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Showing papers on "Chromosome 21 published in 2008"


Journal ArticleDOI
TL;DR: Analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte, and emphasizes the fact that human nondisJunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors.
Abstract: Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors.

170 citations


Journal ArticleDOI
03 Jan 2008-Nature
TL;DR: Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.
Abstract: Epidemiological studies spanning more than 50 yr reach conflicting conclusions as to whether there is a lower incidence of solid tumours in people with trisomy 21 (Down's syndrome). We used mouse models of Down's syndrome and of cancer in a biological approach to investigate the relationship between trisomy and the incidence of intestinal tumours. Apc(Min)-mediated tumour number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Trisomy for orthologues of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumours. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumours. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumour number. The action of Ets2 as a repressor when it is overexpressed differs from tumour suppression, which requires normal gene function to prevent cellular transformation. Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.

155 citations


Journal ArticleDOI
TL;DR: It is hypothesized that trisomic 21 gene dosage overexpression of Hsa21-derived miRNAs results in the decreased expression of specific target proteins and contribute, in part, to features of the neuronal and cardiac DS phenotype.

152 citations


Journal ArticleDOI
TL;DR: Twenty-two of the 114 studied CGIs on chromosome 21 showed epigenetic differences between samples of placenta and maternal blood cells; these CGIs may provide a rich source of markers for noninvasive prenatal diagnosis.
Abstract: Background: The presence of fetal DNA in maternal plasma represents a source of fetal genetic material for noninvasive prenatal diagnosis; however, the coexisting background maternal DNA complicates the analysis of aneuploidy in such fetal DNA. Recently, the SERPINB5 gene on chromosome 18 was shown to exhibit different DNA-methylation patterns in the placenta and maternal blood cells, and the allelic ratio for placenta-derived hypomethylated SERPINB5 in maternal plasma was further shown to be useful for noninvasive detection of fetal trisomy 18. Methods: To develop a similar method for the noninvasive detection of trisomy 21, we used methylation-sensitive single nucleotide primer extension and/or bisulfite sequencing to systematically search 114 CpG islands (CGIs)—76% of the 149 CGIs on chromosome 21 identified by bioinformatic criteria—for differentially methylated DNA patterns. The methylation index (MI) of a CpG site was estimated as the proportion of molecules methylated at that site. Results: We identified 22 CGIs which were shown to contain CpG sites that were either completely unmethylated (MI = 0.00) in maternal blood cells and methylated in the placenta (MI range, 0.22–0.65), or completely methylated (MI = 1.00) in maternal blood cells and hypomethylated in the placenta (MI range, 0.00–0.75). We detected, for the first time, placental DNA-methylation patterns on chromosome 21 in maternal plasma during pregnancy and observed their postpartum clearance. Conclusion: Twenty-two (19%) of the 114 studied CGIs on chromosome 21 showed epigenetic differences between samples of placenta and maternal blood cells; these CGIs may provide a rich source of markers for noninvasive prenatal diagnosis.

139 citations


Journal ArticleDOI
TL;DR: The results suggest that DNA methylation and heterochromatinization play an important role in the early stage of sex chromosome evolution.
Abstract: Sex chromosomes evolved from autosomes. Recombination suppression in the sex-determining region and accumulation of deleterious mutations lead to degeneration of the Y chromosomes in many species with heteromorphic X/Y chromosomes. However, how the recombination suppressed domain expands from the sex-determining locus to the entire Y chromosome remains elusive. The Y chromosome of papaya (Carica papaya) diverged from the X chromosome approximately 2-3 million years ago and represents one of the most recently emerged Y chromosomes. Here, we report that the male-specific region of the Y chromosome (MSY) spans approximately 13% of the papaya Y chromosome. Interestingly, the centromere of the Y chromosome is embedded in the MSY. The centromeric domain within the MSY has accumulated significantly more DNA than the corresponding X chromosomal domain, which leads to abnormal chromosome pairing. We observed four knob-like heterochromatin structures specific to the MSY. Fluorescence in situ hybridization and immunofluorescence assay revealed that the DNA sequences associated with the heterochromatic knobs are highly divergent and heavily methylated compared with the sequences in the corresponding X chromosomal domains. These results suggest that DNA methylation and heterochromatinization play an important role in the early stage of sex chromosome evolution.

