The Origins of Cellular Life

Understanding the origin of cellular life on Earth requires the discovery of plausible pathways for the transition from complex prebiotic chemistry to simple biology, defined as the emergence of chemical assemblies capable of Darwinian evolution. We have proposed that a simple primitive cell, or protocell, would consist of two key components: a protocell membrane that defines a spatially localized compartment, and an informational polymer that allows for the replication and inheritance of functional information. Recent studies of vesicles composed of fatty-acid membranes have shed considerable light on pathways for protocell growth and division, as well as means by which protocells could take up nutrients from their environment. Additional work with genetic polymers has provided insight into the potential for chemical genome replication and compatibility with membrane encapsulation. The integration of a dynamic fatty-acid compartment with robust, generalized genetic polymer replication would yield a laboratory model of a protocell with the potential for classical Darwinian biological evolution, and may help to evaluate potential pathways for the emergence of life on the early Earth. Here we discuss efforts to devise such an integrated protocell model.The emergence of the first cells on the early Earth was the culmination of a long history of prior chemical and geophysical processes. Although recognizing the many gaps in our knowledge of prebiotic chemistry and the early planetary setting in which life emerged, we will assume for the purpose of this review that the requisite chemical building blocks were available, in appropriate environmental settings. This assumption allows us to focus on the various spontaneous and catalyzed assembly processes that could have led to the formation of primitive membranes and early genetic polymers, their coassembly into membrane-encapsulated nucleic acids, and the chemical and physical processes that allowed for their replication. We will discuss recent progress toward the construction of laboratory models of a protocell (Fig. 1), evaluate the remaining steps that must be achieved before a complete protocell model can be constructed, and consider the prospects for the observation of spontaneous Darwinian evolution in laboratory protocells. Although such laboratory studies may not reflect the specific pathways that led to the origin of life on Earth, they are proving to be invaluable in uncovering surprising and unanticipated physical processes that help us to reconstruct plausible pathways and scenarios for the origin of life.Open in a separate windowFigure 1.A simple protocell model based on a replicating vesicle for compartmentalization, and a replicating genome to encode heritable information. A complex environment provides lipids, nucleotides capable of equilibrating across the membrane bilayer, and sources of energy (left), which leads to subsequent replication of the genetic material and growth of the protocell (middle), and finally protocellular division through physical and chemical processes (right). (Reproduced from Mansy et al. 2008 and reprinted with permission from Nature Publishing ©2008.)The term protocell has been used loosely to refer to primitive cells or to the first cells. Here we will use the term protocell to refer specifically to cell-like structures that are spatially delimited by a growing membrane boundary, and that contain replicating genetic information. A protocell differs from a true cell in that the evolution of genomically encoded advantageous functions has not yet occurred. With a genetic material such as RNA (or perhaps one of many other heteropolymers that could provide both heredity and function) and an appropriate environment, the continued replication of a population of protocells will lead inevitably to the spontaneous emergence of new coded functions by the classical mechanism of evolution through variation and natural selection. Once such genomically encoded and therefore heritable functions have evolved, we would consider the system to be a complete, living biological cell, albeit one much simpler than any modern cell (Szostak et al. 2001).     

Proteome Oxidative Modifications and Impairment of Specific Metabolic Pathways During Cellular Senescence and Aging

Accumulation of oxidatively modified proteins is a hallmark of organismal aging in vivo and of cellular replicative senescence in vitro. Failure of protein maintenance is a major contributor to the age‐associated accumulation of damaged proteins that is believed to participate to the age‐related decline in cellular function. In this context, quantitative proteomics approaches, including 2‐D gel electrophoresis (2‐DE)‐based methods, represent powerful tools for monitoring the extent of protein oxidative modifications at the proteome level and for identifying the targeted proteins, also referred as to the “oxi‐proteome.” Previous studies have identified proteins targeted by oxidative modifications during replicative senescence of human WI‐38 fibroblasts and myoblasts and have been shown to represent a restricted set within the total cellular proteome that fall in key functional categories, such as energy metabolism, protein quality control, and cellular morphology. To provide mechanistic support into the role of oxidized proteins in the development of the senescent phenotype, untargeted metabolomic profiling is also performed for young and senescent myoblasts and fibroblasts. Metabolomic profiling is indicative of energy metabolism impairment in both senescent myoblasts and fibroblasts, suggesting a link between oxidative protein modifications and the altered cellular metabolism associated with the senescent phenotype of human myoblasts and fibroblasts.     

