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Human Chromosome (human + chromosome)
Selected AbstractsSequencing of real-world samples using a microfabricated hybrid device having unconstrained straight separation channelsELECTROPHORESIS, Issue 21 2003Shaorong Liu Abstract We describe a microfabricated hybrid device that consists of a microfabricated chip containing multiple twin-T injectors attached to an array of capillaries that serve as the separation channels. A new fabrication process was employed to create two differently sized round channels in a chip. Twin-T injectors were formed by the smaller round channels that match the bore of the separation capillaries and separation capillaries were incorporated to the injectors through the larger round channels that match the outer diameter of the capillaries. This allows for a minimum dead volume and provides a robust chip/capillary interface. This hybrid design takes full advantage, such as sample stacking and purification and uniform signal intensity profile, of the unique chip injection scheme for DNA sequencing while employing long straight capillaries for the separations. In essence, the separation channel length is optimized for both speed and resolution since it is unconstrained by chip size. To demonstrate the reliability and practicality of this hybrid device, we sequenced over 1000 real-world samples from Human Chromosome 5 and Ciona intestinalis, prepared at Joint Genome Institute. We achieved average Phred20 read of 675 bases in about 70 min with a success rate of 91%. For the similar type of samples on MegaBACE 1000, the average Phred20 read is about 550,600 bases in 120 min separation time with a success rate of about 80,90%. [source] A Metric Linkage Disequilibrium Map of a Human ChromosomeANNALS OF HUMAN GENETICS, Issue 6 2003W. J. Tapper Summary We used LDMAP (Maniatis et al. 2002) to analyse SNP data spanning chromosome 22 (Dawson et al. 2002), to obtain a whole-chromosome metric LD map. The LD map, with map distances analogous to the centiMorgan scale of linkage maps, identifies regions of high LD as plateaus (,blocks') and characterises steps which define the relationship between these regions. From this map we estimate that block regions comprise between 32% and 55% of the euchromatic portion of chromosome 22 and that increasing marker density within steps may increase block coverage. Steps are regions of low LD which correspond to areas of variable recombination intensity. The intensity of recombination is related to the height of the step and thus intense recombination hot-spots can be distinguished from more randomly distributed historical events. The LD maps are more closely related to the high-resolution linkage map (Kong et al. 2002) than average measures of , with recombination accounting for between 34% and 52% of the variance in patterns of LD (r = 0.58 , 0.71, p = 0.0001). Step regions are closely correlated with a range of sequence motifs including GT/CA repeats. The LD map identifies holes in which greater marker density is required and defines the optimal SNP spacing for positional cloning, which suggests that some multiple of around 50,000 SNPs will be required to efficiently screen Caucasian genomes. Further analyses which investigate selection of informative SNPs and the effect of SNP allele frequency and marker density will refine this estimate. [source] Human Chromosome 17 in Essential HypertensionANNALS OF HUMAN GENETICS, Issue 2 2003J. Knight Summary Hypertension affects up to 30% of the adult population in Western societies and is a major risk factor for kidney disease, stroke and coronary heart disease. It is a complex trait thought to be influenced by a number of genes and environmental factors, although the precise aetiology remains unknown at this time. A number of methods have been successfully used to identify mutations that cause Mendelian traits and these are now being applied to the investigation of complex diseases. This review summarises the data gathered, using such approaches, that suggest there is a gene or genes on chromosome 17 causing human essential hypertension. Studies in rodent models are discussed first, followed by studies of human hypertension that include the investigation of pseudohypoaldosteronism type II, a monogenic trait that manifests with hypertension alongside other phenotypic variables. In addition, candidate gene studies, genome screens and linkage studies based on comparative mapping are outlined. To date no gene has been identified on human chromosome 17 that influences blood pressure and causes human essential hypertension. However, results of ongoing fine mapping and candidate gene studies in both rodents and man are eagerly awaited. [source] LRRN6A/LERN1 (leucine-rich repeat neuronal protein 1), a novel gene with enriched expression in limbic system and neocortexEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2003Laura Carim-Todd Abstract Human chromosome 15q24-q26 is a very complex genomic region containing several blocks of segmental duplications to which susceptibility to anxiety disorders has been mapped (Gratacos et al., 2001, Cell, 106, 367,379; Pujana et al., 2001, Genome Res., 11, 98,111). Through an in silico gene content analysis of the 15q24-q26 region we have identifie1d a novel gene, LRRN6A (leucine-rich repeat neuronal 6A), and confirmed its location to the centromeric end of this complex region. LRRN6A encodes a transmembrane leucine-rich repeat protein, LERN1 (leucine-rich repeat neuronal protein 1), with similarity to proteins involved in axonal guidance and migration, nervous system development and regeneration processes. The identification of homologous genes to LRRN6A on chromosomes 9 and 19 and the orthologous