several cycle checkpoints [Roeder and Bailis Citation2000; Eaker et al. Citation2001] which will typically result in a low production of gametes.
Production of unbalanced gametes: The production of a certain amount of spermatozoa with chromosomal imbalances also determines fertility in structural reorganization carriers. Imbalances primarily originate from the occurrence of some unbalanced segregation modes of the rearranged chromosomes. It has also been described that these rearrangements can perturb disjunction and segregation of other chromosome pairs thus favoring the formation of numerical abnormalities in the resulting gametes. This phenomenon of interference has been called interchromosomal effect (ICE).
Interchromosomal effect
Lejeune first postulated the existence of ICE in 1963 [Lejeune Citation1963] when he detected an increased frequency of reciprocal translocation carriers among fathers of children with Down syndrome.
The occurrence of these disturbances is related to the formation of heterosynapsis between the meiotic configurations adopted by the chromosomes involved in the reorganization –which, as stated before, usually present asynaptic regions-, and other susceptible regions of the genome [Guichaoua et al. Citation1990; Cheng et al. Citation1999; Oliver-Bonet et al. Citation2005]. Some genomic regions display a higher propensity to be involved in these ‘illicit’ associations. Among them there are those with a higher tendency of suffering heterosynapsis (e.g., short arms of the acrocentric chromosomes, the sex chromosomes) or presenting gaps and splits in the synaptonemal complex [Codina-Pascual et al. Citation2006].
Some studies have related the occurrence of these heterosynaptic interchromosomal interactions with the meiotic arrest [Gabriel-Robez et al. Citation1986; Johannisson et al. Citation1987]. This even alters the seminal parameters of the individuals which, in fact, is a common feature among reorganization carriers [De Braekeleer and Dao Citation1991]. Nevertheless, the occurrence of heterosynapsis has also been proposed as a cellular mechanism to rescue the meiotic arrest caused by the existence of asynaptic regions [Chandley et al. Citation1986; Saadallah and Hulten Citation1986; Navarro et al. Citation1991]. The perturbing effect of these interactions could be translated into a significant increase of numerical chromosome abnormalities in the resulting cells which would account for an additional source of chromosomal imbalance in reorganization carriers.
Several studies have been performed to assess the occurrence of ICE by analyzing the frequencies of numerical abnormalities in the gametes using fluorescent in situ hybridization (FISH). Data show divergent results regarding the occurrence and distribution of ICE among carriers. Whereas some authors have observed a significant increase of numerical abnormalities for many of the chromosomes analyzed [Rousseaux et al. Citation1995a; Rousseaux et al. Citation1995b; Van Hummelen et al. Citation1997; Blanco et al. Citation1998; Mercier et al. Citation1998; Blanco et al. Citation2000; Amiel et al. Citation2001; Morel et al. Citation2001; Oliver-Bonet et al. Citation2001; Baccetti et al. Citation2002; Oliver-Bonet et al. Citation2002; Anton et al. Citation2004a; Anton et al. Citation2004b; Morel et al. Citation2004; Baccetti et al. Citation2005; Douet-Guilbert et al. Citation2005; Machev et al. Citation2005; Anton et al. Citation2006; Chen et al. Citation2007; Wiland et al. Citation2007; Anton et al. Citation2008; Vozdova et al. Citation2008; Juchniuk de Vozzi et al. Citation2009; Anton et al. Citation2010; Pellestor et al. Citation2011; Vozdova et al. Citation2011b], others have not [Martini et al. Citation1998; Cifuentes et al. Citation1999; Honda et al. Citation1999; Estop et al. Citation2000; Rives et al. Citation2003; Mikhaail-Philips et al. Citation2004; Oliver-Bonet et al. Citation2004; Mikhaail-Philips et al. Citation2005; Hatakeyama et al. Citation2006; Kekesi et al. Citation2007; Vialard et al. Citation2007].
Most of the studies include the sex chromosomes due to their singular characteristics that make them especially prone to be involved in heterosynapsis. In addition, probes for one or up to eight extra autosomes have been used. Data from chromosomes 1, 4, 6, 7, 8, 9, 13, 14, 15, 16, 17, 18, 20, 21, and 22 have been reported.
