Transplantation of bone marrow with constitutional chromosomal anomalies. Cytogenetic studies and clinical implications

We report on two cases of transplantation of bone marrow with constitutional chromosomal anomalies. A female patient with acute myelocytic leukemia (FAB, M 3) in first complete remission received a bone marrow graft from her sister with the karyotype 47 XXX (triple-X-syndrome). A male patient with Ph-positive CML and a constitutional Robertsonian t(14; 15) received HLA and MLC loci compatible bone marrow from his sister who was also a carrier of the Robertsonian t(14; 15). Our findings indicate that transplantation of marrow from donors with balanced chromosomal translocation is possible, although no conclusion can be made regarding long term results as both recipients died early from infectious complications.     

Recombination Suppression by Heterozygous Robertsonian Chromosomes in the Mouse

Robertsonian chromosomes are metacentric chromosomes formed by the joining of two telocentric chromosomes at their centromere ends. Many Robertsonian chromosomes of the mouse suppress genetic recombination near the centromere when heterozygous. We have analyzed genetic recombination and meiotic pairing in mice heterozygous for Robertsonian chromosomes and genetic markers to determine (1) the reason for this recombination suppression and (2) whether there are any consistent rules to predict which Robertsonian chromosomes will suppress recombination. Meiotic pairing was analyzed using synaptonemal complex preparations. Our data provide evidence that the underlying mechanism of recombination suppression is mechanical interference in meiotic pairing between Robertsonian chromosomes and their telocentric partners. The fact that recombination suppression is specific to individual Robertsonian chromosomes suggests that the pairing delay is caused by minor structural differences between the Robertsonian chromosomes and their telocentric homologs and that these differences arise during Robertsonian formation. Further understanding of this pairing delay is important for mouse mapping studies. In 10 mouse chromosomes (3, 4, 5, 6, 8, 9, 10, 11, 15 and 19) the distances from the centromeres to first markers may still be underestimated because they have been determined using only Robertsonian chromosomes. Our control linkage studies using C-band (heterochromatin) markers for the centromeric region provide improved estimates for the centromere-to-first-locus distance in mouse chromosomes 1, 2 and 16.     

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.     

46,XX,t(15;21)/47,XX,15p-,+21 mosaicism in a child with Down's syndrome

We report here the first case of a mosaic Down's syndrome in which both clones are trisomic for chromosome 21, one of them (90%) by a Robertsonian translocation (15;21) appearing de novo, and the other (10%) by an additional chromosome 21. Three hypotheses can explain the appearance of such a mosaic: that of a chimera formed by the fusion of two trisomy 21 zygotes, one of which had a Robertsonian translocation, the other an additional trisomy 21 zygote; that of a fusion between a chromosome 15 and a chromosome 21 in one of the early segmentation blastomeres of a trisomy 21 zygote; the more probable hypothesis of the occurrence of a fission at the break-attachment point of a Robertsonian translocation (15;21) in one of the cells arising from the early postzygotic divisions of a zygote which was a trisomy 21 by Robertsonian translocation (15;21).     

Identification of uniparental disomy following prenatal detection of Robertsonian translocations and isochromosomes

Rearrangements of the acrocentric chromosomes (Robertsonian translocations and isochromosomes) are associated with an increased risk of aneuploidy. Given this, and the large number of reported cases of uniparental disomy (UPD) associated with an acrocentric rearrangement, carriers are presumed to be at risk for UPD. However, an accurate risk estimate for UPD associated with these rearrangements is lacking. A total of 174 prenatally identified acrocentric rearrangements, including both Robertsonian translocations and isochromosomes, were studied prospectively to identify UPD for the chromosomes involved in the rearrangements. The overall goal of the study was to provide an estimate of the risk of UPD associated with nonhomologous Robertsonian translocations and homologous acrocentric rearrangements. Of the 168 nonhomologous Robertsonian translocations studied, one showed UPD for chromosome 13, providing a risk estimate of 0.6%. Four of the six homologous acrocentric rearrangements showed UPD, providing a risk estimate of 66%. These cases have also allowed delineation of the mechanisms involved in producing UPD unique to Robertsonian translocations. Given the relatively high risk for UPD in prenatally identified Robertsonian translocations and isochromosomes, UPD testing should be considered, especially for cases involving the acrocentric chromosomes 14 and 15, in which UPD is associated with adverse clinical outcomes.     

A new Robertsonian translocation in cattle, rob(15;25).

