Showing papers on "Chromosome 21 published in 2012"
TL;DR: Cultured cerebral cortex neurons generated from human Down syndrome induced pluripotent stem cells rapidly develop Alzheimer’s disease pathologies, suggesting that complex neurodegenerative diseases that take decades to manifest in human patients can be modeled reliably in cultured neurons over a period of months.
Abstract: Human cellular models of Alzheimer's disease (AD) pathogenesis would enable the investigation of candidate pathogenic mechanisms in AD and the testing and developing of new therapeutic strategies. We report the development of AD pathologies in cortical neurons generated from human induced pluripotent stem (iPS) cells derived from patients with Down syndrome. Adults with Down syndrome (caused by trisomy of chromosome 21) develop early-onset AD, probably due to increased expression of a gene on chromosome 21 that encodes the amyloid precursor protein (APP). We found that cortical neurons generated from iPS cells and embryonic stem cells from Down syndrome patients developed AD pathologies over months in culture, rather than years in vivo. These cortical neurons processed the transmembrane APP protein, resulting in secretion of the pathogenic peptide fragment amyloid-β42 (Aβ42), which formed insoluble intracellular and extracellular amyloid aggregates. Production of Aβ peptides was blocked by a γ-secretase inhibitor. Finally, hyperphosphorylated tau protein, a pathological hallmark of AD, was found to be localized to cell bodies and dendrites in iPS cell-derived cortical neurons from Down syndrome patients, recapitulating later stages of the AD pathogenic process.
297 citations
TL;DR: Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease.
Abstract: Next-generation sequencing of DNA from human tumors or individuals with developmental abnormalities has led to the discovery of a process we term chromoanagenesis, in which large numbers of complex rearrangements occur at one or a few chromosomal loci in a single catastrophic event. Two mechanisms underlie these rearrangements, both of which can be facilitated by a mitotic chromosome segregation error to produce a micronucleus containing the chromosome to undergo rearrangement. In the first, chromosome shattering (chromothripsis) is produced by mitotic entry before completion of DNA replication within the micronucleus, with a failure to disassemble the micronuclear envelope encapsulating the chromosomal fragments for random reassembly in the subsequent interphase. Alternatively, locally defective DNA replication initiates serial, microhomology-mediated template switching (chromoanasynthesis) that produces local rearrangements with altered gene copy numbers. Complex rearrangements are present in a broad spectrum of tumors and in individuals with congenital or developmental defects, highlighting the impact of chromoanagenesis on human disease.
235 citations
TL;DR: A few examples of how trisomy for specific genes affects the development of the cortex and cerebellum are provided to illustrate how gene dosage effects might contribute to divergence between the trisomic and euploid brains.
183 citations
TL;DR: DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation, and the same pathway can be both proleukemic in children and antitumorigenic in adults.
Abstract: Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor–encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation–regulated kinase 1A, was a potent megakaryoblastic tumor–promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.
153 citations
TL;DR: It is found that trisomic cells of hES, iPS, or isogenic origins exhibited a two- to fivefold increase in a population of CD43+(Leukosialin)/CD235+(Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony- forming assays.
Abstract: Trisomy 21 is associated with hematopoietic abnormalities in the fetal liver, a preleukemic condition termed transient myeloproliferative disorder, and increased incidence of acute megakaryoblastic leukemia. Human trisomy 21 pluripotent cells of various origins, human embryonic stem (hES), and induced pluripotent stem (iPS) cells, were differentiated in vitro as a model to recapitulate the effects of trisomy on hematopoiesis. To mitigate clonal variation, we isolated disomic and trisomic subclones from the same parental iPS line, thereby generating subclones isogenic except for chromosome 21. Under differentiation conditions favoring development of fetal liver-like, γ-globin expressing, definitive hematopoiesis, we found that trisomic cells of hES, iPS, or isogenic origins exhibited a two- to fivefold increase in a population of CD43(+)(Leukosialin)/CD235(+)(Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony-forming assays. These findings establish an intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage.