In this work we have revisited previously published results from sperm FISH studies where the occurrence of ICE has been evaluated. The methodology evaluated combined the use of different fluorescently labeled DNA probes expressely selected according to each study. The protocol usually involved a sperm chromatin decondensation step. Once hybridized, the presence of their target regions can be detected by evaluating the emmitted fluorescence. Seven carriers of complex/multiple rearrangements related with these three previous groups have also been considered ().
Table 1. ICE studies in Robertsonian translocation carriers. Incidences of diploidies and disomies for the chromosomes analyzed are displayed.
Table 2. ICE studies in reciprocal translocation carriers. Incidences of diploidies and disomies for the chromosomes analyzed are displayed.
Table 3. ICE studies in inversion carriers. Incidences of diploidies and disomies for the chromosomes analyzed are displayed.
Table 4. ICE studies in carriers of complex or multiple rearrangements. Incidences of diploidies and disomies for the chromosomes analyzed are displayed.
RESULTS AND DISCUSSION
Robertsonian translocation carriers
In this review, only those studies that assess the aneuploidy/diploidy rates individually have been considered. Data from three populations of individual carriers of the most prevalent structural reorganization in humans was gathered. A total of 44 Robertsonian translocation carriers (), 66 reciprocal translocation carriers (), and 13 inversion carriers () were examined. Among the carriers of non-complex/multiple rearrangements, Robertsonian translocation carriers appear to be the population with a higher incidence of ICE. A significant increase in chromosome numerical abnormalities have been detected in 24 of the 44 carriers analyzed (), representing 54.5% of this group.
This high incidence could be related with the specific cytogenetic features that display the acrocentric chromosomes involved in these rearrangements. For example, acrocentric chromosomes present satellites at the polymorphic heterochromatic p-arms. Variations can hinder synapsis between homologous segments [Metzler-Guillemain et al. Citation1999] thus favoring heterologous pairing with other asynaptic regions of the genome (e.g., bivalent XY). This synaptic adjustment can represent a rescue mechanism for meiosis [Saadallah and Hulten Citation1986] and can also be promoted by the existence of a certain degree of homology between regions (see below). Non-centromeric heterochromatin of chromosomes 15 and Y display a high degree of homology [Burk et al. Citation1985]. This fact has been related to the frequent association observed between the synaptonemal complexes of these two chromosomes [Metzler-Guillemain et al. Citation1999]. A degree of homology between the p-arm sequences of some acrocentric chromosomes (13, 14, 15, and 21) and the Xp/Yq subtelomeric region [Brown et al. Citation1990; Smeets et al. Citation1991; Stergianou et al. Citation1992; Wilkinson and Crolla Citation1993; Ciccodicola et al. Citation2000; Kuhl et al. Citation2001] has been described. This could also explain some of the associations observed between these chromosomes at the pachytene stage [Codina-Pascual et al. Citation2006]. Moreover, the predisposing effect of these features can also be enhanced by the co-localization of the acrocentric chromosomes in the spermatocyte nucleus. Until the pachytene stage, the localization of the acrocentric chromosomes in the interphasic nucleus is narrowly linked to nucleolus formation. This structure maintains all the acrocentric chromosomes in a relative close position [Stahl et al. Citation1976; Stahl et al. Citation1991; Schwarzacher and Mosgoeller Citation2000; Tres Citation2005]. However it has also been described that nucleolar fragments come near the XY bivalent during the formation of the sex body [Tres Citation2005]. This would locate the acrocentric chromosomes in close proximity to the gonosomes thus favoring a possible interaction.
Data compiled regarding the diversity of the Robertsonian translocations, include results of der(13;14), der(13;15), der(13;21), der(13:22), der(14;15), der(14;21), and der(14;22) and until now, no data has been published in relation to der(15;21) and der(15;22) rearrangements. Significant ICEs have been detected in carriers of all the types of Robertsonian translocations analyzed, but its occurrence does not present a preferential distribution among them as it has been already reported elsewhere [Anton et al. Citation2010]. In any case, the reason why some Robertsonian translocations carriers display a positive ICE and others do not remains unknown. As described previously, the existence of polymorphic variants in the karyotype of these individuals may have an implication [Anton 2004]. In particular, it has been described that the differences in the size of the acrocentric chromosomes can be so huge that, in some extreme cases, the p-arm can be larger than the q-arm [Friedrich et al. 1996] whereas in others it can be almost nonexistent [Earle et al. Citation1992]. Maybe these inter-individual variations could explain the differences in the propensity of individuals with the same Robertsonian translocations to interfere in the correct segregation of other chromosome pairs. Further studies are required to shed more light into the genetic basis of ICE as well as to determine its occurrence in the rare der(15:21) and der(15:22) rearrangements.
