Pleiotropic constraints promote the evolution of cooperation in cellular groups

The evolution of cooperation in cellular groups is threatened by lineages of cheaters that proliferate at the expense of the group. These cell lineages occur within microbial communities, and multicellular organisms in the form of tumours and cancer. In contrast to an earlier study, here we show how the evolution of pleiotropic genetic architectures—which link the expression of cooperative and private traits—can protect against cheater lineages and allow cooperation to evolve. We develop an age-structured model of cellular groups and show that cooperation breaks down more slowly within groups that tie expression to a private trait than in groups that do not. We then show that this results in group selection for pleiotropy, which strongly promotes cooperation by limiting the emergence of cheater lineages. These results predict that pleiotropy will rapidly evolve, so long as groups persist long enough for cheater lineages to threaten cooperation. Our results hold when pleiotropic links can be undermined by mutations, when pleiotropy is itself costly, and in mixed-genotype groups such as those that occur in microbes. Finally, we consider features of multicellular organisms—a germ line and delayed reproductive maturity—and show that pleiotropy is again predicted to be important for maintaining cooperation. The study of cancer in multicellular organisms provides the best evidence for pleiotropic constraints, where abberant cell proliferation is linked to apoptosis, senescence, and terminal differentiation. Alongside development from a single cell, we propose that the evolution of pleiotropic constraints has been critical for cooperation in many cellular groups.

The evolution of cooperation in cellular groups is threatened by lineages of cheaters that proliferate at the expense of the group. In this study, an age-structured model of cellular groups shows that pleiotropy promotes the evolution of cooperation and may have been important for the origins of multicellularity.     

Molecular evolution of the vesicle coat component betaCOP in Toxoplasma gondii

Coatomer coated (COPI) vesicles play a pivotal role for multiple membrane trafficking steps throughout the eukaryotic cell. Our focus is on betaCOP, one of the most well known components of the COPI multi-protein complex. Amino acid differences in betaCOP may dictate functional divergence across species during the course of evolution, especially with regards to the evolutionary pressures on obligate intracellular parasites. A bioinformatic analysis of betaCOP amino acid sequences was conducted for 49 eukaryotic species. Cloning and sequence analysis of the Toxoplasma gondii betaCOP homologue revealed several amino acid insertions unique to T. gondii and one C-terminal insertion that is unique to apicomplexan parasites. These findings led us to investigate the possibility that betaCOP experienced functional divergence during the course of its evolution. Bayesian phylogenetic analysis revealed a tree consistent with pan eukaryote distribution and long-branch lengths were observed among the apicomplexans. Further analysis revealed that kinetoplast betaCOP underwent the most amount of change, leading to perhaps an overall change of function. In comparison, T. gondii exhibited subtle yet specific amino acid changes. The amino acid substitutions did not occur in the same places as other lineages, suggesting that TgbetaCOP has a role specific to the apicomplexans. Our work identifies 48 residues that are likely to be functionally important when comparing apicomplexan, kinetoplastid, and fungal betaCOP.     

Molecular engineering of exocytic vesicle traffic enhances the productivity of Chinese hamster ovary cells

A complex vesicle trafficking system manages the precise and regulated distribution of proteins, membranes and other molecular cargo between cellular compartments as well as the secretion of (heterologous) proteins in mammalian cells. Sec1/Munc18 (SM) proteins are key components of the system by regulating membrane fusion. However, it is not clear how SM proteins contribute to the overall exocytosis. Here, functional analysis of the SM protein Sly1 and Munc18c suggested a united, positive impact upon SNARE-based fusion of ER-to-Golgi- and Golgi-to-plasma membrane-addressed exocytic vesicles and increased the secretory capacity of different therapeutic proteins in Chinese hamster ovary cells up to 40 pg/cell/day. Sly1- and Munc18c-based vesicle traffic engineering cooperated with Xbp-1-mediated ER/Golgi organelle engineering. Our study supports a model for united function of SM proteins in stimulating vesicle trafficking machinery and provides a generic secretion engineering strategy to improve biopharmaceutical manufacturing of important protein therapeutics.     

