X-chromosome In Females Research Articles

The karyotype of the long-finned pilot whale, Globicephala melaena.

The chromosomes obtained by culturing lymphocytes from blood samples of the long-finned pilot whale Globicephala melaena, were studied by Q- and C-banding. The culture method was very difficult to handle. The karyotype of the long-finned pilot whale has a typical cetacean 2n = 44 chromosome number. The O-band revealed a characteristic banding pattern, which showed a heteromorphism between individuals but not within individuals. These observations were supported by the C-banding, which disclosed clear size variation of heterochromatin in some chromosome pairs. A species specific C-band pattern was observed in comparison between Globicephala melaena and Globicephala macrorhynchus, the short-finned pilot whale. O- and C-band markers can be used in family- and population studies if a good technical quality can be achieved. The finding of an inactivation of one of the X-chromosomes in females opens the possibility of using the method of staining the sex chromatin to determine the sex of small foetuses (<12cm).

Recombination in the X-chromosome in hybrid females with and without a marked centromere from three inbred lines of Drosophila melanogaster.

Hybrid females of three inbred lines of Drosophila melanogaster, with and without BSYL attached to the marker line centromere, were produced by reciprocal crosses. The recombination frequency was scored along the X-chromosome. In XX females one inter-line cross showed differences between reciprocal crosses in all regions examined, indicating maternal influence, while the other inter- and intra-line crosses showed no obvious effects. Only the inter-line cross manifesting effects in XX females showed maternal effects in XX-YL females. Of special interest was the brood pattern of the f-centromere region. Concerning the effects of the YL arm, the recombination in the y-cx region seemed to increase in early broods and decrease in late broods. In the v-f region there were decreases in both early and late broods, while in the cx-v region the YL-effects were varying. These results are discussed in the light of recombination in XXY females from former tests, and the brood pattern of the f-centromere is compared with findings of higher frequencies of non-disjunction in early broods compared with later ones. The spatial location of the chromosomes in the nucleus during meiosis is discussed as a possible explanation for the discrepancy between crosses.

Involvement of Chromosomes 7, 18 and X in Mitomycin C-Induced Micronuclei

Involvement of Chromosomes 7, 18 and X in Mitomycin C-Induced MicronucleiThe involvement of specific chromosomes in the formation of micronuclei (MN) is neither well studied nor understood. We studied the involvement of chromosomes 7, 18 and X in mitomycin C (MMC)-induced MN. A total of 1,202 female MN were studied by three-color fluorescence in situ hybridization (FISH) using centromere-specific probes. After a second round of hybridization, using whole chromosome painting probes, 916 MN were evaluated. The frequency of MN containing whole chromosome painting signals for chromosomes X in 916 male MN was analyzed. Different frequency of involvement of selected chromosomes in MN formation was revealed. Chromosome interphase position, size and inactive (heterochromatinized) state of X chromosome in females was discussed as possible reasons of their non random involvement in MN formation. There was no clear relationship between chromosome interphase position and size and migration in MN. However, it was shown that X-chromosomal material was over represented in female- and under represented in male-derived MN. We speculated about a preferred inclusion of the inactive female X-chromosome into MN.

Spectrum of cardiovascular abnormalities in Turner syndrome

Haploinsufficiency for the X-chromosome in females has important and multifaceted effects upon the cardiovascular system. Girls with Turner syndrome (TS) may demonstrate anatomic malformations affecting the heart, aorta and other major vessels, hypertension and abnormalities of heart rate, cardiac conduction and repolarization. The aorta is dilated in almost 50% of patients and aortic deterioration with aneurysm, dissection and rupture occurs with increased frequency in young and middle-aged patients. Finally many women with TS experience premature onset of coronary artery disease. This chapter reviews the more recent scientific literature regarding these abnormalities.

X-chromosome inactivation and human genetic disease

The inactivation of one X-chromosome in females in early development is the process by which the effective dosage of X-linked genes is equalized between XX females and XY males. The mechanism that brings this about is the subject of intense research. The X-linked gene Xist is a key player, which is necessary but not sufficient for the initiation of X-inactivation. It codes for an untranslated RNA that coats the inactive X-chromosome, which takes on properties characteristic of heterochromatin, but how this change in chromatin is brought about remains unknown. Because of X-inactivation, females heterozygous for X-linked genes are mixtures of two types of cells and show a variable phenotype. The proportion s of the two types of cells can depart from equality due to cell selection either at the tissue or whole organism level. In rare cases, changes in the Xist gene can cause skewing of X-inactivation. A few genes escape from X-inactivation either wholly or partially. Conclusion: X-chromosome inactivation is a physiological mechanism that equalizes gene-dosage effects on the sex chromosomes. The occurrence of this normal process affects the phenotype seen in females carrying X-linked mutant genes or chromosome anomalies.

