Unequal nondisjunction frequencies of trivalent chromosomes in male mice heterozygous for two Robertsonian translocations

Robertsonian (Rb) translocation heterozygosity may cause pairing problems during prophase and segregation irregularities at anaphase of meiosis I. These stages of meiosis I were studied in male mice doubly heterozygous for the two Rb chromosomes Rb(9.19)163H and Rb(16.17)8Lub. At pachytene both Rb chromosomes similarly showed pairing irregularities like unpaired segments. However, highly different nondisjunction frequencies of chromosomes forming the respective trivalents were found. The nondisjunction frequency of the Rb8Lub trivalent chromosomes was about 40%, whereas a very low frequency of nondisjunction was found in combination with the Rb163H trivalent. Since both trivalents were together in the same cell, differences in kinetochore function are assumed to be responsible for the diverse frequency of nondisjunction.     

Radiation-induced nondisjunction and Robertsonian translocation in Drosophila

In Drosophila melanogaster, gametes formed by oocytes in which Robertsonian translocations were induced in an immature stage usually show chromosomal imbalance. It is estimated that fewer than 20% of the gametes bearing newly induced Robertsonian translocations “fusing” X and fourth chromosomes are of balanced constitution. In contrast, when the two acrocentric pairs, X and fourth chromosomes, are replaced by an X-4 Robertsonian translocation, treatment of immature oocytes of homozygotes produces some 5–6-fold fewer sex-chromosome trisomics than do females of normal karyotype. In the place of such trisomics (having separate sex chromosomes), there is a much smaller number of compound-X chromosomes formed and a number of compound-fourth chromosomes as well. However, the production of “XO” males is not appreciably smaller in the translocation homozygotes. A number of possible mechanisms to account for this are suggested. The findings are consistent with the expectations of the hypothesis that radiation-induced nondisjunction results from improper conjunctions of heterologues, brought about by chromatid interchange^{7–12, 16}.     

Chromosome analysis of spermatozoa from a male heterozygous for a 13;14 Robertsonian translocation

Summary Cytogenetic analysis of 78 spermatozoa from a man heterozygous for a t(13;14) Robertsonian translocation was performed. R banding was applied for chromosomal identification. Incidence of normal and balanced complements were respectively 50% and 41.3%. Six unbalanced complements (7.7%) were observed, resulting from adjacent segregation. Although alternate segregation is the most common mode of distribution, the possibility of producing unbalanced zygotes exists. The frequency of abnormalities unrelated to the translocation was 16.5% including 12.8% hypohaploïdy, 2.5% hyperhaploidy, and 1.2% of structural aberrations. An excess of t(13;14) X complements was observed (24 with X versus 14 with Y). This may result from the close association between trivalent (13;14) and X chromosome observed in the pachytene spermatocyte nucleus.     

Cytogenetic analysis of sperm from a male heterozygous for a 13;14 Robertsonian translocation

Summary Cytogenetic analysis of 121 sperm from a man heterozygous for a t(13;14) Robertsonian translocation was performed using the technique of in vitro penetration of hamster eggs. The frequency of sperm that were chromosomally unbalanced with respect to the translocation was 27%. The frequency of chromosomally normal (36%) and balanced (38%) complements was approximately equal, as theoretically expected. There was no evidence for an interchromosomal effect since the frequency of numerical chromosomal abnormalities (2.5%) and structural chromosomal abnormalities (10.7%) — both unrelated to the translocation — were within the normal range of control donors. The ratio of X-and Y-chromosome bearing sperm was equal, and there was no evidence for preferential segregation of the X chromosome with the translocation.     

Kinetics of oogenesis in mice heterozygous for Robertsonian translocations

The total number of oocytes at different postmating time intervals (18-40 days) was determined in mice homozygous and heterozygous for different Robertsonian (Rb) translocations, of both laboratory and feral origin. The number of oocytes was lower in heterozygous than in homozygous mice throughout the period studied. Independently of the genetic background (i.e. laboratory or feral), structural heterozygosity had a progressive detrimental effect on oocyte numbers: open, or chain diakinetic configurations had a greater detrimental effect than close, or ring, configurations. The genetic background, however, affected the ovarian constitution in terms of the total number of germ cells, which are more numerous in laboratory than in feral mice. The kinetics of oogenesis seems to be faster in feral than in laboratory mice. At the light of the data here presented, and of those already available from the literature on male and female gametogenesis in conditions of structural heterozygosity, it appears that factors other than unsaturation of pairing sites or interference with pachytene X-chromosome inactivation have to be considered. In the wild, the reduced oocyte numbers in Rb heterozygous female can contribute to the retention of isolated populations in contact zones.     