112 citations


Journal ArticleDOI
TL;DR: It is demonstrated in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression, which is linked to upregulation of the water channel aquaporin 4 (AQP4).
Abstract: Down syndrome (DS) is caused by trisomy of chromosome 21 and is characterized by mental retardation, seizures and premature Alzheimer's disease. To examine neuropathological mechanisms giving rise to this disorder, we generated multiple human DS neural progenitor cell (NPC) lines from the 19-21 week frontal cortex and characterized their genomic and functional properties. Microarray profiling of DS progenitors indicated that increased levels of gene expression were not limited to chromosome 21, suggesting that increased expression of genes on chromosome 21 altered transcriptional regulation of a subset of genes throughout the entire genome. Moreover, many transcriptionally dysregulated genes were involved in cell death and oxidative stress. Network analyses suggested that upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 (AQP4). We further demonstrate in DS NPCs that S100B is constitutively overexpressed, that overexpression leads to increased reactive oxygen species (ROS) formation and activation of stress response kinases, and that activation of this pathway results in compensatory AQP4 expression. In addition, AQP4 expression could be induced by direct exposure to ROS, and siRNA inhibition of AQP4 resulted in elevated levels of ROS following S100B exposure. Finally, elevated levels of S100B-induced ROS and loss of AQP4 expression led to increased programmed cell death. These findings suggest that dysregulation of chromosome 21 genes in DS neural progenitors leads to increased ROS and thereby alters transcriptional regulation of cytoprotective, non-chromosome 21 genes in response to ongoing cellular insults.

104 citations


Journal ArticleDOI
15 Jan 2008-Blood
TL;DR: In this paper, the effects of trisomy 21 on hematopoiesis were investigated in the Ts65Dn mouse model of Down syndrome (DS) and the results showed that trisommy for Aml1/Runx1 is not required for megakaryocyte hyperplasia and myelofibrosis.

103 citations


Journal ArticleDOI
01 Oct 2008-Genetics
TL;DR: In this paper, stepwise restriction of recombination between the protosex chromosomes of birds has resulted in regions of the chicken Z chromosome showing discrete levels of divergence from W homologs (gametologs).
Abstract: Birds have female heterogamety with Z and W sex chromosomes. These evolved from different autosomal precursor chromosomes than the mammalian X and Y. However, previous work has suggested that the pattern and process of sex chromosome evolution show many similarities across distantly related organisms. Here we show that stepwise restriction of recombination between the protosex chromosomes of birds has resulted in regions of the chicken Z chromosome showing discrete levels of divergence from W homologs (gametologs). The 12 genes analyzed fall into three levels of estimated divergence values, with the most recent divergence (dS = 0.18–0.21) displayed by 6 genes in a region on the Z chromosome corresponding to the interval 1–11 Mb of the assembled genome sequence. Another 4 genes show intermediate divergence (dS = 0.27–0.38) and are located in the interval 16–53 Mb. Two genes (at positions 42 and 50 Mb) with higher dS values are located proximal to the most distal of the 4 genes with intermediate divergence, suggesting an inversion event. The distribution of genes and their divergence indicate at least three evolutionary strata, with estimated times for cessation of recombination between Z and W of 132–150 (stratum 1), 71–99 (stratum 2), and 47–57 (stratum 3) million years ago. An inversion event, or some other form of intrachromosomal rearrangement, subsequent to the formation of strata 1 and 2 has scrambled the gene order to give rise to the nonlinear arrangement of evolutionary strata currently seen on the chicken Z chromosome. These observations suggest that the progressive restriction of recombination is an integral feature of sex chromosome evolution and occurs also in systems of female heterogamety.