genes in the mouse genome and other organisms suggests that LERN proteins constitute a novel subfamily of LRR (leucine-rich repeat)-containing proteins. The LRRN6A expression pattern is specific to the central nervous system, highly and broadly expressed during early stages of development and gradually restricted to forebrain structures as development proceeds. Expression level in adulthood is lower in general but remains stable and significantly enriched in the limbic system and cerebral cortex. Taken together, the confirmation of LRRN6A's expression profile, its predicted protein structure and its similarity to nervous system-expressed LRR proteins with essential roles in nervous system development and maintenance suggest that LRRN6A is a novel gene of relevance in the molecular and cellular neurobiology of vertebrates. [source] Characterization of the cardiac phenotype in neonatal Ts65Dn miceDEVELOPMENTAL DYNAMICS, Issue 2 2008Austin D. Williams 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. Developmental Dynamics 237:426,435, 2008. © 2007 Wiley-Liss, Inc. [source] Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype,phenotype associationsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Domenica Caramazza Abstract Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype,phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL -negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12,1q32 in PV, 1q21,32,1q32,44 in post-PV MF or PMF), deletions (e.g. 1p13,36,pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21,25;p21.3,23), and other partner chromosomes involving 1q10/1p11 and 1q21,25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21,1q32 and 1p11,13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN. [source] Type,I interferon-dependent and -independent expression of tripartite motif proteins in immune cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2008Ricardo Rajsbaum Abstract The tripartite motif (TRIM) proteins are important in a variety of cellular functions additional to anti-viral activity. We systematically analysed mRNA expression of representative TRIM molecules in mouse macrophages, myeloid and plasmacytoid dendritic cells, and a selection of CD4+ T cell subsets. We defined four clusters of TRIM genes based on their selective expression in these cells. The first group of TRIM genes was preferentially expressed in CD4+ T cells and contained the COS-FN3 motif previously shown to be involved in protein interactions. Additional TRIM genes were identified that showed up-regulation in macrophages and dendritic cells upon influenza virus infection in a type,I IFN-dependent manner, suggesting that they have anti-viral activity. In support of this notion, a subset of these TRIM molecules mapped to mouse chromosome,7, syntenic to human chromosome,11, where TRIM family members such as TRIM5, shown to have anti-viral activity, are localized. A distinct group of TRIM was constitutively expressed in plasmacytoid dendritic cells independently of viral infection or signalling through the type,I IFN receptor. Our findings on expression and regulation of TRIM genes in cells of the immune system that have different effector functions in innate and adaptive immune responses, may provide leads for determining functions of this diverse family of molecules. [source] REVIEW: A comparison of selected quantitative trait loci associated with alcohol use phenotypes in humans and mouse modelsADDICTION BIOLOGY, Issue 2 2010Cindy L. Ehlers ABSTRACT Evidence for genetic linkage to alcohol and other substance dependence phenotypes in areas of the human and mouse genome have now been reported with some consistency across studies. However, the question remains as to whether the genes that underlie the alcohol-related behaviors seen in mice are the same as those that underlie the behaviors observed in human alcoholics. The aims of the current set of analyses were to identify a small set of alcohol-related phenotypes in human and in mouse by which to compare quantitative trait locus (QTL) data between the species using syntenic mapping. These analyses identified that QTLs for alcohol consumption and acute and chronic alcohol withdrawal on distal mouse chromosome 1 are syntenic to a region on human chromosome 1q where a number of studies have identified QTLs for alcohol-related phenotypes. Additionally, a QTL on human chromosome 15 for alcohol dependence severity/withdrawal identified in two human studies was found to be largely syntenic with a region on mouse chromosome 9, where two groups have found QTLs for alcohol preference. In both of these cases, while the QTLs were found to be syntenic, the exact phenotypes between humans and mice did not necessarily overlap. These studies demonstrate how this technique might be useful in the search for genes underlying alcohol-related phenotypes in multiple species. However, these findings also suggest that trying to match exact phenotypes in humans and mice may not be necessary or even optimal for determining whether similar genes influence a range of alcohol-related behaviors between the two species. [source] The spatio-temporal and subcellular expression of the candidate Down syndrome gene Mnb/Dyrk1A in the developing mouse brain suggests distinct sequential roles in neuronal developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2008Barbara Hämmerle Abstract It is widely accepted that the neurological alterations in Down syndrome (DS) are principally due to modifications in developmental processes. Accordingly, a large part of the research on DS in recent years has focused on chromosome 21 genes that influence brain development. MNB/DYRK1A is one of the genes on human chromosome 21 that has raised most interest, due to