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Biomedical subjects

J B Fan

Publications and source records attributed to J B Fan.

At least 19 recordsLinked to original sources
PubMed2005

Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia.

The serotonin transporter gene (SLC6A4) is a candidate gene for schizophrenia based on serotonin transporter's crucial role in serotonergic neurotransmission. However, association studies have produced conflicting results regarding the association between two common SLC6A4 gene polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR) polymorphisms, and schizophrenia susceptibility. To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004. Our analyses showed no statistically significant evidence for the association between the Short allele of the 5-HTTLPR polymorphism and schizophrenia (random-effects pooled odds ratio (OR)=0.99, 95% Confidence Interval (CI)=0.92-1.07, Z=-0.23, P=0.82) from 19 population-based association studies consisting of 2990 case and 3875 control subjects. However, highly significant evidence for association between the STin2.12 allele of the STin2 VNTR polymorphism (random-effects pooled OR=1.24, 95% CI=1.11-1.38, Z=3.82, P=0.00014) and schizophrenia was found from 12 population-based association studies consisting of 2177 cases and 2369 control subjects. Our meta-analysis suggests that the STin2.12 allele of the STin2 VNTR polymorphism is likely a risk factor for schizophrenia susceptibility. Our data imply that following completion of the International HapMap Project, a comprehensive evaluation of a set of markers that fully characterize the linkage disequilibrium relationships at the SLC6A4 gene should be tested in large well-characterized clinical samples in order to understand the role of this gene in schizophrenia susceptibility.

Chromosome Mapping↗
PubMed2002

A family-based and case-control association study of the NOTCH4 gene and schizophrenia.

Recently a strong positive association between schizophrenia and Notch4 has been reported. Both individual markers and haplotypes showed association with the disease, with five markers (three microsatellites and two SNPs) being tested. In order to test this finding we genotyped these markers in the Han Chinese population using a sample of 544 cases and 621 controls as well as >300 trios. Analysis of allele, genotype and haplotype frequencies in both samples showed no association between the markers and the disease. Our results would indicate that a significant role for the Notch4 gene in schizophrenia can be ruled out in the Han Chinese. However, similar studies are necessary in the Caucasian population as linkage disequilibrium arrangements and founder effects may differ between these two populations.

Adolescent↗
PubMed2000

Large-scale discovery and genotyping of single-nucleotide polymorphisms in the mouse.

Single-nucleotide polymorphisms (SNPs) have been the focus of much attention in human genetics because they are extremely abundant and well-suited for automated large-scale genotyping. Human SNPs, however, are less informative than other types of genetic markers (such as simple-sequence length polymorphisms or microsatellites) and thus more loci are required for mapping traits. SNPs offer similar advantages for experimental genetic organisms such as the mouse, but they entail no loss of informativeness because bi-allelic markers are fully informative in analysing crosses between inbred strains. Here we report a large-scale analysis of SNPs in the mouse genome. We characterized the rate of nucleotide polymorphism in eight mouse strains and identified a collection of 2,848 SNPs located in 1,755 sequence-tagged sites (STSs) using high-density oligonucleotide arrays. Three-quarters of these SNPs have been mapped on the mouse genome, providing a first-generation SNP map of the mouse. We have also developed a multiplex genotyping procedure by which a genome scan can be performed with only six genotyping reactions per animal.

Animals↗
PubMed2000

Apolipoprotein E is a genetic risk factor for fetal iodine deficiency disorder in China.

Fetal iodine deficiency disorder (FIDD) is the principal form of endemic cretinism, and the most common cause of preventable mental deficiency in the world. However not everyone at risk develops FIDD and familial aggregation is common. This suggests that genetic factors may also be involved. The Apolipoprotein E (APOE) gene encodes for a lipoprotein that possesses a thyroid hormone binding domain, and APOE genotype may affect the efficiency with which thyroid hormone influences neuronal cell growth during the first and second trimesters of fetal development. We have compared ApoE genotypes in 91 FIDD cases with 154 local control subjects, recruited from three iodine deficiency areas in central China. We have also genotyped 42 FIDD family cases and 158 normal individuals from the families of local controls, and 375 population controls from Shanghai. APOE epsilon4 genotypes were significantly enriched in FIDD probands from each of the three iodine deficiency areas; the epsilon4 allele frequency was 16% vs 6% in controls. The same effect was also observed when we compared FIDD family cases with controls and control families. Our data suggest that in iodine-deficient areas, the APOE epsilon4 allele is a genetic risk factor for FIDD. The phenomenon may affect population selection and contribute to the low frequency of the epsilon4 allele in Chinese compared to Caucasian populations.

Adolescent↗
PubMed2000

Parallel genotyping of human SNPs using generic high-density oligonucleotide tag arrays.

