Hum. Reprod. Advance Access originally published online on August 17, 2006
Human Reproduction 2007 22(1):136-141; doi:10.1093/humrep/del317
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Meiotic segregation analysis in spermatozoa of pericentric inversion carriers using fluorescence in-situ hybridization
1 Service de Cytogénétique, Cytologie et Biologie de la Reproduction, CHU Morvan 2 Laboratoire d’Histologie, Embryologie et Cytogénétique, Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, Brest 3 Service de Génétique 4 CECOS, Biologie de la Reproduction, CHU Bretonneau, Tours and 5 CECOS Franche-Comté, Service de Génétique, Histologie, Biologie du Développement et de la Reproduction, CHU Saint Jacques, Besançon, France
6 To whom correspondence should be addressed at: Laboratoire de Cytogénétique, Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale, 22, avenue Camille Desmoulins, CS 93837, F-29238 Brest cedex 3, France. E-mail: marc.debraekeleer{at}univ-brest.fr
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Abstract |
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BACKGROUND: Pericentric inversions are structural chromosomal abnormalities resulting from two breaks, one on either side of the centromere, within the same chromosome, followed by 180° rotation and reunion of the inverted segment. They can perturb spermatogenesis and lead to the production of unbalanced gametes through the formation of an inversion loop. METHODS: We report here the analysis of the meiotic segregation in spermatozoa from six pericentric inversion carriers by multicolour fluorescence in-situ hybridization (FISH) and review the literature. RESULTS: The frequencies of the non-recombinant products (inversion or normal chromosomes) were 80% for the inv(20), 91.41% for the inv(12), 99.43% for the inv(2), 68.12% for the inv(1), 97% for the inv(8)(p12q21) and 60.94% for the inv(8)(p12q24.1). The meiotic segregation of 20 pericentric inversions (including ours) is now available. The frequency of unbalanced spermatozoa varies from 0 to 37.85%. The probability of a crossover within the inverted segment is affected by the chromosome and region involved, the length of the inverted segment and the location of the breakpoints. CONCLUSIONS: No recombinant chromosomes were produced when the inverted segment involved <30% of the chromosome length (independent of the size of the inverted segment). Between 30 and 50%, few recombinant chromosomes were produced, inducing a slightly increased risk of aneusomy of recombination in the offspring. The risk of aneusomy became very important when the inverted segment was >50% of the chromosome length. Studies on spermatozoa from inversion carriers help in the comprehension of the mechanisms of meiotic segregation. They should be integrated in the genetic exploration of the infertile men to give them a personalized risk assessment of unbalanced spermatozoa.
Key words: meiotic segregation/molecular cytogenetics/pericentric inversion
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Introduction |
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Pericentric inversions are structural chromosomal abnormalities resulting from two breaks, one on either side of the centromere, within the same chromosome, followed by 180° rotation and reunion of the inverted segment. Generally, chromosomal inversions are without consequence for the carrier; however, if a breakpoint disrupts a critical gene, an abnormal phenotype would be expressed (Shashi et al., 1996
). Pericentric inversions can involve all chromosomes but most frequently chromosomes 2 and 8. Few pericentric inversions affect heterochromatin only; they are considered as chromosomal polymorphisms.
Pericentric inversions are common, with an incidence of 0.012% in newborns. The frequency in the general population is estimated at 1–2% (Kaiser, 1984). It is 13 times higher among infertile men than in the general population (De Braekeleer and Dao, 1991). Indeed, these chromosomal abnormalities can perturb spermatogenesis and lead to the production of unbalanced gametes.
During meiosis, the pairing of the normal and inverted chromosomes requires the formation of an inversion loop. Loop formation and synapsis were observed in humans heterozygous for inversions using meiotic studies at the pachytene stage (Guichaoua et al., 1986). An odd number of crossovers within the loop results in one spermatozoon bearing the normal chromosome, one the inverted chromosome and two recombinants with both duplicated and deficient chromosome segments including the regions distal to the inversion [duplication q/deletion p (dup q/del p) or del q/dup p].
The fecundation of these recombinant gametes will lead to an embryo with partial trisomy and monosomy (Groupe Français des Cytogénéticiens Français, 1986). According to losses and gains of distal segments, these unbalanced gametes can cause repeated spontaneous abortion, children with a polymalformation syndrome and/or mental retardation etc.
