Balkan Journal of Medical Genetics

ANALYSIS OF MEIOTIC SEGREGATION PATTERNS AND INTERCHROMOSOMAL EFFECTS IN SPERM FROM 13 ROBERTSONIAN TRANSLOCATIONS
Wang B1,*, Nie B1,*, Tang D2,*, Li R3,*, Liu X1, Song J1, Wang W1, Liu Z1,** *These authors contributed equally to this study.
*Corresponding Author: Dr. Zhi Liu, Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, 745 WuLuo Road, Wuhan, Hubei, People’s Republic of China. Tel: +86-27-8716-9190. Fax: +86-27-8716-9097. E-mail: wangbo1005@163.com.
page: 43

DISCUSSION

Sperm chromatin is a highly organized, compact structure consisting of DNA and heterogeneous nucleoproteins, which are essential for the accurate transmission of genetic information to offspring [22]. Sperm FISH is most commonly used to determine the proportion of aneuploidy present in sex chromosomes and autosomes of infertile men. Furthermore, it can also quantify the probability of transmitting aneuploidies and complex chromosomal rearrangements, such as translocations and inversions [22]. As a result, sperm FISH analysis is increasingly included in infertility diagnostic protocols, providing useful information for genetic consulting. In our study, we performed sperm FISH analyses on 13 male ROB translocation carriers. In our study, we had one homozygous carrier (P1) and 12 heterozygous carriers (P2-P13). In P1, the frequency of unbalanced spermatozoa was only 0.3% that was similar to controls and is consistent with previous publications [5-7]. In contrast, in P2-P13, the frequency of normal/ balanced spermatozoa resulting from alternate segregation varied between 70.4 and 85.2% (Table 2). This is consistent with previous studies showing that alternate segregation is predominant in sperm of Robertsonian translocation carriers [11,20,21]. The high prevalence of the alternate segregation is presumably due to cis-configuration of the trivalent during meiosis, which favors an alternate segregation in all ROB translocations [21-24]. However, the frequency of unbalanced spermatozoa resulting from adjacent segregation varied between 14.8 and 29.6% (Table 2), which is significantly higher than controls. Robertsonian translocations consist of a fusion of two acrocentric chromosomes at the centromere level to form a derivative chromosome (group D: 13, 14 and 15; group G: 21 and 22). Robertsonian translocation can be separated into three subtypes: D/D, D/G and G/G translocation. Patients P2P8 were D/D ROB translocation carriers; P13 was a G/G ROB translocation carrier, and P9-P12 were D/G carriers. The frequency of unbalanced spermatozoa was highest in the D/G carriers and lowest in the D/D carriers and the differences between D/D and D/G, D/D and G/G were significant (p <0.05). In contrast, the difference between G/G and D/G was not significant (p >0.05). This is consistent with previous publications [6,17]. We speculated that in D/D ROB translocation, the derivative chromosome is a metacentric chromosome, so it is prone to alternate segregation rather than adjacent segregation at the end of meiosis I. In the G/G ROB translocation, the derivative chromosome is a metacentric chromosome, but the derivative chromosome is shorter than the derivative chromosome of D/D ROB translocation, so the rate of adjacent segregation is higher than D/D ROB translocation. In the D/G ROB translocation, the derivative chromosome is a submetacentric chromosome, it is more chaotic than D/D and G/G ROB translocations at the end of meiosis I, so the rate of unbalanced spermatozoa is significantly higher than D/D and G/G ROB translocations. The homozygous ROB translocation carrier (P1) is healthy and has a balanced chromosomal complement. Assessment of a semen sample from P1 showed normal sperm number and morphology. Given his karyotype of 44,XY,der(14;15)(q10;q10),der(14;15)(q10;q10), we hypothesized that the person’s sperm karyotype to be consistently 22,X,der(14;15)and 22,Y,der(14;15), then, our hypothesis was proven by this research. Most of the sperm from P1 are balanced haploid (not normal haploid) (Table 2, Table 3). Homozygous ROB translocations in man have been described before. A fetus with two t(14;21) chromosomes was found by Dallapiccola et al. [25]. The related parents were heterozygous for the same translocation. Martinez et al. [26] described three adult siblings homozygous for t(13;14). Their parents were first cousins and both were heterozygous carriers. Rajangam et al. [27] found a unique DS karyotype 45,XY,der(14;21)pat,der(14;21)mat, +21mat. While translocation heterozygosity is associated with meiotic disturbances that cause infertility and subfecundity, translocation homozygosity should not, at least in theory, have any effect on meiosis [28]. In our study, we have one patient with homozygous ROB translocation. Inter-chromosomal effect remains controversial in the literature [29]. Some publications have indicated its relevance [12,13], while others showed no evidence of ICE in ROB translocation carriers [9,18]. Inter-chromosomal effect could be explained by the formation of heterosynapses between chromosomes involved in the translocation and the sex vesicle, which could also involve other chromosomes [11,29]. In our study, we observed higher frequency of aneuploidy for the sex chromosome in 10 ROB translocation carriers (P2-P8, P10-P12) and higher frequencies of aneuploidy for chromosome 18 in 10 ROB translocation carriers (P3-P9, P11-P13). In addition, increased rates of diploid were found in 11 ROB translocation carriers (P2P9, P11-P13). Increased rates of unbalanced sperms were found in all ROB translocation heterozygote (P2-P13). The incidence of spermatozoa with nullisomy, disomy and diploid for the sex chromosomes of ROB translocation heterozygotes (P2-P13) was significantly higher compared to that of ROB translocation homozygosity (P1) (p <0.05). Robertsonian translocation rearrangements are common chromosomal changes that can lead to rapid and efficient reproductive isolation between karyotypically similar populations, especially when many ROB metacentric chromosomes display monobrachial homologies [30]. In the case of Muntjac deer, also called Cervidae, which are of great interest to evolutionary biologists and cytogeneticists because of the considerable diversity of their karyotypes, despite their morphological similarity [28]. To conclude, our study confirmed that alternate segregation is dominant in ROB translocation carriers. However, despite the high number of normal/balanced spermatozoa, there are still a lot unbalanced spermatozoa resulting from adjacent mode of segregation. Our study provides further evidence of ICE on chromosome X, Y and 18 in ROB translocation carriers. Therefore, preimplantation genetic diagnosis (PGD) is recommended for ROB translocation carriers to minimize the risk of having an affected child or the distress of pregnancy termination, and to reduce the risk of miscarriage due to abnormal segregation of the translocation [31-34]. Since the proband is phenotypically normal with normal fertility, we considered the chromosomal rearrangement of the person to be a balanced polymorphism [35]. The aberration can provide material for evolution. The establishment of a new human subspecies with a diploid complement of 44 chromosomes could occur if a small population with the karyotype of the proband undergoes long-term reproductive isolation [36].

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