From gene to genome as an integrated system . Scientific , historical , and philosophical perspectives

Ramon Birnbaum, Ben-Gurion University of the Negev Genomic view of gene regulatory elements and their role in human disease As less than 2% of our genome codes for proteins, the majority of our genome (>98%) encompasses important sequences that function as gene regulatory elements, instructing genes when, where and at what levels to turn ON or OFF. Increasing evidences suggest that non-coding variation is a significant risk factor for human disease, but how these variants contribute to the phenotype remain elusive. In my talk, I will focus on distal transcription enhancers that promote gene expression, enabling spatiotemporal control of genetic programs such as those required in developmental processes. I will describe how to identify and functionally characterize enhancers and I will describe several examples of how mutations in these elements have been found to cause human disease. As the sequencing technologies tremendously improved, our ability to identify disease-associated mutations in these regulatory elements is rapidly increasing. Thus, deciphering the regulatory code is necessary to accelerate our basic knowledge about the human genome and diseases. Eric Davidson, Caltech Evolutionary perspectives on developmental gene regulatory network structure/function: the causal bases of phylogeny, of body plan stasis, and of innovation in deep time Evolution of the animal body plan is the outcome of change in the encoded genomic regulatory program for development. Major features of Phanerozoic animal evolution relate directly to developmental GRN hierarchy. In this Chapter, we consider rapid and continuously adaptive changes occurring at the species level, in terms of regulation of effector gene expression at the periphery of developmental GRNs. Developmental processes responsible for the generation of definitive characters of the body plan shared amongst all members of given phyla or classes occur at upper levels of GRN hierarchy. We discuss regulatory mechanisms accounting for the evolutionary stasis of such developmental characters. Evolutionary mechanisms operating at different levels of GRN hierarchy are fundamentally distinct, ranging from cis-regulatory adaptation at individual genes to co-optive redeployment of whole regulatory circuits. Conservation of regulatory circuitry within GRN hierarchy leads to an explanation for the nested organization of shared character sets underlying animal phylogeny. Eric Davidson, Caltech Formalizing the genomic logic of spatial gene regulation in development Developmental process operates as an automaton in which the inputs that control each successive step are the outputs of the prior steps. We show that if knowledge of the regulatory molecular biology of a developmental process is sufficiently complete, this essential property of state progression in life can be captured in a Boolean automaton model. The consequence is the demonstration that genomically encoded logic processing causes development. Recently such analysis has been extended to almost the whole of an embryo, diminishing to insignificance the external inputs, and providing a direct path to abstract visualization of the organism as an entirely self-sufficient mechanism that operates by processing internally generated regulatory information. Ute Deichmann, Ben-Gurion University of the Negev Chromatin Its history, the seminal researchers and their philosophy The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. The interest in chromatin declined rapidly at the beginning of the 20th century. Only decades later, a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. I will highlight the major milestones in chromatin research, analyze its decline and reappearance, and introduce the major investigators and their scientific and philosophical context. Nir Friedman, Weizmann Institute of Science Acquired immunity for all: somatic processes allow individuals to learn from their own