X-chromosome inactivation and human genetic disease.

The inactivation of one X-chromosome in females in early development is the process by which the effective dosage of X-linked genes is equalized between XX females and XY males. The mechanism that brings this about is the subject of intense research. The X-linked gene Xist is a key player, which is necessary but not sufficient for the initiation of X-inactivation. It codes for an untranslated RNA that coats the inactive X-chromosome, which takes on properties characteristic of heterochromatin, but how this change in chromatin is brought about remains unknown. Because of X-inactivation, females heterozygous for X-linked genes are mixtures of two types of cells and show a variable phenotype. The proportions of the two types of cells can depart from equality due to cell selection either at the tissue or whole organism level. In rare cases, changes in the Xist gene can cause skewing of X-inactivation. A few genes escape from X-inactivation either wholly or partially. X-chromosome inactivation is a physiological mechanism that equalizes gene-dosage effects on the sex chromosomes. The occurrence of this normal process affects the phenotype seen in females carrying X-linked mutant genes or chromosome anomalies.

Autism in Association with Turner Syndrome: Genetic Implications for Male Vulnerability to Pervasive Developmental Disorders

Abstract Genetic factors play a substantial part in the aetiology of autism, although no satisfactory model has been proposed that could account for the excess of male phenotypes. We present five cases of autism from an unselected sample of 150 subjects with Turner syndrome, a genetic disorder associated with either the absence, or a structural abnormality, of the second X-chromosome in females. The population prevalence of autism is no more than 1:lO 000 normal females. All of the cases considered possessed an intact maternal X-chromosome and a structurally abnormal or absent paternal X-chromosome. We have previously presented evidence that cases of Turner syndrome in which the single X-chromosome is maternal have impaired social cognitive skills, compared with those in whom it is paternal. Based on these earlier findings, we suggested that an imprinted X-linked genetic locus could exist, which is expressed from the paternal X-chromosome of normal females, but which is silent in normal males whose single X is always maternal. This mechanism could serve to protect normal females (who always possess a paternal X-chromosome) from neurodevelopmental disorders affecting social cognition, such as autism. These case reports are the first account of autism in association with Turner syndrome.

Autism in association with Turner syndrome: Genetic implications for male vulnerability to pervasive developmental disorders

Genetic factors play a substantial part in the aetiology of autism, although no satisfactory model has been proposed that could account for the excess of male phenotypes. We present five cases of autism from an unselected sample of 150 subjects with Turner syndrome, a genetic disorder associated with either the absence, or a structural abnormality, of the second X-chromosome in females. The population prevalence of autism is no more than 1:lO 000 normal females. All of the cases considered possessed an intact maternal X-chromosome and a structurally abnormal or absent paternal X-chromosome. We have previously presented evidence that cases of Turner syndrome in which the single X-chromosome is maternal have impaired social cognitive skills, compared with those in whom it is paternal. Based on these earlier findings, we suggested that an imprinted X-linked genetic locus could exist, which is expressed from the paternal X-chromosome of normal females, but which is silent in normal males whose single X is always maternal. This mechanism could serve to protect normal females (who always possess a paternal X-chromosome) from neurodevelopmental disorders affecting social cognition, such as autism. These case reports are the first account of autism in association with Turner syndrome.

Induction of female Sex-lethal RNA splicing in male germ cells: implications for Drosophila germline sex determination.