its relationship with the brain functions that are altered in DS. Although a number of interesting experimental mouse models for DS are being developed, we still know little about the expression of Mnb/Dyrk1A during mouse brain development. Here, we report that Mnb/Dyrk1A displays a rather dynamic spatio-temporal expression pattern during mouse central nervous system development. Our data indicate that Mnb/Dyrk1A is specifically expressed in four sequential developmental phases: transient expression in preneurogenic progenitors, cell cycle-regulated expression in neurogenic progenitors, transient expression in recently born neurones, and persistent expression in late differentiating neurones. Our results also suggest that the subcellular localization of MNB/DYRK1A, including its translocation to the nucleus, is finely regulated. Thus, the MNB/DYRK1A protein kinase could be a key element in the molecular machinery that couples sequential events in neuronal development. This rich repertoire of potential functions in the developing central nervous system is suitable to be linked to the neurological alterations in DS through the use of mouse experimental models. [source] Retention of the duplicated cellular retinoic acid-binding protein 1 genes (crabp1a and crabp1b) in the zebrafish genome by subfunctionalization of tissue-specific expressionFEBS JOURNAL, Issue 14 2005Rong-Zong Liu The cellular retinoic acid-binding protein type I (CRABPI) is encoded by a single gene in mammals. We have characterized two crabp1 genes in zebrafish, designated crabp1a and crabp1b. These two crabp1 genes share the same gene structure as the mammalian CRABP1 genes and encode proteins that show the highest amino acid sequence identity to mammalian CRABPIs. The zebrafish crabp1a and crabp1b were assigned to linkage groups 25 and 7, respectively. Both linkage groups show conserved syntenies to a segment of the human chromosome 15 harboring the CRABP1 locus. Phylogenetic analysis suggests that the zebrafish crabp1a and crabp1b are orthologs of the mammalian CRABP1 genes that likely arose from a teleost fish lineage-specific genome duplication. Embryonic whole mount in situ hybridization detected zebrafish crabp1b transcripts in the posterior hindbrain and spinal cord from early stages of embryogenesis. crabp1a mRNA was detected in the forebrain and midbrain at later developmental stages. In adult zebrafish, crabp1a mRNA was localized to the optic tectum, whereas crabp1b mRNA was detected in several tissues by RT-PCR but not by tissue section in situ hybridization. The differential and complementary expression patterns of the zebrafish crabp1a and crabp1b genes imply that subfunctionalization may be the mechanism for the retention of both crabp1 duplicated genes in the zebrafish genome. [source] Cloning, chromosomal localization and characterization of the murine mucin gene orthologous to human MUC4FEBS JOURNAL, Issue 13 2002Jean-Luc Desseyn We report here the full coding sequence of a novel mouse putative membrane-associated mucin containing three extracellular EGF-like motifs and a mucin-like domain consisting of at least 20 tandem repeats of 124,126 amino acids. Screening a cosmid and a BAC libraries allowed to isolate several genomic clones. Genomic and cDNA sequence comparisons showed that the gene consists of 25 exons and 24 introns covering a genomic region of ,,52 kb. The first intron is ,,16 kb in length and is followed by an unusually large exon (, 9.5 kb) encoding Ser/Thr-rich tandemly repeated sequences. Radiation hybrid mapping localized this new gene to a mouse region of chromosome 16, which is the orthologous region of human chromosome 3q29 encompassing the large membrane-anchored mucin MUC4. Contigs analysis of the Human Genome Project did not reveal any other mucin on chromosome 3q29 and, interestingly, our analysis allowed the determination of the genomic organization of the human MUC4 and showed that its exon/intron structure is identical to that of the mouse gene we cloned. Furthermore, the human MUC4 shares considerable homologies with the mouse gene. Based on these data, we concluded that we isolated the mouse ortholog of MUC4 we propose as Muc4. Expression studies showed that Muc4 is ubiquitous like SMC and MUC4, with highest levels of expression in trachea and intestinal tract. [source] Localization of the mosaic transmembrane serine protease corin to heart myocytesFEBS JOURNAL, Issue 23 2000John D. Hooper Corin cDNA encodes an unusual mosaic type II transmembrane serine protease, which possesses, in addition to a trypsin-like serine protease domain, two frizzled domains, eight low-density lipoprotein (LDL) receptor domains, a scavenger receptor domain, as well as an intracellular cytoplasmic domain. In in vitro experiments, recombinant human corin has recently been shown to activate pro-atrial natriuretic peptide (ANP), a cardiac hormone essential for the regulation of blood pressure. Here we report the first characterization of corin protein expression in heart tissue. We generated antibodies to two different peptides derived from unique regions of the corin polypeptide, which detected immunoreactive corin protein of approximately 125,135 kDa in lysates from human heart tissues. Immunostaining of sections of human heart showed corin expression was specifically localized to the cross striations of cardiac myocytes, with a pattern of expression consistent with an integral membrane localization. Corin was not detected in sections of skeletal or smooth muscle. Corin has been suggested to be a candidate gene for the rare congenital heart disease, total anomalous pulmonary venous return (TAPVR) as the corin gene colocalizes to the TAPVR locus on human chromosome 4. However examination