Showing papers on "Chromosome 21 published in 2009"

Chromosome instability is common in human cleavage-stage embryos

Abstract: Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.

The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies

Abstract: Down syndrome (DS), or trisomy 21, is a common disorder associated with several complex clinical phenotypes. Although several hypotheses have been put forward, it is unclear as to whether particular gene loci on chromosome 21 (HSA21) are sufficient to cause DS and its associated features. Here we present a high-resolution genetic map of DS phenotypes based on an analysis of 30 subjects carrying rare segmental trisomies of various regions of HSA21. By using state-of-the-art genomics technologies we mapped segmental trisomies at exon-level resolution and identified discrete regions of 1.8-16.3 Mb likely to be involved in the development of 8 DS phenotypes, 4 of which are congenital malformations, including acute megakaryocytic leukemia, transient myeloproliferative disorder, Hirschsprung disease, duodenal stenosis, imperforate anus, severe mental retardation, DS-Alzheimer Disease, and DS-specific congenital heart disease (DSCHD). Our DS-phenotypic maps located DSCHD to a <2-Mb interval. Furthermore, the map enabled us to present evidence against the necessary involvement of other loci as well as specific hypotheses that have been put forward in relation to the etiology of DS-i.e., the presence of a single DS consensus region and the sufficiency of DSCR1 and DYRK1A, or APP, in causing several severe DS phenotypes. Our study demonstrates the value of combining advanced genomics with cohorts of rare patients for studying DS, a prototype for the role of copy-number variation in complex disease.

Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1

Abstract: Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. New work from Baek et al. shows that a mouse model with an extra copy of the chromosome 21 gene Dscr1 (encoding Down syndrome critical region protein 1) exhibits decreased tumour growth due to reduced angiogenesis. They provide evidence that together with another chromosome 21 gene, Dyrk1a, a modest increase in Dscr1 expression limits angiogenesis by decreasing the activity of the calcineurin pathway. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals. Individuals with Down's syndrome are known to have a lower rate of certain solid cancers. Now, a mouse model with one extra copy of Dscr1, a gene located on chromosome 21, is shown to display decreased tumour growth; this is thought to be via suppression of angiogenesis mediated by decreasing the activity of the calcineurin pathway. The incidence of many cancer types is significantly reduced in individuals with Down’s syndrome1,2,3,4, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down’s syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway5,6,7,8,9,10. Here we show that DSCR1 is increased in Down’s syndrome tissues and in a mouse model of Down’s syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down’s syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

Abstract: Down syndrome (DS) is one of the most frequent congenital birth defects, and the most common genetic cause of mental retardation. In most cases, DS results from the presence of an extra copy of chromosome 21. DS has a complex phenotype, and a major goal of DS research is to identify genotype-phenotype correlations. Cases of partial trisomy 21 and other HSA21 rearrangements associated with DS features could identify genomic regions associated with specific phenotypes. We have developed a BAC array spanning HSA21q and used array comparative genome hybridization (aCGH) to enable high-resolution mapping of pathogenic partial aneuploidies and unbalanced translocations involving HSA21. We report the identification and mapping of 30 pathogenic chromosomal aberrations of HSA21 consisting of 19 partial trisomies and 11 partial monosomies for different segments of HSA21. The breakpoints have been mapped to within approximately 85 kb. The majority of the breakpoints (26 of 30) for the partial aneuploidies map within a 10-Mb region. Our data argue against a single DS critical region. We identify susceptibility regions for 25 phenotypes for DS and 27 regions for monosomy 21. However, most of these regions are still broad, and more cases are needed to narrow down the phenotypic maps to a reasonable number of candidate genomic elements per phenotype.

Genome comparisons reveal a dominant mechanism of chromosome number reduction in grasses and accelerated genome evolution in Triticeae