Developmental stability in house mice heterozygous for single Robertsonian fusions

Fluctuating asymmetry (FA) of tooth traits has been reported to be increased in Down syndrome patients as well as hybrids between chromosomal races of the house mouse differing in several Robertsonian (Rb) fusions. Developmental stability, assessed by FA, is thus thought to be impaired by spontaneous chromosomal abnormality or by chromosomal heterozygosity. Although the effect of a single fusion on developmental stability could theoretically be expected, it has never been documented. Crosses involving two chromosomal races of the house mouse diverging for one Rb fusion were performed to assess developmental stability in parental homozygous races as well as in their hybrids. Moreover, the occurrence of a spontaneous chromosomal mutation (WART type-b) allowed us to study the instantaneous effect of such a translocation on developmental stability. No difference in fluctuating asymmetry levels was detected among the groups considered in this study. This result suggested that a single stable or spontaneous balanced structural rearrangement did not inherently disturb developmental stability. In addition, the differential effect on developmental stability of one versus many heterozygous Rb fusions highlights the role of their quantitative accumulation in the disruption of coadaptation in chromosomal hybrids.     

Homozygosity for a Robertsonian translocation (13q14q) in three offspring of heterozygous parents

A family containing three homozygous carriers for a Robertsonian (13q14q) translocation, 44,XX or XY,t(13q14q),t(13q14q), is reported. Their parents are first cousins, and both are heterozygous carriers of the same (13q14q) translocation. The fertility of both the heterozygous and homozygous carriers is discussed.     

Transmission ratio distortion in offspring of mouse heterozygous carriers of a (7.18) Robertsonian translocation

Transmission ratio distortion (TRD) is defined as a significant departure from expected Mendelian ratios of inheritance of an allele or chromosome. TRD is observed among specific regions of the mouse and human genome and is frequently associated with chromosome rearrangements such as Robertsonian (Rb) chromosomes. We intercrossed mice heterozygous for a (7.18) Rb translocation and genotyped chromosomes 7 and 18 in 1812 individuals, 47% of which were informative for chromosome segregation. We substantiated previous findings that females were less likely than expected to transmit the Rb chromosome to their offspring. Surprisingly, however, we report that heterozygous males transmitted the Rb translocation chromosome significantly more frequently than the acrocentrics. The transmission of the Rb chromosome was not significantly influenced by either the sex of the Rb grandparent or the strain of the Rb.     

Obligate short-arm exchange in de novo Robertsonian translocation formation influences placement of crossovers in chromosome 21 nondisjunction

Robertsonian translocations (ROBs) involving chromosome 21 are found in approximately 5% of patients with Down syndrome (DS). The most common nonhomologous ROB in DS is rob(14q21q). Aberrant recombination is associated with nondisjunction (NDJ) leading to trisomy 21. Haplotype analysis of 23 patients with DS and de novo rob(14q21q) showed that all translocations and all nondisjoined chromosomes 21 were maternally derived. Meiosis II NDJ occurred in 21 of 23 families. For these, a ROB DS chromosome 21 genetic map was constructed and compared to a normal female map and a published trisomy 21 map derived from meiosis II NDJ. The location of exchanges differed significantly from both maps, with a significant shift to a more distal interval in the ROB DS map. The shift may perturb segregation, leading to the meiosis II NDJ in this study, and is further evidence for crossover interference. More importantly, because the event in the short arms that forms the de novo ROB influences the placement of chiasmata in the long arm, it is most likely that the translocation formation occurs through a recombination pathway in meiosis. Additionally, we have demonstrated that events that occur in meiosis I can influence events, such as chromatid segregation in meiosis II, many decades later.     

Robertsonian translocation in a Zebu bull

Karyotypes were prepared for ten Rahaji bulls using cultured peripheral blood lymphocytes. C-banded metaphases were prepared to identify the sex chromosomes and possible translocations. Out of the ten bulls, studied one bull had a 2n number of 59 chromosomes and carried a Robertsonian translocation. The possible importance of the Robertsonian translocation in Zebu cattle in Nigeria is discussed.     