A new Robertsonian translocation, rob(15;25), was discovered in a Portuguese Barrosa cow. The animal (2n = 59,XX) was found by G- and R-banding to be a heterozygous carrier of a centric fusion translocation involving chromosomes 15 and 25. C-banding revealed the dicentric nature of this new centric fusion. Comparison of this new translocation with the well-known Robertsonian translocation rob(1;29), which is often found in the same breed, confirmed that two different chromosomes (25 and 29) were involved in the short arms of these two Robertsonian translocations.     

Robertsonian translocations in wheat arise by centric misdivision of univalents at anaphase I and rejoining of broken centromeres during interkinesis of meiosis II

The mechanism of origin of Robertsonian translocations was investigated in plants monosomic for chromosome 1A of wheat and 1H(t) of Elymus trachycaulus by GISH. Chromosomes 1A and 1H(t) stayed univalent in all metaphase I cells analyzed, suggesting that Robertsonian translocations do not originate from meiotic recombination in centromeric regions with shared DNA sequence homology. At ana-/telophase I, the 1H(t) and 1A univalents underwent either chromosome or chromatid segregation and misdivided in 6-7% of the pollen mother cells. None of the ana-/telophases I analyzed had Robertsonian translocations, which were only observed in 2% of the "half tetrads" at ana-/telophase II. The frequency of Robertsonian translocations observed at ana-/telophase II corresponds well with the number of Robertsonian translocations (1-4%) detected in progenies derived from plants monosomic for group-1 chromosomes of wheat (1A, 1B, and 1D) and 1H(t) of E. trachycaulus. Our data suggest that Robertsonian translocations arise from centric misdivision of univalents at ana-/telophase I, followed by segregation of the derived telocentric chromosomes to the same nucleus, and fusion of the broken ends during the ensuing interkinesis.     

Effects of stock differences in the acceleration of puberty in female mice

Newly born TO strain female mice were exposed daily to the urine from male albino mice of the same and CFLP strains, from feral mice carrying Robertsonian translocation chromosomes and to water as a control condition. At 21 days of age, when exposure was discontinued, there were differences in body weight between treatments which were not present when adult. Exposure to urine from mice with Robertsonian translocations did not accelerate puberty and the interval between vaginal opening and first oestrus was longer (4.2 days) than in mice exposed to the urine from the albino strains (1.8 days). Mice exposed to the urine from the Robertsonian stock were in dioestrus more often than those exposed to the urine from laboratory strains. The Robertsonian mice also differed in their behaviour in an open arena in that they passed fewer faecal pellets than those exposed to the urine from the albino mice. The water control mice defecated the least frequently. The mice exposed to the Robertsonian urine were less active than the laboratory strains but the differences did not reach an acceptable level (P less than 0.06) of significance.     

Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations

Robertsonian translocations are the most common structural rearrangements of human chromosomes. Although segregation of Robertsonian chromosomes has been examined in many families, there is little consensus on whether inheritance in the balanced progeny conforms to Mendelian ratios. To address this question, we have compiled previously reported segregation data, by sex of parent, for 677 balanced offspring of Robertsonian carriers from 82 informative families and from a prenatal diagnosis study on the risk of unbalanced offspring in carriers of chromosome rearrangements. Care was taken to avoid any source of ascertainment bias. Our analysis supports the following conclusions: (1) the transmission ratio is not independent of the sex of the carrier; (2) the transmission ratio distortion is observed consistently only among the offspring of carrier females; (3) the transmission ratio distortion does not appear to be dependent on the presence of a specific acrocentric chromosome in the rearrangement. The sex-of-parent-specific origin of the non-Mendelian inheritance, the finding that the rearranged ("mutant") chromosomes are recovered at significantly higher frequency than the acrocentric ("normal") chromosomes, and the similarities between these observations and the segregation of analogous rearrangements through female meiosis in other vertebrates strongly support the hypothesis that the transmission ratio distortion in favor of Robertsonian translocations in the human results from the preferential segregation of chromosomes during the first meiotic division. This non-Mendelian inheritance will result in increased overall risk of aneuploidies in the families of Robertsonian translocation carriers, independently of the origin of the transmission ratio distortion.     

Nondisjunction frequencies in Robertsonian heterozygotes from natural populations of the common shrew, Sorex araneus L

Pregnant female common shrews were collected from an area of Robertsonian polymorphism, involving five different arm combinations, around Oxford (England). The females and their fetuses were karyotyped, and the karyotypes of the sires were deduced. Ten pregnancies where at least one parent was known to be either a single or double Robertsonian heterozygote were available for analysis. From these pregnancies, upper and lower estimates of anaphase I nondisjunction arising from Robertsonian heterozygosity were calculated to be 1.0-2.5% per heterozygous arm combination and 1.5-3.7% per heterozygous parent. One trisomic fetus with retarded development was identified. This trisomy can be attributed to anaphase I nondisjunction of a trivalent in a female Robertsonian heterozygote.     