Abstract: Single-nucleotide polymorphism was used in the construction of an expressed sequence tag map of Aegilops tauschii, the diploid source of the wheat D genome. Comparisons of the map with the rice and sorghum genome sequences revealed 50 inversions and translocations; 2, 8, and 40 were assigned respectively to the rice, sorghum, and Ae. tauschii lineages, showing greatly accelerated genome evolution in the large Triticeae genomes. The reduction of the basic chromosome number from 12 to 7 in the Triticeae has taken place by a process during which an entire chromosome is inserted by its telomeres into a break in the centromeric region of another chromosome. The original centromere–telomere polarity of the chromosome arms is maintained in the new chromosome. An intrachromosomal telomere–telomere fusion resulting in a pericentric translocation of a chromosome segment or an entire arm accompanied or preceded the chromosome insertion in some instances. Insertional dysploidy has been recorded in three grass subfamilies and appears to be the dominant mechanism of basic chromosome number reduction in grasses. A total of 64% and 66% of Ae. tauschii genes were syntenic with sorghum and rice genes, respectively. Synteny was reduced in the vicinity of the termini of modern Ae. tauschii chromosomes but not in the vicinity of the ancient termini embedded in the Ae. tauschii chromosomes, suggesting that the dependence of synteny erosion on gene location along the centromere–telomere axis either evolved recently in the Triticeae phylogenetic lineage or its evolution was recently accelerated.

Function and regulation of Dyrk1A: towards understanding Down syndrome

Abstract: Down syndrome (DS) is associated with a variety of symptoms, such as incapacitating mental retardation and neurodegeneration (i.e., Alzheimer’s disease), that prevent patients from leading fully independent lives. These phenotypes are a direct consequence of the overexpression of chromosome 21 genes, which are present in duplicate due to non-disjunction of chromosome 21. Accumulating data suggest that the chromosome 21 gene product, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1A), participates in the pathogenic mechanisms underlying the mental and other physical symptoms of DS. In this review, we summarize the evidence supporting a role for Dyrk1A in DS, especially DS pathogenesis. Recently, several natural and synthetic compounds have been identified as Dyrk1A inhibitors. Understanding the function and regulation of Dyrk1A may lead to the development of novel therapeutic agents aimed at treating DS.

Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects

Abstract: We examined the association between maternal age and chromosome 21 nondisjunction by origin of the meiotic error. We analyzed data from two population-based, case–control studies: Atlanta Down Syndrome Project (1989–1999) and National Down Syndrome Project (2001–2004). Cases were live born infants with trisomy 21 and controls were infants without trisomy 21 delivered in the same geographical regions. We enrolled 1,215 of 1,881 eligible case families and 1,375 of 2,293 controls. We report four primary findings. First, the significant association between advanced maternal age and chromosome 21 nondisjunction was restricted to meiotic errors in the egg; the association was not observed in sperm or in post-zygotic mitotic errors. Second, advanced maternal age was significantly associated with both meiosis I (MI) and meiosis II (MII). For example, compared to mothers of controls, mothers of infants with trisomy 21 due to MI nondisjunction were 8.5 times more likely to be ≥40 years old than 20–24 years old at the birth of the index case (95% CI = 5.6–12.9). Where nondisjunction occurred in MII, mothers were 15.1 times more likely to be ≥40 years (95% CI = 8.4–27.3). Third, the ratio of MI to MII errors differed by maternal age. The ratio was lower among women <19 years of age and those ≥40 years (2.1, 2.3, respectively) and higher in the middle age group (3.6). Lastly, we found no effect of grand-maternal age on the risk for maternal nondisjunction. This study emphasizes the complex association between advanced maternal age and nondisjunction of chromosome 21 during oogenesis.

The role of repetitive DNA in structure and evolution of sex chromosomes in plants

Abstract: Eukaryotic genomes contain a large proportion of repetitive DNA sequences, mostly transposable elements (TEs) and tandem repeats. These repetitive sequences often colonize specific chromosomal (Y or W chromosomes, B chromosomes) or subchromosomal (telomeres, centromeres) niches. Sex chromosomes, especially non-recombining regions of the Y chromosome, are subject to different evolutionary forces compared with autosomes. In non-recombining regions of the Y chromosome repetitive DNA sequences are accumulated, representing a dominant and early process forming the Y chromosome, probably before genes start to degenerate. Here we review the occurrence and role of repetitive DNA in Y chromosome evolution in various species with a focus on dioecious plants. We also discuss the potential link between recombination and transposition in shaping genomes.

A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome

Abstract: Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory.

Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations

Abstract: Down syndrome caused by meiotic nondisjunction of chromosome 21 in humans, is well known to be associated with advanced maternal age, but success in identifying and understanding other risk factors has been limited. Recently published work in a U.S. population suggested intriguing interactions between the maternal age effect and altered recombination patterns during meiosis, but some of the results were counter-intuitive. We have tested these hypotheses in a population sample from India, and found that essentially all of the results of the U.S. study are replicated even in our ethnically very different population. We examined meiotic recombination patterns in a total of 138 families from the eastern part of India, each with a single free trisomy 21 child. We genotyped each family with a set of STR markers using PCR and characterized the stage of origin of nondisjunction and the recombination pattern of maternal chromosome 21 during oogenesis. Our sample contains 107 maternal meiosis I errors and 31 maternal meiosis II errors and we subsequently stratified them with respect to maternal age and the number of detectable crossover events. We observed an association between meiosis I nondisjuncion and recombination in the telomeric 5.1 Mb of chromosome 21. By contrast, in meiosis II cases we observed preferential peri-centromeric exchanges covering the proximal 5.7 Mb region, with interaction between maternal age and the location of the crossover. Overall reduction of recombination irrespective of maternal age is also evident in meiosis I cases. Our findings are very consistent with previously reported data in a U.S. population and our results are the first independent confirmation of those previous reports. This not only provides much needed confirmation of previous results, but it suggests that the genetic etiology underlying the occurrence of trisomy 21 may be similar across human populations.

Classification of genes, rearrangements and chromosomes according to the chromosome field

Abstract: The study of over 700 species, from algae to humans, reveals that specific DNA sequences, have an optimal territory within the centromere-telomere field. These DNA sequences have maintained their territory within the chromosome field for millions of years irrespective of variation in arm length, of change in chromosome type and of species evolution. Some of these DNA sequences have been isolated biochemically or analysed at the molecular level. They include, e.g., the proximal heterochromatic segments, the genes for ribosomal RNA, and the telomeric heterochromatin. Order prevails in the eukaryotic chromosome. This order allows classification of genes, rearrangements and chromosomes on a genetic basis. Genes are classified as centrons, medons and telons. Rearrangements are classified as: conservative, discordant, disruptive, destructive and incompatible. Chromosomes are also classified depending on their length, arm size and number. These chromosome properties and features now acquire an organizatory meaning which they lacked previously. The available molecular information supports the evidence from the field. The study of the split gene reveals that it is the relative position of the DNA sequences which determines their function. On the basis of the chromosome field, predictions can be made concerning gene organization, gene function and chromosome evolution.

The complex relationship between folate/homocysteine metabolism and risk of Down syndrome

Abstract: Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. A deficiency in cellular folates results in aberrant DNA methylation, point mutations, chromosome breakage, defective chromosome recombination and aneuploidy. In 1999 it was first reported that impairments in folate/homocysteine metabolism, due to genetic polymorphisms of metabolic enzymes, could increase the risk for having an infant with Down syndrome (DS). That paper stimulated considerable investigation into the possible role of folate/homocysteine metabolism in the risk of having a DS child and several studies have been performed so far in different countries to better address this issue. However, despite 10 years of active research, the question is still unsolved. Overall, both in vitro and in vivo studies indicate that an impaired folate/homocysteine metabolism can result in chromosome 21 nondisjunction; however, the birth of a DS child seems to be the result of the interplay of several factors of genetic, epigenetic, environmental, and stochastic origin, making it difficult to discriminate the single contribution of each of them. My opinion is that it is now time for the design of a collaborative study large enough to have the power to separate trisomy 21 into all its component parts and to test for the contribution of folate/homocysteine gene polymorphisms to each of them. This study should be paralleled by in vitro and in vivo studies aimed at clarifying the contribution, if any, of folate/homocysteine metabolism to the methylation pattern of regions involved in recombination and segregation of chromosome 21. Further studies are also required to address the possible contribution of both the paternal diet and the maternal grandmother dietary habits to chromosome 21 nondisjunction events.

Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks.