Genetic constraints on protein evolution

Evolution requires the generation and optimization of new traits ("adaptation") and involves the selection of mutations that improve cellular function. These mutations were assumed to arise by selection of neutral mutations present at all times in the population. Here we review recent evidence that indicates that deleterious mutations are more frequent in the population than previously recognized and that these mutations play a significant role in protein evolution through continuous positive selection. Positively selected mutations include adaptive mutations, i.e. mutations that directly affect enzymatic function, and compensatory mutations, which suppress the pleiotropic effects of adaptive mutations. Compensatory mutations are by far the most frequent of the two and would allow potentially adaptive but deleterious mutations to persist long enough in the population to be positively selected during episodes of adaptation. Compensatory mutations are, by definition, context-dependent and thus constrain the paths available for evolution. This provides a mechanistic basis for the examples of highly constrained evolutionary landscapes and parallel evolution reported in natural and experimental populations. The present review article describes these recent advances in the field of protein evolution and discusses their implications for understanding the genetic basis of disease and for protein engineering in vitro.     

Physiopathologic dynamics of vesicle traffic in astrocytes

The view of how astrocytes, a type of glial cells, contribute to the functioning of the central nervous system (CNS) has changed greatly in the last decade. Although glial cells outnumber neurons in the mammalian brain, it was considered for over a century that they played a subservient role to neurons. This view changed. Functions thought to be exclusively present in neurons, i.e. excitability mediated release of chemical messengers, has also been demonstrated in astrocytes. In this process, following an increase in cytosolic calcium activity, membrane bound vesicles, storing chemical messengers (gliotransmitters), fuse with the plasma membrane, a process known as exocytosis, permitting the exit of vesicle cargo into the extracellular space. Vesicles are delivered to and are removed from the site of exocytosis by an amazingly complex set of processes that we have only started to learn about recently. In this paper we review vesicle traffic, which is subject to physiological regulation and may be changed under pathological conditions.     

Molecular features and functional constraints in the evolution of the mammalian X chromosome

Recent advances in genomic sequencing of multiple organisms have fostered significant advances in our understanding of the evolution of the sex chromosomes. The integration of this newly available sequence information with functional data has facilitated a considerable refinement of our conceptual framework of the forces driving this evolution. Here we address multiple functional constraints that were encountered in the evolution of the X chromosome and the impact that this evolutionary history has had on its modern behavior.     

Selective constraints on P-element evolution.

P elements, like mariners, inhabit eukaryotic genomes and transpose via a DNA intermediate. Mutant and wild-type elements in the same genome should be transposed with equal probability by trans-acting transposase, and so no selection should counteract the accumulation of inactivating mutations in transposase genes. Thus, copies of mariner elements diverge within a host species under no selection (Robertson and Lampe 1995). It is unknown whether or not this pattern holds for P elements, which are unrelated to mariner elements but share the same life history. Publicly available P-element sequences were analyzed for evidence of conservative selection for the function of P-element-encoded proteins. Results were compared to predictions derived from several hypotheses that could explain selection, or the lack of it. P-element protein-coding sequences do evolve under conservative selection but apparently because of more than one selective force. Of the four exons in the P-element transposase, the first three (exons 0, 1, and 2) can be translated alone into a repressor of transposition, while the last (exon 3) is only expressed as part of the full-length transposase and probably serves a transposition-specific role. As full-length P-element copies diverge from each other within a host population, selection maintains exons 0-2 but apparently not exon 3. The selection acting on exons 0-2 may act at the host level for repression of transposition (since host level selection does act on orthologous truncated elements that contain only exons 0-2). Evidence of selection on exon 3 is only found in comparisons of more diverged elements from different species, suggesting that selection for transposition acts primarily at horizontal transfer events. Thus, horizontal transfer events may be the sole source of the selection that is crucial to the maintenance of autonomous P elements in the face of mutation (as suggested by Robertson and Lampe 1995). The predictions derived here suggest a strategy for collecting sequence data that could definitively answer these questions.     

Selective constraints on intron evolution in Drosophila

Intron sizes show an asymmetrical distribution in a number of organisms, with a large number of "short" introns clustered around a minimal intron length and a much broader distribution of longer introns. In Drosophila melanogaster, the short intron class is centered around 61 bp. The narrow length distribution suggests that natural selection may play a role in maintaining intron size. A comparison of 15 orthologous introns among species of the D. melanogaster subgroup indicates that, in general, short introns are not under greater DNA sequence or length constraints than long introns. There is a bias toward deletions in all introns (deletion/insertion ratio is 1.66), and the vast majority of indels are of short length (<10 bp). Indels occurring on the internal branches of the phylogenetic tree are significantly longer than those occurring on the terminal branches. These results are consistent with a compensatory model of intron length evolution in which slightly deleterious short deletions are frequently fixed within species by genetic drift, and relatively rare larger insertions that restore intron length are fixed by positive selection. A comparison of paralogous introns shared among duplicated genes suggests that length constraints differ between introns within the same gene. The janusA, janusB, and ocnus genes share two short introns derived from a common ancestor. The first of these introns shows significantly fewer indels than the second intron, although the two introns show a comparable number of substitutions. This indicates that intron-specific selective constraints have been maintained following gene duplication, which preceded the divergence of the D. melanogaster species subgroup.     