of corin protein expression in TAPVR heart tissue did not show evidence of abnormal corin expression. The demonstrated corin protein expression by heart myocytes supports its proposed role as the pro-ANP convertase, and thus a potentially critical mediator of major cardiovascular diseases including hypertension and congestive heart failure. [source] Molecular analyses and identification of promising candidate genes for loci on mouse chromosome 1 affecting alcohol physical dependence and associated withdrawalGENES, BRAIN AND BEHAVIOR, Issue 5 2008D. L. Denmark We recently mapped quantitative trait loci (QTLs) with large effects on predisposition to physical dependence and associated withdrawal severity following chronic and acute alcohol exposure (Alcdp1/Alcw1) to a 1.1-Mb interval of mouse chromosome 1 syntenic with human chromosome 1q23.2-23.3. Here, we provide a detailed analysis of the genes within this interval and show that it contains 40 coding genes, 17 of which show validated genotype-dependent transcript expression and/or non-synonymous coding sequence variation that may underlie the influence of Alcdp1/Alcw1 on ethanol dependence and associated withdrawal. These high priority candidates are involved in diverse cellular functions including intracellular trafficking, oxidative homeostasis, mitochondrial respiration, and extracellular matrix dynamics, and indicate both established and novel aspects of the neurobiological response to ethanol. This work represents a substantial advancement toward identification of the gene(s) that underlies the phenotypic effects of Alcdp1/Alcw1. Additionally, a multitude of QTLs for a variety of complex traits, including diverse behavioral responses to ethanol, have been mapped in the vicinity of Alcdp1/Alcw1, and as many as four QTLs on human chromosome 1q have been implicated in human mapping studies for alcoholism and associated endophenotypes. Thus, our results will be primary to further efforts to identify genes involved in a wide variety of behavioral responses to alcohol and may directly facilitate progress in human alcoholism genetics. [source] Characterization and gene expression profiling in glioma cell lines with deletion of chromosome 19 before and after microcell-mediated restoration of normal human chromosome 19GENES, CHROMOSOMES AND CANCER, Issue 10 2009Kristen L. Drucker Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65,80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression. © 2009 Wiley-Liss, Inc. [source] Chromosome 18 suppresses tumorigenic properties of human prostate cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 3 2006Audrey Gagnon Although prostate cancer is still the most diagnosed cancer in men, most genes implicated in its progression are yet to be identified. Chromosome abnormalities have been detected in human prostate tumors, many of them associated with prostate cancer progression. Indeed, alterations (including deletions or amplifications) of more than 15 human chromosomes have been reported in prostate cancer. We hypothesized that transferring normal human chromosomes into human prostate cancer cells would interfere with their tumorigenic and/or metastatic properties. We used microcell-mediated chromosome transfer to introduce human chromosomes 10, 12, 17, and 18 into highly tumorigenic (PC-3M-Pro4) and highly metastatic (PC-3M-LN4) PC-3-derived cell lines. We tested the in vitro and in vivo properties of these hybrids. Introducing chromosome 18 into the PC-3M-LN4 prostate cancer cell line greatly reduced its tumorigenic phenotype. We observed retarded growth in soft agar, decreased invasiveness through Matrigel, and delayed tumor growth into nude mice, both subcutaneously and orthotopically. This phenotype is associated with a marker in the 18q21 region. Combined with the loss of human chromosome 18 regions often seen in patients with advanced prostate cancer, our results show that chromosome 18 encodes one or more tumor-suppressor genes whose inactivation contributes to prostate cancer progression. © 2005 Wiley-Liss, Inc. [source] Microcell-mediated transfer of chromosome 4 into HeLa cells suppresses telomerase activityGENES, CHROMOSOMES AND CANCER, Issue 2 2001Claudia Backsch Telomerase activity can be detected in most human cancers and immortal cell lines. In contrast, the lack of telomerase activity in normal diploid fibroblasts has been correlated with progressive reduction of telomere lengths to critically short sizes followed by the cessation of cell division and the onset of senescence. Several investigators have provided evidence for the localization of a telomerase suppressor gene on chromosome 3. The aim of our study was to determine whether other chromosomes are involved in telomerase repression. Beside human chromosome 3 (serving as positive control), chromosomes 4, 6, and 11 were introduced into HeLa cells via microcell-mediated chromosome transfer. Telomerase activity from different hybrid cell lysates was determined at an early time point after fusion using a Telomerase ELISA kit. Strong repression of telomerase activity was only found in a subset of HeLa hybrids in which chromosome 3 or chromosome 4 had been introduced. Telomerase suppression induced by chromosome 3 or 4 transfer was paralleled by a high frequency (30% or 43%, respectively) of a senescent-like phenotype. Chromosomes 6 and 11, the functional loss of which is also implicated in cervical cancer, had no effect. These results indicate that normal human chromosomes 3 and 4 carry a gene or genes that suppress telomerase activity and induce cellular senescence in HeLa cells.