Centre of Excellence in Genomics

Joint Research Activities

One may notice that the 7-year period of the project cannot, in our fast-moving fields, be planned at the level of detailed experiments. Therefore, and because of already mentioned severe space limits, we can provide hereby only brief overview and description of some joint research activities planned within the first years. Proposed CoE in Genomics will perform innovative, cutting edge research in studying human genome. Our main focus will be on genome variation, on genetics of human diseases, human evolution and migrations, and computational methods for studying genomes. In a few years time we will extend our technological capacity to second generation sequencing technology and will increase further our existing high-throughput genotyping platforms. In addition to DNA studies we will perform large-scale analyses of RNA, biomarkers and epigenetic effects and plan to extend our work to metabolomics and molecular structural biology. The planned research relies equally so on extensive use of bioinformatics and biostatistics for analysis of the data obtained from the high-throughput technological platforms and other methods. This is reflected in our budget which devotes a large share of resources to consumables.

Synergy between partners

Need for synergy and substantial gain from it as an added value has been obvious for all the teams involved already for some time and was also used, though sporadically. As for molecular evolution team, analyzing haploid genomes does not raise major bioinformatics challenges. However, scenarios potentially involving interplay of adaptive sweeps, convergent evolution, natural selection versus random processes in phenotypic change and a myriad of other factors comprise a formidable analytical challenge. To build up an independent bioinformatics group "of its own", in particular in a (very) small country, would be a waste of resources. In turn, it is equally so that the experience of the molecular evolution team in the reconstruction of the origin of genetic structure of human populations is an asset in a long way in making the best out of the Estonian Genome Project, while the very problems they face, are intellectually challenging for the development of bioinformatics. Likewise, the human genetics and the molecular evolution teams share much in technical approaches and the latter will learn a lot from the search of "candidate genes" of common diseases. As for the bioinformatics team, close link with technologically powerful "wet labs" would allow for them a quite unique opportunity to design their own wet lab experiments to test new algorithms. Finally, an intellectual environment where dedicated team of bioinformaticists participates from the very beginning in the design of high-throughput experiments, would certainly allow now and then to avoid costly pitfalls. Indirect organizational elements like regular joint monthly work seminars and "journal clubs" will further facilitate close intellectual contacts between the members of teams involved.

Synergy in human capital development

Though this aspect of synergy is very important, we mention here only briefly that independent sizable sums are already available for the consortium for a search of new post-doc level talents from other countries via the aforementioned FP7 ECOGENE grant, as well as other open schemes.

Synergy in sharing equipment and infrastructure

Though intellectual synergy lies in the foundation of the consortium, it would be supercilious to neglect aspects related to experimental research, because both equipment and their running costs are considerable in genomics. Hence, "free sharing" of analyzers, as well as costs for skilled technical personnel, promises sizable gains. In particular because Estonian Biocentre plans to obtain a next-generation sequencing equipment (as an extension and further modernization of its DNA Sequencing and Genotyping Core Facility) perhaps at the end of 2009 - first half of 2010. Since these technologies only start to emerge and spread, at present we collaborate closely with a few labs in Europe and USA, running different platforms (Roche 454, Illumina Genome Analyzer, ABI SOLiD). It helps us to make our final choice in the next year. The choice might as well be in using services of commercial providers of these technologies.

Some examples of planned research activities

We provide a list of some initial research plans where added value from combined efforts is a priori apparent.

Relationship between genes and various human traits. We plan to use genome-wide association approach for studying several different phenotypes using case-control and cohort studies (e.g., nicotine addiction, panic disorder, antidepressant responders-non-responders, personality traits, differences between early-active and late-active people). Genes related to skin color pigmentation will be studied on samples from South Asia, Near East and Europe, of donors with quantitatively estimated skin colour indexes. Other phenotypes planned to study in collaboration with colleagues from Cambridge, include, among others, "the pygmy phenotype" from populations from South Asia, Philippines and sub-Saharan Africa in order to understand phenotype-genotype interactions of this particular phenotype.

Genes and infertility. Infertility is a complex phenotype with strong genetic component which, if known, could be used in counselling of infertile couples and improves the IVF outcome. We shall develop an APEX based SNP microarray using candidate gene approach for analysis of genetic variations associated with implantation failure, and perform a case-control association study of candidate gene variations contributing susceptibility to implantation failure.

Genetic variation and mental retardation. Mapping genetic variation of mental retardation patients from Eastern Europe is planned with extensive characterization of their chromosomal rearrangements (CNVs) using Illumina microarrays. Corresponding database that stores information about locations of CNV and phenotype data will be created and web-interface will be created for public use.

Computational analysis of genome rearrangements. One line of work that utilizes microarray and sequencing data is computational genome analysis. One planned project will be computational discovery of inversions and other structural variations in genome sequences using raw sequencing data (traces). Potential rearrangements of the genome will be validated in wet lab laboratories.

Natural selection in admixture zones. Another sub-project in a planning stage which will essentially extend our previous studies will concentrate on "continental admixture zones" both in East-West and South-North dimensions. We cannot predict what exactly will emerge, but the search will seek for the detection and characterization of putative signals of natural selection in human populations as a consequence of occupation of different habitats, changes in nutrition and other environmental aspects. If such patterns will be found, we will make attempts to understand biochemical-physiological mechanisms, using already "postgenomic" approaches.

Several of the listed concrete projects would include colleagues and labs from Europe, USA and Asia.

We trust that the CoE, if financed, would be in a good starting position to reach one of the central goals of the proposal - to be intellectually resourceful in exploring the wealth of the "mature" Estonian biobank from 2010 onwards.

Estonian Biocentre | Riia 23b, 51010 Tartu, Estonia | Update