Effect of polymorphisms on transcriptional regulation in mice

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Presentation transcript:

Effect of polymorphisms on transcriptional regulation in mice Preliminary study of SNPs in the promoter region of genes with strong cis-eQTL Manish Anand Advisors: Dr. Debraj GuhaThakurta, Dr. Sun Kim ROSETTA INPHARMATICS, and INDIANA UNIVERSITY 24th Sep, 2004

Overview Background Methods Results Conclusions TFBS predictions genome-wide TF specific analysis Motifs in Promoter Regions Results Conclusions

Background

Central dogma ZOOM IN tRNA transcription DNA rRNA snRNA translation POLYPEPTIDE mRNA

Transcription – key steps Initiation Elongation Termination DNA

Transcription – key steps Initiation Elongation Termination DNA

Transcription – key steps Initiation Elongation Termination DNA DNA + RNA

Methods

Regulation of Genes Transcription Factor RNA polymerase DNA Coding region Regulatory Element

Gene Upstream region (-0.5/1/5Kb) SNP

SNP Gene 1 SNP Gene 2 SNP Gene 3

SNPs Upstream 1 Upstream 2 Upstream 3 Upstream 4 TF predictions

Selected Predictions

T G T C A A A G

PATSER / MATCH SCORE = 0.95 T PATSER / MATCH SCORE = 0.22 A

TF T 0.95 TF 0.22 A

T Gene Expression A Gene Expression Mice images taken from Terry Speed’s lecture ‘How many genes? Mapping mouse traits, January 20, 2004’

Consequences of point mutations in the promoter for the b-globin gene (From T. Maniatis, S. Goodbourn, and J. A. Fischer, Science 236, 1987, 1237.)

TFBS Predictions Analysis

General Summary

MATCH Score Difference Analysis

TF specific analysis

Motifs whose predicted binding sites are disrupted (show score differences)

Motifs whose predicted binding sites are disrupted (site drops)

MOTIF DISCOVERY

Novel MOTIFs in positive set

MOTIFs in negative set

Future Investigations

Future Investigations Mapping of real (experimentally verified) binding sites in TRANSFAC onto the genome Observing whether SNPs that disrupt these binding sites are in gene regions that show strong cis-acting eQTLs. Selection of several genes that show strong cis-eQTLs and have either real or predicted transcription factor binding sites disrupted in their upstream regions for experimental follow-up/validation with genotyping and measurement of expressions with different variants observed in the different strains of mice. Such experiments would help in identification of causal variants for expression changes in these genes.

Conclusions

Conclusions Amongst genes with cis-eQTLs, more genes have polymorphisms in their promoter regions Significantly more genes in the set with cis-acting eQTLs show score differences in putative TFBSs compared to control set Identification of specific TFs whose binding site predictions are disrupted in genes with cis-acting eQTLs Identification of novel DNA motifs around SNP regions in the positive set

Acknowledgements Rosetta Inpharmatics Indiana University Dr. Debraj GuhaThakurta Dr. Eric Schadt Dr. John Lamb Dr. Stephen Edwards Dr. Barmak Modrek Indiana University Dr. Sun Kim Dr. Gary Wiggins Dr. Marty Siegel Few images were taken from ‘Basic Biology for CS262’ - OMKAR DESHPANDE, Stanford University