©2001 Wiley-Liss, Inc. [source] Oosp1 encodes a novel mouse oocyte-secreted proteinGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 3 2001Changning Yan Abstract Summary: Oocyte-somatic cell communication is necessary for normal ovarian function. However, the identities of the majority of oocyte-secreted proteins remain unknown. A novel cDNA encoding mouse oocyte- secreted protein 1 (OOSP1) was identified using a modified subtractive hybridization screen. The Oosp1 cDNA encodes a 202-amino acid protein that contains a 21-amino acid signal peptide sequence, 5 putative N-linked glycosylation consensus sequences, and 6 cysteines that are predicted to form 3 disulfide bonds. OOSP1 shares amino acid identity with placental-specific protein 1 (PLAC1), a secreted protein expressed in the placenta and the ectoplacental cone. The Oosp1 mRNA is approximately 1.0 kb and is present at high levels in the oocytes of adult ovaries and at lower levels in the spleen. The mouse Oosp1 gene is 5 exons, spans greater than 16.4 kb, and localizes to chromosome 19 at a position that shares synteny with human chromosome 11q12,11q13. The identification of OOSP1 as a new oocyte-secreted protein permits future in vitro and in vivo functional analyses to define its role in ovarian folliculogenesis. genesis 31:105,110, 2001. © 2001 Wiley-Liss, Inc. [source] Understanding the recent evolution of the human genome: insights from human,chimpanzee genome comparisons,HUMAN MUTATION, Issue 2 2007Hildegard Kehrer-Sawatzki Abstract The sequencing of the chimpanzee genome and the comparison with its human counterpart have begun to reveal the spectrum of genetic changes that has accompanied human evolution. In addition to gross karyotypic rearrangements such as the fusion that formed human chromosome 2 and the human-specific pericentric inversions of chromosomes 1 and 18, there is considerable submicroscopic structural variation involving deletions, duplications, and inversions. Lineage-specific segmental duplications, detected by array comparative genomic hybridization and direct sequence comparison, have made a very significant contribution to this structural divergence, which is at least three-fold greater than that due to nucleotide substitutions. Since structural genomic changes may have given rise to irreversible functional differences between the diverging species, their detailed analysis could help to identify the biological processes that have accompanied speciation. To this end, interspecies comparisons have revealed numerous human-specific gains and losses of genes as well as changes in gene expression. The very considerable structural diversity (polymorphism) evident within both lineages has, however, hampered the analysis of the structural divergence between the human and chimpanzee genomes. The concomitant evaluation of genetic divergence and diversity at the nucleotide level has nevertheless served to identify many genes that have evolved under positive selection and may thus have been involved in the development of human lineage-specific traits. Genes that display signs of weak negative selection have also been identified and could represent candidate loci for complex genomic disorders. Here, we review recent progress in comparing the human and chimpanzee genomes and discuss how the differences detected have improved our understanding of the evolution of the human genome. Hum Mutat 28(2), 99,130, 2007. © 2006 Wiley-Liss, Inc. [source] Epigenetic detection of human chromosome 14 uniparental disomy,HUMAN MUTATION, Issue 1 2003S.K. Murphy Abstract The recent demonstration of genomic imprinting of DLK1 and MEG3 on human chromosome 14q32 indicates that these genes might contribute to the discordant phenotypes associated with uniparental disomy (UPD) of chromosome 14. Regulation of imprinted expression of DLK1 and MEG3 involves a differentially methylated region (DMR) that encompasses the MEG3 promoter. We exploited the normal differential methylation of the DLK1/MEG3 region to develop a rapid diagnostic PCR assay based upon an individual's epigenetic profile. We used methylation-specific multiplex PCR in a retrospective analysis to amplify divergent lengths of the methylated and unmethylated MEG3 DMR in a single reaction and accurately identified normal, maternal UPD14, and paternal UPD14 in bisulfite converted DNA samples. This approach, which is based solely on differential epigenetic profiles, may be generally applicable for rapidly and economically screening for other imprinting defects associated with uniparental disomy, determining loss of heterozygosity of imprinted tumor suppressor genes, and identifying gene-specific hypermethylation events associated with neoplastic progression. Hum Mutat 22:92,97, 2003. © 2003 Wiley-Liss, Inc. [source] The genomic context of natural killer receptor extended gene familiesIMMUNOLOGICAL REVIEWS, Issue 1 2001John Trowsdale Summary: The two sets of inhibitory and activating natural killer (NK) receptor genes belong either to the Ig or to the C-type lectin superfamilies. Both are extensive and diverse, comprising genes of varying degrees of relatedness, indicative of a process of iterative duplication. We have constructed gene maps to help understand how and when NK receptor genes developed and the nature of their polymorphism. A cluster of over 15 C-type lectin genes, the natural killer complex is located on human chromosome 12p13.1, syntenic with a region in mouse that borders multiple Ly49 loci. The equivalent locus in man is occupied by a single pseudogene, LY49L. The immunoglobulin superfamily of loci, the leukocyte receptor complex (LRC), on chromosome 19q13.4, contains many polymorphic killer cell immunoglobulin-like receptor (KIR) genes as well as multiple related sequences. These include immunoglobulin-like transcript (ILT) (or leukocyte immunoglobulin-like receptor genes), leukocyte-associated