Biomedical subjects

Imtiaz Yakub

Publications and source records attributed to Imtiaz Yakub.

3 recordsLinked to original sources

PubMed2005

SNPdetector: a software tool for sensitive and accurate SNP detection.

Identification of single nucleotide polymorphisms (SNPs) and mutations is important for the discovery of genetic predisposition to complex diseases. PCR resequencing is the method of choice for de novo SNP discovery. However, manual curation of putative SNPs has been a major bottleneck in the application of this method to high-throughput screening. Therefore it is critical to develop a more sensitive and accurate computational method for automated SNP detection. We developed a software tool, SNPdetector, for automated identification of SNPs and mutations in fluorescence-based resequencing reads. SNPdetector was designed to model the process of human visual inspection and has a very low false positive and false negative rate. We demonstrate the superior performance of SNPdetector in SNP and mutation analysis by comparing its results with those derived by human inspection, PolyPhred (a popular SNP detection tool), and independent genotype assays in three large-scale investigations. The first study identified and validated inter- and intra-subspecies variations in 4,650 traces of 25 inbred mouse strains that belong to either the Mus musculus species or the M. spretus species. Unexpected heterozygosity in CAST/Ei strain was observed in two out of 1,167 mouse SNPs. The second study identified 11,241 candidate SNPs in five ENCODE regions of the human genome covering 2.5 Mb of genomic sequence. Approximately 50% of the candidate SNPs were selected for experimental genotyping; the validation rate exceeded 95%. The third study detected ENU-induced mutations (at 0.04% allele frequency) in 64,896 traces of 1,236 zebra fish. Our analysis of three large and diverse test datasets demonstrated that SNPdetector is an effective tool for genome-scale research and for large-sample clinical studies. SNPdetector runs on Unix/Linux platform and is available publicly (http://lpg.nci.nih.gov).

Algorithms↗

PubMed2005

Single nucleotide polymorphisms in genes for 2'-5'-oligoadenylate synthetase and RNase L inpatients hospitalized with West Nile virus infection.

BACKGROUND: Infection with the flavivirus West Nile virus (WNV) is a growing problem across the United States, where there is a case-fatality rate of 15%-29% in individuals >70 years old and no consistently effective treatment. Susceptibility to WNV disease in inbred strains of mice was mapped to a nonsense mutation in the gene encoding the 1b isoform of 2'-5'-oligoadenylate synthetase (OAS), a member of the OAS/RNase L system of innate viral resistance. Genetic susceptibility to severe WNV disease in humans has not been determined. METHODS: We sequenced each exon within all OAS and RNASEL genes in 33 individuals hospitalized with WNV infection in Houston to assess if there is a defect in this system in patients with severe WNV disease. RESULTS: Sequencing did not reveal any insertions, deletions, or nonsense mutations in any OAS or RNASEL gene. However, comparison of the exonic sequences between case patients and control subjects identified 23 single nucleotide polymorphisms (SNPs), including a synonymous SNP in OASL exon 2 (rs3213545), in which the reference allele occurred at a higher frequency in case patients (P < .004). CONCLUSION: Because the reference allele contains a splice enhancer site, our finding suggests that the RNA transcripts generated from this allele may undergo increased splicing, which results in a dominant-negative OASL isozyme similar to the nonsense/truncation mutant form of Oas1b in mice.

2',5'-Oligoadenylate Synthetase↗

PubMed2004

Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia.

GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. In a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNPs, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.

Adult↗