99 citations


Journal ArticleDOI
TL;DR: It is suggested that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation.
Abstract: Down syndrome, characterized by an extra chromosome 21 is the most common genetic cause for congenital malformations and learning disability. It is well known that the extra chromosome 21 most often originates from the mother, the incidence increases with maternal age, there may be aberrant maternal chromosome 21 recombination and there is a higher recurrence in young women. In spite of intensive efforts to understand the underlying reason(s) for these characteristics, the origin still remains unknown. We hypothesize that maternal trisomy 21 ovarian mosaicism might provide the major causative factor. We used fluorescence in situ hybridization (FISH) with two chromosome 21-specific probes to determine the copy number of chromosome 21 in ovarian cells from eight female foetuses at gestational age 14–22 weeks. All eight phenotypically normal female foetuses were found to be mosaics, containing ovarian cells with an extra chromosome 21. Trisomy 21 occurred with about the same frequency in cells that had entered meiosis as in pre-meiotic and ovarian mesenchymal stroma cells. We suggest that most normal female foetuses are trisomy 21 ovarian mosaics and the maternal age effect is caused by differential selection of these cells during foetal and postnatal development until ovulation. The exceptional occurrence of high-grade ovarian mosaicism may explain why some women have a child with Down syndrome already at young age as well as the associated increased incidence at subsequent conceptions. We also propose that our findings may explain the aberrant maternal recombination patterns previously found by family linkage analysis.

95 citations


Journal ArticleDOI
TL;DR: The interpretation of the extra chromosome as composed of two short arms of chromosome 12 is confirmed, using molecular methods, and restriction fragment length polymorphisms indicate that the two arms are identical, which is compatible with the hypothesis of an isochromosome 12p.
Abstract: Pallister-Killian syndrome is a dysmorphic syndrome characterized by a tissue-limited mosaicism: a majority of fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. In this study, the interpretation of the extra chromosome as composed of two short arms of chromosome 12 is confirmed, using molecular methods. Furthermore, restriction fragment length polymorphisms indicate that the two arms are identical, which is compatible with the hypothesis of an isochromosome 12p. A new feature which may be important in understanding the mechanism of origin of the abnormality is described: the proportion of abnormal mitoses falls dramatically during long-term culture of fibroblasts.

93 citations


Journal ArticleDOI
TL;DR: It is concluded that APP overeexpression seems to be absent during the development of DS brain up to 18–19 weeks of gestational age, however, its overexpression in adult DS brain could lead to disturbance of normal function of APP contributing to neurodegeneration.
Abstract: Down syndrome (DS) is the most common human chromosomal abnormality caused by an extra copy of chromosome 21. The phenotype of DS is thought to result from overexpression of a gene or genes located on the triplicated chromosome or chromosome region. Several reports have shown that the neuropathology of DS comprises developmental abnormalities and Alzheimer-like lesions such as senile plaques. A key component of senile plaques is amyloid beta-peptide which is generated from the amyloid precursor protein (APP) by sequential action of beta-secretases (BACE1 and BACE2) and gamma-secretase. While BACE1 maps to chromosome 11, APP and BACE2 are located on chromosome 21. To challenge the gene dosage effect and gain insight into the expressional relation between beta-secretases and APP in DS brain, we evaluated protein expression levels of BACE1, BACE2 and APP in fetal and adult DS brain compared to controls. In fetal brain, protein expression levels of BACE2 and APP were comparable between DS and controls. BACE1 was increased, but did not reach statistical significance. In adult brain, BACE1 and BACE2 were comparable between DS and controls, but APP was significantly increased. We conclude that APP overexpression seems to be absent during the development of DS brain up to 18-19 weeks of gestational age. However, its overexpression in adult DS brain could lead to disturbance of normal function of APP contributing to neurodegeneration. Comparable expression of BACE1 and BACE2 speaks against the hypothesis that increased beta-secretase results in (or even underlies) increased production of amyloidogenic A beta fragments. Furthermore, current data indicate that the DS phenotype cannot be fully explained by simple gene dosage effect.