135 citations
TL;DR: This study generated induced pluripotent stem cells from DS fibroblasts and introduced a TKNEO transgene into one copy of chromosome 21 by gene targeting and described a targeted removal of a human trisomy, which could prove useful in both clinical and research applications.
130 citations
TL;DR: In vivo alterations of mitochondrial function are consistent with a prooxidant state as a phenotypic hallmark in DS, and these alterations were reported in mitochondria from human DS patients and from trisomy 16 mice.
Abstract: Down syndrome (DS) or trisomy 21 is the genetic disease with highest prevalence displaying phenotypic features that both include neurologic deficiencies and a number of clinical outcomes. DS-associated neurodegeneration recalls the clinical course of Alzheimer disease (AD), due to DS progression toward dementia and amyloid plaques reminiscent of AD clinical course. Moreover, DS represents one of the best documented cases of a human disorder aetiologically related to the redox imbalance that has long been attributed to overexpression of Cu,Zn-superoxide dismutase (SOD-1), encoded by trisomic chromosome 21. The involvement of oxidative stress has been reported both in genes located else than at chromosome 21 and in transcriptional regulation of genes located at other chromosomes. Another well documented hallmark of DS phenotype is represented by a set of immunologic defects encompassing a number of B and T-cell functions and cytokine production, together prompting a proinflammatory state. In turn, this condition can be directly interrelated with an in vivo prooxidant state. As an essential link to oxidative stress, mitochondrial dysfunctions are observed whenever redox imbalances occur, due to the main roles of mitochondria in oxygen metabolism and this is the case for DS. Ultrastructural and biochemical abnormalities were reported in mitochondria from human DS patients and from trisomy 16 (Ts16) mice, to be reviewed in this chapter. Together, in vivo alterations of mitochondrial function are consistent with a prooxidant state as a phenotypic hallmark in DS.
101 citations
TL;DR: It is hypothesized that the gene content of chromosome 4a might be relevant in its transition to a sex chromosome, based on the presence of genes that could offer a selective advantage when associated to Z-linked sex determination loci.
Abstract: Neo-sex chromosomes often originate from sex chromosome–autosome fusions and constitute an important basis for the study of gene degeneration and expression in a sex chromosomal context. Neo-sex chromosomes are known from many animal and plant lineages, but have not been reported in birds, a group in which genome organization seems particularly stable. Following indications of sex linkage and unexpected sex-biased gene expression in warblers (Sylvioidea; Passeriformes), we have conducted an extensive marker analysis targeting 31 orthologues of loci on zebra finch chromosome 4a in five species, representative of independent branches of Passerida. We identified a region of sex linkage covering approximately the first half (10 Mb) of chromosome 4a, and associated to both Z and W chromosomes, in three Sylvioidea passerine species. Linkage analysis in an extended pedigree of one species additionally confirmed the association between this part of chromosome 4a and the Z chromosome. Markers located between 10 and 21 Mb of chromosome 4a showed no signs of sex linkage, suggesting that only half of the chromosome was involved in this transition. No sex linkage was observed in non-Sylvioidea passerines, indicating that the neo-sex chromosome arose at the base of the Sylvioidea branch of the avian phylogeny, at 47.4–37.6 millions years ago (MYA), substantially later than the ancestral sex chromosomes (150 MYA). We hypothesize that the gene content of chromosome 4a might be relevant in its transition to a sex chromosome, based on the presence of genes (for example, the androgen receptor) that could offer a selective advantage when associated to Z-linked sex determination loci.
87 citations
TL;DR: It is shown that viable XO individuals are relatively frequently found in species with small PARs, such as horses, humans and mice but are rare or absent in species in which the PAR is substantially larger, like in cattle/ruminants, dogs, pigs, and alpacas.