Many factors seem to influence the production of recombinant chromosomes. The probability of a crossover within the inverted segment is affected by the chromosome and region involved, the length of the inverted segment and the location of the breakpoints. Pericentric inversions affecting heterochromatin only induce very little aneusomy of recombination, because heterochromatin is rarely a site of crossover (Stahl and Hartung, 1981); studies on chiasma distribution showed an absence of chiasmata in these regions (Laurie and Hulten, 1985).
Several meiotic studies on pericentric inversions show that the rate of recombination varies according to the size of the inverted segment. If the inverted segment has a size >30% of the total chromosome size, synapsis usually occurs, and recombinant chromosomes are induced (Winsor et al., 1978). In these unbalanced spermatozoa, duplicated and deficient chromosome segments are small, and thus fertilization by these gametes results in a viable fetus, even to term. In a small pericentric inversion, asynapsis within the inverted segment is likely. Moreover, if the pairing of the normal and inverted chromosomes forms a loop and if there is an odder number of crossovers within the loop, gametes with large duplicated/deleted segments are produced and thus an embryo with such a chromosomal disequilibrium would be lost early in pregnancy.
Ashley (1988) and de Perdigo et al. (1989) found a correlation between the breakpoint positions and the production of recombinant chromosomes. Breaks in G dark bands result in nonhomologous synapsis causing crossover to be suppressed, whereas breaks in G light bands lead to homologous synapsis producing recombinant chromosomes because of crossover in the inversion loop.
Direct investigation of human sperm chromosomes became possible by karyotyping spermatozoa after penetration of zona-free hamster oocytes (Rudak et al., 1978; Balkan and Martin, 1983; Martin, 1984; Burns et al., 1986). Few pericentric inversions were studied using this technique (Balkan et al., 1983; Martin, 1991, 1993; Jenderny et al., 1992; Navarro et al., 1993; Martin et al., 1994; Colls et al., 1997). However, the number of cells analysed by heterospecific fecundation was generally low (Spriggs et al., 1992). Indeed, the oligozoospermia sometimes associated with the presence of an inversion made this technique difficult. Moreover, because of in vitro cross-fertilization, heterospecific fertilization remained controversial, but some results, although limited, were obtained (Martin, 1984; Sele et al., 1985). The frequency of the unbalanced gametes was found to be highly variable from one inversion to another.
More recently, fluorescence in-situ hybridization (FISH) has been used to study spermatozoa chromosomal equipment from pericentric inversion carriers. During the last decade, only seven studies using FISH to estimate meiotic segregation in spermatozoa from pericentric inversion carriers were published (Jaarola et al., 1998; Anton et al., 2002, 2005, 2006; Yakut et al., 2003; Mikhaail-Philips et al., 2004, 2005).
In this study, we analysed the meiotic segregation in spermatozoa from six pericentric inversion carriers by multicolour FISH and discussed the data available in the literature.
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Materials and methods |
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Patients, cytogenetic analysis and sperm parameters
Clinical and laboratory data regarding all six patients are summarized in Table I. Patient 5 was ascertained during the familial investigation following the prenatal diagnosis of a 69,XXY,inv(8)(p12q21) fetus. Patient 6 was discovered following the birth of his child with a recombinant chromosome 8 (partial duplication of 8p and partial deletion of 8q). Before the study, the patients were informed of the investigations and gave their consent.
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Analysis of recombinant products
The sperm samples of the six patients were analysed in triple FISH with the q (Spectrum Orange, Abbott, Rungis, France) and the p (Spectrum Green, Abbott) subtelomere probes of the chromosome implicated in the inversion and the specific alphoid probe of chromosome 9 (probe D9Z, Spectrum Aqua, Abbott).
