Showing papers on "Dosage compensation published in 1991"
TL;DR: This gene, called XIST (for Xi-specific transcripts), is a candidate for a gene either involved in or uniquely influenced by the process of X inactivation, and is described as an X-linked gene with a novel expression pattern.
Abstract: X-chromosome inactivation results in the cis-limited dosage compensation of genes on one of the pair of X chromosomes in mammalian females. Although most X-linked genes are believed to be subject to inactivation, several are known to be expressed from both active and inactive X chromosomes. Here we describe an X-linked gene with a novel expression pattern--transcripts are detected only from the inactive X chromosome (Xi) and not from the active X chromosome (Xa). This gene, called XIST (for Xi-specific transcripts), is a candidate for a gene either involved in or uniquely influenced by the process of X inactivation.
1,397 citations
TL;DR: Structurally distinct sex chromosomes are the most familiar mode of genetic sex determination and have evolved independently in many different taxa and the evolutionary paths by which their characteristic properties may have evolved are reviewed.
Abstract: Structurally distinct sex chromosomes (X and Y) are the most familiar mode of genetic sex determination and have evolved independently in many different taxa. The evolutionary paths by which their characteristic properties may have evolved are reviewed. These properties include the failure of X and Y to recombine through much or all of their length, the genetic inertness of much of the Y chromosome, dosage compensation of the activity of X chromosomal loci, and the accumulation of repeated DNA sequences on the Y chromosome.
765 citations
TL;DR: Conservation between man and mouse of chromosomal position and unique expression exclusively from the inactive X chromosome lends support to the hypothesis that XIST and its mouse homologue are involved in X-chromosome inactivation.
Abstract: X-chromosome inactivation in mammals is a regulatory phenomenon whereby one of the two X chromosomes in female cells is genetically inactivated, resulting in dosage compensation for X-linked genes between males and females. In both man and mouse, X-chromosome inactivation is thought to proceed from a single cis-acting switch region or inactivation centre (XIC/Xic). In the human, XIC has been mapped to band Xq13 (ref. 6) and in the mouse to band XD (ref. 7), and comparative mapping has shown that the XIC regions in the two species are syntenic. The recently described human XIST gene maps to the XIC region and seems to be expressed only from the inactive X chromosome. We report here that the mouse Xist gene maps to the Xic region of the mouse X chromosome and, using an interspecific Mus spretus/Mus musculus domesticus F1 hybrid mouse carrying the T(X;16)16H translocation, show that Xist is exclusively expressed from the inactive X chromosome. Conservation between man and mouse of chromosomal position and unique expression exclusively from the inactive X chromosome lends support to the hypothesis that XIST and its mouse homologue are involved in X-chromosome inactivation.
604 citations
TL;DR: The maleless (mle) gene is one of four known regulatory loci required for increased transcription (dosage compensation) of X-linked genes in D. melanogaster males and a strong candidate to be a direct regulator of dosage compensation.
282 citations
TL;DR: A system to analyse whether specific genes on the mouse X chromosome are inactivated, and demonstrate that both ZFX and RPS4X undergo normal X-inactivation in mice, which may explain the relative viability of XO mice compared to XO humans.
Abstract: ONLY about 1% of human XO conceptuses survive to birth and these usually have the characteristics of Turner's syndrome, with a complex and variable phenotype including short stature, gonadal dysgenesis and anatomical defects1. Both the embryonic lethality and Turner's syndrome are thought to be due to monosomy for a gene or genes common to the X and Y chromosomes2. These genes would be expected to be expressed in females from both active and inactive X chromosomes to ensure correct dosage of gene product. Two genes with these properties are ZFX and RPS4X, both of which have been proposed to play a role in Turner's syndrome3,4. In contrast to humans, mice that are XO are viable with no prenatal lethality (P. Burgoyne, personal communication) and are anatomically normal and fertile. We have devised a system to analyse whether specific genes on the mouse X chromosome are inactivated, and demonstrate that both Zfx and Rps4X undergo normal X-inactivation in mice. Thus the relative viability of XO mice compared to XO humans may be explained by differences between the two species in the way that dosage compensation of specific genes is achieved.
129 citations
TL;DR: It is concluded that methylation of CpG-rich islands is a general feature of X Chr inactivation.