With a focus on Sex-lethal (Sxl), the master regulator of Drosophila somatic sex determination, we compare the sex determination mechanism that operates in the germline with that in the soma. In both cell types, Sxl is functional in females (2X2A) and nonfunctional in males (1X2A). Somatic cell sex is determined initially by a dose effect of X:A numerator genes on Sxl transcription. Once initiated, the active state of SXL is maintained by a positive autoregulatory feedback loop in which Sxl protein insures its continued synthesis by binding to Sxl pre-mRNA and thereby imposing the productive (female) splicing mode. The gene splicing-necessary factor (snf), which encodes a component of U1 and U2 snRNPs, participates in this RNA splicing control. Here we show that an increase in the dose of snf+ can trigger the female Sxl RNA splicing mode in male germ cells and can feminize triploid intersex (2X3A) germ cells. These snf+ dose effects are as dramatic as those of X:A numerator genes on Sxl in the soma and qualify snf as a numerator element of the X:A signal for Sxl in the germline. We also show that female-specific regulation of Sxl in the germline involves a positive autoregulatory feedback loop on RNA splicing, as it does in the soma. Neither a phenotypically female gonadal soma nor a female dose of X chromosomes in the germline is essential for the operation of this feedback loop, although a female X-chromosome dose in the germline may facilitate it. Engagement of the Sxl splicing feedback loop in somatic cells invariably imposes female development. In contrast, engagement of the Sxl feedback loop in male germ cells does not invariably disrupt spermatogenesis; nevertheless, it is premature to conclude that Sxl is not a switch gene in germ cells for at least some sex-specific aspects of their differentiation. Ironically, the testis may be an excellent organ in which to study the interactions among regulatory genes such as Sxl, snf, ovo and otu which control female-specific processes in the ovary.

Interphase Cytogenetics of Renal Cortical Neoplasms:Correlation With DNA Ploidy by Flow Cytometry

The genotypic changes in 22 renal cortical neoplasms and 16 of the corresponding normal kidney tissues by fluorescence in situ hybridization (FISH) were studied using directly labelled probes for chromosomes 7, 8, 10, 11, 12, 17, 18, X, and Y, and by flow cytometry (FCM). DNA ploidy analysis revealed 8 DNA aneuploid and 14 DNA diploid neoplasms. The mean single spot hybridization in normal kidney was 5 +/- 0.9% for chromosomes 7, 8, 10, 11, 12, and the X in females. The mean single spot hybridization for chromosomes 17 and 18 was 14.9% and 18.5%, respectively. The mean number of more than two (> 2) hybridization signals in normal kidney cells for all autosomes and the X-chromosome in females was 3 +/- 1.2%. Significant chromosomal loss was restricted to chromosomes 8, 18, X, and Y. The net chromosomal gain and loss correlated with the DIs in aneuploid tumors. All DNA diploid neoplasms showed both chromosomal loss and gain with a tendency to a net loss. No apparent correlation between the chromosomal aberrations and the clinicopathologic factors was found in this cohort. Our study demonstrates that: (1) tissue specific controls may provide better information for definable performance criteria for this technique; (2) monosomy can more reliably be assessed on fresh samples; (3) chromosomal loss is confined to certain chromosomes; (4) DNA diploid tumors manifest heterogeneous gain and loss of various chromosomes with a tendency to a net loss; and (5) integrated FISH and FCM analysis provide more information on the chromosomal abnormalities of these neoplasms.

Inversions of the factor VIII gene in Swedish patients with severe haemophilia A.

The series comprised 49 Swedish patients with severe haemophilia A [belonging to 49 families (21 with known and 28 with sporadic haemophilia)], of whom 12 had developed F. VIII inhibitors. Using Southern blotting, 45% (22/49) were found to have inversions, i.e., intrachromosomal rearrangements of the tip of the X-chromosome. Twenty patients had one or the other of the two variants of inversions recently published, whereas 2 patients manifested novel band patterns. Inversions were found in 50% of the families with sporadic haemophilia, and in 38% of those with known haemophilia. Fourteen families with sporadic haemophilia A had inversions, the proband carrying the de novo mutation in 4 cases and the proband's mother in 10 cases. Six inversions derived from a male and five from a female X-chromosome meiosis, the origin of the remaining three was not established. Genetic counselling of patients with severe haemophilia A and their families will be considerably improved, as inversions occur in half the severe cases and can be detected by a simple Southern blotting procedure.

Estimate of the Intrafamilial Correlation for Serum Creatine Kinase and Pyruvate Kinase in Females at Risk for Duchenne and Becker Muscular Dystrophies

In order to verify the possibility of nonrandom X-inactivation in females heterozygous for Duchenne (DMD) and Becker (BMD) muscular dystrophies, intrafamilial correlations and the heritabilities for serum creatine kinase (CK) and pyruvate kinase (PK) were estimated in a large sample of females belonging to families with affected patients. The results of the present investigation suggest that the apparent intrafamilial correlations for serum CK reported in previous studies in DMD families are not related with the presence of the DMD/BMD gene. Our data do not seem to support the hypothesis of a gene leading to a preferential inactivation of the X-chromosome in females at risk for the dystrophin gene.

