Emergence Of New Phenotypes Research Articles

Hereditary Transthyretin Amyloidosis Polyneuropathy.

In the last decade, we have witnessed dramatic improvements in the diagnosis, workup, management, and monitoring of patients with hereditary transthyretin amyloidosis (ATTRv). Updated imaging techniques (e.g., 99mTc-PYP scan) are increasingly being used in place of tissue biopsies for confirmation of disease. Novel treatments now include antisense oligonucleotide and RNA interference drugs, whereas new applications such as CRISPR and amyloid antibodies are being studied for potential use in the future. These treatments have dramatically improved quality of life and increased survival in patients with ATTRv. Despite these breakthroughs, many challenges remain. Some of these challenges include early recognition and diagnosis of ATTRv, monitoring and initiation of treatment in asymptomatic or paucisymptomatic carriers, adequate treatment in people with mixed phenotype (i.e., cardiac and neurological), and the emergence of new phenotypes in people living longer with the disease (i.e., central nervous system and ocular complications). Research in those areas of deficit is ongoing, and in the future, we may have preventive therapies, better biomarkers, more efficient therapies for organs that we cannot currently target, and enhanced diagnostic techniques with the help of novel imaging techniques and artificial intelligence. In this review, we will summarize the current knowledge about polyneuropathy related to ATTRv and its management, discuss methods to improve early diagnosis and monitoring, and discuss emerging trends.

Evolutionary analysis of conserved non-coding elements subsequent to whole-genome duplication in opium poppy.

Whole-genome duplication (WGD) leads to the duplication of both coding and non-coding sequences within an organism's genome, providing an abundant supply of genetic material that can drive evolution, ultimately contributing to plant adaptation and speciation. Although non-coding sequences contain numerous regulatory elements, they have been understudied compared to coding sequences. In order to address this gap, we explored the evolutionary patterns of regulatory sequences, coding sequences and transcriptomes using conserved non-coding elements (CNEs) as regulatory element proxies following the recent WGD event in opium poppy (Papaver somniferum). Our results showed similar evolutionary patterns in subgenomes of regulatory and coding sequences. Specifically, the biased or unbiased retention of coding sequences reflected the same pattern as retention levels in regulatory sequences. Further, the divergence of gene expression patterns mediated by regulatory element variations occurred at a more rapid pace than that of gene coding sequences. However, gene losses were purportedly dependent on relaxed selection pressure in coding sequences. Specifically, the rapid evolution of tissue-specific benzylisoquinoline alkaloid production in P. somniferum was associated with regulatory element changes. The origin of a novel stem-specific ACR, which utilized ancestral cis-elements as templates, is likely to be linked to the evolutionary trajectory behind the transition of the PSMT1-CYP719A21 cluster from high levels of expression solely in P. rhoeas root tissue to its elevated expression in P. somniferum stem tissue. Our findings demonstrate that rapid regulatory element evolution can contribute to the emergence of new phenotypes and provide valuable insights into the high evolvability of regulatory elements.

Developmental plasticity reveals hidden fish phenotypes and enables morphospace diversification.

The establishment of a given phenotype is only one expression from a range of hidden developmental possibilities. Developmental plasticity at hidden reaction norms might elicit phenotypic diversification under new developmental environments. Current discussion benefits from empirical analyses that integrate multiple environmental stimuli to evaluate how plastic responses may shape phenotypic variation. We raised Megaleporinus macrocephalus fish in different environmental settings to address contributions of developmental plasticity for emergence of new phenotypes and subsequent morphospace diversification. Plastic morphotypes were evaluated at two complementary scales, the M. macrocephalus morphospace and the higher taxonomic level of Anostomidae family. Morphospace analyses demonstrated that developmental plasticity quickly releases distinct head morphotypes that were hidden in the parental monomorphic population. Plastic morphotypes occupied discrete and previously unfilled morphospace regions, a result obtained from comparisons with a control population and in analyses including several Anostomidae species. Plastic responses involved adjustments in shape and relative position of head bonesets, and fish raised under specific environmental combinations rescued phenotypic patterns described for different genera. Therefore, developmental plasticity possibly contributes to adaptive radiation in Anostomidae. Results illustrate how plastic responses enable morphospace diversification and contribute to evolution.

