The peculiarities of cytogenetic changes in different types of myelodysplastic syndrome

A cytogenetic study of bone marrow aspirate from 32 patients with different types of myelodysplastic syndrome (MDS) has been carried out. The patients were from eight regions of Ukraine. Chromosome deletions prevailed in the spectrum of karyotype changes. The largest number of chromosome abnormalities was revealed in patients with a refractory anemia with an excess of blasts (66.6% of cases). Chromosomal changes that involved three or more chromosomes occurred among 27% of all karyotype changes examined by us. Transformation of myelodysplastic syndrome to acute myeloid leukemia (AML) was found in 5 patients (45.4% of the cases) among 11 patients with abnormal karyotypes. We propose that cytogenetic confirmation of increased apoptosis in the bone marrow from the myelodysplastic syndrome patients is a phenomenon of chromosome fragmentation. The risk of transformation of myelodysplastic syndrome to acute myeloid leukemia was measured with the use of a new international score system, IPSS.     

Trisomy 18 and prune belly syndrome

Ultrasonic examination in a thirty five years old woman about to undergo midtrimester amniocentesis suggested an intra abdominal fetal mass. The mass was a grossly distended urinary bladder. The pregnancy was terminated at 20 weeks. Necropsy was confirmative for a prune-belly syndrome. Chromosomal analysis demonstrated a 47 XY + 18 karyotype.     

Chromosomal abnormalities associated with mental retardation in female subjects

Chromosomal abnormalities are thought to be the most common cause of mental retardation (MR). However, apart from a few selected types with typical aneuploidy, like Downs syndrome, Klinefelter syndrome, Turner syndrome, etc., the frequency of detectable chromosomal abnormalities in association with idiopathic MR is very low. In this study, we have investigated chromosomal abnormalities in female MR subjects (n = 150) by high-resolution GTG banding. Of them, 30 cases were diagnosed as Downs syndrome. Among the remaining (n = 120), chromosomal abnormalities/marked polymorphisms were detectable in only three MR cases (0.025).     

Families with recurrent cases of Waardenburg-Klein syndrome

Deaf children with the type I Waardenburg--Klein syndrome were studied. Secondary cases were found in 14 unrelated and 1 incest families. In 10 families probands and all their affected relatives had the type I Waardenburg--Klein syndrome. In 4 families patients were discovered with both type I and type II syndromes. In an incest family the proband seemed to have the type III, while his mother and father (sibs) had type II and their grandmother the type I syndrome. These results contradict the hypothesis claiming the origin of different types of Waardenburg--Klein syndrome to be due to the action of different genes. It is proposed that types I and II, or all types of the syndrome are caused by a single dominant gene. Potential mechanisms for clinical polymorphism of Waardenburg--Klein syndrome are related to incomplete penetrance and varying expression of this gene.     

Chromosomal variability in natural populations of Chironomus cingulatus meigen (Diptera, Chironomidae)

Chromosomal polymorphism has been studied in seven natural populations of Chironomus cingulatus from Western Europe, Western Siberia, and the Republic of Sakha (Yakutia). The banding sequences pool of the species includes 15 banding sequences. Chromosomal polymorphism was revealed in five out of seven chromosomal arms. Arm B is the most polymorphic with four banding sequences. There are three banding sequences in arm A. Arms D, E, and G have two banding sequences. None of the chromosome rearrangements were revealed in arms C and F. The populations of C. cingulatus differ clearly in their number and frequency of banding sequences, which indicates that different gene sequences are adaptive in different populations.     

Linkage of usher syndrome type I gene (USH1B) to the long arm of chromosome 11

Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization establishes the existence of a new and independent locus for Usher syndrome.     

Disentangling structural genomic and behavioural barriers in a sea of connectivity

Genetic divergence among populations arises through natural selection or drift and is counteracted by connectivity and gene flow. In sympatric populations, isolating mechanisms are thus needed to limit the homogenizing effects of gene flow to allow for adaptation and speciation. Chromosomal inversions act as an important mechanism maintaining isolating barriers, yet their role in sympatric populations and divergence with gene flow is not entirely understood. Here, we revisit the question of whether inversions play a role in the divergence of connected populations of the marine fish Atlantic cod (Gadus morhua), by exploring a unique data set combining whole‐genome sequencing data and behavioural data obtained with acoustic telemetry. Within a confined fjord environment, we find three genetically differentiated Atlantic cod types belonging to the oceanic North Sea population, the western Baltic population and a local fjord‐type cod. Continuous behavioural tracking over 4 year revealed temporally stable sympatry of these types within the fjord. Despite overall weak genetic differentiation consistent with high levels of gene flow, we detected significant frequency shifts of three previously identified inversions, indicating an adaptive barrier to gene flow. In addition, behavioural data indicated that North Sea cod and individuals homozygous for the LG12 inversion had lower fitness in the fjord environment. However, North Sea and fjord‐type cod also occupy different depths, possibly contributing to prezygotic reproductive isolation and representing a behavioural barrier to gene flow. Our results provide the first insights into a complex interplay of genomic and behavioural isolating barriers in Atlantic cod and establish a new model system towards an understanding of the role of genomic structural variants in adaptation and diversification.     