Dosage compensation and template organisation in Drosophila: In situ transcriptional analysis of the chromatin template activity of the X and autosomes of D. melanogaster strains trisomic for the left arm of the second and third chromosomes

The chromatin template activity of the fixed polytene chromosomes of larval salivary glands of Drosophila melanogaster strains trisomic for the entire left arm of chromosome 2 or chromosome 3 was monitored using 3H-UTP and Escherichia coli RNA polymerase holoenzyme. The three doses of active loci in the trisomic strains were found to synthesize 30%–40% more RNA than the normal double dose of the same region in the wild-type male and female. The higher template activity of the genes on 2L or 3L in the trisomic strains, had no marked effect on the chromatin template activity of the X chromosomes of the male or female. These results suggest that (1) the template activity of an autosomal gene must be viewed as a basal level, comparable to the female X-chromosome and (2) hyperploids for any region of chromosome 2L or 3L have very little or no recognisable influence on X chromosomal organisation.

Absence of Late-Replicating X-Chromosome in a Female Patient With Acute Myeloid Leukemia and the 8;21 Translocation&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;

Autoradiography was used to demonstrate that the x-chromosome of the 45,X,-X,t(8;21) stemline of a female patient with acute myeloid leukemia (AML) was the active X-chromosome. This suggested that in patients housing AML with the 8;21 translocation, the loss of the inactive X-chromosome in females and of the Y in males (which is known to occur in nearly half of the patients) entails selective advantage to the stemline.

ISOLATION AND CHARACTERIZATION OF X-LINKED MUTANTS OF DROSOPHILA MELANOGASTER WHICH ARE SENSITIVE TO MUTAGENS

Thirteen X-linked mutants have been isolated in Drosophila melanogaster which render male and homozygous female larvae sensitive to the mutagen methyl methanesulfonate. Their characterization and preliminary assignment to functional groups is described. Four of these mutants are alleles of mei-41 (Baker and Carpenter 1972). Like previously isolated alleles of this locus, these mutants reduce fertility and increase loss and nondisjunction of the X-chromosome in homozygous females. The remaining mutants have been tentatively assigned to six functional groups (two mutants to the mus(1)101 locus, two to mus(1)102 , two to mus(1)103, and one each to mus(1)104, mus(1)105 , and mus(1)106). Several of the complementation groups can be distinguished on the basis of nondisjunction and cross sensitivity to mutagens. Females homozygous for the mei-41, mus(1)101 and mus(1)102 mutants exhibit elevated levels of nondisjunction. Mutants belonging to complementation groups mei-41, mus(1)101, and mus(1)104 are sensitive to nitrogen mustard (HN2) in addition to their MMS sensitivity. Among these mutants there is currently a direct correlation between sensitivity to HN2, sensitivity to 2-acetylaminofluorene and a deficiency in post-replication repair ( Boyd and Setlow 1976). Only the mei-41 mutants are hypersensitive to UV radiation, although several of the mutants exhibit sensitivity to gamma-rays. Semidominance is observed in female larvae of the mei-41, mus(1)104, and mus(1)103 mutants after exposure to high concentrations of MMS. The properties of the mutants generally conform to a pattern which has been established for related mutants in yeast. Additional properties of these mutants are summarized in Table 9.

Comparative study of the function of polytene chromosomes in laboratory stocks of Drosophila melanogaster and the l(3)tl mutant (lethal tumorous larvae). II. Changes of banding pattern and transcriptional activity in the salivary chromosome of l(3)tl.

The salivary chromosomes of the l(3)tl mutant of D. melanogaster are considerably thicker and shorter than those of normal larvae. In most nuclei, chromosome shortening is associated with morphological changes of two types. a) The bands lose their distinctive pattern and become loose. The chromosome appears as a granular mass. In extreme cases pompon-like chromosomes arise. Most frequently male X-chromosomes undergo such changes and begin to shorten as early as in the middle of third larval instar. "Pompon" transformation is not associated with a change in the relative intensity of RNA synthesis: the ratio of silver grain number over the male X-chromosome to that over regions 61A-63F is the same in pompon-like l(3)tl chromosomes and in the male and female X-chromosomes of the normal lines. b) Shortened chromosomes occassionally retain distinct band organization and, in these cases, chromosome shortening is observed to be due to the condensation of the chromatin of many puffs and interbands resulting in the fusion of a large number of bands into "new" chromatin blocks. In regions of fused bands, transcriptional activity is decreased as compared with regions where this union does not occur. The chromosomes of l(3)tl larvae lack ecdysone-stimulated puffs and other prominent puffs. In 144-192 hour larvae, puffs can be induced by ecdysone and until 384 hours by temperature shock. The capacity of puff induction decreases with larval age.