Journal ArticleDOI
TL;DR: A novel cell line SKNO‐1 was established from the bone marrow cells of a 22‐year‐old male suffering from acute myeloblastic leukaemia (AML) M2 with t(8;21) whose disease became resistant to chemotherapy after acquisition of 17 monosomy.
Abstract: A novel cell line SKNO-1 was established from the bone marrow cells of a 22-year-old male suffering from acute myeloblastic leukaemia (AML) M2 with t(8;21) whose disease became resistant to chemotherapy after acquisition of 17 monosomy. SKNO-1 has been maintained for more than 36 months as a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent line. Morphologically, SKNO-1 cells were myeloblasts somewhat maturated. The cells grow in suspension with a doubling time of 48-72 h. The survival and growth of SKNO-1 cells was absolutely dependent on granulocyte-macrophage colony stimulating factor (GM-CSF). SKNO-1 cells possessed t(8;21) and monosomy 17 which were observed in original leukaemic cells. We confirmed that the AML1 gene, located on chromosome 21, was rearranged and the AML1-MTG8 fusion transcript was expressed in SKNO-1 cells. Over-expression and mutation of the p53 gene were also detected in SKNO-1. It is likely that alterations of AML1 or MTG8 gene and p53 gene contribute to a disease progression in this case. Since t(8;21) translocation is a common chromosome abnormality in AML, and inactivation of the p53 gene may play a crucial role in disease progression in AML, SKNO-1 would be a useful tool for analysing the molecular mechanisms in myeloid leukaemogenesis.

Journal ArticleDOI
15 Aug 2008-Blood
TL;DR: It is recommended that children with syndromic thrombocytopenia have clinical array-comparative genomic hybridization analysis and appropriate cytogenetic studies to facilitate the ability to provide a definitive diagnosis.

Journal ArticleDOI
TL;DR: This study explores what is known about the ENS dysfunction in DS and reviews the possible importance of chromosome 21 located and other genes in its etiology, which is thought to be the site of a modifier gene for HSCR.
Abstract: Down syndrome (DS) is the most common chromosomal abnormality occurring in humans. Up to 77% of DS children have associated gastrointestinal (GI) abnormalities, which may be structural or functional in nature. Functional disturbances may, in turn, affect the outcome of corrective surgical procedures, prompting to caution. It is becoming clear that the processes affecting the enteric nervous system (ENS) in DS not only affect the micro-anatomy but also nerve function, and there is some histological evidence of ENS variations in both human and DS animal models. This suggests that developmental disorders of the ENS are probably fundamental to the functional GI disturbances encountered in patients with DS. The anomalous brain development, function and resulting intellectual impairment associated with DS appears to result from the genetic imbalance created by the trisomy of chromosome 21. The possible links between the brain, GI and ENS involvement are not as yet entirely clear. Neurotropic factors affecting brain development during embryogenesis are probably interlinked with ENS development, but the precise mechanism of how this occurs has yet to be established. This study explores what is known about the ENS dysfunction in DS and reviews the possible importance of chromosome 21 located and other genes in its etiology. Functional motor disturbances of the esophagus and colon are not uncommon and may be congenital or acquired in nature. The most prominent of these include esophageal dysmotility syndromes (e.g. achalasia, gastroesophageal reflux, dysphagia) as well as a higher incidence of chronic constipation and Hirschsprung's disease (HSCR) (2-15%) occurring in association with DS. Chromosome 21 itself is thought to be the site of a modifier gene for HSCR. Recently identified candidate genetic mechanisms provide unique insights into the genetic background of the neurological and cognitive disorders associated with DS. Although the role of the triplicated chromosome 21 and genetic dosage remain important, the additional role of other chromosome 21 genes in the etiology of ENS developmental anomalies remains undetermined and requires ongoing research.