The hybridization procedure and analysis have been previously described (Morel et al., 2003). Briefly, before hybridization, sperm nuclei were partially decondensed for 1 min with a solution of 1 mol/l NaOH; DNA slides were immersed in 2x SSC/0.4% NP40 solution for 30 min at 37°C and then immediately passed through an ethanol series (70, 90 and 100%). The denaturation was performed simultaneously on spermatozoa and probes for 1 min at 75°C. The slides were incubated overnight in a dark humidified chamber at 37°C. The slides were washed for 45 s in 0.4x SSC/0.3% NP40 at 72°C and 20 s in 2x SSC/0.1% NP40 at room temperature. Finally, they were counterstained with 4,6-diamidino-2-phenylindole (DAPI).
The slides were analysed using a Zeiss AxioPlan Microscope (Zeiss, Le Pecq, France). Subsequent image acquisition was performed using a CCD camera with Isis (significant in-situ imaging system) (MetaSystems, Altlussheim, Germany).
Sperm nuclei were analysed using strict selection criteria (Morel et al., 1997). Clumped or overlapping nuclei, disrupted nuclei with indistinct margins, heads without tails and nuclei that were not swollen or were swollen more than three times their original size were excluded from scoring. Nuclei with one blue, one green and one orange signal represented spermatozoa bearing non-recombinant chromosomes (normal or inverted). A nucleus with one blue and two orange signals represented a spermatozoon bearing a recombinant dup q/del p chromosome. A nucleus with one blue and two green signals represented a spermatozoon bearing a recombinant del q/dup p chromosome. A spermatozoon was scored with two fluorescent signals of the same colour when two signals comparable in brightness and size and at least one signal apart were clearly identified with the sperm head.
Statistical analysis
Statistical analysis was performed using the chi-square test. Pearson’s correlation coefficient was used to study the relation between the frequency of recombinants and the inversion size.
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Results |
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A total of 625 (Patient 1), 5051 (Patient 2), 702 (Patient 3), 69 (Patient 4), 3402 (Patient 5) and 2601 (Patient 6) spermatozoa were analysed (Table II). The frequencies of the non-recombinant products (inversion or normal chromosomes) were 80% for the inv(20), 91.41% for the inv(12), 99.43% for the inv(2), 68.12% for the inv(1), 97% for the inv(8)(p12q21) and 60.94% for the inv(8)(p12q24.1).
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The estimations of frequencies of sperm with recombinant chromosomes ranged from 0 (Patient 3) to 37.71% (Patient 6). There was a significant difference between the frequencies of the recombinant products among the six pericentric inversion carriers (P < 0.001) and also among both men heterozygous for a pericentric inversion of chromosome 8 (P < 0.001).
The frequencies of the two types of recombinant products (dup q/del p or del q/dup p) were not statistically different from the expected 1:1 ratio (P > 0.05).
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Discussion |
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In this study, we used multicolour FISH to score recombination frequency among six pericentric inversion carriers. For the inv(12)(p11q23) carrier, the inverted segment size corresponds to 51% of the total length of chromosome 12, and the frequency of recombinant product was 7.5%. No segregation study of pericentric inversion involving chromosome 12 has yet been published.
For the inv(2) patient, the inverted segment size corresponds to 10% only of chromosome 2; no recombinant chromosome was found. A similar result was obtained by Anton et al. (2005) in a carrier of the same inversion. The inv(2)(p11q13) could be considered as a polymorphism; it is probable that the risk of abnormal progeny is not increased in comparison with that of the general population. Mikhaail-Philips et al. (2004) reported that the frequencies of non-recombinant and recombinant products in a 46,XY,inv(2)(p23q33) carrier were 61 and 37.7%, respectively. In this patient, the inverted segment included more than two-thirds of the chromosome length and both breakpoints are in the G light bands.
For the inv(20) patient, the inverted segment size corresponds to 84% of chromosome 20; the frequency of gamete exhibiting a chromosomal imbalance is 18.24%. Jenderny et al. (1992) found no spermatozoa containing a recombinant chromosome 20 in a man heterozygous for inv(20)(p13q11.2) although the inverted segment size accounted for 51% of the length of the chromosome. However, the lack of recombinant chromosomes could possibly be due to the small number of spermatozoa analysed (26 spermatozoa).
