Research Report 2000 - MDC

Genetics, Bioinformatics
and Structural Biology
Research in molecular genetics is
currently undergoing a fundamental
change triggered by the rapid progress
of genome sequencing projects,
notably the Human Genome Project.
Landmark events such as the
completion of the human chromosome
22 sequence or the announcement of a
first working draft of the human
genome sequence by the Spring of
2000 testify to the pace and vigor of
this collaborative international project.
At the same time, concepts for science
in the post-genome era are gaining
clearer contours. These concepts are
directed towards obtaining a
comprehensive and general view of
processes including protein synthesis
and processing, signal transduction
from the cell surface to the nucleus,
cell differentiation, or the
development and function of entire
organs. These topics are often
summarized under the term functional
genomics. Proteomics, aiming at
establishing the complete cellular
protein inventory in a defined
physiological or pathophysiological
state, or structural genomics, an effort
to map the entire protein “universe” at
the level of protein domain folds, are
important components of functional
genomics. MDC scientists are aware
of the relevance of genome research
and functional genomics to molecular
medicine. We have already taken the
first initial steps and are determined to
move into these fields in the near
future.
The research program Genetics,
Bioinformatics, and Structural
Biology combines groups active in
very different areas of research from
patient-oriented genetics, genetic field
working and genotyping projects to
experimental and theoretical studies of
macromolecular folding and structural
characteristics. The connecting theme
of these research endeavors is that
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together they provide the core
expertise for research into functional
genomics. Crucial methodological
approaches in that context include
animal models for studying gene
function and disease pathways, as
well as bioinformatics to evaluate
genomic sequences and diseaserelated
genetic variations. Part of the
research in structural biology is
devoted to pilot projects in the areas
of proteomics and structural
genomics.
Important insights into the
pathogenesis of human disorders can
be obtained by studying animal model
systems. In hypertension and vascular
research, multiple non-transgenic and
transgenic rodent strains offer the
opportunity to identify causative or
modifying genetic components of
various disease phenotypes. Detlev
Ganten’s group is spearheading efforts
at MDC to generate rat genome tools
(genetic and physical maps, genomic
and cDNA libraries etc.) necessary for
the identification of genetic
abnormalities in the rat. The generation
and molecular characterization of
congenic rat strains should ultimately
allow fine mapping and identification
of complex genetic traits.
Three groups in the program employ
mice as model organisms to study the
function of genes, using targeted
mutations, conditional mutations or
other YAC transgenic technologies.
Thomas E. Willnow is analyzing the
low density lipoprotein (LDL)
receptor gene family and the role of
these gene products in the physiology
and pathophysiology of lipid
metabolism and other disorders. By
generating mice that lack the gene for
the LDL receptor, the LDL receptorrelated
protein (LRP) or both, his
group has shown that the clearance of
dietary lipids proceeds via a dual
lipoprotein receptor system, the LDL
receptor and LRP. Megalin, another
member of the LDL receptor gene
family, has been found to act as an
endocytic receptor for the uptake of
lipophilic vitamins and regulates
transport and renal conversion of
vitamin D 3 metabolites.
Andreas Schedl is analyzing the
Wilms’ tumor gene (WT1) that, when
mutated, causes Wilms’ tumor, a
common childhood malignancy, and
the Frasier and Denys-Drash
Syndromes, which are characterized
by abnormal gonadal development.
WT1 plays a crucial role in renal
development. Following analysis of
YAC transgenic mice, WT1 has been
shown to be required continuously
during nephrogenesis, in particular,
during the formation of mature
glomeruli.
Carmen Birchmeier’s group has found
that the EGF-like factor, neuregulin
and its receptor, erbB2, play a dual
role during the expansion of the
Schwann cell precursor pool and
during myelination. Moreover, the
group has elucidated the function of
cryptic, another EGF-like factor, that
has been found to be essential for
establishing the left-right axis. Cryptic
mutant mice display laterality defects,
such as malposition of the great
arteries, right isomerism of the lung
and splenic hypoplasia. This
phenotype is reminiscent of the
asplenic syndrome in humans that is
typically associated with laterality
defects.
Further development of miniaturized
technology for a more detailed
characterization of whole animals,
isolated organs, and functional units
will be required for a better
understanding of pathophysiological
disease pathways in rodent models.
Friedrich Luft’s group has developed
sophisticated tools to study rodent
models in vivo. His group, as well as
the groups of Michael Bader and
Ludwig Thierfelder have applied these
tools to the characterization of rodents
with various genetic cardiovascular
modifications.
Although rodents and other animals
can be extremely useful in elucidating
disease pathways, the ultimate model
system for human diseases is man.
Great progress has been made in
recent years in the molecular
characterization of single gene