Analysis of meiotic segregation in a man heterozygous for a 13;15 Robertsonian translocation and a review of the literature

Summary Meiotic segregation was studied in a male heterozygous for a 13;15 Robertsonian translocation using in vitro sperm penetration of hamster eggs. Sixty-seven sperm chromosome complements were obtained and R-banded. Alternate segregation produced equal numbers of normal (31) and balanced (29) gametes, as was theoretically expected. Incidence of unbalanced complements was 10.4%, and the frequency of abnormalities unrelated to the translocation was 7.4%. This study confirms the predominance of alternate meiotic segregation in Robertsonian translocation carriers. Four sperm studies of Robertsonian translocation have been previously reported. A review of the combined results points out the low incidence of imbalance in the sperm of Robertsonian translocation carrier and the lack of evidence for an interchromosomal effect.     

Monosomy and trisomy in bovine embryos sired by bulls heterozygous for the 1 29 Robertsonian translocation chromosome

Mature cows (n = 37) were superovulated and inseminated with semen from either bulls heterozygous for the 1 29 Robertsonian translocation or bulls with a normal karyotype. A total of 163 embryos was recovered, and preparations suitable for cytogenetic analysis were obtained from 67 (41.1%) of these. The karyotype was unbalanced in three (4.5%) of the embryos sired by semen from a bull carrying the translocation, whereas no karyotypic imbalance was recognized in the control group of embryos. Two of the unbalanced embryos were monosomic, while the third embryo was trisomic.     

Trisomy of an autosome in mice heterozygous by a Robertson translocation]

From 866 embryos of mice heterozygous by Roberstsonian translocations 54 ones (6,2%) had trisomy of one of translocated chromosomes. The frequency of trisomy is unique for each translocation, dependent on other chromosomal redistributions in the karyotype and on sex of heterozygous individuals. Trisomy of all the autosomes studied (N 1, 5, 8, 9, 14, 15, 17, 19) results in a characteristic complex of non-specific malformations which includes general delay in development, reduction of the cephalic portion of the nervous tube, cranio-fascial malformations, hypertrophy of the heart cavities. In a number of cases autosomal trisomy (N 15,8) is responsible for certain specific disturbances of morphogenesis. The excess of majority of autosomes (N 5, 8, 9, 15, 16 and 17) causes death of embryos in the period of active organogenesis. Embryos with trisomy of the 1st, 14th and 19th pairs of autosomes in certain cases reach the fetal period but have severe malformations and are non-survival. In mice karyotype there seems to be no autosomes whose trisomy is compatible with postnatal development. Signs of similarity and difference in manifestation of numericle chromosomal aberrations were noted in embryogenesis of mice and man. Principle possibility of modelling chromosomal embryopathy of man in mice with Robertsonian translocations is supposed.     

Synaptonemal complexes analysis in a bull carrying a 4;8 Robertsonian translocation

Synaptonemal complexes analysis was performed using electron microscopy on surface-spread spermatocytes of a bull heterozygous for the 4;8 Robertsonian translocation. In 19 cells examined, the longest autosomal complex showed kinetochores in a central position whereas the remaining autosomal complexes showed terminal kinetochores. Synapsis in the trivalent appeared complete in all cells, and the trivalents usually showed a CIS configuration. The arm ratio varied from 1.05 to 2.04 with an average of 1.32 +/- 0.43. Out of 47 cells showing X-Y bivalents, 34 showed a small synaptonemal complex at one extremity of the X chromosome, and an unstained gap in the Y chromosome. There was no association between the X-Y bivalent and the trivalent. The absence of association would explain the normal spermatogenesis noted in this bull, in contrast to human and mouse carriers of translocations which show impaired spermatogenesis due to the association between the rearranged chromosomes and the sex vesicle. Further studies involving bulls carrying one or more Robertsonian translocations are needed to determine whether this absence of association is a constant feature in cattle.     

The origin of a Robertsonian chromosomal translocation in house mice inferred from linked microsatellite markers

The western European house mouse, Mus domesticus, includes many distinct Robertsonian (Rb) chromosomal races. Two competing hypotheses may explain the distribution of Rb translocations found in different populations: they may have arisen independently multiple times, or they may have arisen once and been spread through long-distance dispersal. We investigated the origin of the Rb 5.15 translocation using six microsatellite loci linked to the centromeres of chromosomes 5 and 15 in 84 individuals from three Rb populations and four neighboring standard-karyotype populations. Microsatellite variation on the 5.15 metacentric chromosomes was significantly reduced relative to the amount of variation found on acrocentric chromosomes 5 and 15, suggesting that linked microsatellite loci can track specific mutational events. Phylogenetic analyses resulted in trees which are consistent with multiple origins of the 5.15 metacentric chromosomes found in the three Rb populations. These results suggest that cytologically indistinguishable mutations have arisen independently in natural populations of house mice.