Abstract: Single copy probes derived from CpG-rich island clones fromEag I andNot I linking libraries and nine rare-cutter restriction endonucleases were used to investigate the methylation status of CpG-rich islands on the inactive and active X chromosomes (Chr) of the mouse. Thirteen of the 14 probes used detected CpG-rich islands in genomic DNA. The majority of island CpGs detected by rare-cutter restriction endonucleases were methylated on the inactive X Chr and unmethylated on the active X Chr, but some heterogeneity within the cell population used to make genomic DNA was detected. The CpG-rich islands detected by two putative pseudoautosomal probes remained unmethylated on both the active and inactive X Chrs. Otherwise, distance from the X Chr inactivation center did not affect the methylation profile of CpG-rich islands. We conclude that methylation of CpG-rich islands is a general feature of X Chr inactivation.
109 citations
TL;DR: The results enhance the general understanding of sex determination strategies, which are already known to involve transcriptional regulation1 and alternative RNA splicing2,3 in Drosophila melanogaster, DNA rearrangements in Saccharomyces cerevisiae4, and transcriptionalregulation in mammals.
Abstract: THE sdc-1 gene acts at an early step in the regulatory hierarchy that controls the choice of sexual fate in Caenorhabditis elegans. It functions at a point before the control of sex determination and X-chromosome dosage compensation diverge. Here we report that sdc-1 encodes a protein of 1,203 amino acids containing seven zinc fingers. This protein motif in combination with other genetic and molecular information suggests that sdc-1 is likely to function as an embryonic transcription factor regulating downstream genes involved specifically in the sex determination and dosage compensation pathways, or regulating other genes involved in the coordinate control of both processes. These results enhance our general understanding of sex determination strategies, which are already known to involve transcriptional regulation1 and alternative RNA splicing2,3 in Drosophila melanogaster, DNA rearrangements in Saccharomyces cerevisiae4, and transcriptional regulation in mammals5,6.
62 citations
TL;DR: It is demonstrated that a single regulatory gene can exert an inverse effect on a target structural locus, a situation postulated from segmental aneuploid studies of gene expression and dosage compensation.
Abstract: A trans-acting regulatory gene, Inr-a, that alters the level of expression of the white eye color locus as an inverse function of the number of its functional copies is described. Several independent lines of evidence demonstrate that this regulatory gene interacts with white via the promoter sequences. Among these are the observations that the inverse regulatory effect is conferred to the Adh gene when fused to the white promoter and that cis-regulatory mutants of white fail to respond. The phenotypic response to Inr-a is found in all tissues in which white is expressed, and mutants of the regulator exhibit a recessive lethality during larval periods. Increased white messenger RNA levels in pupal stages are found in Inr-a/+ individuals versus +/+ and a coordinate response is observed for mRNA levels from the brown and scarlet loci. All are structurally related and participate in pigment deposition. These experiments demonstrate that a single regulatory gene can exert an inverse effect on a target structural locus, a situation postulated from segmental aneuploid studies of gene expression and dosage compensation.
62 citations
TL;DR: It is shown here that the lethal phase of sc- females is embryonic and caused by the lack of Sxl function, and the results support the view that the control of SXl by the X:A signal occurs at the transcriptional level.
Abstract: The gene scute (sc) has a dual function: the scute function which is involved in neurogenesis and the sisterless-b function which is involved in generating the X:A signal that determines the state of activity of Sxl, a gene that controls sex determination and dosage compensation. We show here that the lethal phase of sc- females is embryonic and caused by the lack of Sxl function. We also analyze the time in development when sc and Sxl interact by means of (a) determining the thermosensitive phase (TSP) of the interaction between Sxl and sc and (b) a chimeric gene in which sc is under the control of a heat-shock promoter (HSSC-3). Pulses of sc expression from the HSSC-3 activate Sxl only at a very specific and early stage in development, which coincides with the TSP of the interaction between sc and Sxl. It corresponds to the syncytial blastoderm stage and coincides with the time when the X:A signal regulates Sxl. At this stage sc undergoes a homogeneous transient expression in wild-type flies. We conclude that the sc expression at the syncytial blastoderm is responsible for its sisterless-b function. Since sc expression from the HSSC-3 fully suppresses the sisterless-b phenotype, we further conclude that the sisterless-b function is exclusively provided by the sc protein. Finally, we have analyzed, by in situ hybridization, the effect of sc and sis-a mutations on the embryonic transcription of Sxl. Our results support the view that the control of Sxl by the X:A signal occurs at the transcriptional level.
40 citations
TL;DR: The compensation behavior of the transposed genes was, therefore, not determined by closely linked sequences but instead was determined in each case by their new chromosomal environment.