Large scale human genetic studies require technologies for generating millions of genotypes with relative ease but also at a reasonable cost and with high accuracy. We describe a highly parallel method for genotyping single nucleotide polymorphisms (SNPs), using generic high-density oligonucleotide arrays that contain thousands of preselected 20-mer oligonucleotide tags. First, marker-specific primers are used in PCR amplifications of genomic regions containing SNPs. Second, the amplification products are used as templates in single base extension (SBE) reactions using chimeric primers with 3' complementarity to the specific SNP loci and 5' complementarity to specific probes, or tags, synthesized on the array. The SBE primers, terminating one base before the polymorphic site, are extended in the presence of labeled dideoxy NTPs, using a different label for each of the two SNP alleles, and hybridized to the tag array. Third, genotypes are deduced from the fluorescence intensity ratio of the two colors. This approach takes advantage of multiplexed sample preparation, hybridization, and analysis at each stage. We illustrate and test this method by genotyping 44 individuals for 142 human SNPs identified previously in 62 candidate hypertension genes. Because the hybridization results are quantitative, this method can also be used for allele-frequency estimation in pooled DNA samples.

Blood Pressure↗
PubMed1999

High-throughput polymorphism screening and genotyping with high-density oligonucleotide arrays.

A highly reliable and efficient technology has been developed for high-throughput DNA polymorphism screening and large-scale genotyping. Photolithographic synthesis has been used to generate miniaturized, high-density oligonucleotide arrays. Dedicated instrumentation and software have been developed for array hybridization, fluorescent detection, and data acquisition and analysis. Specific oligonucleotide probe arrays have been designed to rapidly screen human STSs, known genes and full-length cDNAs. This has led to the identification of several thousand biallelic single-nucleotide polymorphisms (SNPs). Meanwhile, a rapid and robust method has been developed for genotyping these SNPs using oligonucleotide arrays. Each allele of an SNP marker is represented on the array by a set of perfect match and mismatch probes. Prototype genotyping chips have been produced to detect 400, 600 and 3000 of these SNPs. Based on the preliminary results, using oligonucleotide arrays to genotype several thousand polymorphic loci simultaneously appears feasible.

Genetic Markers↗
PubMed1999

Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis.

Sequence variation in human genes is largely confined to single-nucleotide polymorphisms (SNPs) and is valuable in tests of association with common diseases and pharmacogenetic traits. We performed a systematic and comprehensive survey of molecular variation to assess the nature, pattern and frequency of SNPs in 75 candidate human genes for blood-pressure homeostasis and hypertension. We assayed 28 Mb (190 kb in 148 alleles) of genomic sequence, comprising the 5' and 3' untranslated regions (UTRs), introns and coding sequence of these genes, for sequence differences in individuals of African and Northern European descent using high-density variant detection arrays (VDAs). We identified 874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to reveal a discordancy rate of 21% for VDA detection. The SNPs detected have an average minor allele frequency of 11%, and 387 are within the coding sequence (cSNPs). Of all cSNPs, 54% lead to a predicted change in the protein sequence, implying a high level of human protein diversity. These protein-altering SNPs are 38% of the total number of such SNPs expected, are more likely to be population-specific and are rarer in the human population, directly demonstrating the effects of natural selection on human genes. Overall, the degree of nucleotide polymorphism across these human genes, and orthologous great ape sequences, is highly variable and is correlated with the effects of functional conservation on gene sequences.

3' Untranslated Regions↗
PubMed1999

Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays.

Here we report the application of high-density oligonucleotide array (DNA chip)-based analysis to determine the distant history of single nucleotide polymorphisms (SNPs) in current human populations. We analysed orthologues for 397 human SNP sites (identified in CEPH pedigrees from Amish, Venezuelan and Utah populations) from 23 common chimpanzee, 19 pygmy chimpanzee and 11 gorilla genomic DNA samples. From this data we determined 214 proposed ancestral alleles (the sequence found in the last common ancestor of humans and chimpanzees). In a diverse human population set, we found that SNP alleles with higher frequencies were more likely to be ancestral than less frequently occurring alleles. There were, however, exceptions. We also found three shared human/pygmy chimpanzee polymorphisms, all involving CpG dinucleotides, and two shared human/gorilla polymorphisms, one involving a CpG dinucleotide. We demonstrate that microarray-based assays allow rapid comparative sequence analysis of intra- and interspecies genetic variation.

Alleles↗
PubMed1998

Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome.

Single-nucleotide polymorphisms (SNPs) are the most frequent type of variation in the human genome, and they provide powerful tools for a variety of medical genetic studies. In a large-scale survey for SNPs, 2.3 megabases of human genomic DNA was examined by a combination of gel-based sequencing and high-density variation-detection DNA chips. A total of 3241 candidate SNPs were identified. A genetic map was constructed showing the location of 2227 of these SNPs. Prototype genotyping chips were developed that allow simultaneous genotyping of 500 SNPs. The results provide a characterization of human diversity at the nucleotide level and demonstrate the feasibility of large-scale identification of human SNPs.

Algorithms↗
PubMed1997

An STS-based radiation hybrid map of the human genome.

