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Research Interests: Genetics, Psychology, Psychiatry, Polymorphism, Gender, and 15 moreMedicine, Humans, Female, Male, Obsessive Compulsive Disorder, Genotype, Linkage Disequilibrium, Asian Continental Ancestry Group, Psychiatric, Haplotype, Psychiatric Status Rating Scales, Sex Characteristics, Psychology and Cognitive Sciences, Medical and Health Sciences, and Genetic predisposition to disease
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Research Interests: Neuroscience, Psychology, Computer Science, Polymorphism, Magnetic Resonance Imaging, and 15 moreAdolescent, Medicine, Memory, Image Interpretation, Dopamine, Hippocampus, Humans, Female, Neuroimage, Male, Genotype, Neurotensin, Hippocampal formation, Medical and Health Sciences, and Computer Assisted
Research Interests: Psychology, Decision Making, Experimental games, Nonparametric Statistics, Adolescent, and 15 moreMedicine, Nucleus Accumbens, Humans, Gambling, Female, Male, Genetic Association Studies, Adult, Analysis of Variance, Iowa Gambling Task, Amino Acid Substitution Rates, Life Change Events, Functional polymorphism, Association Analysis, and Prediction errors
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Publisher Summary Twenty-five percent of human DNAconsists of repetitive DNA sequences. A general outline of the chromosomal organization of these repetitive sequences is discussed in the chapter. The working hypothesis is that certain... more
Publisher Summary Twenty-five percent of human DNAconsists of repetitive DNA sequences. A general outline of the chromosomal organization of these repetitive sequences is discussed in the chapter. The working hypothesis is that certain classes of human repetitive DNA sequences “encode” the information necessary for defining genomic structure. Using a combination of biochemical, computational, and recombinant DNA approaches, the organization of interspersed, centromeric, and telomeric repetitive DNA in the human genome has been investigated. The distribution of interspersed repeats can be adequately described by models that assume a random spacing, with an average distance of 3 kb. This observed distribution for the integration of interspersed repetitive DNA is the expected result for the sequences that transpose randomly throughout the genome. However, local regions of “preference” or “exclusion” for the integration of repetitive DNA are suggested by the data. Research has isolated three recombinant DNA clones of human repetitive DNA sequences that hybridize specifically to the heterochromatic positions, lqh, 9qh, and 16qh, respectively. These locations were determined by fluorescent in situ hybridization and confirmed by DNA hybridizations to human chromosomes sorted by flow cytometry.
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One of the major goals of the human genome project is to establish a physical map of each human chromosome with a density of sequence-tagged site (STS) markers exceeding one every 100 kb. We report here the generation of a human... more
One of the major goals of the human genome project is to establish a physical map of each human chromosome with a density of sequence-tagged site (STS) markers exceeding one every 100 kb. We report here the generation of a human chromosome 5-specific radiation hybrid (RH) map that includes 556 markers. Of these markers, 132 loci are ordered with a maximum likelihood ratio of >1000:1 compared with the next most likely order. An additional 113 loci were ordered relative to these backbone markers with a maximum likelihood ratio of >10:1 but <1000:1. Together, these 245 loci form an ordered framework map for the chromosome. Using this framework, >300 more markers were localized based on two-point analysis with the ordered set. On average, there are 50 markers in common with the RH map presented here and other chromosome 5 maps included in the current whole genome cytogenetic, genetic, and physical maps. The accuracy of all the maps is evident in that there are no more than t...
Research Interests: Genetics, Biology, Medicine, Biological Sciences, Gene Mapping, and 12 moreHumans, Fluorescence in situ hybridization, Polymerase Chain Reaction, Genome, Hybrid Solar Cells, Chromosome, Likelihood Functions, Genetic Markers, Contig, Molecular Sequence Data, centromere, and Medical and Health Sciences
We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of... more
We used a combination of cDNA selection, exon amplification, and computational prediction from genomic sequence to isolate transcribed sequences from genomic DNA surrounding the familial Mediterranean fever (FMF) locus. Eighty-seven kb of genomic DNA aroundD16S3370, a marker showing a high degree of linkage disequilibrium with FMF, was sequenced to completion, and the sequence annotated. A transcript map reflecting the minimal number of genes encoded within the ∼700 kb of genomic DNA surrounding the FMF locus was assembled. This map consists of 27 genes with discreet messages detectable on Northerns, in addition to three olfactory-receptor genes, a cluster of 18 tRNA genes, and two putative transcriptional units that have typical intron–exon splice junctions yet do not detect messages on Northerns. Four of the transcripts are identical to genes described previously, seven have been independently identified by the French FMF Consortium, and the others are novel. Six related zinc-fing...
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Basic and applied sciences have led to enormous progress in both the prevention and treatment of a spectrum of human diseases. Many of these accomplishments are reviewed and discussed elsewhere in this volume. Some of the most notable... more
Basic and applied sciences have led to enormous progress in both the prevention and treatment of a spectrum of human diseases. Many of these accomplishments are reviewed and discussed elsewhere in this volume. Some of the most notable successes have come in preventing or treating diseases of bacterial or viral etiology. In this context the relatively recent increased incidence of AIDS (acquired immunodeficiency syndrome) and viral hepatitis (caused by the hepatitis B virus) has presented new and urgent challenges to the pharmaceutical sciences and the biotechnology industry (see Chapters 10 and 11, this volume).
