Showing papers on "Chromosome 22 published in 2001"
TL;DR: The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that a child with all the features of 22q13.3 deletion syndrome displays all signs and symptoms of the syndrome suggests that Pro SAP2 haploinsufficiency is the cause.
Abstract: The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.
286 citations
TL;DR: These mouse models have provided new insights into the pathogenesis of del22q11 syndrome and have established strategies for research into chromosomal-deletion and -duplication syndromes.
Abstract: Identifying the genes that underlie the pathogenesis of chromosome deletion and duplication syndromes is a challenge because the affected chromosomal segment can contain many genes. The identification of genes that are relevant to these disorders often requires the analysis of individuals that carry rare, small deletions, translocations or single-gene mutations. Research into the chromosome 22 deletion (del22q11) syndrome, which encompasses DiGeorge and velocardiofacial syndrome, has taken a different path in recent years, using mouse models to circumvent the paucity of informative human material. These mouse models have provided new insights into the pathogenesis of del22q11 syndrome and have established strategies for research into chromosomal-deletion and -duplication syndromes.
257 citations
TL;DR: A model is proposed that tries to explain – with a minimum number of essential steps – the origin, progression, infiltration, and recurrence of meningiomas.
Abstract: Meningioma is the most frequent tumor of neuroectodermal origin in humans. It is usually benign. Only a minority of cases shows progression to an anaplastic tumor (WHO grade II and III). Meningioma is generally a sporadic tumor. Multiple and familial cases are rare and mostly associated with (hereditary) neurofibromatosis 2 (NF2). Meningiomas show an unexpectedly high recurrence rate. Also, completely removed low-grade tumors can recur. Recurrence and multiplicity are correlated with the formation of a peritumoral edema. On the cytogenetic level, meningioma is the best-studied tumor in humans. Grade I tumors show either uniform monosomy 22 or a diploid karyotype. The majority of high-grade, but only a minority of low-grade, meningiomas show loss of merlin, a cytoskeleton-cytoplasm-linker protein. Merlin is the product of the NF2 gene located on chromosome 22. A second tumor suppressor gene on chromosome 22 has not yet been detected. In contrast to other solid tumors, progression of meningiomas is correlated with increasing hypodiploidy, showing characteristic clonal evolutions that mostly include chromosomes 14, 18, and 19 and, more rarely, 6 and 10. Structural aberrations are infrequent, except for the loss of the short arm of chromosome 1, which appears to be the decisive step for anaplastic growth. Comparative histochemical and molecular cytogenetic studies point to the alkaline phosphatase gene (ALPL, liver-bone-kidney type) located on 1p36.1→p34 as a candidate tumor suppressor gene. A model is proposed that tries to explain – with a minimum number of essential steps – the origin, progression, infiltration, and recurrence of meningiomas.
145 citations
TL;DR: The data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.
Abstract: Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas. © 2001 Cancer Research Campaign http://www.bjcancer.com
124 citations
TL;DR: Using comparative mapping of human Y-borne genes, it is directly shown that the eutherian Y is also composed of a conserved and an added region which contains most of the ubiquitously expressed Y-bourne genes.
Abstract: Mapping of human X-borne genes in distantly related mammals has defined a conserved region shared by the X chromosome in all three extant mammalian groups, plus a region that was recently added to the eutherian X but is still autosomal in marsupials and monotremes Using comparative mapping of human Y-borne genes, we now directly show that the eutherian Y is also composed of a conserved and an added region which contains most of the ubiquitously expressed Y-borne genes Little of the ancient conserved region remains, and the human Y chromosome is largely derived from the added region
115 citations
TL;DR: It is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base, and an association between chromosome 22 status and histological subtype was observed.
