EST analysis online: WWW tools for detection of SNPs and alternative splice forms

Brett, David; Lehmann, Gerrit; Hanke, Jens; Gross, S R; Reich, Jens; Bork, Peer

doi:10.1016/s0168-9525(00)02089-8

Cited by 18 publications

(10 citation statements)

References 13 publications

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“…Several genome-wide studies estimate that 40% to 75% of human genes have alternative splice forms (42)(43)(44)(45)(46). Alternative splicing plays a major role in modulating gene function by increasing the diversity of expressed mRNA transcripts (44,47) and is considered to be particularly prevalent in human brain, which has a greater number of splice variants than any other organ (48,49).…”

Section: Discussionmentioning

confidence: 99%

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Nakata

Lipska

Hyde

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

162

146

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Disrupted-In-Schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (⌬3), exons 7 and 8 (⌬7⌬8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms ⌬7⌬8, Esv1, and ⌬3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of ⌬3 and ⌬7⌬8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1⌬7⌬8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.alternative splicing ͉ genetic ͉ hippocampus ͉ psychiatric illness S chizophrenia is a common mental disorder with a lifetime prevalence of Ϸ 1% (1). It has been assumed, on the basis of evidence from twin, family, and adoption studies, that genetic factors play a strong etiologic role in schizophrenia (2, 3). The genetic predisposition is likely to be determined by a complex network of interactions between genes and environmental risk factors (4).The Disrupted-In-Schizophrenia-1 (DISC1) gene was identified as a potential susceptibility gene for mental disorders based on studies of a chromosomal translocation found in a large Scottish family that had a high frequency of schizophrenia and other psychiatric disorders, including bipolar disorder and major depression (5-7). Although the translocation identified in the Scottish family has not been observed in any other families, independent support for involvement of DISC1 in the etiology of mental illness has come from a number of genetic linkage and association studies in diverse populations (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the specific SNPs, alleles, and haplotypes have varied across these studies, raising issues of allelic and populations heterogeneity, the overall evidence implicates DISC1 as a promising candidate susceptibility gene for schizophrenia. However, the mechanism by which DISC1 contributes to the pathophysiology of schizophrenia remains unknown. Although reduced expression of DISC1 mRNA was found in lymphoblastoid cell lines of family members with the translocation (26) and in bipolar disorder patients with a putative risk-associated haplotype (27), no changes were detected in the brain tissue of unre...

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Section: Discussionmentioning

confidence: 99%

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Nakata

Lipska

Hyde

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

162

146

View full text Add to dashboard Cite

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“…ESTs were chosen for SNP analysis based on three criteria (Brett et al, 2000): (1) an expect value smaller than 1e -100 in a BLASTN search; (2) over 95 % identity over 100 bp; and (3) only if at least two different ESTs contained the same polymorphic change, it was considered as an SNP site. No SNPs were found within the coding region of Dnmt3l; however, the 3)-UTR contained several potential SNPs.…”

Section: Genomic Organization Of Dnmt3lmentioning

confidence: 99%

Isolation and initial characterization of the mouse <i>Dnmt3l</i> gene

Aapola

Lyle

Krohn

et al. 2001

Cytogenet Genome Res

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We have isolated and sequenced the mouse zinc finger gene, Dnmt3l (DNA cytosine-5-methyltransferase 3-like), on mouse chromosome 10, showing similarity to members of the DNMT3/Dnmt3 family. The Dnmt3l protein contains an ADD zinc finger, which Dnmt3l shares with other Dnmt3 family members and Atrx. RT-PCR analysis showed Dnmt3l expression in testis, thymus, ovary, and heart, as well as in 7-day, 15-day, and 17-day mouse embryos.

