of the Max - MDC

Structure of the Group
Group Leader
Prof. Dr. Norbert Hübner
Scientists
Dr. Kathrin Saar
Dr. Franz Rüschendorf
Dr. Herbert Schulz
Oliver Hummel
Dr. Maolian Gong
Dr. Claudia Gösele
Dr. Svetlana Paskas
Graduate Students
Henrike Maatz
Judith Fischer
Katharina Grunz
Mattihas Heinig
Samreen
Technical Assistants
Heide Kistel
Anita Müller
Sabine Schmidt
Susanne Blachut
Giannino Patone
Matthias Gerhardt
Heike Fischer
Secretariat
Kornelia Dokup
pathophysiological phenotypes in this RI panel, make SHR
an excellent model for dissection of complex cardiovascular
and metabolic traits. We applied integrated gene expression
profiling and linkage analysis to the regulation of gene
expression in fat, kidney, and adrenal tissue in the
BXH/HXB panel of rat RI strains. About 15 % of the eQTLs
detected independently in the three tissues investigated
were commonly regulated, with the majority acting in cis.
This suggests that the preponderance of trans-acting eQTLs
observed in the three separate tissues belong to tissue-specific
networks for control of gene regulation. To investigate
the overall effect of polymorphisms on gene expression levels
we compared the SNP frequency across the genome with
the SNP frequency in eQTL genes. We found a highly significant
enrichment of SNPs in the cis-regulated eQTL genes
compared with either the trans-regulated eQTL genes or the
observed rate across the genome. Cis-acting eQTLs are of
particular interest as positional candidate genes for QTLs.
We applied a comparative mapping strategy to explore the
applicability of the detected cis-acting eQTLs to human
hypertension. By forming a robust dataset of cis-acting eQTL
genes with a false discovery rate 5% that were contained
within rat blood pressure related QTLs we identified the
human orthologs and compared with the location of previously
mapped human blood pressure QTLs. This analysis
defined a set of 73 attractive candidate genes for testing in
human hypertension data sets. By identifying several of
robustly mapped cis- and trans-acting expression QTLs in a
model with large number of existing physiological QTLs we
generated a permanent resource to test the hypothesis that
genetic variation in gene expression has a key role in the
molecular evolution of complex physiological and pathophysiological
phenotypes that may be shared in common
with similar disorders in humans.
Selected Publications
Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee
YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C,
Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt
RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J,
Hubner N. (2007). Mutations in the gene encoding the 3’-5’
DNA exonuclease TREX1 are associated with systemic lupus erythematosus.
Nature Genetics 39, 1065-7.
Hubner, N. (2006). Expressing physiology. Nature Genetics 38,
140-141.
Complexity of eQTL data. The graph shows a 3D schematic view of
the high-dimensionality of the eQTL dataset generated from the
BXH/HXB RI strain panel presented in Hubner et al 2005 (10) and
unpublished. The x-axis represents the location (cM) of the eQTLs
mapped on the rat genome; the y-axis represents the tissues (fat,
kidney, adrenal) where the eQTLs were mapped; the z-axis represents
the eQTL significance (P-value). Blue and red circles represent
cis- and trans-acting eQTLs, respectively.
Hubner, N, Wallace, CA, Zimdahl, H, Petretto, E, Schulz, H,
Maciver, F, Müller, M, Hummel, O, Monti, J, Zidek, V, Musilova,
A, Kren, V, Causton, H, Game, L, Born, G, Schmidt, S, Müller, A,
Cook, SA, Kurtz, TW, Whittaker, J, Pravenec, M, Aitman, TJ.
(2005). Integrated transcriptional profiling and linkage analysis
for disease gene identification. Nature Genetics. 37,
243-253.
Rat Genome Sequencing Project Consortium. (2004). Genome
Sequence of the Brown Norway rat yields insights into mammalian
evolution. Nature. 428, 493-521.
Zimdahl, H, Nyakatura, G, Brandt, P, Schulz, H, Hummel, O,
Fartmann, B, Brett, D, Droege, M, Monti, J, Lee, YA, Sun, Y,
Zhao, S, Winter, E, Ponting, C, Chen, Y, Kasprzyk, A, Birney, E,
Ganten, D, Hubner, N. (2004). A SNP map of the rat genome
generated from transcribed sequences. Science. 303, 807.
Cardiovascular and Metabolic Disease Research 57