Abstract: In approximately 60% of sporadic meningiomas, the tumour suppressor gene NF2, located on chromosome 22q, is inactivated. Mutations in the NF2 gene have been specifically reported in transitional and fibrous, but not meningothelial, meningiomas. Since meningothelial meningiomas frequently occur in anterior parts of the skull base, the association between tumour localization, size, histological subtype and NF2 status was investigated in a group of 42 sporadic meningiomas. NF2 status was determined by LOH analysis, karyotyping and FISH. Tumour size and site were evaluated by CT scans and MRIs. A strong correlation between tumour localization in the anterior skull base and intact 22q was revealed (p=0.003). On the other hand, tumour localization at the convexity was associated with disruption of NF2 (p=0.023). Furthermore, an association between chromosome 22 status and histological subtype was observed: abnormalities of chromosome 22q were more frequent in transitional and fibrous meningiomas than in the meningothelial variant (p<0.001). Also, the meningothelial meningiomas were more often located in the anterior skull base (p<0.006). Based on these findings, it is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base. Copyright © 2001 John Wiley & Sons, Ltd.
102 citations
TL;DR: A 1.1-Mb region of human chromosome 22q containing the dosage-sensitive gene(s) responsible for cat eye syndrome as well as the 450-kb homologous region on mouse chromosome 6 is sequenced, and fourteen putative genes were identified within or adjacent to the human CES critical region (CESCR).
Abstract: We have sequenced a 1.1-Mb region of human chromosome 22q containing the dosage-sensitive gene(s) responsible for cat eye syndrome (CES) as well as the 450-kb homologous region on mouse chromosome 6. Fourteen putative genes were identified within or adjacent to the human CES critical region (CESCR), including three known genes (IL-17R, ATP6E, and BID) and nine novel genes, based on EST identity. Two putative genes (CECR3 and CECR9) were identified, in the absence of EST hits, by comparing segments of human and mouse genomic sequence around two solitary amplified exons, thus showing the utility of comparative genomic sequence analysis in identifying transcripts. Of the 14 genes, 10 were confirmed to be present in the mouse genomic sequence in the same order and orientation as in human. Absent from the mouse region of conserved synteny are CECR1, a promising CES candidate gene from the center of the contig, neighboring CECR4, and CECR7 and CECR8, which are located in the gene-poor proximal 400 kb of the contig. This latter proximal region, located approximately 1 Mb from the centromere, shows abundant duplicated gene fragments typical of pericentromeric DNA. The margin of this region also delineates the boundary of conserved synteny between the CESCR and mouse chromosome 6. Because the proximal CESCR appears abundant in duplicated segments and, therefore, is likely to be gene poor, we consider the putative genes identified in the distal CESCR to represent the majority of candidate genes for involvement in CES.
102 citations
TL;DR: The cytogenetic classification of meningiomas provides a significant contribution to the predictability of tumor recurrence and is, therefore, a valuable criterion for the neurosurgeon's postoperative management protocol.
Abstract: Object. The goal of this study was to determine whether in meningiomas cytogenetic findings are suitable as a predictive parameter relevant to prognosis. Methods. Between 1992 and 1998 at the Department of Neurosurgery, Saarland University, 198 patients underwent surgery to resect meningiomas. The meningiomas were investigated cytogenetically and the patients were followed up for a mean period of 33 months. On the basis of the cytogenetic findings, the meningiomas were subdivided into four groups: Group 0 meningiomas displayed a normal diploid chromosome set; Group 1 tumors were found to have monosomy 22 as the sole cytogenetic aberration; Group 2 tumors were markedly hypodiploid meningiomas with loss of additional autosomes in addition to monosomy 22; and Group 3 meningiomas had deletions of the short arm of a chromosome 1, as well as additional chromosomal aberrations including loss of one chromosome 22. One hundred ninety-eight patients in whom tumor resections were determined to be Simpson Grade I or ...
99 citations
TL;DR: Observations indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.
Abstract: Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.
91 citations
TL;DR: The chromosome instability identified here demonstrates that the loss of 8p can occur by multiple whole‐arm translocations, indicating a new pathway for the Loss of a specific chromosome region in MM.
