Gene Structure Prediction and Alternative Splicing Analysis Using Genomically Aligned ESTs

Kan, Zhengyan; Rouchka, Eric C.; Gish, Warren; States, David J.

doi:10.1101/gr.155001

Cited by 359 publications

(231 citation statements)

References 23 publications

Supporting

Mentioning

221

Contrasting

Unclassified

Order By: Relevance

“…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.

161

146

View full text Add to dashboard Cite

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...

show abstract

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.

161

146

View full text Add to dashboard Cite

show abstract

“…Mironov et al (1999) have also studied alternative splicing of human genes by using EST contigs from the TIGR Human Gene Index . Recently, a software tool, Transcript Assembly Program (TAP), which deduces the gene structure by genomic EST alignments, was developed (Kan et al, 2001;Kan et al, 2002). Databases for alternatively spliced mRNAs including AsMamDB, HASDB, PALS and SpliceNest, all of which are based on UniGene clusters, have been constructed Modrek et al, 2001;Coward et al, 2002;Huang et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment

Hui

Zhang

et al. 2004

Oncogene

View full text Add to dashboard Cite

Several databases have been published to predict alternative splicing of mRNAs by analysing the exon linkage relationship by alignment of expressed sequence tags (ESTs) to the genome sequence; however, little effort has been made to investigate the relationship between cancers and alternative splicing. We developed a program, Alternative Splicing Assembler (ASA), to look for splicing variants of human gene transcripts by genome-wide ESTs alignment. Using ASA, we constructed the biosino alternative splicing database (BASD), which predicted splicing variants for reference sequences from the reference sequence database (RefSeq) and presented them in both graph and text formats. EST clusters that differ from the reference sequences in at least one splicing site were counted as splicing variants. Of 4322 genes screened, 3490 (81%) were observed with at least one alternative splicing variants. To discover the variants associated with cancers, tissue sources of EST sequences were extracted from the UniLib database and ESTs from the same tissue type were counted. These were regarded as the indicators for gene expression level. Using Fisher's exact test, alternative splicing variants, of which EST counts were significantly different between cancer tissues and their counterpart normal tissues, were identified. It was predicted that 2149 variants, or 383 variants after Bonferroni correction, of 26 812 variants were likely tumor-associated. By reverse transcription-PCR, 11 of 13 novel alternative splicing variants and eight of nine variants' tissue specificity were confirmed in hepatocelluar carcinoma and in lung cancer. The possible involvement of alternative splicing in cancer is discussed.

show abstract

“…Many transcripts are cleaved and polyadenylated at alternative sites that may depend on cellular contexts (1)(2)(3)(4)(5). The 3Ј UTRs of transcripts frequently contain motifs that regulate their stability and ribosomal translation (6) and their translocation to the cytoplasm.…”

mentioning

confidence: 99%

Identification of gene 3′ ends by automated EST cluster analysis

Muro

Herrington

Janmohamed

et al. 2008

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

View full text Add to dashboard Cite

The properties and biology of mRNA transcripts can be affected profoundly by the choice of alternative polyadenylation sites, making definition of the 3 ends of transcripts essential for understanding their regulation. Here we show that 22-52% of sequences in commonly used human and murine ''full-length'' transcript databases may not currently end at bona fide polyadenylation sites. To identify probable transcript termini over the entire murine and human genomes, we analyzed the EST databases for positional clustering of EST ends. The analysis yielded 58,282 murine-and 86,410 human-candidate polyadenylation sites, of which 75% mapped to 23,091 known murine transcripts and 22,891 known human transcripts. The murine dataset correctly predicted 97% of the 3 ends in a manually curated and experimentally supported benchmark transcript set. Of currently known genes, 15% had no associated prediction and 25% had only a single predicted termination site. The remaining genes had an average of 3-4 alternative polyadenylation sites predicted for each murine or human transcript, respectively. The results are made available in the form of tables and an interactive web site that can be mined for rapid assessment of the validity of 3 ends in existing collections, enumeration of potential alternative 3 polyadenylation sites of known transcripts, direct retrieval of terminal sequences for design of probes, and detection of polyadenylation sites not currently mapped to known genes.3Ј UTR ͉ gene prediction ͉ alternative polyadenylation ͉ transcriptome ͉ transcript probe design

show abstract

Gene Structure Prediction and Alternative Splicing Analysis Using Genomically Aligned ESTs

Cited by 359 publications

References 23 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

Identification of alternatively spliced mRNA variants related to cancers by genome-wide ESTs alignment

Identification of gene 3′ ends by automated EST cluster analysis

Contact Info

Product

Resources

About