Cytogenetic studies on three pheochromocytomas derived from patients with von Hippel-Lindau syndrome

Summary Chromosomal analyses of three pheochromocytomas from patients with von Hippel-Lindau syndrome are reported. One pheochromocytoma revealed a normal karyotype, another tumor showed a trisomy 7 as the only chromosomal abnormality, whereas in a further sample a polyclonal chromosome constitution was detected. In addition to a normal 46,XX cell line, four distinct chromosomally abnormal cell lines could be identified. One cell line revealed partial trisomy for the long arm of chromosome 1 and additionally exhibited the phenomenon of telomeric association. Most interestingly, three further cell clones showed rearrangements of chromosome 3 including the region where the von Hippel-Lindau gene was mapped; three rearrangements resulted in a partial or total trisomy of 3p. Our findings are discussed in relation to previously reported cytogenetic and molecular results regarding von Hippel-Lindau syndrome.     

Arrangement of chromosomes in the interphase nucleus of plants

Chromosomal arrangement in the interphase nucleus has two main aspects: (1) arrangement of chromosomes with respect to nuclear polarity and to other nuclear components, and (2) arrangement of chromosomes with respect to one another. The latter aspect consists of two main types of spatial relationships; (a) relationships between different members of one chromosomal set, (b) relationships between different chromosomal sets. Data concerning various aspects of chromosomal arrangement in the interphase nucleus are presented and discussed and the genetic control as well as subcellular mechanisms which are involvled in nuclear organization, are elucidated. Evidence is presented indicating that, in common wheat, the gene system that determines the specific pattern of chromosomal arrangement in the nucleus is operating via the microtubular elements of the spindle system. The significance of ordered arrangement of chromosomes in the nucleus for the regularity of genetic activity and chromosomal behavior, is pointed out.Supported in part by a grant from the Stiftung Volkswagenwerk AZ I/34 075/76     

Esterase gene expression in Chinese hamster and mouse lymphoma hybrids isolated under nonselective pressure

Hybrids between a fibroblastic Chinese hamster cell line (CH23) and a mouse lymphoma cell line (P388F36) were produced and isolated by a simple new method without using selective media and avoiding contact with the parental cells. The chromosomal situation in the two hybrid types (PCM and PCS) isolated suggested that growth on glass surface (PCM) or in suspension (PCS) depended on the number of hamster and mouse chromosomes which existed in the hybrids. Chromosomal stability in hybrids grown as monolayers (PCM) was reached at a stage in which two to four mouse chromosomes coexisted with no fewer than 19 hamster chromosomes. In a study of gene linkage utilizing clones of this hybrid population, five out of nine genes regulating the synthesis of different esterases in the mouse cells used were found to be unlinked.     

MITOCHONDRIAL DNA AND PROTEIN DIFFERENTIATION BETWEEN HYBRIDIZING CYTOTYPES OF THE WHITE-FOOTED MOUSE,PEROMYSCUS LEUCOPUS

Restriction-enzyme analysis of mitochondrial DNA and protein electrophoresis were used to document patterns of gene flow across a hybrid zone between chromosomal races of Peromyscus leucopus. Chromosomal markers (three inversions) are such that individuals can be classified as potential F₁'s, backcrosses, or parental types. Allozymic characterization of the hybrid zone is congruent with the chromosomal data (Stangl, 1986) and indicates an assymetrical distribution of markers, with the northeastern markers being distributed at a higher frequency into southwestern populations. Restriction patterns of mtDNA suggest that the two cytotypes may have had different evolutionary histories, and the distribution of haplotypes is concordant with other genetic markers used to identify the hybrid zone. Concordant changes in chromosomes, allozymes, and mtDNA suggest that the most viable hypothesis for the origin of the zone is secondary contact. A unique aspect of this study is that the same individuals were used for protein electrophoresis, mtDNA analysis, and chromosomal analysis. Thus, patterns of genetic variation can be interpreted free of any historical bias associated with samples collected at different times.     

Description and molecular analysis of SRY and AR genes in a patient with 46,XY pure gonadal dysgenesis (Swyer syndrome)

46,XY pure gonadal dysgenesis, first described in 1955 by Swyer, results from testicular tissue loss during the first 8 weeks of fetal life, a critical period for male differentiation. We describe a case of an 18 years old patient presented to us with a chief complain of primary amenorrhea. Chromosomal analysis revealed a 46,XY karyotype. A molecular investigation was undertaken in an attempt to determine mutations in SRY and AR genes through DNA sequencing. Mutations were shown to be absent. The molecular basis of Swyer syndrome is still unknown, although the presence of mutations in testicular organizing genes downstream of SRY is still to rule out. The patient, who is considered as female, was placed on estrogen replacement therapy, while bilateral prophylactic laparoscopic gonadectomy was programmed due to the high prevalence of gonadal tumors in this syndrome. No signs of malignance were detected in the gonadal tissue, which predicts that an intact SRY gene is usually, but not always, not related to the formation of malignancies like dysgeminomas or gonadoblastomas.     