Abstract: The pseudoautosomal region (PAR) is a unique and specialized segment on the mammalian sex chromosomes with known functions in male meiosis and fertility. Detailed molecular studies of the region in human and mouse show dramatic differences between the 2 PARs. Recent mapping efforts in horse, dog/cat, cattle/ruminants, pig and alpaca indicate that the PAR also varies in size and gene content between other species. Given that PAR genes escape X inactivation, these differences might critically affect the genetic consequences, such as embryonic survival and postnatal phenotypes of sex chromosome aneuploidies. The aim of this review is to combine the available information about the organization of the PAR in domestic species with the cytogenetic data on sex chromosome aneuploidies. We show that viable XO individuals are relatively frequently found in species with small PARs, such as horses, humans and mice but are rare or absent in species in which the PAR is substantially larger, like in cattle/ruminants, dogs, pigs, and alpacas. No similar correlation can be detected between the PAR size and the X chromosome trisomy in different species. Recent evidence about the likely involvement of PAR genes in placenta formation, early embryonic development and genomic imprinting are presented.
77 citations
TL;DR: The findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.
Abstract: G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via Gi/o protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.
75 citations
TL;DR: The results provide novel insights into the very early stages of sex chromosome evolution and B chromosome origination, and suggest an unprecedented connection between the births of these two systems in D. albomicans.
Abstract: Drosophila albomicans is a unique model organism for studying both sex chromosome and B chromosome evolution. A pair of its autosomes comprising roughly 40% of the whole genome has fused to the ancient X and Y chromosomes only about 0.12 million years ago, thereby creating the youngest and most gene-rich neo-sex system reported to date. This species also possesses recently derived B chromosomes that show non-Mendelian inheritance and significantly influence fertility. We sequenced male flies with B chromosomes at 124.5-fold genome coverage using next-generation sequencing. To characterize neo-Y specific changes and B chromosome sequences, we also sequenced inbred female flies derived from the same strain but without B's at 28.5-fold. We assembled a female genome and placed 53% of the sequence and 85% of the annotated proteins into specific chromosomes, by comparison with the 12 Drosophila genomes. Despite its very recent origin, the non-recombining neo-Y chromosome shows various signs of degeneration, including a significant enrichment of non-functional genes compared to the neo-X, and an excess of tandem duplications relative to other chromosomes. We also characterized a B-chromosome linked scaffold that contains an actively transcribed unit and shows sequence similarity to the subcentromeric regions of both the ancient X and the neo-X chromosome. Our results provide novel insights into the very early stages of sex chromosome evolution and B chromosome origination, and suggest an unprecedented connection between the births of these two systems in D. albomicans.
TL;DR: A biological basis for an interaction supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population of Down syndrome and of genes associated with congenital heart disease.
Abstract: Background —About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD). However, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both Down syndrome and euploid populations for the number of genetic perturbations that can be tolerated before CHD results.
Methods and Results —We ascertained a group of individuals with DS and complete atrioventricular septal defect (AVSD) and sequenced two candidate genes for CHD, CRELD1 , which is associated with AVSD in people with or without DS, and HEY2 , whose mouse ortholog produces septal defects when mutated. Several deleterious variants were identified but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of Down syndrome. Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that although either of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together.
Conclusions —Using mouse models of Down syndrome and of genes associated with congenital heart disease we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.
TL;DR: It is observed that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthesis kinase4-β activity and it is possible that a similar mechanism may also occur in people with DS.
TL;DR: The derivation of DS-specific induced pluripotent stem cells (iPSCs) provides novel DS models that can be used to determine the DS mechanism and to devise therapeutic approaches for DS patients.