Abstract: Pediatric acute lymphoblastic leukemia (ALL) comprises genetically distinct subtypes. However, 25% of cases still lack defined genetic hallmarks. To identify genomic aberrancies in childhood ALL patients nonclassifiable by conventional methods, we performed a single nucleotide polymorphisms (SNP) array-based genomic analysis of leukemic cells from 29 cases. The vast majority of cases analyzed (19/24, 79%) showed genomic abnormalities; at least one of them affected either genes involved in cell cycle regulation or in B-cell development. The most relevant abnormalities were CDKN2A/9p21 deletions (7/24, 29%), ETV6 (TEL)/12p13 deletions (3/24, 12%), and intrachromosomal amplifications of chromosome 21 (iAMP21) (3/24, 12%). To identify variation in expression of genes directly or indirectly affected by recurrent genomic alterations, we integrated genomic and gene expression data generated by microarray analyses of the same samples. SMAD1 emerged as a down-regulated gene in CDKN2A homozygous deleted cases compared with nondeleted. The JAG1 gene, encoding the Jagged 1 ligand of the Notch receptor, was among a list of differentially expressed (up-regulated) genes in ETV6-deleted cases. Our findings demonstrate that integration of genomic analysis and gene expression profiling can identify genetic lesions undetected by routine methods and potential novel pathways involved in B-progenitor ALL pathogenesis. © 2008 Wiley-Liss, Inc.

Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

Abstract: At the neuronal level of Down syndrome (DS) brains, there are evidences of altered shape, number, and density of synapses, as well as aberrant endocytosis associated with accumulation of enlarged endosomes, suggesting that proteins involved in synaptic vesicle recycling may play key roles in DS neurons. However, the exact mechanism underlying those anomalies is not well understood. We hypothesize that overexpression of three genes, dap160/itsn1, synj/synj1, and nla/dscr1, located on human chromosome 21 play important roles in DS neurons. Here, we systematically investigate the effects of multiple gene overexpression on synaptic morphology and endocytosis to identify possible dominant gene or genes. We found that overexpression of individual genes lead to abnormal synaptic morphology, but all three genes are necessary to cause impaired vesicle recycling and affect locomotor vigor. Furthermore, we report that dap160 overexpression alters the subcellular distribution of synaptojanin, and overexpression of nla regulates the phosphoinositol 5′ phosphatase activity of synaptojanin. These findings imply that restoring the level of any one of these genes may reduce endocytic defects seen in DS.

Remarkably Little Variation in Proteins Encoded by the Y Chromosome's Single-Copy Genes, Implying Effective Purifying Selection

Abstract: Y-linked single-nucleotide polymorphisms (SNPs) have served as powerful tools for reconstructing the worldwide genealogy of human Y chromosomes and for illuminating patrilineal relationships among modern human populations. However, there has been no systematic, worldwide survey of sequence variation within the protein-coding genes of the Y chromosome. Here we report and analyze coding sequence variation among the 16 single-copy "X-degenerate" genes of the Y chromosome. We examined variation in these genes in 105 men representing worldwide diversity, resequencing in each man an average of 27 kb of coding DNA, 40 kb of intronic DNA, and, for comparison, 15 kb of DNA in single-copy Y-chromosomal pseudogenes. There is remarkably little variation in X-degenerate protein sequences: two chromosomes drawn at random differ on average by a single amino acid, with half of these differences arising from a single, conservative Asp-->Glu mutation that occurred approximately 50,000 years ago. Further analysis showed that nucleotide diversity and the proportion of variant sites are significantly lower for nonsynonymous sites than for synonymous sites, introns, or pseudogenes. These differences imply that natural selection has operated effectively in preserving the amino acid sequences of the Y chromosome's X-degenerate proteins during the last approximately 100,000 years of human history. Thus our findings are at odds with prominent accounts of the human Y chromosome's imminent demise.

Interaction Between a Chromosome 10 RET Enhancer and Chromosome 21 in the Down Syndrome-Hirschsprung Disease Association

Abstract: Individuals with Down syndrome (DS) display a 40-fold greater risk of Hirschsprung disease (HSCR) than the general population of newborns implicating chromosome 21 in HSCR etiology. Here we demonstrate that the RET enhancer polymorphism RET+9.7 (rs2435357:C>T) at chromosome 10q11.2 is associated with HSCR in DS individuals both by transmission disequilibrium (P=0.0015) and case-control (P=0.0115) analysis of matched cases. Interestingly, the RET+9.7 T allele frequency is significantly different between individuals with DS alone (0.26+/-0.04), HSCR alone (0.61+/-0.04), and those with HSCR and DS (0.41+/-0.04), demonstrating an association and interaction between RET and chromosome 21 gene dosage. This is the first report of a genetic interaction between a common functional variant (rs2435357) and a not infrequent copy number error (chromosome 21 dosage) in two human developmental disorders.

Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development.

Abstract: Background Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them. The impact of this gene dosage effect on the whole transcriptome is still debated and longitudinal studies assessing the variability among samples, tissues and developmental stages are needed.

Dicentric human X chromosomes

Abstract: Cytological findings in 5 individuals with structurally abnormal X chromosomes are presented. Of 4 patients with an i(Xq) chromosome, 2 had an apparently dicentric, and 2 an apparently monocentric isochromosome. The former type of chromosome had twice as much centric heterochromatin (2 distinct C-bands) as the latter. In the apparently dicentric isochromosomes, it could not be determined whether one or both centromeres were functional. These findings confirm our previously presented hypothesis that transverse breakage of the X chromosome in the centromere region leading to isochromosome formation may occur at more than one site. A 60-year-old female, 154 cm in height, with primary amenorrhoea and no other signs of Turner's syndrome, had 46 chromosomes, including a normal X and a giant chromosome composed of two X chromosomes joined end to end by their short arms. By conventional staining this chromosome had 1 centromere, but C-banding revealed centric heterochromatin both in the centromere and at the site where the centromere of the second component chromosome should have occurred. It is inferred that centric heterochromatin can occur elsewhere than at the centromere and is not necessarily associated with kinetochore function.

Chromosome homologies of the highly rearranged karyotypes of four Akodon species (Rodentia, Cricetidae) resolved by reciprocal chromosome painting: the evolution of the lowest diploid number in rodents

Abstract: Traditionally comparative cytogenetic studies are based mainly on banding patterns. Nevertheless, when dealing with species with highly rearranged genomes, as in Akodon species, or with other highly divergent species, cytogenetic comparisons of banding patterns prove inadequate. Hence, comparative chromosome painting has become the method of choice for genome comparisons at the cytogenetic level since it allows complete chromosome probes of a species to be hybridized in situ onto chromosomes of other species, detecting homologous genomic regions between them. In the present study, we have explored the highly rearranged complements of the Akodon species using reciprocal chromosome painting through species-specific chromosome probes obtained by chromosome sorting. The results revealed complete homology among the complements of Akodon sp. n. (ASP), 2n = 10; Akodon cursor (ACU), 2n = 15; Akodon montensis (AMO), 2n = 24; and Akodon paranaensis (APA), 2n = 44, and extensive chromosome rearrangements have been detected within the species with high precision. Robertsonian and tandem rearrangements, pericentric inversions and/or centromere repositioning, paracentric inversion, translocations, insertions, and breakpoints, where chromosomal rearrangements, seen to be favorable, were observed. Chromosome painting using the APA set of 21 autosomes plus X and Y revealed eight syntenic segments that are shared with A. montensis, A. cursor, and ASP, and one syntenic segment shared by A. montensis and A. cursor plus five exclusive chromosome associations for A. cursor and six for ASP chromosome X, except for the heterochromatin region of ASP X, and even chromosome Y shared complete homology among the species. These data indicate that all those closely related species have experienced a recent extensive process of autosomal rearrangement in which, except for ASP, there is still complete conservation of sex chromosomes homologies.

Microdissection and chromosome painting of X and B chromosomes in Locusta migratoria.

Abstract: Acquisition of knowledge of the nature and DNA content of B chromosomes has been triggered by a collection of molecular techniques, one of which, microdissection, has provided interesting results in a number of B chromosome systems. Here we provide the first data on the molecular composition of B chromosomes in Locusta migratoria, after microdissection of the B and X chromosomes, DNA amplification by one (B) or two (X) different methods, and chromosome painting. The results showed that B chromosomes share at least two types of repetitive DNA sequences with the A chromosomes, suggesting that Bs in this species most likely arose intraspecifically. One of these repetitive DNAs is located on the heterochromatic distal half of the B chromosome and in the pericentromeric regions of about half of the A chromosomes, including the X. The other type of repetitive DNA is located interspersedly over the non-centromeric euchromatic regions of all A chromosomes and in an interstitial part of the proximal euchromatic half of the B chromosome. Chromosome painting, however, did not provide results sufficiently reliable to determine, in this species, which A chromosome gave rise to the B; this might be done by detailed analysis of the microdissected DNA sequences

Proliferation deficits and gene expression dysregulation in Down's syndrome (Ts1Cje) neural progenitor cells cultured from neurospheres