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We have developed an approach for identifying overlapping cosmid clones by exploiting the high density of repetitive sequences in complex genomes. Individual clones are fingerprinted, using a combination of restriction enzyme digestions... more
We have developed an approach for identifying overlapping cosmid clones by exploiting the high density of repetitive sequences in complex genomes. Individual clones are fingerprinted, using a combination of restriction enzyme digestions followed by hybridization with selected classes of repetitive sequences. This "repeat fingerprinting" technique allows small regions of clone overlap (10-20%) to be unambiguously assigned. We demonstrate the utility of this approach, using the fingerprinting of 3145 cosmid clones (1.25 x coverage), containing one or more (GT)n repeats, from human chromosome 16. A statistical analysis was used to link these clones into 460 contiguous sequences (contigs), averaging 106 kilobases (kb) in length and representing approximately 54% (48.7 Mb) of the euchromatic arms of this chromosome. These values are consistent with theoretical calculations and indicate that 150- to 200-kb contigs can be generated with 1.5 x coverage. This strategy requires the ...
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Research Interests: Cognition, Biology, Databases, Biological Sciences, Brain, and 15 moreHumans, Expression, Gene, Association, Brain metabolism, Genotype, European Continental Ancestry Group, Asian Continental Ancestry Group, Allele, EQTL, Case Control Studies, Genetic, alleles, Medical and Health Sciences, and Genetic predisposition to disease
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This patent describes a method for determining specific nucleotide sequences useful in forming a probe which can identify specific chromosomes, preferably through in situ hybridization within the cell itself. In one embodiment, chromosome... more
This patent describes a method for determining specific nucleotide sequences useful in forming a probe which can identify specific chromosomes, preferably through in situ hybridization within the cell itself. In one embodiment, chromosome preferential nucleotide sequences are first determined from a library of recombinant DNA clones having families of repetitive sequences. In another embodiment, variant sequences are selected from a sequence of a known repetitive DNA family. The selected variant sequence is classified as chromosome specific, chromosome preferential, or chromosome nonspecific. Sequences which are classified as chromosome preferential are further sequenced and regions are identified having a low homology with other regions of the chromosome preferential sequence or with known sequences of other family members and consensus sequences of the repetitive DNA families for the chromosome preferential sequences. The selected low homology regions are then hybridized with chro...
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The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in... more
The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele...
Research Interests: Evolutionary Biology, Genetics, Computational Biology, Biotechnology, Cancer, and 15 moreFamily, Biology, Adolescent, Humans, Child, Female, Genetic Polymorphism, Asian Continental Ancestry Group, Chinese Population, Allele, Haplotype, Genetic, Attention deficit disorder with hyperactivity, Attention deficit hyperactivity disorder, and Gene frequency
In order to investigate DNA-protein interactions in defined chromosome regions, the authors have initiated studies to detect the specific binding of proteins from a crude HeLe cell nuclear extract to a cloned human chromosome 9 specific... more
In order to investigate DNA-protein interactions in defined chromosome regions, the authors have initiated studies to detect the specific binding of proteins from a crude HeLe cell nuclear extract to a cloned human chromosome 9 specific satellite III DNA sequence. Approximately 150,000 copies of this sequence, representing 0.23% of human DNA, are localized in chromosome region 9qh. Using a band
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An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA... more
An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA sequences are thought to arise by many mechanisms, from direct sequence amplification by the unequal recombination of homologous DNA regions to the reverse flow of genetic information. A general outline of the chromosomal organization of these repetitive sequences will be discussed. Our working hypothesis is that certain classes of human repetitive DNA sequences ''encode'' the information necessary for defining long-range genomic structure. Evidence will be presented that the first goal of this research, the identification and cloning of the human telomere, has been achieved. A human repetitive DNA library was constructed from randomly sheared, reassociated, and oligo(G/center dot/C)-tailed DNA, a method that minimizes the potential loss of sequences devoid of a given restriction enzyme site. Sequences too large to clone efficiently in cosmid or /lambda/ vectors, such as centromeric repeats, or telomeric sequences with an end incompatible for cloning, should be present in this library. In order to isolate highly conserved repetitive DNA sequences, this library was screened with radiolabeled hamster Cot50 repetitive DNA. Two clones, more » containing tandem arrays of the sequence (TTAGGG), were isolated by this method. 30 refs., 1 fig., 2 tabs. « less
Research Interests: Genetics, Fluorescence Microscopy, Biology, DNA replication, Medicine, and 15 moreDNA, Humans, Animals, Nucleic acid hybridization, Tetrahymena, Molecular cloning, Human Genome, Genomic Library, Base Sequence, Chromosomes, Genetic Markers, Scientific American, DNA probes, Molecular Sequence Data, and fluorescent dyes
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Using the 2.6 million single nucleotide polymorphism (SNP) genotype datasets from Perlegen Sciences and the Haplotype Map (HapMap) project (Phase I freeze), a probabilistic search for the landscape exhibited by positive Darwinian... more
Using the 2.6 million single nucleotide polymorphism (SNP) genotype datasets from Perlegen Sciences and the Haplotype Map (HapMap) project (Phase I freeze), a probabilistic search for the landscape exhibited by positive Darwinian selection was conducted (Wang et al., 2006). By sorting each high frequency allele by homozygosity, we search for the expected decay of adjacent SNP linkage disequilibrium (LD) at recently selected alleles, eliminating the need for inferring haplotype. We designate this approach the LD decay (LDD) test. Cluster analysis indicates that approximately 3000 sites of recent inferred selection are present in human DNA, representing approximately 1800 genes. Prior simulation studies (Wang et al., 2006) indicate that this novel LDD test, at the Mb scale employed, effectively distinguishes selection from other causes of extensive LD, such as inversions, population bottlenecks and admixture. Based on over-representation analysis, these prior studies have shown that s...