Origin and Evolution of the Mitochondrial Proteome

The endosymbiotic theory for the origin of mitochondria requires substantial modification. The three identifiable ancestral sources to the proteome of mitochondria are proteins descended from the ancestral α-proteobacteria symbiont, proteins with no homology to bacterial orthologs, and diverse proteins with bacterial affinities not derived from α-proteobacteria. Random mutations in the form of deletions large and small seem to have eliminated nonessential genes from the endosymbiont-mitochondrial genome lineages. This process, together with the transfer of genes from the endosymbiont-mitochondrial genome to nuclei, has led to a marked reduction in the size of mitochondrial genomes. All proteins of bacterial descent that are encoded by nuclear genes were probably transferred by the same mechanism, involving the disintegration of mitochondria or bacteria by the intracellular membranous vacuoles of cells to release nucleic acid fragments that transform the nuclear genome. This ongoing process has intermittently introduced bacterial genes to nuclear genomes. The genomes of the last common ancestor of all organisms, in particular of mitochondria, encoded cytochrome oxidase homologues. There are no phylogenetic indications either in the mitochondrial proteome or in the nuclear genomes that the initial or subsequent function of the ancestor to the mitochondria was anaerobic. In contrast, there are indications that relatively advanced eukaryotes adapted to anaerobiosis by dismantling their mitochondria and refitting them as hydrogenosomes. Accordingly, a continuous history of aerobic respiration seems to have been the fate of most mitochondrial lineages. The initial phases of this history may have involved aerobic respiration by the symbiont functioning as a scavenger of toxic oxygen. The transition to mitochondria capable of active ATP export to the host cell seems to have required recruitment of eukaryotic ATP transport proteins from the nucleus. The identity of the ancestral host of the α-proteobacterial endosymbiont is unclear, but there is no indication that it was an autotroph. There are no indications of a specific α-proteobacterial origin to genes for glycolysis. In the absence of data to the contrary, it is assumed that the ancestral host cell was a heterotroph.     

The Proteome Folding Problem and Cellular Proteostasis

Stunning advances have been achieved in addressing the protein folding problem, providing deeper understanding of the mechanisms by which proteins navigate energy landscapes to reach their native states and enabling powerful algorithms to connect sequence to structure. However, the realities of the in vivo protein folding problem remain a challenge to reckon with. Here, we discuss the concept of the “proteome folding problem”—the problem of how organisms build and maintain a functional proteome—by admitting that folding energy landscapes are characterized by many misfolded states and that cells must deploy a network of chaperones and degradation enzymes to minimize deleterious impacts of these off-pathway species. The resulting proteostasis network is an inextricable part of in vivo protein folding and must be understood in detail if we are to solve the proteome folding problem. We discuss how the development of computational models for the proteostasis network’s actions and the relationship to the biophysical properties of the proteome has begun to offer new insights and capabilities.     

Compensatory Evolution and the Origins of Innovations

Cryptic genetic sequences have attenuated effects on phenotypes. In the classic view, relaxed selection allows cryptic genetic diversity to build up across individuals in a population, providing alleles that may later contribute to adaptation when co-opted—e.g., following a mutation increasing expression from a low, attenuated baseline. This view is described, for example, by the metaphor of the spread of a population across a neutral network in genotype space. As an alternative view, consider the fact that most phenotypic traits are affected by multiple sequences, including cryptic ones. Even in a strictly clonal population, the co-option of cryptic sequences at different loci may have different phenotypic effects and offer the population multiple adaptive possibilities. Here, we model the evolution of quantitative phenotypic characters encoded by cryptic sequences and compare the relative contributions of genetic diversity and of variation across sites to the phenotypic potential of a population. We show that most of the phenotypic variation accessible through co-option would exist even in populations with no polymorphism. This is made possible by a history of compensatory evolution, whereby the phenotypic effect of a cryptic mutation at one site was balanced by mutations elsewhere in the genome, leading to a diversity of cryptic effect sizes across sites rather than across individuals. Cryptic sequences might accelerate adaptation and facilitate large phenotypic changes even in the absence of genetic diversity, as traditionally defined in terms of alternative alleles.     