Differences in DNA replication patterns in the X-chromosome of males, females and intersexes of Drosophila melanogaster

The rate of replication in the polytene X-chromosome has been determined as a function of the ratio of the X-chromosomes to autosomes (X:A). After pulse labeling with 3H-thymidine the labeling frequency and DNA replication patterns were studied in the 1A1-3C8 region of the polytene X-chromosome of Drosophila melanogaster diploid males (1X2A) and females (2X2A), triploid females (3X3A) and triploid intersexes (2X3A). — Only negligible changes in frequency of labeling and sequence of DNA synthesis in a given region of the X-chromosome were observed in individuals of a given sex as a result of differences in genotypical constitution. The replication patterns and labeling frequency were identical in diploid and triploid females. — The previously reported data (Berendes, 1966; Lakhotia, 1970) showing a faster replication in the regions of the male, as compared with the female X-chromosome were confirmed. An intermediate rate of replication in most of the studied regions in the 1A1-3C8 segment of the X-chromosome in triploid intersexes (2X3A) was observed. There is a marked positive correlation between the rates of replication and previously reported (Maroni et al., 1973a; Ananiev and Gvozdev, 1974) transcription rates in the X-chromosome of intersexes.

Synthesis of RNA by Escherichia coli RNA polymerase on the chromosomes of Drosophila melanogaster.

Preparations of polytene chromosomes of D. melanogaster fixed with acetic acid have been used as templates for RNA synthesis by E. coli RNA polymerase complete or core enzymes in the presence of 3H-nucleoside triphosphates. Radioautographic experiments showed that on a single X-chromosome from male larvae twice as much RNA is synthesized as on each of the two female X-chromosomes. Thus, such a heterologous transcription system shows the dosage compensation effect which had been observed earlier for the X-chromosomes in the intact cells in vivo. It is suggested that the dosage compensation of sex-linked genes is due to a difference in the structure of the X-chromosomes of males and females. This difference is also demonstrated by the fact that a male X-chromosome binds twice as many molecules of 3H-labelled RNA polymerase as does each of the female X-chromosomes. The difference in the in vitro template activities of male and female X-chromosomes cannot be overcome by pretreating them with deoxyribonuclease S1 specific for single-stranded DNA which implies that single-stranded regions are not important for the phenomenon of dosage compensation.

The role of genetic balance in control of transcription rate in the X-chromosomes of Drosophila melanogaster.

The intensity of transcription in the polytene X-chromosome of the salivary glands of Drosophila melanogaster has been determined as a function of the ratio of X-chromosomes to autosomes (X:A). Autoradiographic measurements revealed that the single X-chromosome in males (1X2A) incorporates twice as much label as each of the two X-chromosomes in females (2X2A) which confirms the earlier report of Mukherjee and Beermann (1965). The addition of the third autosome set in super-males (1X3A) does not result in an increase of RNA synthesis in the X-chromosomes as compared to normal males (1X2A). In superfemales (3X2A) carrying an extra X-chromosome the transcription in each of the X-chromosomes proceeds with the same rate as in diploid (2X2A) or triploid (3X3A) females. In intersexes (2X3A) the rate of transcription in each of X-chromosomes is intermediate between male and female levels. — The comparison of transcription rates in X-chromosomes with the levels of two enzymes coded for by sex-linked genes in males, females, super-females and intersexes (Faizullin and Gvozdev, 1972, 1973) revealed that the dosage compensation of the enzyme synthesis is effected at the level of transcription.

Differential replication of male and female X-chromosomes in Drosophila

The replication patterns of larval salivary gland chromosomes of D. hydei and D. melanogaster were studied by autoradiography with tritiated thymidine injected in mid third instar larvae. The male X chromosome showed a different replication behavior in comparison to that of the female X chromosome and autosomes. It is concluded that the male X chromosome finishes its replication earlier than the female X chromosome. Moreover, the time needed for a complete replication cycle of individual identical replication units was found to be shorter in the male than in the female X chromosome. Although the whole X chromosomes behave different there were no differences observed in the sequence of the discontinuous labeling patterns of the two types of X chromosome. One autosomal replication unit was observed which showed a different replication behavior in males and females. The possible origin of the differential behavior of the two X chromosomes is discussed in terms of their difference in degree of polyteny.