Journal ArticleDOI
TL;DR: Details of a cytogenetic survey of 1,255 patients over 15 years of age in a hospital for the mentally subnormal are reported in this and a previous communication.
Abstract: Details of a cytogenetic survey of 1,255 patients over 15 years of age in a hospital for the mentally subnormal are reported in this and a previous communication. In this hospital only 17 % of the male patients and 11 % of the female patients had I.Q levels above 50 %. A total of 128 patients were found to have an abnormal chromosome complement. Of these, 10 had abnormalities of the sex chromosome complement, 104 had the clinical and cytogenetic features of Down's Syndrome and 14 had other abnormalities of the autosomes. Of the 104 patients with Down's Syndrome, 95 were trisomic for chromosome 21 (1 patient also had a Robertsonian translocation between two D group choromosomes), 4 had a mosaic constitution with one cell line trisomic for chromosome 21 and 5 patients had translocations of the D/G or G/G type. The 14 patients with autosomal abnormalities not associated with Down's Syndrome included 4 with an apparently balanced translocation, 3 with deletions of chromosome material, and 7 with additional chromosome material either translocated onto another chromosome or in the form of a supernumerary chromosome. Clinical and cytogenetic details and family studies are reported.

Journal ArticleDOI
TL;DR: This study shows that genome‐wide allelotyping using SNP array is a powerful new tool for the analysis of allelic imbalances in well‐differentiated neuroendocrine tumors, and some of these alterations are tumor site‐dependent and are different than in PETs.
Abstract: Well-differentiated neuroendocrine tumors (WDNT, carcinoid tumors) are uncommon indolent neoplasms. The genetic alterations of these tumors are not well characterized. We used genome-wide high-density single nucleotide polymorphism (SNP) array analysis to detect copy number alterations in 29 WDNTs, including seven lung, seven nonileal gastrointestinal, and 15 ileal tumors, and compared with allelic imbalances in 15 pancreatic endocrine tumors (PETs). Most frequent allelic imbalances in WDNTs were losses of chromosome 18 in 10 tumors (34%), chromosome 21 or 21q in six (21%), chromosome 13 or 13q in five (17%) and chromosome 16 or 16q in four (14%) tumors, and amplification of chromosome 20 or 20p in seven (24%) tumors. We also found one tumor with loss of heterozygosity of chromosomes 10 and 15 without copy number loss. These allelic imbalances were associated with primary site of tumor: loss of chromosome 18 was present exclusively in ileal WDNTs (P = 0.001), and loss of chromosome 21 or 21q was more frequent in nonileal gastrointestinal WDNTs (P = 0.02). The tumors with loss of chromosome 21 were larger compared to tumors without loss (P = 0.03). Chromosomal aberrations were less common in WDNTs from lung and gastrointestinal tract compared to PETs (P = 0.001). Our study shows that genome-wide allelotyping using SNP array is a powerful new tool for the analysis of allelic imbalances in WDNTs, and some of these alterations are tumor site-dependent and are different than in PETs.

Journal ArticleDOI
TL;DR: This report describes a 26‐year‐old female with the typical clinical symptoms and signs of Melkersson‐Rosenthal syndrome, an autosomal dominant disorder with variable expression, and suggests that the “Melkersson-Rosenthal gene” is located at 9p11.
Abstract: In this report we describe a 26-year-old female with the typical clinical symptoms and signs of Melkersson-Rosenthal syndrome, an autosomal dominant disorder with variable expression, and a de novo t(9;21)(p11;p11), and suggest that the “Melkersson-Rosenthal gene” is located at 9p11.