We have constructed a physical map of the human genome by using a panel of 83 whole genome radiation hybrids (the Stanford G3 panel) in conjunction with 10,478 sequence-tagged sites (STSs) derived from random genomic DNA sequences, previously mapped genetic markers, and expressed sequences. Of these STSs, 5049 are framework markers that fall into 1766 high-confidence bins. An additional 945 STSs are indistinguishable in their map location from one or more of the framework markers. These 5994 mapped STSs have an average spacing of 500 kb. An additional 4484 STSs are positioned with respect to the framework markers. Comparison of the orders of markers on this map with orders derived from independent meiotic and YAC STS-content maps indicates that the error rate in defining high-confidence bins is < 5%. Analysis of 322 random cDNAs indicates that the map covers the vast majority of the human genome. This STS-based radiation hybrid map of the human genome brings us one step closer to the goal of a physical map containing 30,000 unique ordered landmarks with an average marker spacing of 100 kb.

Animals↗
PubMed1997

High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, PGD type I) is an autosomal recessive disease enriched in the Finnish population. Previously, we have assigned APECED to a 2.6-cM interval on chromosome 21q22.3 by linkage analysis in 14 Finnish families. This subtelomeric region of 21q22.3 seems to have sequence features resulting in its under-representation in large insert genomic libraries, and only a few large insert clones have been available for positional cloning to date. Here, we report the refined localization of the APECED gene and a visual physical map of 800 kb covering the critical chromosomal region for the gene. In the construction of the physical map, the recently developed fiber FISH techniques were essential for the orientation of the cosmid PI, PAC, and BAC clones in relation to each other. We also localized two cDNAs within this genomic region by fiber FISH combined with the highly sensitive tyramide-based detection method. These data will facilitate the final cloning of the APECED gene and any other novel gene in this complex genomic region.

Chromosome Mapping↗
PubMed1996

A gene map of the human genome.

The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.

Amino Acid Sequence↗
PubMed1996

Construction of a 750-kb bacterial clone contig and restriction map in the region of human chromosome 21 containing the progressive myoclonus epilepsy gene.

The gene responsible for progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is located on human chromosome 21q22.3 in a region defined by recombination breakpoints and linkage disequilibrium. As part of an effort to clone the EPM1 gene on the basis of its chromosomal location, we have constructed a 753-kb bacterial clone contig that encompasses the region containing the gene. Because DNA markers from the region did not identify intact yeast artificial chromosome (YAC) clones after screening several libraries, we built the contig from cosmid clones and used bacterial artificial chromosome (BAC) and bacteriophage P1 clones to fill gaps. In addition to constructing the clone contig, we determined the locations of the EcoRI, SacII, EagI, and NotI restriction sites in the clones, resulting in a high-resolution restriction map of the region. Most of the contig is represented by a level of redundancy that allows the orders of most restriction sites to be determined, provides multiple data points supporting the clone orders and orientations, and allows a set of clones with a minimum degree of overlap to be chosen for efficient additional analysis. The clone and restriction maps are in excellent agreement with maps generated of the region by other methods. These ordered bacterial clones and the mapping information obtained from them provide valuable reagents for isolating candidate genes for EPM1, as well as for determining the nucleotide sequence of a 750 kb region of the human genome.

Base Sequence↗
PubMed1995

Endogenous endonuclease hypersensitive sites in Schizosaccharomyces pombe chromosomes.

A novel method was used to characterize the long range susceptibility of Schizosaccharomyces pombe chromosomal DNA to endogenous endonuclease cleavage. Analyses of pulsed field gel experiments revealed two periodicities in the distribution of endogenous endonuclease hypersensitive sites. Endonuclease cleavage sites occurred, roughly at 30-509 kilobase pairs (kb) intervals under physiological conditions (25 mM KCl). At higher salt concentrations (250 mM KCl or 0.2 M and 0.9 M NaCl), endonuclease hypersensitive sites occurred at 200-300 kb intervals. Endonuclease hypersensitive sites in different chromosomal regions were monitored during different stages of the cell cycle. DNA sequencing around the endonuclease hypersensitive sites revealed the presence of clusters of A+T-rich motifs, autonomously replicating sequences (ARSs) in sequences (a characteristic of the scaffold-associated regions (SARs) and the presence of a CTG trinucleotide at most sites.

Base Sequence↗
PubMed1994

Isolation of yeast artificial chromosome clones from 54 polymorphic loci mapped with high odds on human chromosome 4.

We constructed a yeast artificial chromosome (YAC) framework map of human chromosome 4 by screening a YAC library with 63 polymorphic DNA markers located on the chromosome. These genetic markers are from two framework meiotic maps that had previously been constructed by two research groups, and are placed on the two maps with odds for their order of 1000:1 or greater. In addition to isolating and determining the sizes of 141 YAC clones for 54 of these markers, we combined the two framework meiotic maps to produce a single integrated map. These combined maps and the YAC clones provide a set of extended DNA loci ordered at high odds that can be used to isolate additional polymorphic loci and genes, and to serve as a framework for obtaining a higher resolution physical map of the chromosome.

Chromosome Mapping↗