Abstract: Measurements were made of the amounts of larval RNA transcribed from the autosomal Adh gene of Drosophila melanogaster and the X chromosomal Hsp82 gene of Drosophila pseudoobscura carried on the same P-element transposon inserted at various sites in the D. melanogaster genome. Both genes were fully compensated at sites in euchromatic regions of the X chromosome but neither was compensated at a site in the centric beta-heterochromatin of the X chromosome. No compensation of the D. pseudoobscura Hsp82 gene was found at any of 10 autosomal insertion sites tested. The compensation behavior of the transposed genes was, therefore, not determined by closely linked sequences but instead was determined in each case by their new chromosomal environment.
17 citations
TL;DR: Female heterogamety is predominant in birds, reptiles and amphibians, all of which have megalecithal eggs containing several thousand times more maternal RNA and other maternal messages than eggs of mammals, Caenorhabditis elegans, orDrosophila, and the increase in egg size, yolk content and, concomitantly, the size of the maternal legacy to the embryo, may have facilitated female heterogAMety and the absence of dosage compensation.
Abstract: When the male is the heterogametic sex (XX♀-XY♂ or XX♀-XO♂), as inDrosophila, orthopteran insects, mammals andCaenorhabditis elegans, X-linked genes are subject to dosage compensation: the single X in the male is functionally equivalent to the two Xs in the female. However, when the female is heterogametic (ZZ♂-ZW♀), as in birds, butterflies and moths, Z-linked genes are apparently not dosage-compensated. This difference between X-linked and Z-linked genes raises fundamental questions about the role of dosage compensation. It is argued that (i) genes which require dosage compensation are primarily those that control morphogenesis and the prospective body plan; (ii) the products of these genes are required in disomic doses especially during oogenesis and early embryonic development; (iii) heterogametic females synthesize and store during oogenesis itself morphogenetically essential gene products - including those encoded by Z-linked genes — in large quantities; (iv) the abundance of these gene products in the egg and their persistence relatively late into embryogenesis enables heterogametic females to overcome the monosomic state of the Z chromosome in ZW embryos. Female heterogamety is predominant in birds, reptiles and amphibians, all of which have megalecithal eggs containing several thousand times more maternal RNA and other maternal messages than eggs of mammals,Caenorhabditis elegans, orDrosophila. This increase in egg size, yolk content and, concomitantly, the size of the maternal legacy to the embryo, may have facilitated female heterogamety and the absence of dosage compensation.
TL;DR: Cytogenetic studies suggested that two XMchromosomes remain active in the trophectoderm and possibly also the primitive endoderm, in which XP is preferentially inactivated in normal female embyos.
Abstract: An extra maternally derived X chromosome (XM) but not a paternally derived one (XP) is detrimental in early mouse embryogenesis resulting in failure to form the ectoplacental cone and extra-embryonic ectoderm. Cytogenetic studies suggested that two XMchromosomes remain active in the trophectoderm and possibly also the primitive endoderm, in which XPis preferentially inactivated in normal female embyos. Two copies of an active X chromosome due to maternal imprinting seem to prevent further differentiation of the trophectoderm.
TL;DR: No evidence exists for a nonrandom X chromosome inactivation in the fra(X) syndrome in females, as biased patterns were also observed in control females.
Abstract: Over 30% of female carriers of the fragile X [fra(X)] syndrome are clinically affected. A nonrandom X chromosome inactivation in these cases could be a plausible explanation. A review of previous studies addressing this question showed inconclusive results; thus, we analysed the X inactivation pattern in fibroblasts of 4 unrelated, mentally retarded fra(X) carriers with a high expression of the fragile site Xq27.3. Using Southern analysis with a highly polymorphic probe M27 beta that recognizes methylation differences between the active and inactive X chromosome we found a 50/50 inactivation pattern in 2 cases and skewed patterns in the other 2. As biased patterns were also observed in control females we conclude that at present no evidence exists for a nonrandom X chromosome inactivation in the fra(X) syndrome in females.
TL;DR: Limiting analysis and cross-specific DNA and RNA blot hybridization revealed the presence of extensive restriction pattern polymorphism and lack of sequence similarity in some areas of the 507 mr and 507 ml DNA, including the 3′ portion of the transcribed region, indicating that gene 507 is dosage compensated in D. miranda.