inhibitory receptor genes (LAIR), NKp46, Fc,R and the platelet glycoprotein receptor VI locus, which encodes a collagen-binding molecule. KIRs are expressed mostly on NK cells and some T cells. The other LRC loci are more widely expressed. Further centromeric of the LRC are sets of additional loci with weak sequence similarity to the KIRs, including the extensive CD66(CEA) and Siglec families. The LRC-syntenic region in mice contains no orthologues of KIRs. Some of the KIR genes are highly polymorphic in terms of sequence as well as for presence/absence of genes on different haplotypes. Some anchor loci, such as KIR2DL4, are present on most haplotypes. A few ILT loci, such as ILT5 and ILT8, are polymorphic, but only ILT6 exhibits presence/absence variation. This knowledge of the genomic organisation of the extensive NK superfamilies underpins efforts to understand the functions of the encoded NK receptor molecules. It leads to the conclusion that the functional homology of human KIR and mouse Ly49 genes arose by convergent evolution. NK receptor immunogenetics has interesting parallels with the major histocompatibility complex (MHC) in which some of the polymorphic genes are ligands for NK molecules. There are hints of an ancient genetic relationship between NK receptor genes and MHC-paralogous regions on chromosomes 1, 9 and 19. The picture that emerges from both complexes is of eternal evolutionary restlessness, presumably in response to resistance to disease. This work was funded by the Wellcome Trust and the MRC [source] A to G transitions at 260, 386 and 437 in DAZL gene are not associated with spermatogenic failure in Indian populationINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 5 2006K. Thangaraj Summary The autosomal DAZL (Deleted-in- Azoospermic- Like) gene, mapped to the short arm of the human chromosome 3, is the precursor for the Y-chromosomal DAZ cluster, which encodes for putative RNA-binding proteins. Mutations in the DAZL have been reported to be associated with spermatogenic failure in Taiwanese population but not in Caucasians. As there was no study on Indian populations, we have analysed the entire coding sequences of exons 2 and 3 of DAZL in a total of 1010 men from Indian subcontinent, including 660 infertile men with 598 non-obstructive azoospermia, 62 severe oligozoospermia and 350 normozoospermic fertile control men, to investigate whether mutation(s) in the DAZL is associated with male infertility. Interestingly, none of our samples (1010) showed A386G (T54A) mutation, which was found to be associated with spermatogenic failure in Taiwanese population. In contrast, A260G (T12A) mutation was observed in both infertile and normozoospermic fertile control men, without any significant association with infertile groups (,2 = 0.342; p = 0.556). Similarly, we have found a novel A437G (I71V) mutation, which is also present in both infertile and normozoospermic fertile control men without any significant difference (,2 = 0.476; p = 0.490). Our study clearly demonstrates the complete absence of the A386G (T54A) mutation in Indian subcontinent and the other two mutations , A260G (T12A) and A437G (I71V) , observed are polymorpic. Therefore, we conclude that these mutations in the DAZL gene are not associated with male infertility in Indian subcontinent. [source] Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3,mouse fibrosarcoma hybrids in severe combined immunodeficiency miceINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Irina D. Kholodnyuk Abstract We have applied a functional test for tumour antagonizing genes based on human chromosome 3 (chr3),mouse fibrosarcoma A9 MCHs that were studied in vitro and after growth as tumours in severe combined immunodeficiency (SCID) mice. Previously, we reported that 9 out of the 36 SCID-tumours maintained the transferred chr3 ("chr3+" tumours), but lost the expression of the known human TSG fragile histidine triad gene (FHIT) in contrast to 14 other 3p-genes examined. Here we report the results of the duplex RT-PCR analysis of 9 "chr3+" tumours and 3 parental MCHs. We have examined the expression of 34 human 3p-genes from known cancer-related regions of instability, including 13 genes from CER1 defined by us previously at 3p21.33,p21.31 and 10 genes from the LUCA region at 3p21.31. We have found that in addition to FHIT, expression of the LTF gene from CER1 at 3p21.33-p21.31 was lost in all 9 tumours analyzed. The transcript of the solute carrier family 38 member 3 gene (SLC38A3) gene from LUCA region at 3p21.31 was not found in 8 and was greatly reduced in 1 out of these 9 tumours. Expression of the down-regulated in renal cell carcinoma gene (DRR1) gene at 3p14.2 was lost in 7 and down regulated in 2 "chr3+" tumours. In the SCID-tumour derived cell lines treatment with 5-aza-2,-deoxycytidine restored the mRNA expression of LTF, indicating the integrity of DNA sequences. Notably that transcription of the LTF and 2 flanking genes, LRRC2 and TMEM7, as well as transcription of the SLC38A3 gene, were also impaired in all 5 RCC cell lines analyzed. Our data indicate these genes as putative tumour suppressor genes. © 2006 Wiley-Liss, Inc. [source] Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down's syndrome and related neurodegenerative diseasesJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Andrea Contestabile Abstract Ts65Dn mice, trisomic for a portion of chromosome 16 segmentally homologous to human chromosome 21, are an animal model for Down's syndrome and related neurodegenerative diseases, such as dementia of the Alzheimer type. In these mice, cognitive deficits and alterations in number of basal forebrain cholinergic neurons have been described. We have measured in Ts65Dn mice the