Understanding the Genetic Origin of Human Diseases and Natural Differences

In biology, we are now at the point where the latest advances of experimental and computational methods have opened a new perspective - quick and non-expensive DNA sequencing. Next-generation sequence technologies, among them exome sequencing, have brought the dream of individual genome identification close to reality. However, new advances in genome sequencing are necessary but not sufficient for understanding the allelic variation in human genes and identifying functionally important variants. Specific human phenotype is largely determined by stability, activity, and interactions between numerous biomolecules which work together to provide specific cellular functions. Although the majority of genetic variations are likely to be neutral, a substantial fraction of them might explain the origins of Mendelian and complex diseases. For example, somatic mutations may contribute significantly to tumorigenesis, and driver mutations may alter key signaling pathways which allow cancer cells to sustain proliferative signaling. However, finding functionally important mutations and distinguishing positively-selected from passenger mutations remains an unsolved problem.

Many computational and experimental methods have been developed to estimate the effects of mutations on proteins. Computational approaches are available to estimate the folding or binding free energy change of mutants using detailed atomic models, empirical or statistical potentials. Large-scale mutagenesis, alanine scanning, biochemical, and structural studies assess the experimental effects of mutations and amino acid substitutions on conformation, activity, and function of proteins. Discussion of new developments and new approaches in this field will be one of the main topics of this Gordon Conference. In parallel, significant efforts were invested to catalog naturally occurring genetic differences, those found in the general population (dbSNP, HGVbase, the Human Gene Mutation Database, the TopoSNP database and many others); and those known to be disease-associated (a few examples include the Online Mendelian Inheritance in Man database (OMIM) and the COSMIC database). The rapid growth of these databases and the current status of collection and categorization of genomic variation data will be another important topic of the conference. Database developers and researchers will have the opportunity to get together and bridge their research.

Another aspect of the conference is to bring together researchers working in the field of biological networks and pathways. Indeed, a defect in a single gene may sometimes be pathological, while in other cases a series of mutations in different genes are responsible for a disease. How can the understanding of biomolecular interaction networks contribute to predictions of the effects of mutations on cellular function? The conference participants will be able to share ideas about how to reveal the interplay between molecular characteristics of individual elements within a network and the network’s topological properties.

The conference will bring together people that work on diverse experimental and computational aspects related to inferring and analyzing the effect of human mutations on protein function and their role in causing cancer and rare diseases. The topic of this conference, which has not been addressed in previous Gordon meetings, will attract researchers for essential discussions and exchanging ideas. It will help to advance the field by merging genomics and proteomics approaches, and by bringing together scientists who work on the same problems from different perspectives. We especially hope that it will provide a stimulating environment where students, postdocs and junior investigators can present and discuss their research with the best minds in the field. We hope the meeting will have significant impact on the research and development in the field of genetic variations and rare mutations. We have designed a meeting agenda to include researchers from the US, Europe, and Asia, representing both basic and applied research in the field.