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Consciousness as an Emergent Property of Thalamocortical Activity

Complexity Evolution at the Molecular Level



Nature Volume: 481, 360–364  (19 January 2012)

Evolution of increased complexity in a molecular machine

Gregory C. Finnigan, Victor Hanson-Smith, Tom H. Stevens & Joseph W. Thornton

Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA

Institute for Ecology and Evolution, University of Oregon, Eugene, Oregon 97403, USA

Department of Computer and Information Science, University of Oregon, Eugene, Oregon 97403, USA

Howard Hughes Medical Institute, Eugene, Oregon 97403, USA

Departments of Human Genetics and Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA


Many cellular processes are carried out by molecular ‘machines’assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine—the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump—increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine  evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes.

Comparative genomic approaches suggest that the components of many molecular machines have appeared sequentially during evolution and that complexity increased gradually by incorporating new parts into simpler assemblies. Such horizontal analyses of extant systems, however, cannot decisively test these hypotheses or reveal the mechanisms by which additional parts became obligate components of larger complexes. In contrast, vertical approaches that combine computational phylogenetic analysis with gene synthesis and molecular assays allow changes in the sequence, structure and function of reconstructed ancestral proteins to be experimentally traced through time. Here we apply this approach to characterize the evolution of a small molecular machine and dissect the mechanisms that caused it to increase in complexity.

How complexity and novel functions evolve has been a longstanding question in evolutionary biology, because mutations that compromise existing functions are far more frequent than those that generate new ones. Our results indicate that the architectural complexity of molecular assemblies can evolve because of a few simple, relatively high-probability mutations that degrade ancestral interfaces but leave other functions intact. The specific roles of subunits Vma3 and Vma11 seem to have been acquired when duplicated genes lost some, but not all, of the capacity of the ancestral protein to participate in interactions with copies of itself and another protein required for proper ring assembly. Because complementary losses occurred in both lineages, the two descendant subunits became obligate components, and the complexity of the ring increased. It is possible that specialization of the duplicated subunits allowed increases in fitness, but genome-wide interaction screens and the phenotype of vma11Δ yeast provide no evidence that Vma11 evolved novel functions in addition to those that it inherited from Anc.3-11 in the V0 ring.

All molecular machines involve differentiated parts in specific spatial orientations, and many such complexes are entirely or partially composed of paralogous proteins. In the evolution of any such assembly, additional paralogues could become obligate components because of gene duplication and subsequent mutations that cause specific interaction interfaces among them to degenerate.

This view of the evolution of molecular machines is related to recent models that explain other biological phenomena—such as the retention of large numbers of duplicate genes and mobile genetic elements within genomes—as the product of degenerative processes acting on modular biological systems. Although mutations that enhanced the functions of individual ring components may have occurred during evolution, our data indicate that simple degenerative mutations are sufficient to explain the historical increase in complexity of a crucial molecular machine. There is no need to invoke the acquisition of ‘novel’ functions caused by low-probability mutational combinations.

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