Research Interests: Genetics, Molecular Evolution, Biology, DNA damage, DNA repair, and 15 moreMedicine, High Frequency, Humans, Mutation, Cluster Analysis, Molecular Phylogenetics and Evolution, Genetic linkage analysis, Balancing selection, Human Genome, Linkage Disequilibrium, Genetic Recombination, DNA binding proteins, Haplotype, Genetic Linkage Map, and alleles
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Research Interests: Chemistry, Crystallography, Molecular Biology, DNA replication, NMR Spectroscopy, and 15 moreMagnetic Resonance Spectroscopy, Medicine, Molecular, Humans, Computer Simulation, Insulin, RMS, Minisatellite, Base Sequence, PPM, Nucleic Acid Conformation, Biochemistry and cell biology, Dimerization, Molecular Sequence Data, and cytosine
Highly polymorphic DNA triplet repeats, (CAG)n, are located inside the first exon of the Huntington&amp;amp;#39;s disease gene. Inordinate expansion of this repeat is correlated with the onset and progression of the disease. NMR... more
Highly polymorphic DNA triplet repeats, (CAG)n, are located inside the first exon of the Huntington&amp;amp;#39;s disease gene. Inordinate expansion of this repeat is correlated with the onset and progression of the disease. NMR spectroscopy, gel electrophoresis, digestion by single-strand specific P1 enzyme, and in vitro replication assay have been used to investigate the structural basis of (CAG)n expansion. Nondenaturing gel electrophoresis and 1D 1H NMR studies of (CAG)5 and (CAG)6 reveal the presence of hairpins and mismatched duplexes as the major and minor populations respectively. However, at high DNA concentrations (i.e., 1.0-2.0 mM that is typically required for 2D NMR experiments) both (CAG)5 and (CAG)6 exist predominantly in mismatched duplex forms. Mismatched duplex structures of (CAG)5 and (CAG)6 are useful, because they adequately model the stem of the biologically relevant hairpins formed by (CAG)n. We, therefore, performed detailed NMR spectroscopic studies on the duplexes of (CAG)5 and (CAG)6. We also studied a model duplex, (CGCAGCG)2 that contains the underlined building block of the duplex. This duplex shows the following structural characteristics: (i) all the nucleotides are in (C2&amp;amp;#39;-endo, anti) conformations, (ii) mismatched A x A base pairs are flanked by two Watson-Crick G x C base pairs and (iii) A x A base pairs are stably stacked (and intra-helical) and are formed by a single N6-H--N1 hydrogen bond. The nature of A x A pairing is confirmed by temperature-dependent HMQC and HMQC-NOESY experiments on the [(CA*G)5]2 duplex where the adenines are 15N-labeled at N6. Temperature- and pH-dependent imino proton spectra, nondenaturing electrophoresis, and P1 digestion data demonstrate that under a wide range of solution conditions longer (CAG)n repeats (n&amp;amp;gt; or =10) exist exclusively in hairpin conformation with two single-stranded loops. Finally, an in vitro replication assay with (CAG)8,21 inserts in the M13 single-stranded DNA templates shows a replication bypass for the (CAG)21 insert but not for the (CAG)8 insert in the template. This demonstrates that for a sufficiently long insert (n=21 in this case), a hairpin is formed by the (CAG)n even in presence of its complementary strand. This observation implies that the formation of hairpin by the (CAG)n may cause slippage during replication and thus may explain the observed length polymorphism.
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Thirty-one sequence tagged sites and a highly polymorphic short tandem repeat polymorphism have been isolated from 5q34-q35 and integrated into the yeast artificial chromosome (YAC) contig of 5q34-q35. In addition, four genes (MSX2, CSX,... more
Thirty-one sequence tagged sites and a highly polymorphic short tandem repeat polymorphism have been isolated from 5q34-q35 and integrated into the yeast artificial chromosome (YAC) contig of 5q34-q35. In addition, four genes (MSX2, CSX, DRD1, and CL100) and a pseudogene (GLUT6) were localized on this map. The high density of new markers in the region allowed further refinement of the YAC contig of distal 5q. This is a prerequisite for the conversion of this YAC into a cosmid contig.