Abstract: Down syndrome (DS), a major cause of mental retardation, is caused by trisomy of some or all of human chromosome 21 and includes three basic karyotypes: trisomy 21, translocation, and mosaicism. The derivation of DS-specific induced pluripotent stem cells (iPSCs) provides us novel DS models that can be used to determine the DS mechanism and to devise therapeutic approaches for DS patients. In the present study, fibroblasts from patients with DS of various karyotypes were reprogrammed into iPSCs via the overexpression of four factors: OCT4, SOX2, KLF4, and c-MYC, by using lentiviral vectors. The abilities of the iPSC-DS in the self-renewal and pluripotency in vitro and in vivo were then examined. The iPSC-DS showed characteristics similar to those of human embryonic stem cells, particularly the morphology, surface marker (SSEA4, TRA-1-60, and TRA-1-81) expression, pluripotent-specific transcription-factor expression levels, and methylation status of the OCT4 promoter. The pluripotency of iPSC-DS was also tested in vitro and in vivo. Embryoid bodies were formed and showed the expression of differentiated markers for three germ layers. Furthermore, iPSC-DS formed classic teratomas when injected into nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. iPSCs were generated from patients with DS. The iPSCs derived from different types of DS may be used in DS modeling, patient-care optimization, drug discovery, and eventually, autologous cell-replacement therapies.
TL;DR: It is concluded that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21, and large CNVs do not appear to be an additive risk factor for AVSD in the DS population.
Abstract: Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150 kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.
TL;DR: It is hypothesize that this decoupling of genome size from chromosome number helps explain the high lability of chromosome number in the genus, as it reduces indirect selection on chromosome number.
Abstract: The effects of chromosome rearrangement on genome size are poorly understood. While chromosome duplications and deletions have predictable effects on genome size, chromosome fusion, fission, and translocation do not. In this study, we investigate genome size and chromosome number evolution in 87 species of Carex, one of the most species-rich genera of flowering plants and one that has undergone an exceptionally high rate of chromosome rearrangement. Using phylogenetic generalized least-squares regression, we find that the correlation between chromosome number and genome size in the genus grades from flat or weakly positive at fine phylogenetic scales to weakly negative at deeper phylogenetic scales. The rate of chromosome evolution exhibits a significant increase within a species-rich clade that arose approximately 5 million years ago. Genome size evolution, however, demonstrates a nearly constant rate across the entire tree. We hypothesize that this decoupling of genome size from chromosome number helps explain the high lability of chromosome number in the genus, as it reduces indirect selection on chromosome number.
TL;DR: The present review focuses on the current understanding of age‐related aneuploidy and provides an overview of the mechanisms involved, and refers to recent data to illustrate some of the new paradigms that have arisen in this field.
Abstract: Aneuploidy is one of the most common and serious pregnancy complications in humans. Most conceptuses with autosomal aneuploidy die in utero, resulting in early pregnancy loss. However, some fetuses with aneuploidy survive to term but suffer from disorders associated with congenital anomalies and mental retardation, such as Down syndrome with trisomy 21. Three general characteristics of this condition are well acknowledged: (i) in most cases the extra chromosome is of maternal origin; (ii) most cases are derived from a malsegregation event in meiosis I; and (iii) the frequency of these errors increases with maternal age. The basis for the age-dependent increase in meiosis I errors has been a long-standing enigma. Many investigators have addressed the nature of this biological phenomenon through genomic analyses of extra chromosome 21 using polymorphic markers to determine the frequency or location of crossovers that should ensure faithful chromosome segregation. Cytogenetic analyses of in vitro unfertilized oocytes have also been performed. However, no definitive conclusions regarding meiosis I errors have yet been reached from such studies. Recent findings in conditional knock-out mice for meiosis-specific cohesin have shed further light on this issue. The present review focuses on the current understanding of age-related aneuploidy and provides an overview of the mechanisms involved. We refer to recent data to illustrate some of the new paradigms that have arisen in this field.
TL;DR: Comparison of the locations of two site-specific repetitive DNA sequences on the X and Y chromosomes demonstrated that the centromere shift was the result of centROMere repositioning, not of pericentric inversion, suggesting that S. crassicollis X andY chromosomes are at an early stage of sex chromosome differentiation.
