Origins of the Adaptive Immune Systems: New Functions for Old Players

The presented project proposal attempts to investigate the evolution and molecular gene regulation of the adaptive immune system. As part of the project we will develop and implement new algorithmic approaches in bioinformatics and genomics and present them as free software to the scientific community. The adaptive immune system of vertebrates is capable of specifically responding to certain infective agents with a high degree of efficiency. It is capable of learning, by means that it remembers antigens that it was exposed to formerly, and reacts to them with higher efficiency in following exposures to the same type of infection. Regarding its high degree of selectivity and adaptation it strongly differs from the innate immune system that is existent in animals and plants, and even some bacteria. Adaptive immunity suddenly emerged as a consequence of some widespread genomic events about 500 million years ago during early evolution of vertebrates, and it is highly complex in organization and regulation. Many of its components cannot be traced back to their origins according to our current level of knowledge. Main components are immunoglobulins (IG), the major histocompatibility complex (MHC), and T-cell receptors (TCR). IGs bind and mark free antigens in the blood stream. TCRs are aimed against intracellular pathogens; those are presented as processed antigens on the cell surface to the TCRs by the MHC. Various factors of adaptive immunity contain IG-domains which are a widely common motif in this context. But the most outstanding characteristic of immunoglobulins and T-cell receptors is their ability to undergo somatic recombination. The Rag genes (rearranging genes) encode these fundamental mechanisms. In principle, it is assumed that some components of adaptive immunity derived their function de novo, while others represent modifications of older functions. The evolution of this new network of genes probably features regulatory functions that are of main importance for our global understanding of the adaptive immune system. The presented approach starts with collecting and evaluating all available sequence data concerning the origin of the adaptive immune system. We will detect exhaustively regulatory upstream elements and use them to build a multiple alignment of regulatory sequences with a high degree of reliability in biological terms. We plan to develop and implement an algorithm that automatically detects all possible conserved RNA secondary structure elements of any length within the alignment, and reliably brings these structures into correlation to all detected conserved sequence motifs. So we will be able to precisely distinguish conserved sequence based signals from conserved non- protein-coding RNA genes. We emphasize not to miss possible long range - interactions on RNA structure level, and we will also be in the position to give each sequence position a phylogenetic weight. Based on this highly differentiated information we will carry out functional and phylogenetic analyses that will allow us to fully incorporate distinctions between conserved and non-conserved (functional and less functional) elements which act as signals on a DNA level or as structured RNAs, we will gain deeper insight into the organization of regulatory upstream regions. We plan to detect correlations between the evolution of protein coding genes, and the evolution of their concerning regulatory elements. We expect new insight into the evolutionary process behind the emergence of a genetic system that is complex in structure and regulation, and which comprises a network of manifold encoded signals and factors that are reciprocally regulated and co-evolve.