Atmospheric constraints on the evolution of metabolism

Earth's early history may have been characterized by coevolution of microbial metabolism and atmospheric composition. Metabolic developments affected the composition of the atmosphere and the resultant changes in the atmosphere stimulated the evolution of new metabolic capabilities.The first organisms were presumably fermenting heterotrophs, exploiting organic molecules abiotically synthesized. These organisms multiplied, developing new biosynthetic capabilities to overcome deficiencies in the abiotic supply of particular compounds, until their growth was limited by the energy source provided by abiotic synthesis of fermentable organic compounds. Further growth required a new energy source, which may have been the chemical energy represented by the mixture of carbon dioxide and hydrogen in the primitive atmosphere. Chemotrophic organisms resembling methane bacteria may have evolved to exploit this source. They would have flourished, along with the heterotrophs that fed on them, until they had decreased the level of atmospheric hydrogen to the point where further extraction of chemical energy from the atmosphere was not possible. Once again, the expansion of life was limited by the availability of energy.The origin of bacterial photosynthesis overcame the second energy crisis. Photosynthetic bacteria could exploit the abundant energy of sunlight while using atmospheric hydrogen and reduced compounds derived from it only as electron donors. Life flourished again, drawing atmospheric hydrogen (replenished only by volcanoes) down to levels so low as to limit even bacterial photosynthesis. Before the full potential of photosynthesis could be exploited the evolution of the metabolic apparatus to process an electron donor of unlimited abundance was necessary. This donor, of course, was water, and the new metabolic process was algal photosynthesis. The oxygen released changed the world from anaerobic to aerobic and made possible the last great advance in energy-yielding metabolism, aerobic respiration.Proceedings of the Fourth College Park Colloquium on Chemical Evolution:Limits of Life, University of Maryland, College Park, 18–20 October 1978.     

Molecular and spatial constraints on NB-LRR receptor signaling

In plants, a large polymorphic family of intracellular NB-LRR receptors lies at the heart of robust resistance to diverse pathogens and mechanisms by which these versatile molecular switches operate in effector-triggered immunity are beginning to emerge. We outline recent advances in our understanding of NB-LRR receptor signaling leading to disease resistance. Themes covered are (i) NB-LRR molecular constraining forces and their intimate relationship with receptor activation in different parts of the cell, (ii) cooperativity between NB-LRR proteins and the formation of higher order NB-LRR signaling complexes, and (iii) the spatial separation of different resistance branches within cells. Finally, we examine evidence for dynamic signaling across cell compartments in coordinating diverse immune outputs.     

Molecular and cellular changes associated with the evolution of novel jaw muscles in parrots

Vertebrates have achieved great evolutionary success due in large part to the anatomical diversification of their jaw complex, which allows them to inhabit almost every ecological niche. While many studies have focused on mechanisms that pattern the jaw skeleton, much remains to be understood about the origins of novelty and diversity in the closely associated musculature. To address this issue, we focused on parrots, which have acquired two anatomically unique jaw muscles: the ethmomandibular and the pseudomasseter. In parrot embryos, we observe distinct and highly derived expression patterns for Scx, Bmp4, Tgfβ2 and Six2 in neural crest-derived mesenchyme destined to form jaw muscle connective tissues. Furthermore, immunohistochemical analysis reveals that cell proliferation is more active in the cells within the jaw muscle than in surrounding connective tissue cells. This biased and differentially regulated mode of cell proliferation in cranial musculoskeletal tissues may allow these unusual jaw muscles to extend towards their new attachment sites. We conclude that the alteration of neural crest-derived connective tissue distribution during development may underlie the spatial changes in jaw musculoskeletal architecture found only in parrots. Thus, parrots provide valuable insights into molecular and cellular mechanisms that may generate evolutionary novelties with functionally adaptive significance.     

Molecular mechanisms of COPII vesicle formation

The first step in protein secretion from eukaryotic cells is mediated by COPII vesicles, known for the cytoplasmic coat proteins that are the minimal machinery required to generate these small transport carriers. The five COPII coat components coordinate to create a vesicle by locally generating membrane curvature and populating the incipient bud with the appropriate cargo. This review describes the molecular details of how the COPII coat sculpts vesicles from the endoplasmic reticulum and highlights some unresolved questions regarding the regulation of this process in the complex environment of the eukaryotic cell.