Fixation of metacentric chromosomes in populations of the common shrew Sorex araneus L. from populations of Eastern Europe

In this review, we discuss the processes of fixation of Robertsonian chromosome fusions in populations of the common shrew Sorex araneus L. Various Robertsonian fusions, accumulating in populations, create an illusion of large chromosomal rearrangements, reciprocal translocations of complete chromosome arms. The use of these rearrangements for phylogenetic reconstructions results in false conclusions. Robertsonian fusions accumulate in populations at such stages of the species evolution, when large open or subdivided populations prevail (populations of warm periods of Pleistocene and many present-day populations) and are fixed in small isolated populations and glacial refugia. The formation of monomorphic chromosome races requires a long time, several glaciation epochs during the whole Pleistocene.     

Phylogenetic relationships among Robertsonian karyomorphs of Graomys griseoflavus (Rodentia,Muridae) by mitochondrial cytochrome b DNA sequencing

Graomys griseoflavus (Waterhouse 1837) is a phyllotine murid rodent with a Robertsonian autosomal polymorphism, having been described 2n = 42, 41, 38, 37, 36, 35 and 34 karyomorphs, and proposed a chromosomal divergence pathway accounted by four sequential Robertsonian fusions. Sequences of a fragment (422 bp long) of the cytochrome b (cyt b) mitochondrial gene and its 5' flanking region (tRNA Glu) were obtained for 19 Graomys griseoflavus from different karyomorphs to infer phylogenetic relationships by using maximum parsimony. Outgroups considered for this analysis were the phyllotine rodents Phyllotis xanthopygus and Eligmodontia typus cyt b sequences. Three trees were produced showing the 2n = 38-34 karyomorphs grouped in a single clade while the 2n = 42-41 animals formed a different one. This is in agreement with a hypothesis of a single origin for 2n = 38-34 Robertsonian karyomorphs from the ancestral 2n = 42.     

Fixation of metacentric chromosomes in eastern Europe populations of the common shrew <Emphasis Type="Italic">Sorex araneus</Emphasis> L.

In this review, we discuss the processes of fixation of Robertsonian chromosome fusions in populations of the common shrew Sorex araneus L. Various Robertsonian fusions, accumulating in populations, create an illusion of large chromosomal rearrangements, reciprocal translocations of complete chromosome arms. The use of these rearrangements for phylogenetic reconstructions results in false conclusions. Robertsonian fusions accumulate in populations at such stages of the species evolution, when large open or subdivided populations prevail (populations of warm periods of Pleistocene and many present-day populations) and are fixed in small isolated populations and glacial refugia. The formation of monomorphic chromosome races requires a long time, several glaciation epochs during the whole Pleistocene.     

Meiotic studies of Robertsonian heterozygotes from natural populations of the common shrew, Sorex araneus L

Adult male common shrews, both Robertsonian heterozygotes and homozygotes, were collected from Oxford and elsewhere in Britain. In both simple Robertsonian heterozygotes and Robertsonian heterozygotes with monobrachial homology, regular chain configurations were observed at meiosis I; only 1-2% were incomplete such that univalents were observed. On the average, there was one chiasma per chromosome arm among those that displayed Robertsonian variation, including both chain configurations and bivalents. According to one hypothesis, a single chiasma per chromosome arm may facilitate proper disjunction of chain trivalents of simple Robertsonian heterozygotes. Based on metaphase II counts, anaphase I nondisjunction frequency can be estimated as 1.0% per heterozygous individual and 0.7% per heterozygous arm combination.     

Robertsonian polymorphism in plaice, Pleuronectes platessa L., and cod, Gadus morhua L., (Pisces Pleuronectiformes and Gadiformes)

Karyotypic analysis of plaice, Pleuronectes platessa L., and cod, Gadus morhua L., revealed that the chromosome numbers in both species vary but that chromosome arm numbers (NF) stay constant. The C-, Q- and R-banding patterns also confirmed that the population of plaice studied shows Robertsonian polymorphism. The tendency of reduction in chromosome number in fishes suggests that Robertsonian fusions play a role in karyotype evolution in fishes.     

Autosomal rearrangements in Graomys griseoflavus (Rodentia): a model of non-random Robertsonian divergence

The south American rodent Graomys griseoflavus exhibits a remarkable chromosome polymorphism as a consequence of four Robertsonian fusions. Focusing on the genetic analysis of the taxon, genome organization of all karyomorphs was studied at chromosome and molecular organization level. Cytogenetic (G, NOR and Re banding) and molecular (satellite and mitochondrial DNAs) events accompanying chromosome divergence allowed tracing a phylogenetic relationship among all karyomorphs. Available data led to propose that chromosome evolution of G. griseoflavus occurred in a non-random sequence of centric fusions, supporting the hypothesis of single origin for Robertsonian karyomorphs.     