Abstract: Multicolour spectral karyotyping (SKY) was performed on primary tumour specimens from 100 patients with multiple myeloma (MM) that showed complex clonal chromosome aberrations not fully characterized by G-banding. In this study, SKY was able to identify or revise translocations with breakpoints involving 14q32, 11q13 or 8q24 in 32 patients (32%). Five new recurring translocations were identified, two of which involved chromosome 22. A subtle reciprocal translocation t(14;22) (q32;q11 approximately 12) was identified using SKY in two patients and a second, much larger, translocation t(11;22)(q13;q13) was identified using G-banding in three patients. A third new translocation was identified in two patients using SKY and G-banding as der(7)t(7;7)(p15 approximately 22;q22 approximately 32). Twenty-three patients (23%) showed the loss of 8p by whole-arm translocations with different whole-arm donor chromosomes. Among this group, two new recurring whole-arm translocations involving the centromeric breakpoint 8q10 were identified as der(8;20)(q10;q10) and der(8;18) (q10;q10) in three patients each. In addition, a novel pattern of three-way translocations involving the clonal evolution of the t(8;22)(q24;q11) by the subsequent loss of 8p by whole-arm translocations was found in three patients. The chromosome instability identified here demonstrates that the loss of 8p can occur by multiple whole-arm translocations, indicating a new pathway for the loss of a specific chromosome region in MM.
90 citations
TL;DR: The repetitive structure of the liverwort Y chromosome is reported through the analysis of male-specific P1-derived artificial chromosome (PAC) clones, pMM4G7 and pMM23-130F12, and a novel Y chromosome-specific gene family was found embedded among these repeat sequences.
Abstract: The haploid liverwort Marchantia polymorpha has heteromorphic sex chromosomes, an X chromosome in the female and a Y chromosome in the male. We here report on the repetitive structure of the liverwort Y chromosome through the analysis of male-specific P1-derived artificial chromosome (PAC) clones, pMM4G7 and pMM23-130F12. Several chromosome-specific sequence elements of ≈70 to 400 nt are combined into larger arrangements, which in turn are assembled into extensive Y chromosome-specific stretches. These repeat sequences contribute 2–3 Mb to the Y chromosome based on the observations of three different approaches: fluorescence in situ hybridization, dot blot hybridization, and the frequency of clones containing the repeat sequences in the genomic library. A novel Y chromosome-specific gene family was found embedded among these repeat sequences. This gene family encodes a putative protein with a RING finger motif and is expressed specifically in male sexual organs. To our knowledge, there have been no other reports for an active Y chromosome-specific gene in plants. The chromosome-specific repeat sequences possibly contribute to determining the identity of the Y chromosome in M. polymorpha as well as to maintaining genes required for male functions, as in mammals such as human.
Journal Article•
TL;DR: Cat-Eye syndrome is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known, and almost 60% of the CES-patients are hard to recognize by their phenotype alone.
Abstract: Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.
TL;DR: Two new genetic balancers for chromosome II of Caenorhabditis elegans were isolated and characterized, showing an inversion of a large central portion of the chromosome that includes most of the genes on the chromosome and a translocation that suppresses recombination on the right arms of chromosomes II and III.
Abstract: Two new genetic balancers for chromosome II of Caenorhabditis elegans were isolated and characterized. mIn1 was shown to be an inversion of a large central portion of the chromosome, extending from lin-31 to rol-1, that includes most of the genes on the chromosome. It balances a region to the left of the gene cluster that was previously not covered by any of the available balancers. mIn1 recombines efficiently with the normal chromosome II in regions outside the rearrangement at both ends, and appears to enhance recombination frequency adjacent to the inversion breakpoints. Eight variant strains of mIn1 were isolated, including forms that carry recessive morphological or lethal markers, an unmarked form, and one that carries an integrated transgene that confers a semi-dominant green fluorescent protein (GFP) phenotype. This set of variants makes mIn1 useful for a wide variety of applications. The second balancer, mT1, was shown to be a II;III translocation that suppresses recombination on the right arms of chromosomes II and III. It balances chromosome II from the region between bli-2 and dpy-10 to the right end of the chromosome, and chromosome III from the region between daf-2 and unc-93 to the right end. These rearrangements provide the means to stabilize efficiently most of the genes on chromosome II, and may be useful for studies of chromosome pairing and recombination.
