DNA Variation

A premise for offering “personalized medicine” is that the genetic variation in the Norwegian population is clearly mapped so that a rational choice can be made, both in prevention and treatment.

Overview

This is necessary for larger diseases, as more genes affect the clinical effects. Today there is little information allowing DNA variation data to be used.

An example of some possibilities can be illustrated in the findings of disease causing gene variations performed on the Icelandic population. Within RR, it is possible to make a stride in this direction of development, provided that bioinformatics is facilitated for. Large-scale screening of SNP in complex diseases has also started to show results through genetic association studies, for example breast cancer.

It is therefore important to establish tools for large scale SNP analyses. Today, there exists Affymetrix and Illumina stations at the institution which can analyze more than one million variants per individual, per attempt. We also have biostatistics competency which allows for meaningful analyses. We believe therefore that it is an important responsibility for RR to be leading in this area, and believe this will also have a large strategic impact and be an important signal to what position the institutions would like to fill. The project leader in the laboratory side supports establishing a high capacity solution for screening of genetic variation and offering this as a service to the region.

Biobank

In conjunction with the biobank, it will make a huge strategic impact. We have pilot studies with previously mentioned technology, and have in families with hereditary breast cancer been able to prove chromosome regions that cause breast cancer and thyroid cancer. Therefore, we now offer both laboratory services and corresponding bioinformatic services also for larger projects, both connection analyses (family material) and genetic association studies (case/control).

Background

We are now established as a national coordinator for human genotyping in both the laboratory and informatics side, through the NFR/FUGE established national network, and are working on profiling this.

Since hereditary factors are population specific, the mapping of allele frequencies will be of great importance for investigations of multifactoral diseases, that is, cancer. We have also led work in studying possible underlying DNA motives for the sites in the genome where the DNA variation has occurred. This includes motive search around each individual polymorphy. The idea is to investigate whether the endogenous mechanism is important.

We are especially interested in whether the replication of DNA itself, including DNA dependent DNA polymerases might be dominating. In collaboration with Per Olaf Ekstrøm, we set up fraction collection of mutant mixes with the help of denatured capillary electrophoresis, and will in 2008 use this technique to analyze spontaneous mutations in the model systems and human DNA.

Roadmap

We would like to enhance the pipeline for SNP chips such that multiple types of platforms can be included, in addition to including association studies. In addition, we have become well known for offering genotyping of biobank material at competitive prices, with the position of being able to function as a partner for the institutions utilization of biobank material and with the goal of customizing medical treatment.

We are also completing a systematic analysis of the international SNP database (dbSNP) both with the aim of determining whether the SNP frequency is comparable to the mutations found in duplicated regions in the human genome, and we are studying whether the selection works on simple gene functions (through studies of gene ontology and SNP frequencies). We will soon publish three works in this area. We will show that DNA variation reported in international databases is contaminated with paralog sequence variation and that the frequency of CpG mutations are increasing in evolution over time.

Further characterization of the human smeltekart in conjunction with DNA variation is ongoing. We are now in a position where we have defined a subject area. We have been invited to a special number of Physics Condensed Matter where we will contribute an article tied to defining precisely how DNA can be denatured locally. We are further working on examining the correlation between melting properties and other properties of human DNA, in addition to the further development of algorithms having the goal of modeling physical properties of DNA in chromatin.

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