Functional Diversity and Evolution of the Drosophila Sperm Proteome

Spermatozoa are central to fertilization and the evolutionary fitness of sexually reproducing organisms. As such, a deeper understanding of sperm proteomes (and associated reproductive tissues) has proven critical to the advancement of the fields of sexual selection and reproductive biology. Due to their extraordinary complexity, proteome depth-of-coverage is dependent on advancements in technology and related bioinformatics, both of which have made significant advancements in the decade since the last Drosophila sperm proteome was published. Here, we provide an updated version of the Drosophila melanogaster sperm proteome (DmSP3) using improved separation and detection methods and an updated genome annotation. Combined with previous versions of the sperm proteome, the DmSP3 contains a total of 3176 proteins, and we provide the first label-free quantitation of the sperm proteome for 2125 proteins. The top 20 most abundant proteins included the structural elements α- and β-tubulins and sperm leucyl-aminopeptidases. Both gene content and protein abundance were significantly reduced on the X chromosome, consistent with prior genomic studies of X chromosome evolution. We identified 9 of the 16 Y-linked proteins, including known testis-specific male fertility factors. We also identified almost one-half of known Drosophila ribosomal proteins in the DmSP3. The role of this subset of ribosomal proteins in sperm is unknown. Surprisingly, our expanded sperm proteome also identified 122 seminal fluid proteins (Sfps), proteins originally identified in the accessory glands. We show that a significant fraction of ‘sperm-associated Sfps’ are recalcitrant to concentrated salt and detergent treatments, suggesting this subclass of Sfps are expressed in testes and may have additional functions in sperm, per se. Overall, our results add to a growing landscape of both sperm and seminal fluid protein biology and in particular provides quantitative evidence at the protein level for prior findings supporting the meiotic sex-chromosome inactivation model for male-specific gene and X chromosome evolution.     

The Origins and Evolution of Culture

This article outlines a deductive theory that creates a new way to think about the origins and evolution of culture. It is Darwinian in the sense that it posits that novel concepts and behavior, like novel genes, appear randomly and are subject to selection on the basis of specific criteria that are established by the properties of living things. The theory permits us to hypothesize properties of the genome that generate culture and to infer the conditions under which selection would favor the origins of culture. Theoretical deductions lead to the conclusion that the organisms that create culture actively participate in the creation of descendants who exhibit increasing cultural abilities and who generate increases in productivity and more reliable flows of resources. Culture is not something that has evolved solely and relatively recently in the hominid line of evolution. Fossil evidence suggests that culture may have existed at least 50 million years ago, and may have originated more than 200 million years ago.     

Origins and Evolution of Antibiotic Resistance

Summary: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man''s overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.     

The Evolution of Human Origins

Because humans are the product of our evolutionary past, learning how we evolved is fundamental to all anthropological investigations. We now realize that reconstructing why unique human attributes evolved requires an understanding of our starting point, but this is a relatively recent perspective. One hundred years ago, the question of human origins was identical to that of hominin origins. Accepting Australopithecus into human ancestry, coupled with the modern synthesis of evolution, led anthropologists to consider humans as products of natural selection. They realized that increased intelligence did not initially distinguish our lineage, and that early hominins were apelike in many ways. Australopithecus brought bipedalityr and brain expansion came with Homo . Because the human mind and behavior are products of evolution, we must reconstruct the selective pressures that shaped our lineage in order to understand ourselves today. Paleoanthropology, as with all anthropology, is becoming ever more question oriented, drawing on many areas of inquiry. [Keywords: human origins, human evolution, history, data, theory]     

Global Self-Regulation of the Cellular Metabolic Structure

Background

Different studies have shown that cellular enzymatic activities are able to self-organize spontaneously, forming a metabolic core of reactive processes that remain active under different growth conditions while the rest of the molecular catalytic reactions exhibit structural plasticity. This global cellular metabolic structure appears to be an intrinsic characteristic common to all cellular organisms. Recent work performed with dissipative metabolic networks has shown that the fundamental element for the spontaneous emergence of this global self-organized enzymatic structure could be the number of catalytic elements in the metabolic networks.