catalytic activity of the cholinergic marker, choline acetyltransferase (ChAT), as well as the activity of the acetylcholine-degrading enzyme acetylcholinesterase (AChE), in the hippocampus and in cortical targets of basal forebrain cholinergic neurons. In mice aged 10 months, ChAT activity was significantly higher in Ts65Dn mice, compared to 2N animals, in the hippocampus, olfactory bulb, olfactory cortex, pre-frontal cortex, but not in other neocortical regions. At 19 months of age, on the other hand, no differences in ChAT activity were found. Thus, alterations of ChAT activity in these forebrain areas seem to recapitulate those recently described in patients scored as cases of mild cognitive impairment or mild Alzheimer's disease. Other neurochemical markers putatively associated with the disease progression, such as those implicating astrocytic hyperactivity and overproduction of amyloid precursor protein family, were preferentially found altered in some brain regions at the oldest age examined (19 months). [source] Association Between GABRA1 and Drinking Behaviors in the Collaborative Study on the Genetics of Alcoholism SampleALCOHOLISM, Issue 7 2006Danielle M. Dick Background: A wealth of literature supports the role of , -aminobutyric acid (GABA) in neurobiological pathways contributing to alcohol dependence and related phenotypes. Animal studies have consistently tied rodent homologs of the GABAA receptor genes on human chromosome 5q to alcohol-related behaviors; however, human studies have produced mixed results. Family-based association analyses previously conducted in the Collaborative Study on the Genetics of Alcoholism (COGA) sample yielded no evidence of association with Diagnostic and Statistical Manual of Mental Disorder,fourth edition (DSM-IV) alcohol dependence and these genes. As a follow-up to that study, we examined several alcohol-related behaviors in the COGA sample as follows: (1) a broader definition of alcohol dependence, including DSM-III-R symptoms and Feighner criteria (referred to as COGA alcohol dependence); (2) withdrawal; (3) history of alcohol-induced blackouts; (4) level of response to alcohol; (5) age of onset of regular drinking; and (6) age at first drunkenness. Methods: Family-based association tests were conducted, using multiple single-nucleotide polymorphisms (SNPs) in each of the 4 GABAA receptor genes on chromosome 5q. Results: In GABRA1, we found evidence of association with several of the drinking behavior phenotypes, including COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. We did not find consistent evidence of association with the remaining genes and any of the phenotypes. Conclusions: We found evidence for association between GABRA1 and COGA alcohol dependence, history of blackouts, age at first drunkenness, and level of response to alcohol. These analyses suggest that efforts to characterize genetic contributions to alcohol dependence may benefit by examining alcohol-related behaviors in addition to clinical alcohol dependence diagnoses. [source] Analysis of the ,-sarcoglycan gene in familial and sporadic myoclonus-dystonia: Evidence for genetic heterogeneityMOVEMENT DISORDERS, Issue 9 2003Enza-Maria Valente MD Abstract The ,-sarcoglycan gene (SGCE) on human chromosome 7q21 has been reported to be a major locus for inherited myoclonus,dystonia. Linkage to the SGCE locus has been detected in the majority of families tested, and mutations in the coding region have been found recently in families with autosomal dominant myoclonus,dystonia. To evaluate the relevance of SGCE in myoclonus,dystonia, we sequenced the entire coding region of the ,-sarcoglycan gene in 16 patients with either sporadic or familial myoclonus,dystonia. No mutations were found. This study suggests that ,-sarcoglycan does not play an important role in sporadic myoclonus,dystonia and supports genetic heterogeneity in familial cases. © 2003 Movement Disorder Society [source] Transient neonatal diabetes mellitus type 1,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 3 2010Deborah J.G. Mackay Abstract Transient neonatal diabetes mellitus type 1 (TNDM1) is a rare but remarkable form of diabetes which presents in infancy, resolves in the first months of life, but then frequently recurs in later life. It is caused by overexpression of the imprinted genes PLAGL1 and HYMAI on human chromosome 6q24. The expression of these genes is normally restricted to the paternal allele as a result of maternal DNA methylation. TNDM1 is not associated with mutation of PLAGL1 or HYMAI, but rather with their overexpression via uniparental disomy, chromosome duplication, or relaxation of imprinting. Study of patients with TNDM1 has provided valuable insights into the causes of imprinting disorders. Over half of patients with maternal hypomethylation at the TNDM1 locus have additional hypomethylation of other maternally methylated imprinted genes throughout the genome, and the majority of these patients have mutations in the transcription factor ZFP57. TNDM1 with maternal hypomethylation has also been observed in patients conceived by assisted reproduction, and in discordant monozygotic twins. The variable clinical features of TNDM1 may be associated with variation in the nature of the underlying epigenetic and genetic mutations, and future study of this disorder is likely to yield further insights not only into the biological mechanisms of imprinting, but also into the contribution of epigenetics to diabetes. © 2010 Wiley-Liss, Inc. [source] Development of microsatellite DNA markers and their chromosome assignment in the common marmosetAMERICAN JOURNAL OF PRIMATOLOGY, Issue 11 2009Hideki Katoh Abstract This study was performed to develop microsatellite DNA markers, which