Organisational Relativity—Changing Our Perspective on Health and Health Care

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD. Copyright © 2013 Elsevier Inc. All rights reserved.

Adaptive radiation is defined as the evolution of ecological and phenotypic diversity within a rapidly multiplying lineage. When it occurs, adaptive radiation typically follows the colonization of a new environment or the establishment of a "key innovation," which opens new ecological niches and/or new paths for evolution. Here, we take advantage of recent developments in speciation theory and modern computing power to build and explore a large-scale, stochastic, spatially explicit, individual-based model of adaptive radiation driven by adaptation to multidimensional ecological niches. We are able to model evolutionary dynamics of populations with hundreds of thousands of sexual diploid individuals over a time span of 100,000 generations assuming realistic mutation rates and allowing for genetic variation in a large number of both selected and neutral loci. Our results provide theoretical support and explanation for a number of empirical patterns including "area effect," "overshooting effect," and "least action effect," as well as for the idea of a "porous genome." Our findings suggest that the genetic architecture of traits involved in the most spectacular radiations might be rather simple. We show that a great majority of speciation events are concentrated early in the phylogeny. Our results emphasize the importance of ecological opportunity and genetic constraints in controlling the dynamics of adaptive radiation.