TL;DR: It is proposed that internal tracts of telomere-like sequence recruit telomersase by binding its anchor site and that Pif1p inhibits telomerase by dissociating DNA primer-telomerase RNA interactions, showing that telomeric DNA is essential for the stable maintenance of linear chromosomes in yeast.
Abstract: Removal of a telomere from yeast chromosome VII in a strain having two copies of this chromosome often results in its loss. Here we show that there are three pathways that can stabilize this broken chromosome: homologous recombination, nonhomologous end joining, and de novo telomere addition. Both in a wild-type and a recombination deficient rad52 strain, most stabilization events were due to homologous recombination, whereas nonhomologous end joining was exceptionally rare. De novo telomere addition was relatively rare, stabilizing <0.1% of broken chromosomes. Telomere addition took place at a very limited number of sites on chromosome VII, most occurring close to a 35-base pair stretch of telomere-like DNA that is normally approximately 50 kb from the left telomere of chromosome VII. In the absence of the Pif1p DNA helicase, telomere addition events were much more frequent and were not concentrated near the 35-base pair tract of telomere-like DNA. We propose that internal tracts of telomere-like sequence recruit telomerase by binding its anchor site and that Pif1p inhibits telomerase by dissociating DNA primer-telomerase RNA interactions. These data also show that telomeric DNA is essential for the stable maintenance of linear chromosomes in yeast.
TL;DR: The identification and characterization of 12,267 potential variants (SNPs and other small insertions/deletions) of human chromosome 22, discovered in the overlaps of 460 clones used for the chromosome sequencing are reported.
Abstract: The recent publication of the complete sequence of human chromosome 22 provides a platform from which to investigate genomic sequence variation. We report the identification and characterization of 12,267 potential variants (SNPs and other small insertions/deletions) of human chromosome 22, discovered in the overlaps of 460 clones used for the chromosome sequencing. We found, on average, 1 potential variant every 1.07 kb and approximately 18% of the potential variants involve insertions/deletions. The SNPs have been positioned both relative to each other, and to genes, predicted genes, repeat sequences, other genetic markers, and the 2730 SNPs previously identified on the chromosome. A subset of the SNPs were verified experimentally using either PCR–RFLP or genomic Invader assays. These experiments confirmed 92% of the potential variants in a panel of 92 individuals. [Details of the SNPs and RFLP assays can be found at http://www.sanger.ac.uk and in dbSNP.]
TL;DR: Twelve patients with varying degrees of mosaicism for a supernumerary ring chromosome were studied, making it possible to determine the chromosomal origin of the ring chromosomes in detail, and thus to compare the phenotypes of similar cases.
Abstract: Twelve patients with varying degrees of mosaicism for a supernumerary ring chromosome were studied. The ring chromosomes were characterized using microdissection in combination with degenerate nucleotide-primed polymerase chain reaction (PCR) and reverse painting (micro-FISH). This method made it possible to determine the chromosomal origin of the ring chromosomes in detail, and thus to compare the phenotypes of similar cases. Eleven of the marker chromosomes were derived from the most proximal part of 1p, 3p, 3q, 5p, 7q, 8p, 8q, 9p, 10p and 20p. One marker chromosome had a complex origin, including the proximal and the most distal part of 20q. Eight of the families were also investigated for uniparental disomy (UPD) using microsatellite analysis. One case with maternal UPD 9 was found in a child with a ring chromosome derived from chromosome 9, r(9)(p10p12). © 2001 Wiley-Liss. Inc.
TL;DR: Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL) and it is shown that the rearranged chromosomes can be switched between “good” and “bad” copies.
Abstract: Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL)
TL;DR: The entire nucleotide sequence of the human immunoglobulin κlocus is determined, comprising a total of 1,010,706 nucleotides, and 132 Vκgenes are identified, including 55 novel Vκrelics and truncated pseudogenes, which establish 5 new families.