Robertsonian house mouse populations in Tunisia: A karyological and biochemical study

A new population of Mus musculus domesticus showing Robertsonian translocations (2n = 22) has been identified in Tunisia. Mice carried 9 pairs of Robertsonian translocations: Rb(1.11), Rb(2.16), Rb(3.12), Rb(4.6), Rb(5.14), Rb(7.18), Rb(8.9), Rb(10.17) and Rb(13.15). Five of the nine translocations are not known to occur elsewhere. In two populations only 2n = 22 mice were present, whereas in a third one a mixture of karyotypes (2n = 22, 38, 39, 40) was found. The slight electrophoretic differentiation observed for other Robertsonian populations as well as the hybrid nature of the karyotypically heterogeneous populations are confirmed. Allele frequency differences between the 2n = 22 and 2n = 40 mice in the latter population show that local electrophoretic differentiation exists and allow to compare chromosome flow and gene flow. The presence of a chromosome-1 polymorphism for additional fragments of heterochromatin present in the Robertsoman population provides a convenient marker of recombinational events in the hybrid zone.     

An overview of chronic myeloid leukemia and its animal models

Chronic myeloid leukemia(CML) is a form of leukemia characterized by the presence of clonal bone marrow stem cells with the proliferation of mature granulocytes(neutrophils, eosinophils, and basophils) and their precursors. CML is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia(Ph) chromosome or t(9;22) translocation(BCR-ABL). CML is now usually treated with targeted drugs called tyrosine kinase inhibitors(TKIs). The mechanism and natural history of CML is still unclear. Here, we summarize the present CML animal disease models and compare them with each other. Meanwhile, we propose that it is a very wise choice to establish zebrafish(Danio rerio) CML model mimics clinical CML. This model could be used to learn more about the mechanism of CML, and to aid in the development of new drugs to treat CML.     

A Robertsonian translocation, rob(2;28), found in Vietnamese cattle

A new Robertsonian translocation, rob(2;28), was discovered in a local population of the Vietnamese Cattle. The animal (2n = 59, XY) was found by Q- and R-banding to be a heterozygous carrier of a centric fusion translocation involving chromosomes 2 and 28. FISH analysis using a bovine satellite I DNA probe demonstrated that the centromeric heterochromatin block of the rob(2;28) chromosome become much smaller than its ancestors suggesting a monocentric nature of this centric fusion. This is the first report identifying a Robertsonian translocation in Southeast Asian cattle by karyotyping of banded chromosomes.     

Variation in fluctuating asymmetry levels across a Robertsonian polymorphic zone of the house mouse

Fluctuating asymmetry (FA) levels were assessed within the Barcelona Robertsonian polymorphic zone of Mus musculus domesticus as a measure of developmental instability (DI). This zone is characterized by populations with a reduced diploid number (2n = 27–39) surrounded by others with standard karyotype (2n = 40). Mice were distributed into four classes according to mean diploid number at each collecting site, and differences in their FA levels were studied. Three different FA indices were calculated on interlandmark distances from two major morphogenetic units of the mandible: the teeth and muscular areas. Three kinds of analysis were performed: trait‐by‐trait, considering the two regions separately and pooling all traits. In univariate analyses few differences were detected between classes. Nevertheless, when characters were pooled, differences in FA values were found between one Robertsonian group and standard mice, and between several Robertsonian classes. Teeth area traits showed higher FA levels in Rb I mice, i.e. those geographically close to the standard populations. However, FA levels decreased in more introgressed Robertsonian groups and showed significant differences with Rb I. Muscular area traits showed lower DI levels in the Robertsonian mice, especially those with an intermediate mean diploid number (Rb II). When all traits were pooled, FA levels increased in Rb I, whilst the other Robertsonian groups showed similar, or even lower, FA values to those of the standard mice. The higher FA levels found in Rb I suggest an increase in the disruption of genetic coadaptation. Furthermore, in Rb I the presence of metacentrics is more recent than in more introgressed populations; we therefore suggest that Rb I have had less time to restore genetic coadaptation. In addition, the teeth region of the mandible seems to be more sensitive to genomic stress than the muscular region. In the light of these results we suggest that hybrids should be separated into groups and that mandible morphogenetic units be differentiated when using FA in hybrid zones to analyse DI.