Journal ArticleDOI
01 Apr 2008-Genetics
TL;DR: It is concluded that the Y chromosome of this species has been derived through multiple rearrangements of the ancestral gene arrangement and that none of the rearrangement so far detected was involved in stopping X–Y recombination.
Abstract: We combine data from published marker genotyping of three sets of S. latifolia Y chromosome deletion mutants with changed sex phenotypes and add genotypes for several new genic markers to refine the deletion map of the Y chromosome and compare it with the X chromosome genetic map. We conclude that the Y chromosome of this species has been derived through multiple rearrangements of the ancestral gene arrangement and that none of the rearrangements so far detected was involved in stopping X–Y recombination. Different Y genotypes may also differ in their gene content and possibly arrangements, suggesting that mapping the Y-linked sex-determining genes will be difficult, even if many further genic markers are obtained. Even in determining the map of Y chromosome markers to discover all the rearrangements, physical mapping by FISH or other experiments will be essential. Future deletion mapping work should ensure that markers are studied in the parents of deletion mutants and should probably include additional deletions that were not ascertained by causing mutant sex phenotypes.

Journal ArticleDOI
TL;DR: Clinical features suggestive of Down's syndrome were also seen in a mildly retarded girl with a mosaic chromosome constitution (one cell line had an isochromosome for the long arm of chromosomes 21 and the other had a deletion of the short arm of chromosome 21).
Abstract: Five patients showing several stigmata of Down's syndrome and a partial trisomy of chromosome 21 are reported Three patients with only a moderate degree of mental retardation had an additional deleted chromosome 21; the characteristic dark G-band region of the long arm of 21 was missing In another patient with a typical Down's syndrome the G-band region and the distal portion of the long arm of 21 were present in excess and were translocated onto the short arm of 15 Clinical features suggestive of Down's syndrome were also seen in a mildly retarded girl with a mosaic chromosome constitution (one cell line had an isochromosome for the long arm of chromosome 21 and the other had a deletion of the short arm of chromosome 21) By correlating clinical and cytogenetic data on these patients, an attempt was made to analyse the phenotypic effects caused by the presence of excess amounts of different segments of chromosome 21

Journal ArticleDOI
TL;DR: In this paper, the authors compared the chromosome structures of Falconinae and delineated the chromosome rearrangements that occurred in this subfamily and found that the drastic chromosome rearrangements occurred independently in the lineages of Accipitridae and Falconinsects.
Abstract: Karyotypes of most bird species are characterized by around 2n = 80 chromosomes, comprising 7–10 pairs of large- and medium-sized macrochromosomes including sex chromosomes and numerous morphologically indistinguishable microchromosomes. The Falconinae of the Falconiformes has a different karyotype from the typical avian karyotype in low chromosome numbers, little size difference between macrochromosomes and a smaller number of microchromosomes. To characterize chromosome structures of Falconinae and to delineate the chromosome rearrangements that occurred in this subfamily, we conducted comparative chromosome painting with chicken chromosomes 1–9 and Z probes and microchromosome-specific probes, and chromosome mapping of the 18S–28S rRNA genes and telomeric (TTAGGG)n sequences for common kestrel (Falco tinnunculus) (2n = 52), peregrine falcon (Falco peregrinus) (2n = 50) and merlin (Falco columbarius) (2n = 40). F. tinnunculus had the highest number of chromosomes and was considered to retain the ancestral karyotype of Falconinae; one and six centric fusions might have occurred in macrochromosomes of F. peregrinus and F. columbarius, respectively. Tandem fusions of microchromosomes to macrochromosomes and between microchromosomes were also frequently observed, and chromosomal locations of the rRNA genes ranged from two to seven pairs of chromosomes. These karyotypic features of Falconinae were relatively different from those of Accipitridae, indicating that the drastic chromosome rearrangements occurred independently in the lineages of Accipitridae and Falconinae.