Abstract: The X1R chromosome of Drosophila miranda and the 3L autosome of Drosophila melanogaster are thought to have originated from the ancestral D chromosomal element and therefore may contain the same set of genes. It is expected that these genes will be dosage compensated in D. miranda because of their X linkage. To test these possibilities and to study evolution of the dosage compensation mechanism, we used the 3L-linked autosomal head-specific gene 507ml of D. melanogaster to isolate the homologous gene (507 mr) from a D. miranda genomic library. In situ hybridization showed that gene 507 is located at the 12A region of the X1R chromosome of D. miranda, indicating that the chromosomal homology deduced by cytogenetic means is correct. Restriction analysis and cross-specific DNA and RNA blot hybridization revealed the presence of extensive restriction pattern polymorphism and lack of sequence similarity in some areas of the 507 mr and 507 ml DNA, including the 3′ portion of the transcribed region. However, the 5′ portion of the transcribed region and the DNA sequences, located approximately 0.8 kb upstream and 3 kb downstream from the 507 ml gene showed a high degreee of similarity with the DNA sequences of comparable regions of the 507 mr gene. In both species gene 507 codes for a highly abundant 1.8 kb RNA which is expressed in the retina of the compound eye. Although in D. miranda the males have one and the females have two copies of the 507 gene, the steady-state levels of the 507 mRNA in both sexes were found to be similar, indicating that gene 507 is dosage compensated in D. miranda. Thus, along with the disparate rates of evolution in different areas of the DNA associated with gene 507, in D. miranda this gene has come under the regulation of the X chromosomal dosage compensation mechanism.
TL;DR: Three female-specific lethal mutations at the gene Sex-lethal (Sxl) are isolated and complementation analysis between these mutations and other previously reported Sxlf mutations suggest that the two complementation groups are related to the two sets of early andLate Sxl transcripts, which are responsible for the early and late SxL functions, respectively.
Abstract: We have isolated three female-specific lethal mutations at the gene Sex-lethal (Sxl): Sxlfb, Sxlfc and Sxlfd. We have carried out the complementation analysis between these mutations and other previously reported Sxlf mutations. It is possible to classify the alleles tested in this report into two complementation groups: the bc group defined by Sxlfb, and Sxlfc, and the LS group defined by SxlfLS. The other alleles tested affect both complementation groups albeit with different degrees. Contrary to what happens with mutations at the LS group, mutations at the bc group do not affect sex determination, nor late dosage compensation nor oogenesis. Both Sxlfb and Sxlfc present a DNA insertion of at least 5 kb between position -10 and -11 on the molecular map, within the fourth intron. On the contrary, Sxlfd, a strong mutation affecting all Sxl functions, is not associated to any detectable DNA alteration in Southern blots, so that it seems to be a "point" mutation. In agreement with their phenotypes, both Sxlfc/SxlfLS and Sxlfc homozygous female larvae express only the late Sxl transcripts characteristic of females, while females homozygous for SxlfLS express only the late Sxl transcripts characteristic of males. Moreover, Sxlfc presents a lethal synergistic interaction with mutations at either da or the X:A ratio, two signals that define the initial activity state of Sxl, while SxlfLS do not. These data suggest that the two complementation groups are related to the two sets of early and late Sxl transcripts, which are responsible for the early and late Sxl functions, respectively: Sxlfb and Sxlfc would affect the early functions and SxlfLS would affect the late Sxl functions.
Journal Article•
TL;DR: It is proposed that low-copy repetitive DNA segments along the X chromosome are responsible for non-homologous pairing and production of inversions and a review of the literature shows that almost half of the breakpoints on the short arm are found at region p22.
Abstract: A large pericentric inversion of the X chromosome [inv(X)(p22.31q26.3)] was found to be transmitted in four generations through phenotypically normal males and females. In one female carrier, the inv(X) was late replicating in 70% of lymphocytes and 46% of skin fibroblasts. Steroid sulfatase (STS), an enzyme which normally escapes inactivation has been located to Xp22.32 and, in our case, has been moved to an aberrant position. We have assayed its activity in clones with the inv(X) inactive or the normal X inactive and found no significant differences. Thus, the STS locus escaped X inactivation in both the normal and the inverted X chromosomes. A review of the literature shows that almost half of the breakpoints on the short arm are found at region p22 and we propose that low-copy repetitive DNA segments along the X chromosome are responsible for non-homologous pairing and production of inversions.
01 Aug 1991
TL;DR: It is concluded that the gene fl(2)d seems to be necessary during the adult life of females for the processes that require Sxl+ activity, and the SxL-independent vital function of fl( 2)d appears to be required in both sexes only during larval development.
