Down syndrome blog

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

2009-07-29T17:23:00.001+02:00

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. "

(Via PNAS - RSS feed of Early Edition articles.)

ERG Is a Megakaryocytic Oncogene

2009-06-24T16:18:00.001+02:00

Original article:

Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis. [Cancer Res 2009;69(11):4665-73]

(Via Cancer Research recent issues.)

[Medical_Sciences] Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

2009-06-24T16:12:00.001+02:00

Original article:

To characterize the differences between second trimester Down syndrome (DS) and euploid fetuses, we used Affymetrix microarrays to compare gene expression in uncultured amniotic fluid supernatant samples. Functional pathway analysis highlighted the importance of oxidative stress, ion transport, and G protein signaling in the DS fetuses. Further evidence supporting these results was derived by correlating the observed gene expression patterns to those of small molecule drugs via the Connectivity Map. Our results suggest that there are secondary adverse consequences of DS evident in the second trimester, leading to testable hypotheses about possible antenatal therapy for DS.

(Via PNAS - RSS feed of Early Edition articles.)

Inverted duplications on acentric markers: mechanism of formation

2009-06-24T14:58:00.001+02:00

Original article:

Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found in patients both with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (three trisomic, six tetrasomic, two polysomic and one X chromosome derived marker) using a combination of fluorescence in situ hybridization, quantitative SNP array and microsatellite analysis. Inv dup markers were found to form either symmetrically with one breakpoint or asymmetrically with two distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. On the basis of the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: following a double-strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker’s survival during cell division and its presence in all cells.

(Via Human Molecular Genetics - recent issues.)

Statistical model for whole genome sequencing and its application to minimally invasive diagnosis of fetal genetic disease

2009-06-24T14:49:00.001+02:00

Original article:

There is currently great interest in the development of methods for the minimally invasive diagnosis of fetal genetic disease using cell-free DNA from maternal plasma samples obtained in the first trimester of pregnancy. With the rapid development of high-throughput sequencing technology, the possibility of detecting the presence of trisomy fetal genomes in the maternal plasma DNA sample has recently been explored. The major concern of this whole genome sequencing approach is that, while detecting the karyotype of the fetal genome from the maternal plasma requires extremely high accuracy of copy number estimation, the majority of the available high-throughput sequencing technologies require polymerase chain reaction (PCR) and are subject to the substantial bias that is inherent to the PCR process. We introduce a novel and sophisticated statistical model for the whole genome sequencing data, and based on this model, develop a highly sensitive method of Minimally Invasive Karyotyping (MINK) for the diagnosis of the fetal genetic disease. Specifically we demonstrate, by applying our statistical method to ultra high-throughput whole sequencing data, that trisomy 21 can be detected in a minor (‘fetal’) genome when it is mixed into a major (‘maternal’) background genome at frequencies as low as 5%. This observation provides additional proof of concept and justification for the further development of this method towards its eventual clinical application. Here, we describe the statistical and experimental methods that illustrate this approach and discuss future directions for technical development and potential clinical applications.

Contact: dgp6@pitt.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

(Via Bioinformatics - current issue.)

DNA Methylation Analysis of Chromosome 21 Gene Promoters at Single Base Pair and Single Allele Resolution

2009-06-24T14:42:00.001+02:00

Original article:

Epigenetics is defined as the inheritance of changes in gene function without changing the DNA sequence. Epigenetic signals comprise methylation of cytosine bases of the DNA and chemical modifications of the histone proteins. DNA methylation plays important roles in development and disease processes. To investigate the biological role of DNA methylation, we analyzed DNA methylation patterns of 190 gene promoter regions on chromosome 21 in five human cell types. Our results show that average DNA methylation levels are distributed bimodally with enrichment of highly methylated and unmethylated sequences, indicating that DNA methylation acts in a switch-like manner. Consistent with the well-established role of DNA methylation in gene silencing, we found DNA methylation in promoter regions strongly correlated with absence of gene expression and low levels of additional activating epigenetic marks. Although methylation levels of individual cells in one tissue are very similar, we observed differences in DNA methylation when comparing different cell types in 43% of all regions analyzed. This finding is in agreement with a role of DNA methylation in cellular development. We identified three cases of genes that are differentially methylated in both alleles that illustrate the tight interplay of genetic and epigenetic processes.

(Via PLoS Genetics: Archived Table of Contents.)

Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

2009-03-20T16:50:00.001+01:00

Original article:

Children with Down syndrome (DS) show a spectrum of clinical anomalies, including cognitive impairment, cardiac malformations, and craniofacial dysmorphy. Moreover, hematologists have also noted that these children commonly show macrocytosis, abnormal platelet counts, and an increased incidence of transient myeloproliferative disease (TMD), acute megakaryocytic leukemia (AMKL), and acute lymphoid leukemia (ALL).

In this review, we summarize the clinical manifestations and characteristics of these leukemias, provide an update on therapeutic strategies and patient outcomes, and discuss the most recent advances in DS-leukemia research. With the increased knowledge of the way in which trisomy 21 affects hematopoiesis and the specific genetic mutations that are found in DS-associated leukemias, we are well on our way toward designing improved strategies for treating both myeloid and lymphoid malignancies in this high-risk population.