are useful for linkage analyses, gene mapping and blood chimera analyses in the common marmoset (Callithrix jacchus). We searched 153 of 295 bacterial artificial clone DNA sequences of the common marmoset that were archived in the NCBI database in 2004. On the basis of the search, we designed 186 PCR primer sets. When tested using 5 unrelated individuals, we successfully detected 154 markers with PCR products, of which 80 (52%) were polymorphic and 74 (48%) were monomorphic. We assigned each of the 154 markers to a human chromosome based on BLAST searches, which was achieved by searching the entire human genome sequences using an ,3,kb section of each forward primer sequence, including ,1.5,kb of the upstream and ,1.5,kb of the downstream sequences. Combining our assignment data and the chromosome painting-assisted karyotype of the common marmoset [Sherlock et al., Genomics 33:214,219, 1996], we prepared a list of 154 microsatellite DNA markers that were assigned to human chromosomes, except for the Y chromosome, which is equivalent to a chromosome map. Using five microsatellite DNA markers, we have established a fragment analysis method with a sequencer, which can be routinely used for blood chimera analysis, parentage diagnosis and individual identification. Am. J. Primatol. 71:912,918, 2009. © 2009 Wiley-Liss, Inc. [source] POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinomaTHE PROSTATE, Issue 6 2010Silvia Kastler Abstract BACKGROUND Association between genetic variants located on human chromosome 8q24.21 with an increased risk for prostatic carcinoma has been well established. POU5F1P1, a processed pseudogene homologous to the pluripotency factor OCT4, is the only sequence with coding capacity in this region. The objective of this study was to investigate the POU5F1P1 expression in prostatic carcinoma and carcinoma surrounding prostatic tissue. METHODS RT-PCR and real-time PCR was used to measure the expression of POU5F1P1 relative to the expression of HPRT1 in cell lines, prostatic carcinoma and carcinoma surrounding prostatic tissue. The structure of the POU5F1P1 mRNA and the promoter sequence were elucidated by 5,-RACE experiments. The POU5F1P1 protein was shown with immunohistochemistry on prostate tissue. RESULTS POU5F1P1 was found to be the only member of the POU5F1 family to be expressed in prostate with over-expression in prostatic carcinoma compared to surrounding prostatic tissue probably because of an increased density of expressing cells. The POU5F1P1 expression is driven by a variety of promoter structures scattered over a genomic region of 860 kB. CONCLUSIONS The over-expression of POU5F1P1 in prostatic carcinoma in addition to its genomic location and the putative function of its gene product render POU5F1P1 a good candidate to harbour functional genetic variants which modulate prostatic cancer susceptibility. Prostate 70: 666,674, 2010. © 2009 Wiley-Liss, Inc. [source] Fine mapping of the FecL locus influencing prolificacy in Lacaune sheepANIMAL GENETICS, Issue 6 2009L. Drouilhet Summary In the Lacaune sheep population, two major loci influencing ovulation rate are segregating: FecX and FecL. The FecXL mutation is a non-conservative substitution (p.Cys53Tyr) in BMP15 that prevents the processing of the protein. Using a statistical approach, FecL has been shown to be an autosomal major gene. A full genome scan localized the FecL locus on sheep chromosome 11. Fine mapping reduced the interval containing FecL to markers BM17132 and FAM117A, corresponding to a synteny block of 1.1 megabases on human chromosome 17, which encompasses 20 genes. The expression of 16 genes from this interval was observed in tissues of the reproductive axis, but expression was not affected in homozygous FecLL females. In this interval, a unique haplotype was associated with the FecLL mutation. This particular haplotype could be predicted by the DLX3:c.*803A>G SNP in the 3, UTR sequence of the DLX3 gene. This SNP provided accurate classification of animals (99.5%) as carriers or non-carriers of the mutation and therefore maybe useful in marker assisted selection. A synergistic action of FecLL and FecXL mutations on both ovulation rate and litter size was demonstrated. Until now, all the Fec genes identified in sheep belong to the bone morphogenetic protein (BMP) system. Based on the human orthologous region, none of the 20 genes in the FecL region corresponds to known molecules in the BMP system. The identification of the FecLL mutation could lead to the discovery of a new pathway involved in the regulation of ovulation rate. [source] Assignment of 128 genes localized on human chromosome 14q to the IMpRH mapANIMAL GENETICS, Issue 4 2009T. Shimogiri Summary To provide a gene-based comparative map and to examine a porcine genome assembly using bacterial artificial chromosome-based sequence, we have attempted to assign 128 genes localized on human chromosome 14q (HSA14q) to a porcine 7000-rad radiation hybrid (IMpRH) map. This study, together with earlier studies, has demonstrated the following. (i) 126 genes were incorporated into two SSC7 RH linkage groups by CarthaGene analysis. (ii) In the remaining two genes, TOX4 linked to TCRA located in SSC7 by two-point analysis, whereas SIP1 showed no significant linkage with any gene/marker registered in the IMpRH Web Server. (iii) In the two groups, the gene clusters located from 19.9 to 36.5 Mb on HSA14q11.2-q13.3 and from 64.0 to 104.3 Mb on HSA14q23-q32.33 respectively were assigned to SSC7q21-q26. (iv) Comparison of the gene order between the present RH map and the latest porcine sequence assembly revealed some inconsistencies, and a redundant arrangement of 16 genes in the sequence assembly. [source] | |||||||||||||||||||||||||