Journal ArticleDOI
TL;DR: Assessment in the context of the well-resolved Y phylogeny allows their mutational history to be deciphered and an estimation of mutation rate.
Abstract: The Y chromosome is unusual in being constitutively haploid and escaping recombination for most of its length This has led to a correspondingly unusual genomic landscape, rich in segmental duplications, which provide a potent environment for the generation of copy number variation (CNV) Interest in the chromosome comes from diverse fields, including infertility research, population genetics, forensics, and genealogy Together with inclusion in more systematic surveys, this has led to the ascertainment of a variety of CNVs Assessment in the context of the well-resolved Y phylogeny allows their mutational history to be deciphered and an estimation of mutation rate The functional consequences of variants are moderated by the specialization of the chromosome and the presence of functionally equivalent X-chromosomal homologues for some genes However, deletions of the AZFa, b, and c regions cause impaired spermatogenesis, while partial deletions and duplications within these regions, and deletions and duplications elsewhere, may be selectively neutral or have subtle phenotypes

Journal ArticleDOI
TL;DR: The clinical, chromosomal, and familial evidence suggest that these abnormal chromosomes originated in the occurrence of one transverse break of the centromere and subsequent misdivision of a chromosome 18 in an earlier generation of this family.
Abstract: A family is described in which the mother has an 18p- chromosome, one normal 18, and a probable i(18p) One of the daughters of this woman inherited the 18p- chromosome, and her phenotype resembles that of other 18p- cases The other daughter inherited the presumed i(18p) chromosome, and her phenotype resembles that of some cases with extra, small metacentric chromosomes The clinical, chromosomal, and familial evidence suggest that these abnormal chromosomes originated in the occurrence of one transverse break of the centromere and subsequent misdivision of a chromosome 18 in an earlier generation of this family According to this interpretation, the mother is trisomic for 18p, one daughter is monosomic and the other daughter is tetrasomic for this chromosomal region

Journal ArticleDOI
TL;DR: Findings confirm that the gene imbalance present in Ts65Dn disrupts crucial pathways during cardiac development, and the candidate genes for congenital heart defects that are among the 104 triplicated genes in Ts 65Dn mice are implicated in the dysregulation of normal cardiogenic pathways in this model.
Abstract: The Ts65Dn mouse is the most-studied of murine models for Down syndrome Homology between the triplicated murine genes and those on human chromosome 21 correlates with shared anomalies of Ts65Dn mice and Down syndrome patients, including congenital heart defects Lethality is associated with inheritance of the T65Dn chromosome, and anomalies such as right aortic arch with Kommerell's diverticulum and interrupted aortic arch were found in trisomic neonates The incidence of gross vascular abnormalities was 17% in the trisomic population Histological analyses revealed interventricular septal defects and broad foramen ovale, while immunohistochemistry showed abnormal muscle composition in the cardiac valves of trisomic neonates These findings confirm that the gene imbalance present in Ts65Dn disrupts crucial pathways during cardiac development The candidate genes for congenital heart defects that are among the 104 triplicated genes in Ts65Dn mice are, therefore, implicated in the dysregulation of normal cardiogenic pathways in this model

Journal ArticleDOI
TL;DR: It is shown that in euploid mice, the chr21‐encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK‐801 response, and this results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.
Abstract: Down syndrome (DS), caused by trisomy of human chromosome 21 (chr21), is the most common genetic cause of intellectual disability. The Ts65Dn mouse model of DS is trisomic for orthologs of 94 chr21-encoded, confirmed protein-coding genes and displays a number of behavioral deficits. Recently, Ts65Dn mice were shown to be hypersensitive to the locomotor stimulatory effects of the high-affinity N-methyl-d-aspartate (NMDA) receptor (NMDAR) channel blocker, MK-801. This is consistent with the functions of several chr21 proteins that are predicted directly or indirectly to impact NMDAR function or NMDAR-mediated signaling. In this study, we show that a second mouse model of DS, the Ts1Cje, which is trisomic for 70 protein-coding genes, is also hypersensitive to MK-801. To investigate the molecular basis for the responses to MK-801, we have measured levels of a subset of chr21 and phosphorylated non-chr21 proteins, in the cortex and hippocampus of Ts65Dn and Ts1Cje mice and euploid controls, with and without treatment with MK-801. We show that in euploid mice, the chr21-encoded proteins, TIAM1 and DYRK1A, and phosphorylation of AKT, ERK1/2 and the transcription factor ELK are involved in the MK-801 response. However, in both Ts65Dn and Ts1Cje mice, levels of phosphorylation are constitutively elevated in naive, unstimulated mice, and the MK-801-induced changes in TIAM1 and DYRK1A and in phosphorylation are either absent or abnormal, with both genotype and brain-region-specific patterns. These results emphasize the complexities of the pathway perturbations that arise with segmental trisomy.