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“…Although many experimental techniques for high-throughput SNP mining have been developed (for review, see Vignal et al 2002), the generation of dense polymorphism maps is still a laborious and timeconsuming procedure. The alternative, in silico identification of SNPs using large data sets generated by sequencing projects, is a quick and cost-efficient approach for the generation of impressive amounts of candidate SNPs.Several candidate SNP detection pipelines based on EST data analysis have been described previously (Buetow et al 1999;Marth et al 1999;Picoult-Newberg et al 1999;Brett et al 2000). Application of computationally intensive BLAST search and/or Phrap fragment assembler, which are common first steps in most pipelines for candidate SNPs discovery, does not allow incorporation of large amounts of sequence data, as, for example, produced by whole-genome shotgun sequencing (WGS) projects.…”

mentioning

confidence: 99%

“…Several candidate SNP detection pipelines based on EST data analysis have been described previously (Buetow et al 1999;Marth et al 1999;Picoult-Newberg et al 1999;Brett et al 2000). Application of computationally intensive BLAST search and/or Phrap fragment assembler, which are common first steps in most pipelines for candidate SNPs discovery, does not allow incorporation of large amounts of sequence data, as, for example, produced by whole-genome shotgun sequencing (WGS) projects.…”

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confidence: 99%

Single Nucleotide Polymorphisms Associated With Rat Expressed Sequences

et al. 2004

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Single nucleotide polymorphisms (SNPs) are the most common source of genetic variation in populations and are thus most likely to account for the majority of phenotypic and behavioral differences between individuals or strains. Although the rat is extensively studied for the latter, data on naturally occurring polymorphisms are mostly lacking. We have used publicly available sequences consisting of whole-genome shotgun (WGS), expressed sequence tag (EST), and mRNA data as a source for the in silico identification of SNPs in gene-coding regions and have identified a large collection of 33,305 high-quality candidate SNPs. Experimental verification of 471 candidate SNPs using a limited set of rat isolates revealed a confirmation rate of ∼50%. Although the majority of SNPs were identified between Sprague-Dawley (EST data) and Brown Norway (WGS data) strains, we found that 66% of the verified variations are common among different rat strains. All SNPs were extensively annotated, including chromosomal and genetic map information, and nonsynonymous SNPs were analyzed by SIFT and PolyPhen prediction programs for their potential deleterious effect on protein function. Interestingly, we retrieved three SNPs from the database that result in the introduction of a premature stop codon and that could be confirmed experimentally. Two of these "in silico-identified knockouts" reside in interesting QTL regions. Data are publicly available via a Web interface (http://cascad.niob.knaw.nl), allowing simple and advanced search queries.[Supplemental material is available online at www.genome.org. The SNPs identified in this study can be found in the National Center of Biotechnology Information (NCBI) SNP database under submitter handle FGG_NIOB (ss12535137-ss12568440, ss12588074-ss12588105). The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: L.F.M. van Zutphen, B. Smits, M.B. Soares, T. Scheetz, and the Rat Genome Sequencing Consortium.]Single nucleotide polymorphisms (SNPs) are the most common type of DNA variation and the main source of phenotypic differences between individuals. Furthermore, SNPs have proven to be highly stable within populations and very useful as genetic markers in several applications including physical mapping, evolutionary studies, and association genetics. Although many experimental techniques for high-throughput SNP mining have been developed (for review, see Vignal et al. 2002), the generation of dense polymorphism maps is still a laborious and timeconsuming procedure. The alternative, in silico identification of SNPs using large data sets generated by sequencing projects, is a quick and cost-efficient approach for the generation of impressive amounts of candidate SNPs.Several candidate SNP detection pipelines based on EST data analysis have been described previously (Buetow et al. 1999;Marth et al. 1999;Picoult-Newberg et al. 1999;Brett et al. 2000). Application of computationally intensive BLAST search and/or Phrap fragment assembler, which ...

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EST analysis online: WWW tools for detection of SNPs and alternative splice forms

Cited by 18 publications

References 13 publications

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Isolation and initial characterization of the mouse <i>Dnmt3l</i> gene

Single Nucleotide Polymorphisms Associated With Rat Expressed Sequences

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