Reciprocal translocations carriers
Reciprocal translocations present a predisposition for displaying ICE almost as high as Robertsonian translocations. In this group of carriers, 43.9% of the cases analyzed (29 of the 66 individuals) presented increased rates of aneuploid/diploid gametes ().
Given the fact that most of the reciprocal translocations involve different chromosomes and breakpoints, it is difficult to ascertain which chromosomal factors promote the occurrence of ICE. In a previous study performed in our laboratory in the largest series of reciprocal translocation carriers analyzed so far [Anton et al. Citation2008], several cytogenetic features where analyzed according to the occurrence of ICE: symmetry of the tetravalents, reorganizations involving acrocentric chromosomes, or participation of chromosomes with large blocks of heterochromatin (chromosomes 1, 9, and 16). None of these specific cytogenetic features correlated with increased rates of gametes with numerical anomalies. Nevertheless, when considering data from the 66 carriers, we can observe that translocations that involve at least one acrocentric chromosome have higher rates of ICE (52.4%) than reciprocal translocations that do not involve the acrocentric ones (38.8%). More studies in reciprocal translocations with particular cytogenetic characteristics are needed to clarify this predisposition.
Regarding the chromosomes implicated in the rearrangements, some of them tend to be present at a greater frequency in reciprocal translocations that display a positive ICE (i.e., chromosomes 8, 11, 15, and 19; ) although none reach any significant preferential distribution (Fisher test, P = 0.21). This is mainly due to the reduced size of the sample analyzed.
Figure 1. Chromosomes involved in reciprocal translocations according to the occurrence of ICE.
Finally, some ICE studies performed in carriers of the same reciprocal translocation [Rousseaux et al. 1995b; Anton et al. 2004b; Wiland et al. 2007; Vozdova et al. 2008] showed the existence of different outcomes. In the study performed by Rousseaux et al. [1995b] in two brothers that were carriers of the same t(6;11)(q14;p14) reorganization, significant increase in aneuploidy was detected in both cases (). The same results were observed in a study performed with a father and his son, carriers of the same t(4;5)(q15.1;q12) reorganization [Wiland et al. Citation2007]. However, Vozdova et al. [2008] detected different outcomes when a father and his son, carriers of the reciprocal translocation t(11;18)(q22;q21.3) were analyzed. They only observed a significant ICE in the progenitor and the authors attributed this result to the difference in age between carriers. In contrast, a significant ICE was only observed in one of the two brothers of the common t(11;22)(q23;q11) translocation [Anton et al. Citation2004b]. In this case, the results obtained were related to the presence of an acrocentric chromosome in the rearrangement which could imply the presence of polymorphic variants between brothers (depending on the inherited paternal and maternal homolog).
It is worth noting that reciprocal translocations are reorganizations that combine the participation of a much wider range of factors than Robertsonian translocations (e.g., any chromosome with their particularities can be involved, the breakpoints define very different tetravalents) and most of the rearrangements are unique. This complexity makes more difficult the identification of the factors that are directly related with the occurrence of ICE. Further data from new rearrangements may help to elucidate their contribution.
Inversion carriers
Carriers of inverstions appear to be the less prone to display ICE with only a 7.7% incidence corresponding to a single individual (). However, the size of the population analyzed is much smaller than the others (13 individuals in total) representing a limiting factor for estimating this effect in this group of rearrangements.
The only carrier of this population that displays a positive ICE [Amiel et al. Citation2001] presents a particularly singular inversion which involves the polymorphic heterochromatic region of chromosome 9. The authors relate the high incidence of aneuploidies detected in this individual to the large difference between homologous heterochromatic regions.
To confirm the lack of predisposition of inversion carriers to produce aneuploid/diploid gametes it would be necessary to enlarge this population. This information would be useful to discard the existence of an additional reproductive risk coming from the occurrence of ICE in these carriers.
Carriers of complex or multiple rearrangements
It seems that the presence of complex/multiple rearrangements is an important factor to be considered regarding the occurrence of ICE, as 71.4% of the individuals analyzed (5 out of 7 cases) presented higher rates of numerical abnormalities when compared to controls ().