Journal ArticleDOI
TL;DR: Recent findings on the ancestral and neo-X chromosomes in Drosophila that support sexual antagonism as a force shaping gene content evolution of sex chromosomes are discussed and selection could be driving male-biased genes off the X.

Journal ArticleDOI
TL;DR: After analysis of the relationship between AZFc and male infertility, it is concluded that spermatogenesis is controlled by a network of genes, which may locate on the Y chromosome, the autochromosomes, or even on the X chromosome.

Journal ArticleDOI
01 Nov 2008-Genomics
TL;DR: X-Y gene divergence time estimates obtained using Bayesian methods confirm an early origin of Stratum 1 genes prior to the origin of therian mammals and reveal most feline X-degenerate genes have retained housekeeping functions shared by their X chromosome partners and have not been specialized for testis-specific functions.

Journal ArticleDOI
TL;DR: The first study concerning the frequency and type of CHD observed in Turkish children with DS implied that early screening for CHDs by echocardiography is crucial and correction of AVSDs in paediatric patients with DS should be performed in the first 6 months of life to avoid irreversible haemodynamic consequences of the defect.
Abstract: Background — Down’s syndrome (DS) is the most common chromosomal abnormality due to a trisomy of chromosome 21 commonly associated with congenital heart defects (CHDs). This study aimed to evaluate...

Journal ArticleDOI
TL;DR: Results confirmed previous suggestions that the directed nondisjunction of the rye B chromosome is controlled by two elements, pericentromeric sticking sites and a trans-acting element carried at the distal region of the long arm of the B chromosome.
Abstract: The rye B chromosome is a supernumerary chromosome that increases in number in its host by directed postmeiotic drive. Two types of rye B chromosomes that had been introduced into common wheat were dissected into separate segments by the gametocidal system to produce a number of rearranged B chromosomes, such as telosomes, terminal deletions and translocations with wheat chromosomes. A total of 13 dissected B chromosomes were isolated in common wheat, and were investigated for their nondisjunction. properties. Rearranged B chromosomes, separated from their B-specific repetitive sequences on the distal part of the long arm, did not undergo nondisjunction, and neither did a translocated wheat chromosome carrying a long-arm distal segment containing the B-specific repetitive sequences. However, such rearranged B chromosomes, missing their B-specific sequences could undergo nondisjunction when they coexisted with the standard B chromosome or a wheat chromosome carrying the B-specific sequences. Deficiencies of the short arm did not completely abolish the nondisjunction properties of the B chromosome, but did reduce the frequency of nondisjunction. These results confirmed previous suggestions that the directed nondisjunction of the rye B chromosome is controlled by two elements, pericentromeric sticking sites and a trans-acting element carried at the distal region of the long arm of the B chromosome. Additionally, it is now shown that the distal region of the long arm of the B chromosome which provides this function is that which carries the B-specific repetitive sequences.

Journal ArticleDOI
01 Jan 2008-Genome
TL;DR: The results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS.
Abstract: The molecular mechanisms by which trisomy of human chromosome 21 disrupts normal development are not well understood. Global transcriptome studies attempting to analyze the consequences of trisomy ...