Independent Microevolution Mediated by Mobile Genetic Elements of Individual Clostridium difficile Isolates from Clade 4 Revealed by Whole-Genome Sequencing.

Horizontal gene transfer of mobile genetic elements (MGEs) accounts for the mosaic genome of Clostridium difficile, leading to acquisition of new phenotypes, including drug resistance and reconstruction of the genomes. MGEs were analyzed according to the whole-genome sequences of 37 C. difficile isolates with a variety of sequence types (STs) within clade 4 from China. Great diversity was found in each transposon even within isolates with the same ST. Two novel transposons were identified in isolates ZR9 and ZR18, of which approximately one third to half of the genes showed heterogenous origins compared with the usual intestinal bacterial genes. Most importantly, catD, known to be harbored by Tn4453a/b, was replaced by aac(6') aph(2'') in isolates 2, 7, and 28. This phenomenon illustrated the frequent occurrence of gene exchanges between C. difficile and other enterobacteria with individual heterogeneity. Numerous prophages and CRISPR arrays were identified in C. difficile isolates of clade 4. Approximately 20% of spacers were located in prophage-carried CRISPR arrays, providing a new method for typing and tracing the origins of closely related isolates, as well as in-depth studies of the mechanism underlying genome remodeling. The rates of drug resistance were obviously higher than those reported previously around the world, although all isolates retained high sensitivity to vancomycin and metronidazole. The increasing number of C. difficile isolates resistant to all antibiotics tested here suggests the ease with which resistance is acquired in vivo. This study gives insights into the genetic mechanism of microevolution within clade 4. IMPORTANCE Mobile genetic elements play a key role in the continuing evolution of Clostridium difficile, resulting in the emergence of new phenotypes for individual isolates. On the basis of whole-genome sequencing analysis, we comprehensively explored transposons, CRISPR, prophage, and genetic sites for drug resistance within clade 4 C. difficile isolates with different sequence types. Great diversity in MGEs and a high rate of multidrug resistance were found within this clade, including new transposons, Tn4453a/b with aac(6') aph(2'') instead of catD, and a relatively high rate of prophage-carried CRISPR arrays. These findings provide important new insights into the mechanism of genome remodeling within clade 4 and offer a new method for typing and tracing the origins of closely related isolates.

Historical evolution of the concept of anorexia nervosa and relationships with orthorexia nervosa, autism, and obsessive-compulsive spectrum.

Eating disorders have been defined as “characterized by persistence disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food and that significantly impairs health or psychosocial functioning”. The psychopathology of eating disorders changed across time under the influence of environmental factors, determining the emergence of new phenotypes. Some of these conditions are still under investigation and are not clearly identified as independent diagnostic entities. In this review, the historic evolution of the eating disorder concept up to the recent Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, has been evaluated. We also examined literature supporting the inclusion of new emergent eating behaviors within the eating disorder spectrum, and their relationship with anorexia, autism, and obsessive–compulsive disorder. In particular, we focused on what is known about the symptoms, epidemiology, assessment, and diagnostic boundaries of a new problematic eating pattern called orthorexia nervosa that could be accepted as a new psychological syndrome, as emphasized by an increasing number of scientific articles in the last few years.