(Via Blood recent issues.)

Down syndrome--recent progress and future prospects

2009-03-20T16:46:00.001+01:00

Original article:

Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer's disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge.

Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the use of chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype-phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.

(Via Human Molecular Genetics - current issue.)

Regulation of APC/C Activity in Oocytes by a Bub1-Dependent Spindle Assembly Checkpoint

2009-03-13T19:09:00.001+01:00

Original article

Barry E. McGuinness, Martin Anger, Anna Kouznetsova, Ana M. Gil-Bernabé, Wolfgang Helmhart, Nobuaki R. Kudo, Annelie Wuensche, Stephen Taylor, Christer Hoog, Bela Novak, Kim Nasmyth.

Summary

Missegregation of chromosomes during meiosis in human females causes aneuploidy, including trisomy 21, and is thought also to be the major cause of age-related infertility [1]. Most errors are thought to occur at the first meiotic division. The high frequency of errors raises questions as to whether the surveillance mechanism known as the spindle assembly checkpoint (SAC) that controls the anaphase-promoting complex or cyclosome (APC/C) operates effectively in oocytes.

Experimental approaches hitherto used to inactivate the SAC in oocytes suffer from a number of drawbacks.Bub1 protein was depleted specifically in oocytes with a Zp3-Cre transgene to delete exons 7 and 8 from a floxed BUB1F allele. Loss of Bub1 greatly accelerates resolution ofchiasmata and extrusion of polar bodies. It also causes defective biorientation of bivalents, massive chromosome missegregation at meiosis I, and precocious loss of cohesion between sister centromeres.

By using a quantitative assay forAPC/C-mediated securin destruction, we show that the APC/C is activated in an exponential fashion, with activity peaking 1213 hr after GVBD, and that this process is advanced by 5hr in oocytes lacking Bub1. Importantly, premature chiasmata resolution does not occur in Bub1-deficient oocytes also lacking either the APC/C's Apc2 subunit or separase.

Finally, we show that Bub1's kinase domain is not required to delay APC/C activation.We conclude that far from being absent or ineffective, the SAC largely determines the timing of APC/C and hence separase activation in oocytes, delaying it for about 5 hr.

(Via Current Biology.)

Current use of medical eponyms - a need for global uniformity in scientific publications

2009-03-13T19:04:00.001+01:00

Original article

Background:

Although eponyms are widely used in medicine, they arbitrarily alternate between the possessive and nonpossessive forms. As very little is known regarding extent and distribution of this variation, the present study was planned to assess current use of eponymous term taking 'Down syndrome' and 'Down's syndrome' as an example.

Methods:

This study was carried out in two phases - first phase in 1998 and second phase in 2008. In the first phase, we manually searched the terms 'Down syndrome' and 'Down's syndrome' in the indexes 70 medical books, and 46 medical journals. In second phase, we performed PubMed search with both the terms, followed by text-word search for the same.

Results:

In the first phase, there was an overall tilt towards possessive form - 62(53.4%) 'Down's syndrome' versus 54(46.6%) 'Down syndrome.' However, the American publications preferred the nonpossesive form when compared with their European counterpart (40/50 versus 14/66; P<0.001). In the second phase, PubMed search showed, compared to "Down syndrome," term "Down's syndrome" yielded approximately 5% more articles. The text-word search of both forms between January 1970 and June 2008 showed a gradual shift from "Down's syndrome" to "Down syndrome," and over the last 20 years, the frequency of the former was approximately halved (33.7% versus 16.5%; P<0.001). The abstracts having possessive form were mostly published from the European countries, while most American publications used nonpossesive form consistently.

Conclusions:

Inconsistency in the use of medical eponyms remains a major problem in literature search. Because of linguistic simplicity and technical advantages, the nonpossessive form should be used uniformly worldwide."

(Via BioMed Central - Latest articles.)

Heterochromatic Threads Connect Oscillating Chromosomes during Prometaphase I in Drosophila Oocytes

2009-03-04T16:04:00.001+01:00

Link to original article:

Proper chromosome segregation is essential during the production of eggs and sperm. Chromosome missegregation during meiosis results in the lethality of the offspring or in children carrying extra copies of a given chromosome (for example, Down syndrome). Recombination results in homologous chromosomes becoming physically interlocked in a manner that is normally sufficient to ensure proper segregation. Chromosomes that fail to undergo recombination require additional mechanisms to ensure their proper segregation.

In Drosophila melanogaster oocytes we show that chromosomes that fail to recombine undergo dynamic movements on the meiotic spindle prior to their proper segregation. Although previous studies had shown that non-recombinant chromosomes move to opposite sides of the developing meiotic spindle, we show that these chromosomes can cross the spindle and re-associate with their homologs to attempt reorientation.