Crystal structure of human WBSCR16, an RCC1‐like protein in mitochondria

WBSCR16 (Williams‐Beuren Syndrome Chromosomal Region 16) gene is located in a large deletion region of Williams‐Beuren syndrome (WBS), which is a neurodevelopmental disorder. Although the relationship between WBSCR16 and WBS remains unclear, it has been reported that WBSCR16 is a member of a functional module that regulates mitochondrial 16S rRNA abundance and intra‐mitochondrial translation. WBSCR16 has RCC1 (Regulator of Chromosome Condensation 1)‐like amino acid sequence repeats but the function of WBSCR16 appears to be different from that of other RCC1 superfamily members. Here, we demonstrate that WBSCR16 localizes to mitochondria in HeLa cells, and report the crystal structure of WBSCR16 determined to 2.0 Å resolution using multi‐wavelength anomalous diffraction. WBSCR16 adopts the seven‐bladed β‐propeller fold characteristic of RCC1‐like proteins. A comparison of the WBSCR16 structure with that of RCC1 and other RCC1‐like proteins reveals that, although many of the residues buried in the core of the β‐propeller are highly conserved, the surface residues are poorly conserved and conformationally divergent.     

Is there a general relationship between estimated chromosome distances in interphase and location of genes with related functions?

Summary The problem of a possible clustering of human chromosomes containing genes with related functions was examined in the interphase nucleus of lymphocytes by a statistical comparison of distances between chromosomes containing such functionally related genes with all sets of chromosome distances. The gene locus assignments were taken from a recent review (McKusick 1982); the chromosomal distances were those estimated by Hager et al. (1982) from the frequencies of reunion figures between specific chromosomes as observed in chromosome instability syndromes (Fanconi anemia, Bloom syndrome) and after treatment with Trenimon. Chromosomal distances had been estimated by multidimensional scaling. There was no general tendency for closer location of chromosomes containing genes with related function. A few such chromosomes do show below average distances but this could easily be a chance result.     

Localization of the intronless gene coding for calmodulin-like protein CLP to human chromosome 10p13-ter

The functional intronless gene coding for a calmodulin-like protein (CLP) has been localized to human chromosome 10p13-ter. Chromosomal assignment was performed by Southern blot analysis of DNA from human-rodent somatic cell hybrids and amplification of a CLP gene-specific 1090-bp DNA fragment by the polymerase chain reaction (PCR) on DNA from human-hamster cell hybrids. Chromosomal sublocalization was carried out by in situ hybridization of human chromosome metaphase spreads. The CLP gene is the first member of the human calmodulin/calmodulin-like gene family to be chromosomally sublocalized. Its presence near the telomeric end of the short arm of chromosome 10 may be of significance with respect to its highly (epithelial) cell-type restricted expression in vivo and strong downregulation upon malignant transformation. The generation of a human CLP gene-specific sequence tag site specified by the two primers used for PCR should prove useful for future linkage studies.     

Mechanisms predisposing to childhood overgrowth and cancer

Several overgrowth conditions are believed to be associated with elevated risks of cancer, particularly in childhood. Beckwith-Wiedemann syndrome and Sotos syndrome are the most common overgrowth conditions, and both carry increased risks of certain tumors. In recent years, the identification of both the gene causing Sotos syndrome and the epigenetic subgroups underlying Beckwith-Wiedemann syndrome have enabled clarification of the cancer types and risks associated with these conditions. This has revealed striking differences in the cancer phenotypes associated with different molecular abnormalities. Elucidation of the mechanisms underlying cancer in overgrowth syndromes might yield important insights into the molecular basis of childhood tumors.     

Factor XI gene (F11) is located on the distal end of the long arm of human chromosome 4

Chromosomal localization of the gene for human coagulation factor XI (F11) was determined by in situ hybridization using a genomic DNA probe which contained exons VIII, IX, and X of the gene. The results indicate that the gene is located at 4q35.     

Congenital bilateral anorchia: hormonal, molecular and imaging study of a case

The aetiology of congenital bilateral anorchia is unknown. For many years there was speculation of an association between genetic factors and anorchia. We performed different tests in an anorchid boy, 2.5 years old, presented to us with micropenis and absence of both testes, in order to determine any possible factors contributing to the anorchia. Physical examination and hormonal, imaging, chromosomal, and molecular analyses of this case were performed. The basal FSH and LH levels were increased, and their increase in response to gonadotrophin-releasing hormone test was prolonged, while testosterone levels failed to increase after hCG administration. Ultrasonography of the pelvis and magnetic resonance of the abdomen were performed and failed to show any testicular tissue. Lastly, surgical exploration confirmed the absence of testicular structure. Chromosomal analysis revealed a normal male karyotype and molecular analysis did not reveal mutations or polymorphisms in the open reading frame of the SRY gene. Diagnostically, the lack of testosterone response to hCG stimulation is the hormonal hallmark of bilateral congenital anorchia. In addition, according to our case and previous studies, there is lack of association between genetic factors necessary for correct testicular descent and anorchia.