Research Report 2003 - Max-Planck-Institut für molekulare Genetik

Department of Vertebrate Genomics
30
Genetic Variation, Haplotypes & Genetics
of Complex Disease Group
Head:
Margret Hoehe, MD, PhD
The group was established in 2002.
Scientist:
Bernd Timmermann, Dipl.Biol.
Introduction
Haplotype-based approaches to all phases of disease gene discovery have gained a
central role in genetic analysis. In particular, the systematic analysis of candidate genebased
haplotypes is a key step common to all strategies of disease gene identification.
Candidate gene sequences have to be compared in large numbers of patients and controls
in order to identify those specific sequence variants associated with the disease.
In that, haplotype-based approaches to candidate gene analysis are mandatory, because
only the correct determination of the specific combinations of given gene sequence
variants as they occur separately on each of the two chromosomes of an individual
will allow establishment of correlations between genetic variation, gene function,
dysfunction, and disease phenotype.
Scientific overview
We have developed approaches and technologies in order to
1) compare candidate gene sequences systematically at large scale (“Multiplex
Sequence Comparison”, high throughput capillary sequencing)
2) determine the molecular haplotypes
3) predict haplotypes in silico, specifically the most likely haplotype pairs for each
genotype in a given sample
4) perform classification of haplotypes to reduce haplotype complexity and extract
genetic risk haplotypes against a background of high genome sequence diversity.
In the process of research, development and production, we have systematically analysed
more than thirty candidate genes of relevance for several common, complex diseases
in an average of about 300 individuals, one of the largest bodies of comparative sequence
data (more than 25 finished Megabases of sequence), and the greatest depth of
sequence analysis reached to date. This body of data allows addressing important questions
regarding linkage disequilibrium and haplotype structures given in genomic regions
and candidate gene segments, respectively, at the ultimate level of resolution.
This has important implications for all approaches to haplotype-based disease gene
discovery. The analysis of haplotype/genotype-phenotype relationships is presently
being addressed in national and international collaborations (J. Ott, Rockefeller University,
K.K. Kidd, H. Zhao, Yale University, K. M. Weiss, Penn State University, R. Shamir, Tel Aviv
University/Weizmann-Institute, J. Reich, K. Rohde, Max-Delbrück-Center, A. Ullrich, Max
Planck Institute for Biochemistry, R. Reinhardt, Max Planck Institute for Molecular Genetics).
Present work / future developments / co-operations
In this context, approaches to a) cope with the multiplicity of haplotypes through various
approaches to haplotype classification, b) analyse all genes simultaneously for
association with phenotype, c) analyse haplotype-haplotype and gene-gene-environment
interactions are being developed and applied. Moreover, comparative sequence
analyses of novel candidate genes are carried out in order to identify genetoc risk
patterns for complex disease. First significant results on potential genetic risk profiles
for diseases have been obtained.