Abstract: In Drosophila melanogaster, the gene Sex-lethal (Sxl) controls the processes of sex determination, dosage compensation, oogenesis and sexual behaviour. The control of Sxl is by alternative splicing of its primary RNA. We have identified a gene, female-lethal-2-d (fl(2)d), which is needed for the female-specific splicing of Sxl RNA and which also has a vital function independent of Sxl. Here we analyse other aspects of the gene fl(2)d. Specifically, we have analysed the effect of the temperature-sensitive mutation fl(2)d 1 on the viability of adult flies homozygous for this mutation. We have found that the viability of the mutant females is reduced, while that of the mutant males is not affected. In addition, the capacity of the mutant females to be inseminated is considerably reduced, whilst all the mutant males are able to inseminate females. These effects on females are suppressed by Sxl M1. However, the fat body cells of fl(2)d 1 homozygous females are able to synthesize yolk proteins at the restrictive temperature. We have also carried out, in males, a clonal analysis of fl(2)d 2, a mutation lethal in both sexes. We have found that the clones are fully viable. We conclude that the gene fl(2)d seems to be necessary during the adult life of females for the processes that require Sxl + activity. Moreover, the Sxl-independent vital function of fl(2)d seems to be required in both sexes only during larval development.
01 Jan 1991
TL;DR: Barrbodies formed byisodi- centric humanXchromosomes incultured humancells and in mouse-human hybrids using confocal microscopy andDNA probes forcentromere andsubtelomere regions are examined, finding that the Barrbodyconsists ofacondensed X chromosome inanonlinear configuration, withtelomeres inclose proximity.
Abstract: We examined Barrbodies formed byisodi- centric humanXchromosomes incultured humancells andin mouse-human hybrids using confocal microscopy andDNA probes forcentromere andsubtelomere regions. Atinterphase, thetwoendsofthese chromosomes areonly amicron apart, indicating that these inactive Xchromosomes areinanonlinear configuration. Additional studies ofnormal X chromosomes reveal thesametelomere association fortheinactive Xbutnot fortheactive Xchromosome. Thisnonlinear configuration is maintained during mitosis andinamurine environment. Barrbodies areunique chromatin structures formed innuclei ofthemammalian female asameansofsexchromosome dosage compensation. First identified asanucleolar satellite present onlyinfemale cells (1), theBarrbodyrepresents a single inactive X chromosome. Incultured humancells, itis mosteasily identified attheperiphery oftheinterphase nucleus, whenother chromosomes arenotcondensed. Be- causetheBarrbodyisdifficult toseeamongclumped heterochromatin ininterphase mousefibroblasts, andbe- causethesilent humanX reactivates morefrequently in rodent thanhumancells, Dyeretal.(2,3)suggested that mousecells maynotformproper Barrbodies. Analysis of cultured humancells byelectron microscopy (4)orinsitu hybridization (2) places theBarrbodyadjacent tothenuclear envelope in75-80%ofinterphase cells. Comings (5)sug- gested that inactive X chromosomes attach randomly tothe nuclear membrane, andthemultiple Barrbodies inaneuploid cells arewidely distributed (6,7). Nuclear matrix attachment sites aresimilar fortheactive andinactive X chromosomes (8). Yet,theconfiguration oftheBarrbodyhasbeenrela- tively unexplored. DNA hybridization, insitu (9), haspro- vided apowerful method toexamine chromosomes during interphase, revealing anorderly arrangement ofchromo- somesintheinterphase nucleus (10-13) andtissue-specific variation (14, 15). Using suchmethods toexplore thehuman inactive X chromosome, wefind that theBarrbodyconsists ofacondensed X chromosome inanonlinear configuration, withtelomeres inclose proximity. Weexamined theBarrbodyininterphase andmitotic cells using fluorescent probes forcentromere andtelomere regions ofhumanX chromosomes. Inaddition tonormal Xchromo- somes, westudied isodicentric X chromosomes (16), which formbipartite Barrbodies (16). Alwaysinactive, theyare mirror imageduplications withtwocentromeres (onenon- functional) andwithtwoidentical telomeres (see Fig. 1). The duplicate centromeres aswell ascommontelomeres andtheir longer length facilitate structural analysis. Tocompare dis- tancebetween hybridization signals withrelative physical length weexamined three isodicentrics, twojoined bytheir long arms(3935 and7213) andthethird attached attheshort arms(411). We isolated these dicentric chromosomes from their normal homologue inhybrid cells sothatallsignals wouldcomefromthedicentric X chromosome andtoexam- inethehumanBarrbodyinamousecell environ. Finally, we simultaneously hybridized centromere andsubtelomere probes using differential labels andconfocal microscopy. MATERIALSANDMETHODS Cell Lines. These arecharacterized inTable 1.Thehybrids derived fromA9mousefibroblasts wereselected inhypo- xanthine/aminopterin/thymidine medium, backselected in 6-thioguanine toeliminate theactive X;toretain theinactive X,thesilent HPRTlocus wasreactivated by5-azacytidine. Inactive X hybrids derived fromtsA1S9T mousecells were selected directly at390Cforactivity oftheAJS9Tlocus at