For the inv(1) patient, the inverted segment size corresponds to 95% of the length of chromosome 1; a high level of recombinant spermatozoa (30.4%) was found. Yakut et al. (2003) also found a high rate of recombinant gametes (16%) in a large pericentric inversion of chromosome 1 (inv(1)(p36q32)). On the contrary, Jaarola et al. (1998) found almost no recombinant spermatozoa in an inv(1)(p31q12) carrier, the inversion size being 30% of the total chromosomal length (Martin et al., 1994; Jaarola et al., 1998).
For both pericentric inversions of chromosome 8, the unbalanced spermatozoa and the inverted segment size were 1.44 and 31% (Patient 5) and 37.71 and 61% (Patient 6), respectively. For Patient 6, the fecundation of the spermatozoa with del q/dup p leads to an embryo with a 8p12
8pter trisomy and a 8q24.18qter monosomy. Martin (1993) and Jaarola et al. (1998) analysed the sperm of a 46,XY,inv(8)(p23q22) carrier ascertained following the birth of a maternal first cousin with a recombinant chromosome 8; they found over 10% of spermatozoa bearing recombinant chromosomes.
The meiotic segregation of seven pericentric inversions studied by heterospecific fecundation and nine analysed by FISH is reported in the literature (Table III). The number of analysed sperm for each sample was very different, varying from 26 to 314 sperm by heterospecific fecundation and from 915 to 10 723 sperm nuclei by FISH. The frequency of unbalanced spermatozoa varies from 0 to 30.8% using heterospecific fecundation and from 0 to 37.85% using FISH. Jaarola et al. (1998) studied by FISH two different pericentric inversions that had previously been studied with the heterospecific fecundation method (Martin, 1993; Martin et al., 1994; Jaarola et al., 1998). The results obtained by both methods were similar.
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No significant difference from the expected 1:1 ratio is found between the frequency of recombinant sperm having a duplication of the p arm and a deletion of the q arm and the frequency of those with a deletion of the p arm and a duplication of the q arm (Martin, 1991
; Jaarola et al., 1998; Anton et al., 2002; Morel et al., 2005). Thus, no genotypic selection seems to exist in spermatozoa. Two studies found a high rate of unexpected recombinant spermatozoa (13.5 and 25.1%) (Anton et al., 2002; Mikhaail-Philips et al., 2005). A possible explanation would be the production of chromatid breaks in some of the cells (Anton et al., 2002).
On the basis of a statistical analysis using the Pearson’s correlation test, Anton et al. (2005) postulated that the production of a significant level of unbalanced spermatozoa required the inversion of at least 50% of the chromosome length and a minimum size of 100 Mb. We plotted the frequency of recombinant spermatozoa according to the relative size of the inversion [calculated as the length of the inversion over that of the whole chromosome based on the diagrams of the International System for Human Cytogenetic Nomenclature (ISCN, 1995) and expressed in percentage] of 19 men carrier of a pericentric inversion (Figure 1). One patient carrying an inv(20)(p13q11.2) was excluded because only 26 spermatozoa were analysed (Jenderny et al., 1992). A significant correlation was found (R = 0.76, P = 0.001).
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No recombinant chromosomes were produced when the inverted segment involved <30% of the chromosome length (independent of the size of the inverted segment). Between 30 and 50%, few recombinant chromosomes were produced, inducing a slightly increased risk of aneusomy of recombination in the offspring. The risk of aneusomy became very important when the inverted segment was >50% of the chromosome length. The results obtained here, similar to those recently reported by Anton et al. (2005
,2006), confirm that the risks of meiotic imbalances vary essentially according to the size of the inverted segment. They support previously proposed models (Winsor et al., 1978; Stahl and Hartung, 1981; Laurie and Hulten, 1985; Guichaoua et al., 1986; Ashley, 1988; de Perdigo et al., 1989).
In conclusion, the results obtained in this study confirm that pericentric inversions are associated with a risk of aneusomy for the offspring, the risk being higher if the proportion of gametes with unbalanced chromosomal equipment is important (Escudero et al., 2003). The studies on spermatozoa from inversion carriers help in the comprehension of the mechanisms of meiotic segregation. They should be integrated in the genetic exploration of the infertile men to give them a personalized risk assessment of unbalanced spermatozoa.
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References |
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Submitted on February 17, 2006; resubmitted on April 11, 2006; resubmitted on May 12, 2006; accepted on May 16, 2006.
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