of the Max - MDC

Genomic Dissection of
Complex Cardiovascular
Diseases
Norbert Hübner
Our group is investigating the molecular genetic basis of common cardiovascular risk factors and disorders in
experimental rodent and human populations. A substantial part of my group is working with inbred rat strains
since they provide the most relevant models of common multifactorial cardiovascular human disease. It has been
the major model for physiological investigation, providing a body of data on patho-physiology, including detailed
mechanistic, biochemical and metabolic characterisation that cannot easily be replaced by other models. The work
of our group focuses on the development of genomic tools and to utilize these for functional genetic and genomic
approaches for complex disease gene identification. Additionally my group has an increasing interest in translating
findings from model organisms to humans by comparative genome analysis.
Establishment of functional genetic and genomic
resources for the rat
We have developed a large number of genomic resources to
facilitate functional genomic studies in the rat. These
efforts included long-range physical maps and characterization
of single nucleotide variation within the rat genome.
We contributed to the annotation and assembly of the rat
genome sequence. The recent availability of the rat genome
sequence and associated genomic tools has raised the profile
and pace of research into genetic analysis of rat traits
and dramatically accelerated prospects for gene identification.
Decades of exquisite phenotyping and detailed analysis
of crosses of inbred rats have resulted in initial localization
of hundreds of loci involved in complex disease and
quantitative phenotypes, but with very few eventual gene
identifications to date. A clear understanding of the origin
and structure of genetic variation in the rat will provide a
key-missing piece of this puzzle. To fully realize the power
of the recent rat genome sequence, we are currently initiating
the complete genetic dissection of the ancestral segments
making up the most commonly used inbred lines.
Conservation of haplotype structures in
mammals
Genetic variation in genomes is organized in haplotype
blocks and species-specific block structure is defined by differential
contribution of population history effects in combination
with mutation and recombination events.
Haplotype maps characterize the common patterns of linkage
disequilibrium in populations and have important applications
in the design and interpretation of genetic experiments.
Although evolutionary processes are known to drive
the selection of individual polymorphisms, their effect on
haplotype block structure dynamics has not been shown. We
have constructed a high-resolution haplotype map for a 5
Mb genomic region in the rat and compared it with the
orthologous human and mouse segments. Although the size
and fine structure of haplotype blocks are species-dependent,
there is a significant interspecies overlap in structure
and a tendency for blocks to encompass complete genes.
Extending these findings to the complete human genome
using haplotype map phase I data reveals that linkage disequilibrium
values are significantly higher for equally spaced
positions in genic regions, including promoters, as compared
to intergenic regions, indicating that a selective
mechanism exists to maintain combinations of alleles within
potentially interacting coding and regulatory regions. While
this characteristic may complicate the identification of
causal polymorphisms underlying phenotypic traits, conservation
of haplotype structure may be employed for the identification
and characterization of functionally important
genomic regions. We will test whether our findings are representative
for the entire genome with funding from the EU.
Genome approaches to dissecting cardiovascular
and metabolic disease
Heritable differences in gene expression have been proposed
to play critical roles in biomedical phenotype and
evolution including inter-individual susceptibility to common
disease. The spontaneously hypertensive rat (SHR) is a
widely studied model of human hypertension and also has
many features of the metabolic syndrome. SHR and Brown
Norway (BN) are founder strains for the BXH/HXB recombinant
inbred (RI) strains, one of the largest rodent RI panels
for analysis of cardiovascular and metabolic phenotypes.
The reference BN genome sequence, together with availability
of tens of thousands of rat SNPs, a dense genetic map
and the previous mapping of over 70 physiological and
56 Cardiovascular and Metabolic Disease Research