Abstract: The black marsh turtle (Siebenrockiella crassicollis) has morphologically differentiated X and Y sex chromosomes. To elucidate the origin and evolutionary process of S. crassicollis X and Y chromosomes, we performed cross-species chromosome painting with chromosome-specific DNA from Chinese soft-shelled turtle (Pelodiscus sinensis) and chromosome mapping of the sex-linked genes of S. crassicollis using FISH. The X and Y chromosomes of S. crassicollis were hybridized with DNA probe of P. sinensis chromosome 5, which is homologous to chicken chromosome 5. S. crassicollis homologues of 14 chicken chromosome 5-linked genes were all localized to the X long arm, whereas two genes were mapped to the Y short arm and the other 12 genes were localized to the Y long arm in the same order as the X chromosome. This result suggests that extensive linkage homology has been retained between chicken chromosome 5 and S. crassicollis X and Y chromosomes and that S. crassicollis X and Y chromosomes are at an early stage of sex chromosome differentiation. Comparison of the locations of two site-specific repetitive DNA sequences on the X and Y chromosomes demonstrated that the centromere shift was the result of centromere repositioning, not of pericentric inversion.
TL;DR: Characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q are examined to determine whether additional risk factors or mechanisms are suggested and to better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.
Abstract: We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.
TL;DR: Multichromosome bacteria provide opportunities to investigate how split genomes emerged, whether the individual chromosomes communicate to coordinate their replication and segregation, and what selective advantages split genomes might provide.
TL;DR: It is demonstrated that Ts65Dn mice have lost correlations seen in control mice among levels of functionally related proteins, including components of the MAP kinase pathway and subunits of the NMDA receptor.
Abstract: The Ts65Dn mouse model of Down syndrome (DS) is trisomic for orthologs of 88 of 161 classical protein coding genes present on human chromosome 21 (HSA21). Ts65Dn mice display learning and memory impairments and neuroanatomical, electrophysiological, and cellular abnormalities that are relevant to phenotypic features seen in DS; however, little is known about the molecular perturbations underlying the abnormalities. Here we have used reverse phase protein arrays to profile 64 proteins in the cortex, hippocampus, and cerebellum of Ts65Dn mice and littermate controls. Proteins were chosen to sample a variety of pathways and processes and include orthologs of HSA21 proteins and phosphorylation-dependent and -independent forms of non-HSA21 proteins. Protein profiles overall show remarkable stability to the effects of trisomy, with fewer than 30% of proteins altered in any brain region. However, phospho-proteins are less resistant to trisomy than their phospho-independent forms, and Ts65Dn display abnormalities...
TL;DR: A de novo interstitial deletion of chromosome 21q in a patient presenting with characteristic facial features, intellectual disability, and epilepsy is reported, with minimal overlapping region containing only two genes, DYRK1A and KCNJ6, which may play a major role in these patients' phenotype.
TL;DR: This work has shown that the presence of cell‐free fetal DNA in maternal plasma was discovered in 1997 and offered a new noninvasive source of fetal genetic material.
Abstract: Background
Noninvasive prenatal diagnosis of fetal Down syndrome using direct nucleic acid analysis was once an elusive goal. The presence of cell-free fetal DNA in maternal plasma was discovered in 1997 and offered a new noninvasive source of fetal genetic material.
Method
A number of approaches have since been developed for the assessment of fetal chromosome dosage based on cellfree fetal DNA analysis. The most effective approach developed to date is based on massively parallel sequencing of maternal plasma DNA molecules for the detection of an increased representation of chromosome 21 DNA molecules in the plasma of women pregnant with trisomy 21 fetuses when compared with euploid pregnancies.
Result and Conclusion
A number of multicenter studies have since been conducted to evaluate the diagnostic efficacy of the sequencing-based method. To date, the literature contains results for the analysis of a total of 305 trisomy 21 pregnancies and 2061 euploid pregnancies. The overall diagnostic sensitivity and specificity were both 99%. Besides trisomy 21, massively parallel maternal plasma DNA sequencing has also been applied to the noninvasive detection of trisomy 18, trisomy 13 and fetal genetic sequences across the genome. © 2012 John Wiley & Sons, Ltd.
TL;DR: The systematic analysis of chromosome 21 is described using an antibody-based approach for protein profiling using both confocal microscopy and immunohistochemistry, complemented with transcript profiling using next generation sequencing data.