Abstract: We have determined the entire nucleotide sequence of the human immunoglobulin kappa locus, comprising a total of 1,010,706 nucleotides. The 76 Vkappa genes found by a hybridization-based approach and their classification in 7 families were confirmed. A Vkappa orphon located near the locus was also sequenced. In addition, we identified 55 novel Vkappa relics and truncated pseudogenes, which establish 5 new families. Among these 132 Vkappa genes, 46 have open reading frames. According to the databases and the literature, 32 unique Vkappa genes and 5 identical gene pairs form VJ-joints, 27 unique genes and 4 gene pairs are transcribed, and 25 unique genes and 4 gene pairs produce functional proteins. The Vkappa gene locus contains a 360-kb inverted duplication, which harbors 118 Vkappa genes. A comparison of the duplicated Vkappa genes suggests positive selection on the complementarity-determining regions of the duplicated genes by point mutations. The entire duplication unit was divided into 13 blocks, each of which has its distinct nucleotide sequence identity to its duplication counterpart (98.1 - 99.9 %). An inversion-mediated mechanism is suggested to generate the high-homology blocks. Based on the homology blocks and the mutation rates, the inverted duplication is assumed to have taken place approximately 5 million years ago. An orphon Vkappa gene near the kappa locus and a cluster of five Vkappa orphons on chromosome 22 have no counterparts within the kappa locus. This suggests possible mechanisms of the transposition of orphon Vkappa genes.
Journal Article•
TL;DR: The sequence and gene catalogue of the long arm of chromosome 21, the smallest human autosome, is reported, and structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions.
Abstract: Chromosome 21 is the smallest human autosome. An extra copy of chromosome 21 causes Down syndrome, the most frequent genetic cause of significant mental retardation, which affects up to 1 in 700 live births. Several anonymous loci for monogenic disorders and predispositions for common complex disorders have also been mapped to this chromosome, and loss of heterozygosity has been observed in regions associated with solid tumours. Here we report the sequence and gene catalogue of the long arm of chromosome 21. We have sequenced 33,546,361 base pairs (bp) of DNA with very high accuracy, the largest contig being 25,491,867 bp. Only three small clone gaps and seven sequencing gaps remain, comprising about 100 kilobases. Thus, we achieved 99.7% coverage of 21q. We also sequenced 281,116 bp from the short arm. The structural features identified include duplications that are probably involved in chromosomal abnormalities and repeat structures in the telomeric and pericentromeric regions. Analysis of the chromosome revealed 127 known genes, 98 predicted genes and 59 pseudogenes.
TL;DR: This modified small accessory chromosome shows the properties of a useful chromosomal vector: It segregates stably as an independent chromosome, sequences can be inserted in a controlled way and are expressed from the vector, and the HCV is transmitted through the male and female germline in mice.
Abstract: A small accessory chromosome that was mitotically stable in human fibroblasts was transferred into the hprt(-) hamster cell line CH and developed as a human chromosomal vector (HCV) by the introduction of a selectable marker and the 3' end of an HPRT minigene preceded by a loxP sequence. This HCV is stably maintained in the hamster cell line. It consists mainly of alphoid sequences of human chromosome 20 and a fragment of human chromosome region 1p22, containing the tissue factor gene F3. The vector has an active centromere, and telomere sequences are lacking. By transfecting a plasmid containing the 5' end of HPRT and a Cre-encoding plasmid into the HCV(+) hamster cell line, the HPRT minigene was reconstituted by Cre-mediated recombination and expressed by the cells. The HCV was then transferred to male mouse R1-ES cells and it did segregate properly. Chimeras were generated containing the HCV as an independent chromosome in a proportion of the cells. Part of the male and female offspring of the chimeras did contain the HCV. The HCV(+) F1 animals harbored the extra chromosome in >80% of the cells. The HCV was present as an independent chromosome with an active centromere and the human F3 gene was expressed from the HCV in a human-tissue-specific manner. Both male and female F1 mice did transmit the HCV to F2 offspring as an independent chromosome with properties similar to the original vector. This modified small accessory chromosome, thus, shows the properties of a useful chromosomal vector: It segregates stably as an independent chromosome, sequences can be inserted in a controlled way and are expressed from the vector, and the HCV is transmitted through the male and female germline in mice.