Methodology/Principal Findings

In order to investigate the factors that may affect the catalytic dynamics under a global metabolic structure characterized by the presence of metabolic cores we have studied different transitions in catalytic patterns belonging to a dissipative metabolic network. The data were analyzed using non-linear dynamics tools: power spectra, reconstructed attractors, long-term correlations, maximum Lyapunov exponent and Approximate Entropy; and we have found the emergence of self-regulation phenomena during the transitions in the metabolic activities.

Conclusions/Significance

The analysis has also shown that the chaotic numerical series analyzed correspond to the fractional Brownian motion and they exhibit long-term correlations and low Approximate Entropy indicating a high level of predictability and information during the self-regulation of the metabolic transitions. The results illustrate some aspects of the mechanisms behind the emergence of the metabolic self-regulation processes, which may constitute an important property of the global structure of the cellular metabolism.     

The Metabolic Origins of Mannose in Glycoproteins

Mannose in N-glycans is derived from glucose through phosphomannose isomerase (MPI, Fru-6-P ↔ Man-6-P) whose deficiency causes a congenital disorder of glycosylation (CDG)-Ib (MPI-CDG). Mannose supplements improve patients'' symptoms because exogenous mannose can also directly contribute to N-glycan synthesis through Man-6-P. However, the quantitative contributions of these and other potential pathways to glycosylation are still unknown. We developed a sensitive GC-MS-based method using [1,2-¹³C]glucose and [4-¹³C]mannose to measure their contribution to N-glycans synthesized under physiological conditions (5 mm glucose and 50 μm mannose). Mannose directly provides ∼10–45% of the mannose found in N-glycans, showing up to a 100-fold preference for mannose over exogenous glucose based on their exogenous concentrations. Normal human fibroblasts normally derive 25–30% of their mannose directly from exogenous mannose, whereas MPI-deficient CDG fibroblasts with reduced glucose flux secure 80% of their mannose directly. Thus, both MPI activity and exogenous mannose concentration determine the metabolic flux into the N-glycosylation pathway. Using various stable isotopes, we found that gluconeogenesis, glycogen, and mannose salvaged from glycoprotein degradation do not contribute mannose to N-glycans in fibroblasts under physiological conditions. This quantitative assessment of mannose contribution and its metabolic fate provides information that can help bolster therapeutic strategies for treating glycosylation disorders with exogenous mannose.     

Global Metabolic Reconstruction and Metabolic Gene Evolution in the Cattle Genome

The sequence of cattle genome provided a valuable opportunity to systematically link genetic and metabolic traits of cattle. The objectives of this study were 1) to reconstruct genome-scale cattle-specific metabolic pathways based on the most recent and updated cattle genome build and 2) to identify duplicated metabolic genes in the cattle genome for better understanding of metabolic adaptations in cattle. A bioinformatic pipeline of an organism for amalgamating genomic annotations from multiple sources was updated. Using this, an amalgamated cattle genome database based on UMD_3.1, was created. The amalgamated cattle genome database is composed of a total of 33,292 genes: 19,123 consensus genes between NCBI and Ensembl databases, 8,410 and 5,493 genes only found in NCBI or Ensembl, respectively, and 266 genes from NCBI scaffolds. A metabolic reconstruction of the cattle genome and cattle pathway genome database (PGDB) was also developed using Pathway Tools, followed by an intensive manual curation. The manual curation filled or revised 68 pathway holes, deleted 36 metabolic pathways, and added 23 metabolic pathways. Consequently, the curated cattle PGDB contains 304 metabolic pathways, 2,460 reactions including 2,371 enzymatic reactions, and 4,012 enzymes. Furthermore, this study identified eight duplicated genes in 12 metabolic pathways in the cattle genome compared to human and mouse. Some of these duplicated genes are related with specific hormone biosynthesis and detoxifications. The updated genome-scale metabolic reconstruction is a useful tool for understanding biology and metabolic characteristics in cattle. There has been significant improvements in the quality of cattle genome annotations and the MetaCyc database. The duplicated metabolic genes in the cattle genome compared to human and mouse implies evolutionary changes in the cattle genome and provides a useful information for further research on understanding metabolic adaptations of cattle.