TL;DR: Functional analysis revealed that the dysregulated genes in DS were significantly enriched in two and six KEGG pathways in N and C group, respectively, which causally implicated dysfunctional immunity in DS.
Abstract: Down syndrome (DS) is caused by triplication of Human chromosome 21 (Hsa21) and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Genome-wide expression patterns of uncultured peripheral blood cells are useful to understanding of DS-associated immune dysfunction. We used a Human Exon microarray to characterize gene expression in uncultured peripheral blood cells derived from DS individuals and age-matched controls from two age groups: neonate (N) and child (C). A total of 174 transcript clusters (gene-level) with eight located on Hsa21 in N group and 383 transcript clusters including 56 on Hsa21 in C group were significantly dysregulated in DS individuals. Microarray data were validated by quantitative polymerase chain reaction. Functional analysis revealed that the dysregulated genes in DS were significantly enriched in two and six KEGG pathways in N and C group, respectively. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of gene expression patterns in DS at the two developmental stages and pointed towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS.
TL;DR: The current knowledge about the neurobiology of this disease and future perspectives of pharmacological treatments for this condition will be discussed.
Abstract: Down syndrome is characterized by mild to moderate cognitive impairments that are caused by trisomy of chromosome 21. Several anatomical, behavioral, electrophysiological, and developmental abnormalities have been associated with Down syndrome. In this review, the current knowledge about the neurobiology of this disease and future perspectives of pharmacological treatments for this condition will be discussed.
TL;DR: Classes of repetitive DNA identified in the W chromosome suggested that the genetic degeneration of this chromosome in S. taeniurus occurred through accumulation of these repetitive DNAs.
Abstract: The possible origins and differentiation of a ZZ/ZW sex chromosome system in Semaprochilodus taeniurus, the only species of the family Prochilodontidae known to possess heteromorphic sex chromosomes, were examined by conventional (C-banding) and molecular (cross-species hybridization of W-specific WCP, Fluorescence in situ hybridization (FISH) with telomere (TTAGGG)n, and Rex1 probes) cytogenetic protocols. Several segments obtained by W-specific probe were cloned, and the sequences localized on the W chromosome were identified by DNA sequencing and search of nucleotide collections of the NCBI and GIRI using BLAST and CENSOR, respectively. Blocks of constitutive heterochromatin in chromosomes of S. taeniurus were observed in the centromere of all autosomal chromosomes and in the terminal, interstitial, and pericentromeric regions of the W chromosome, which did not demonstrate interstitial telomeric sites with FISH of the telomere probe. The Rex1 probe displayed a compartmentalized distribution pattern in some chromosomes and showed signs of invasion of the pericentromeric region in the W chromosome. Chromosomal painting with the W-specific WCP of S. taeniurus onto its own chromosomes showed complete staining of the W chromosome, centromeric sites, and the ends of the Z chromosome, as well as other autosomes. However, cross-species painting using this WCP on chromosomes of S. insignis, Prochilodus lineatus, and P. nigricans did not reveal a proto-W element, but instead demonstrated scattered positive signals of repetitive DNAs. Identification of the W-specific repetitive sequences showed high similarity to microsatellites and transposable elements. Classes of repetitive DNA identified in the W chromosome suggested that the genetic degeneration of this chromosome in S. taeniurus occurred through accumulation of these repetitive DNAs.
TL;DR: This review will highlight the main molecular and cellular findings recently described for these models of Down syndrome, particularly with respect to their relationship to Down syndrome phenotypes.
Abstract: Down syndrome is a complex disease that has challenged molecular and cellular research for more than 50 years. Understanding the molecular bases of morphological, cellular, and functional alterations resulting from the presence of an additional complete chromosome 21 would aid in targeting specific genes and pathways for rescuing some phenotypes. Recently, progress has been made by characterization of brain alterations in mouse models of Down syndrome. This review will highlight the main molecular and cellular findings recently described for these models, particularly with respect to their relationship to Down syndrome phenotypes.