TL;DR: Fluorescence in situ hybridization studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker chromosomes to analyze the contribution of chromosome 21 in these markers, suggesting an oncogenic role of wild‐type AML1 amplification.
Abstract: Fluorescence in situ hybridization (FISH) studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker chromosomes to analyze the contribution of chromosome 21 in these markers. FISH with a chromosome 21 painting probe confirmed that chromosome 21 was involved in all three cases. FISH with YAC probes showed that the number of extra copies varied according to their location on chromosome 21. Attention was focused on the AML1 gene, which was present as five copies in most of the cells exhibiting the marker chromosomes. As controls, 11 cases of childhood ALL were studied with PAC probes covering AML1. The results agreed with the banded karyotypes in 10 patients. FISH uncovered a clone with four copies of AML1 which were only observed by FISH analysis of interphase nuclei in one patient. No point mutation was detected in exons 3–5, encoding the runt domain of AML1, in the three cases, suggesting an oncogenic role of wild-type AML1 amplification. © 2001 Wiley-Liss, Inc.
TL;DR: Children and adolescents with velocardiofacial syndrome experience major alterations in brain volumes, and significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.
Abstract: Background As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS. Methods Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue. Results Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome. Conclusions Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.
TL;DR: The results suggest that the NHEJ pathway operates after plant cells are exposed to ion particles, and DNA strand breaks induced by carbon ions were found to be rejoined using, if present, only short homologous sequences.
Abstract: To elucidate the nature of structural alterations in plants, three carbon ion-induced mutations in Arabidopsis thaliana, gl1-3, tt4(C1), and ttg1-21, were analyzed. The gl1-3 mutation was found to be generated by an inversion of a fragment that contained GL1 and Atpk7 loci on chromosome 3. The size of the inverted fragment was a few hundred kilobase pairs. The inversion was found to accompany an insertion of a 107-bp fragment derived from chromosome 2. The tt4(C1) mutation was also found to be due to an inversion. The size of the intervening region between the breakpoints was also estimated to be a few hundred kilobase pairs. In the case of ttg1-21, it was found that a break occurred at the TTG1 locus on chromosome 5, and reciprocal translocation took place between it and chromosome 3. From the sequences flanking the breakpoints, the DNA strand breaks induced by carbon ions were found to be rejoined using, if present, only short homologous sequences. Small deletions were also observed around the breakpoints. These results suggest that the nonhomologous end-joining (NHEJ) pathway operates after plant cells are exposed to ion particles.
TL;DR: The high frequency and complexity of alterations at 8q indicate a significant pathogenetic role in breast cancer, and the high-level amplification of c-myc is less common than previously thought.
TL;DR: It is demonstrated that it is possible to identify promoters in silico on the chromosomal level with sufficient reliability for experimental planning and indicates that a wealth of information about regulatory regions can be extracted from current large-scale (megabase) sequencing projects.
Abstract: The publication of the first almost complete sequence of a human chromosome (chromosome 22) is a major milestone in human genomics. Together with the sequence, an excellent annotation of genes was published which certainly will serve as an information resource for numerous future projects. We noted that the annotation did not cover regulatory regions; in particular, no promoter annotation has been provided. Here we present an analysis of the complete published chromosome 22 sequence for promoters. A recent breakthrough in specific in silico prediction of promoter regions enabled us to attempt large-scale prediction of promoter regions on chromosome 22. Scanning of sequence databases revealed only 20 experimentally verified promoters, of which 10 were correctly predicted by our approach. Nearly 40% of our 465 predicted promoter regions are supported by the currently available gene annotation. Promoter finding also provides a biologically meaningful method for "chromosomal scaffolding", by which long genomic sequences can be divided into segments starting with a gene. As one example, the combination of promoter region prediction with exon/intron structure predictions greatly enhances the specificity of de novo gene finding. The present study demonstrates that it is possible to identify promoters in silico on the chromosomal level with sufficient reliability for experimental planning and indicates that a wealth of information about regulatory regions can be extracted from current large-scale (megabase) sequencing projects. Results are available on-line at http://genomatix.gsf.de/chr22/.