This group involves individuals with more complex alterations in their karyotype than those included in the previous sections. Four of these individuals present more than one rearrangement in their karyotype (carriers of multiple rearrangements) which include a carrier of two inversions [Anton et al. Citation2006], a Robertsonian translocation carrier with a marker chromosome [Kirkpatrick et al. Citation2008], a carrier of a double Robertsonian translocation [Juchniuk de Vozzi et al. Citation2009] and a carrier of an inversion plus a reciprocal translocation [Vozdova et al. Citation2009]. The other three individuals are carriers of complex chromosomal rearrangements (structural reorganization that involves at least three breakpoints on two or more chromosomes) and include two 3-breakpoint reciprocal translocation carriers [Kirkpatrick et al. Citation2008; Pellestor et al. Citation2011] and a reciprocal translocation carrier with a derivative chromosome [Vozdova et al. Citation2011a].
The achievement of homosynapsis by all of these rearrangements is still a more intricate process. The presence of a larger amount of reorganized sequences might complicate/delay the proper recognition between homologous regions. This can promote synapsis failure during prophase, thus severely reducing the fertility of these individuals, but it can also entail a major occurrence of heterosynapsis with other regions of the genome as a rescue mechanism of meiosis. These interactions will correspond to ICE and would explain the high incidence of aneuploidies observed in these carriers.
CONCLUSIONS
This study compiles data obtained from previously published studies in 130 structural reorganization carriers. The global incidence of ICE among these individuals is about 45.4%. Robertsonian translocations appear to be the most prone to produce such interference (54.5% of the cases) closely followed by reciprocal translocations (43.9% of the cases). In contrast, carriers of inversions seem to be the least susceptible to suffer these meiotic disturbances, as ICE was only detected in 7.7% of the cases analyzed. Nevertheless the reduced size of this population requires additional studies to corroborate these findings. The presence of complex/multiple rearrangements seems to be an important predisposing factor for the occurrence of ICE as 71.4% of the individuals analyzed presented higher rates of unbalanced gametes for chromosomes unrelated with the rearrangement when they are compared to controls.
It is worth noting that infertile individuals with a normal somatic karyotype usually present increased amounts of gametes with numerical abnormalities [revised by Sarrate et al. Citation2010]. The fact that reorganization carriers frequently present altered seminal parameters leads some authors to relate the augmented rates of aneuploid gametes found in these individuals to their seminal alterations instead of considering them as a result of ICE [Pellestor et al. Citation2001]. Accordingly, the origin of such numerical abnormalities could be either attributed to a generalized alteration of the meiotic process [Egozcue et al. Citation2000], to mutations in regulatory genes that participate in several meiotic stages (synapsis, recombination, and DNA repair) [Baarends et al. Citation2001] and/or to the influence of a compromised testicular environment [Mroz et al. Citation1999].
Supporting the participation of ICE, the incidence of individuals with increased rates of spermatozoa with numerical abnormalities is much higher among carriers exhibiting reorganization than in infertile individuals with a normal karyotype. Whereas in this last group the percentage of individuals with higher rates of aneuploid/diploid gametes is lower than 20% [revised by Egozcue et al. Citation2003], in carriers of structural rearrangements this frequency is considerably much higher: 45.4% (, , , and ). The discrepancy between both values requires the existence of an extra source of numerical anomalies in the reorganization carriers, which could be explained by the participation of ICE.
Altogether, data compiled in this review highlight the fact that approximately half of the carriers of structural reorganization present a higher reproductive risk of producing aneuploid/diploid spermatozoa compared to the rest of the population. Although the reproductive consequences of this phenomenon are still controversial at the embryo level [Gianaroli et al. Citation2002; Munné et al. Citation2005] it is important to take into account that only a small set of chromosomes have been used in each of these analysis. For this reason we believe that these findings could just represent ‘the tip of the iceberg’, and the detection of increased rates of aneuploid gametes for a specific chromosome would in fact cover a more generalized abnormal meiotic functioning [Anton et al. Citation2007]. In this sense, we expect that further ICE studies in structural reorganization carriers will help to clarify the still unknown predisposing cytogenetic features that promote this phenomenon.
Declaration of Interest: This work was funded by project 2009 SGR-282 (Generalitat de Catalunya). EA is recipient of a mobility grant (JC 2010-0247) from the Ministerio de Educación (Gobierno de España). The authors declare no competing financial interests.
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