TL;DR: The present findings indicate that retention of disomy for some chromosomes is pathogenetically important and that the chromosome(s) maintained in two copies is related to cell type or histological context.
Abstract: The chromosome number of human tumors varies widely, from near-haploidy to more than decaploidy. Overt hyperhaploid (24-34 chromosomes) tumors constitute a small minority (0.2-0.3% of cytogenetically investigated lesions), but occur in many different disease entities. In these karyotypes, most chromosomes are present in one copy; one or a few chromosomes are disomic. Published reports on 141 strictly hyperhaploid tumors, supplemented with nine previously unpublished cases, were used for evaluating the pattern of disomic chromosomes. Only one tumor type, acute lymphoblastic leukemia (ALL), was sufficiently common (n = 75) to allow proper evaluation; other neoplasms were lumped together in as reasonably logical groups as possible, including 10 myeloid leukemias (ML), nine plasma cell neoplasms (PCN), 13 chondrosarcomas (CS), 11 soft tissue tumors (STT), nine adeno- or squamous cell carcinomas (ASC), and eight tumors of the nervous system (TNS); the remaining 15 tumors could not be grouped. It was evident that the pattern of disomies is nonrandom. Moreover, unique signatures for each tumor group were detected. Among ALL, most disomies were independent of age and gender, except for disomy 10, which was overrepresented in females. Chromosome 21 was invariably disomic, whereas chromosome 17 was always monosomic. The most frequent disomies were two gonosomes in ML, chromosomes 7, 9, 11, 3, 18, and 19 in PCN, 7, 5, 20, 19, and 21 in CS, 20 in STT, 7 in ASC, and 1, 7, and 9 in TNS. Chromosome 1 was often partially disomic, due to unbalanced structural rearrangements, with segment 1q21-31 in common. Doubling of the hyperhaploid clone was found in at least one-third of the cases, apart from in ML where only one of 10 cases showed chromosome doubling. The present findings indicate that retention of disomy for some chromosomes is pathogenetically important and that the chromosome(s) maintained in two copies is related to cell type or histological context.
TL;DR: Results indicated that the Y chromosome of T. muenninki avoided a loss event, which occurred in an ancestral lineage ofT.
Abstract: The genus Tokudaia comprises three species, two of which have lost their Y chromosome and have an XO/XO sex chromosome constitution. Although Tokudaia muenninki (Okinawa spiny rat) retains the Y chromosome, both sex chromosomes are unusually large. We conducted a molecular cytogenetic analysis to characterize the sex chromosomes of T. muenninki. Using cross-species fluorescence in situ hybridization (Zoo-FISH), we found that both short arms of the T. muenninki sex chromosomes were painted by probes from mouse chromosomes 11 and 16. Comparative genomic hybridization analysis was unable to detect sex-specific regions in the sex chromosomes because both sex probes highlighted the large heterochromatic blocks on the Y chromosome as well as five autosomal pairs. We then performed comparative FISH mapping using 29 mouse complementary DNA (cDNA) clones of the 22 X-linked genes and the seven genes linked to mouse chromosome 11 (whose homologue had fused to the sex chromosomes), and FISH mapping using two T. muenninki cDNA clones of the Y-linked genes. This analysis revealed that the ancestral gene order on the long arm of the X chromosome and the centromeric region of the short arm of the Y chromosome were conserved. Whereas six of the mouse chromosome 11 genes were also mapped to Xp and Yp, in addition, one gene, CBX2, was also mapped to Xp, Yp, and chromosome 14 in T. muenninki. CBX2 is the candidate gene for the novel sex determination system in the two other species of Tokudaia, which lack a Y chromosome and SRY gene. Overall, these results indicated that the Y chromosome of T. muenninki avoided a loss event, which occurred in an ancestral lineage of T. osimensis and T. tokunoshimensis, through fusion with an autosome. Despite retaining the Y chromosome, sex determination in T. muenninki might not follow the usual mammalian pattern and deserves further investigation.