Abstract: Down's syndrome neurophenotypes are characterized by mental retardation and a decreased brain volume. To identify whether deficits in proliferation could be responsible for this phenotype, neural progenitor cells were isolated from the developing E14 neocortex of Down's syndrome partial trisomy Ts1Cje mice and euploid (WT) littermates and grown as neurospheres. Ts1Cje neural progenitors proliferated at a slower rate, because of a longer cell cycle, and a greater number of cells were positive for glial fibrillary acidic protein. An increase in cell death was also noted. Gene expression profiles of neural progenitor cells from Ts1Cje and WT showed that 54% of triploid genes had expression ratios (Ts1Cje/WT) significantly greater than the expected diploid gene ratio of 1.0. Some diploid genes associated with proliferation, differentiation, and glial function were dysregulated. Interestingly, proliferation and gene expression dysregulation detected in the Ts1Cje mice did not require overexpression of the chromosome 21 genes amyloid precursor protein (App) and soluble superoxide dismutase 1 (Sod1).

Monosomy for the X chromosome

Abstract: Dosage compensation serves to equalize X chromosome gene expression in mammalian males and females and involves extensive silencing of the 2nd X chromosome in females. If dosage compensation mechanisms completely suppressed the 2nd X chromosome, then actual physical loss of this “eXtra” chromosome should have few consequences. However, X monosomy has major effects upon normal development, fertility and longevity in humans and some other species. This article reviews observations and arguments attempting to explain the phenotypic effects of X monosomy in humans and other mammals in terms of X chromosome gene dosage.

MTHFR Gene variants C677T, A1298C and association with Down syndrome: A case-control study from South India

Abstract: Background: The 5,10-methylenetetrahydrofolate reductase ( MTHFR ) polymorphisms and low folate levels are associated with inhibition of DNA methyltransferase and consequently DNA hypomethylation. The expanding spectrum of common conditions linked with MTHFR polymorphisms includes certain adverse birth outcome, pregnancy complications, cancers, adult cardiovascular diseases and psychiatric disorders, with several of these associations remaining still controversial. Trisomy 21 or Down syndrome (DS) is the most common genetic cause of mental retardation. It stems predominantly from the failure of chromosome 21 to segregate normally during meiosis. Despite substantial research, the molecular mechanisms underlying non-disjunction leading to trisomy 21 are poorly understood. Materials and Methods: Two common variants C677T and A1298C of the MTHFR gene were screened in 36 parents with DS children and 60 healthy couples from Tamil Nadu and Karnataka. The MTHFR genotypes were studied by RFLP analysis of PCR-amplified products and confirmed by sequencing. Results: The CT genotype was seen in three each (8.3%) of case mothers and fathers. One case father showed TT genotype. All the control individuals exhibited the wild type CC genotype. A similar frequency for the uncommon allele C of the second polymorphism was recorded in case mothers (0.35) and fathers (0.37) in comparison with the control mothers (0.39) and fathers (0.37). Conclusion: This first report on MTHFR C677T and A1298C polymorphisms in trisomy 21 parents from south Indian population revealed that MTHFR 677CT polymorphism was associated with a risk for Down syndrome.

Evolutionary descent of a human chromosome 6 neocentromere: a jump back to 17 million years ago.

Abstract: Molecular cytogenetics provides a visual, pictorial record of the tree of life, and in this respect the fusion origin of human chromosome 2 is a well-known paradigmatic example. Here we report on a variant chromosome 6 in which the centromere jumped to 6p22.1. ChIP-chip experiments with antibodies against the centromeric proteins CENP-A and CENPC exactly defined the neocentromere as lying at chr6:26,407–26,491 kb. We investigated in detail the evolutionary history of chromosome 6 in primates and found that the primate ancestor had a homologous chromosome with the same marker order, but with the centromere located at 6p22.1. Sometime between 17 and 23 million years ago (Mya), in the common ancestor of humans and apes, the centromere of chromosome 6 moved from 6p22.1 to its current location. The neocentromere we discovered, consequently, has jumped back to the ancestral position, where a latent centromereforming potentiality persisted for at least 17 Myr. Because all living organisms form a tree of life, as first conceived by Darwin, evolutionary perspectives can provide compelling underlying explicative grounds for contemporary genomic phenomena.