TL;DR: The cytogenetic behavior of osteoid osteomas described here was different from that of the osteoids of the literature, and the breakpoint of chromosome 22 involves a region where important genes for the regulation of the cell cycle have been mapped.
TL;DR: It is indicated that at least 5000-9000 additional human genes which lack similarity to known genes or proteins exist in the human genome, increasing baseline gene estimates to approximately 41,000-45,000.
TL;DR: It is demonstrated that FISH is an attractive alternative in molecular diagnostics of t(11;22), as PCR assays are not reliable, due to the presence of numerous copies of low copy repeats.
Abstract: The t(11;22)(q23;q11) translocation is the most common recurrent balanced translocation described in humans. Carriers are phenotypically normal and often go undetected until diagnosis as a result of infertility investigations or following the birth of chromosomally unbalanced offspring. Efficient diagnostics of t(11;22) is important for children born to carriers of the translocation and for prenatal and pre-implantation diagnosis. The translocation breakpoint on chromosome 22 is located within a region containing low copy repeats, and this site is one of the last unfilled gaps in the sequence of this chromosome. This autosome harbors multiple other low copy repeats, which have been entirely sequenced. We report a combined sequencing and fiber FISH breakpoint characterization in five translocation carriers. From one carrier a cosmid library was constructed, and two chimeric cosmids (cos4_der11 and cos6_der22) were sequenced, which showed that strong palindromes (or inverted repeats) occur on both chromosomes. The translocation breakpoints occur at the tip of both inverted repeats. The palindrome on chromosomes 22 and 11 is composed of 852 and 166 bases, respectively. Four additional carriers were studied using fiber FISH with a resolution limit of 2 kb. Analysis of breakpoints on the DNA sequence level, or at the level of fiber FISH, indicate that they occur at the same position on both chromosomes in all five carriers. Using cos6_der22, PAC 158L19 and BAC 3009A19, we demonstrate that FISH is an attractive alternative in molecular diagnostics of t(11;22), as PCR assays are not reliable, due to the presence of numerous copies of low copy repeats.
TL;DR: The first results of the application of DNA pooling in systematic analysis of allelic association are encouraging and indicate that genetic effects on diverse cognitive abilities are general rather than specific or modular.
Abstract: Background Multivariate genetic research indicates that genetic effects on diverse cognitive abilities are general rather than specific or modular. General cognitive ability ( g ), a key factor in learning and memory, is among the most heritable behavioural traits.
Aims To give a brief overview of quantitative genetic research on g and to describe initial results from a programme of research that aims to identify genes responsible for the substantial heritability of general cognitive ability.
Method The research uses a new technique called DNA pooling, which combines DNA from individuals within a group and makes it feasible to screen thousands of DNA markers for a systematic scan of the genome for associations between DNA markers and g . Two independent samples of children with very high g scores and two control samples of children with average g scores were compared in a systematic scan of 147 markers on chromosome 4 and 66 markers on chromosome 22.
Results Three replicated associations on chromosome 4 were identified using DNA pooling and confirmed using individual genotyping.
Conclusions These first results of the application of DNA pooling in systematic analysis of allelic association are encouraging.
TL;DR: Recursion segmentation provides a quantitative criterion for identifying isochores in human sequences and confirms that yeast chromosome IV is more homogeneous than yeast chromosome III, human chromosome 21 is morehomogeneous than human chromosome 22, and bacterial genomes may not be homogeneous due to short segments with distinct base compositions.