Additionally, we observed threads connecting separated non-recombinant chromosomes that contained heterochromatic DNA and passenger complex proteins. These threads could assist the non-recombinant chromosomes in locating their homologs during their dynamic movements on the spindle. These chromosome movements and the heterochromatic threads are likely part of the mechanism ensuring proper segregation of nonexchange chromosomes.

[Reviews] Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes

2009-03-04T15:54:00.001+01:00

Link to original article:

Cadherins and the immunoglobulin (Ig) proteins give rise to a multitude of surface receptors, which function as diverse cell adhesion molecules (CAMs) or signal-transducing receptors. These functions are often interdependent, and rely on a high degree of specificity in homophilic binding as well as heterophilic interactions. The Drosophila receptor Dscam is an exceptional example of homophilic binding specificity involved in a number of important biological processes, such as neural wiring and innate immunity.

Combinatorial use of alternatively spliced Ig-domains enables the generation of an estimated 18,000 isoform-specific homophilic receptor pairs. Although isoform diversity of Dscam is unique to arthropods, recent genetic analysis of vertebrate DSCAM (Down Syndrome Cell Adhesion Molecule) genes has revealed an intriguing conservation of molecular functions underlying neural wiring.

This review covers the multiple functions of Dscam across different species highlighting its remarkable versatility as well as its conserved basic functions in neural development. We discuss how an unprecedented expansion of complex alternative splicing has been uniquely employed by arthropods to generate diverse surface receptors, important for cell-cell communication, molecular self-recognition in neurons, and innate immune defenses. We end with a speculative hypothesis reconciling the striking differences in Dscam and DSCAM gene structures with their conserved functions in molecular recognition underlying neural circuit formation.

(Via Genes & Development current issue.)

Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice

2009-03-04T15:48:00.001+01:00

Down syndrome blog

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

ERG Is a Megakaryocytic Oncogene

[Medical_Sciences] Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses

Inverted duplications on acentric markers: mechanism of formation

Statistical model for whole genome sequencing and its application to minimally invasive diagnosis of fetal genetic disease

DNA Methylation Analysis of Chromosome 21 Gene Promoters at Single Base Pair and Single Allele Resolution

Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome

Down syndrome--recent progress and future prospects

Regulation of APC/C Activity in Oocytes by a Bub1-Dependent Spindle Assembly Checkpoint

Current use of medical eponyms - a need for global uniformity in scientific publications

Heterochromatic Threads Connect Oscillating Chromosomes during Prometaphase I in Drosophila Oocytes

[Reviews] Dscam and DSCAM: complex genes in simple animals, complex animals yet simple genes

Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice

[Neuroscience] DSCAM functions as a netrin receptor in commissural axon pathfinding

CleaveLand: a pipeline for using degradome data to find cleaved small RNA targets

Conservation and implications of eukaryote transcriptional regulatory regions across multiple species

MicroRNA target prediction by expression analysis of host genes

Thermodynamic stability and Watson-Crick base pairing in the seed duplex are major determinants of the efficiency of the siRNA-based off-target effect

Protein kinase C epsilon is important for migration of neuroblastoma cells

Genome-Wide siRNA-Based Functional Genomics of Pigmentation Identifies Novel Genes and Pathways That Impact Melanogenesis in Human Cells

Modular control of endothelial sheet migration

Most mammalian mRNAs are conserved targets of microRNAs

Regulation of neural macroRNAs by the transcriptional repressor REST

Position dependent mismatch discrimination on DNA microarrays - experiments and model

MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts

High-throughput stem-loop RT-qPCR miRNA expression profiling using minute amounts of input RNA

Annotation of Mammalian Primary microRNAs

Human multipotent stromal cells from bone marrow and microRNA: Regulation of differentiation and leukemia inhibitory factor expression

[ARTICLE] Deadenylation is a widespread effect of miRNA regulation

[Research Papers] Chromatin structure analyses identify miRNA promoters

Epstein-Barr virus latent membrane protein 1 trans-activates miR-155 transcription through the NF-{kappa}B pathway

Analysis of regulatory network topology reveals functionally distinct classes of microRNAs

A role for the Dicer helicase domain in the processing of thermodynamically unstable hairpin RNAs

Posttranscriptional Regulation of miRNAs Harboring Conserved Terminal Loops

Embryonic stem cell–specific microRNAs regulate the G1-S transition and promote rapid proliferation

11p Microdeletion including WT1 but not PAX6, presenting with cataract, mental retardation, genital abnormalities and seizures: case report

Sall2 is a novel p75NTR-interacting protein that links NGF signalling to cell cycle progression and neurite outgrowth

Genomic copy number determination in cancer cells from SNP microarrays based on quantitative genotyping corrected for aneuploidy

Chromosomal instability mediated by non-B DNA: Cruciform conformation and not DNA sequence is responsible for recurrent translocation in humans

Over half of breakpoints in gene pairs involved in cancer-specific recurrent translocations are mapped to human chromosomal fragile sites

Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis ...

Unbalanced chromosome 1 abnormalities in four infants with Down syndrome and acute megakaryocytic leukemia