Abstract LB-283: Human cancers harbor extensive subclonal mutations

Abstract Recent advances in next-generation DNA sequencing (NGS) have revealed greater than expected mutational heterogeneity, not only between tumors of similar cancer type, but also within individual tumors. This mutational heterogeneity could serve as a reservoir for the emergence of new phenotypes, including resistance to therapy. While mutational diversity has been reported in many human cancers, the high error-rate of conventional NGS limits its ability to confidently resolve mutations present in less than 1.0 to 5% of the cells that comprise a tumor. These low-level subclonal mutations likely contribute to the rapid emergence of resistance to radiation and chemotherapy and the ability of cancer cells to invade adjacent tissues and to metastasize. In order to study subclonal mutations, we have developed a highly accurate sequencing protocol, termed Duplex Sequencing, which takes advantage of the double-stranded nature of DNA to increase the accuracy of DNA sequencing by more than 10,000-fold; Duplex Sequencing has an unprecedented background error frequency of <5×10-8. Additionally, in order to analyze rare subclonal mutations in human diseases, we have also established a highly efficient, targeted capture method, which utilizes sequential rounds of hybridization to enrich targeted genes by >1,000,000-fold, with up to 99.8% of resultant sequencing reads on target. Using these new methodologies, we have investigated the subclonal makeup of several cancers, including acute myeloid leukemia (AML), colon cancers (CRC), and glioblastoma (GBM). Upon targeting genes identified by NGS as drivers of clonal proliferation, we identified multiple subclonal mutations in each of these cancers, some with the potential to elicit drug resistance and others to drive tumor cell proliferation. We also investigated the five human replicative DNA polymerases. No reports have previously implicated mutations in these polymerases in either AML or GBM, nor in sporadic CRC with the exception of mutations in the exonuclease domain of DNA polymerase epsilon. However, our approach, combining targeted gene capture with Duplex Sequencing, revealed multiple subclonal mutations in the catalytic domains of all five replicative DNA polymerases in each of these tumors. The presence of subclonal mutations in the catalytic domains of replicative DNA polymerases supports the mutator phenotype hypothesis, which posits that an increased mutation rate is a driving force during early tumorigenesis. Furthermore, extrapolating the results on the number of subclonal mutations in target genes to the entire genome, our results indicate that sites harboring subclonal mutations are >100-fold more frequent than sites with clonal mutations. Thus, by the time a tumor is clinically diagnosed, every position in the genome could be mutated in at least one cell in the tumor; these subclones could be the reservoir for the emergence of new phenotypes and resistance to therapy. Citation Format: Michael W. Schmitt, Edward J. Fox, Marc J. Prindle, Kate S. Reid – Bayliss, Pamela S. Becker, Lawrence A. Loeb. Human cancers harbor extensive subclonal mutations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-283. doi:10.1158/1538-7445.AM2015-LB-283

Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype.

The self-assembly of alternative conformations of normal proteins into amyloid aggregates has been implicated in both the acquisition of new functions and in the appearance and progression of disease. However, while these amyloidogenic pathways are linked to the emergence of new phenotypes, numerous studies have uncoupled the accumulation of aggregates from their biological consequences, revealing currently underappreciated complexity in the determination of these traits. Here, to explore the molecular basis of protein-only phenotypes, we focused on the S. cerevisiae Sup35/[PSI+] prion, which confers a translation termination defect and expression level-dependent toxicity in its amyloid form. Our studies reveal that aggregated Sup35 retains its normal function as a translation release factor. However, fluctuations in the composition and size of these complexes specifically alter the level of this aggregate-associated activity and thereby the severity and toxicity of the amyloid state. Thus, amyloid heterogeneity is a crucial contributor to protein-only phenotypes.

Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B

Author SummaryThe evolution of drug resistance in human pathogens is considered an inevitable consequence of the selective pressures imposed by antimicrobial drugs. Yet resistance to one antifungal drug, amphotericin B (AmB), remains extremely rare despite decades of widespread use. Here we explore the biological mechanisms underlying this conundrum. By examining natural and experimental populations of Candida albicans, we identify multiple mutations that confer resistance to AmB in vitro. As with the evolution of resistance to other antifungals, we find that the chaperone protein Hsp90 is involved in enabling the evolution of resistance to AmB. We also discover, however, that mutations that confer AmB resistance impose massive costs on other aspects of fungal pathogenicity; strains that are resistant to AmB are hypersensitive to attack by the host immune system and are unable to invade and damage host tissue. Thus, the evolution of resistance to AmB is restricted by a tradeoff between tolerance of the drug and the ability to cause disease. We propose that developing new antibiotics for which resistance presents such dire tradeoffs may be a promising strategy to prevent the evolution of resistance.

Population dynamics and in vitro antibody pressure of porcine parvovirus indicate a decrease in variability

To estimate the impact of porcine parvovirus (PPV) vaccines on the emergence of new phenotypes, the population dynamic history of the virus was calculated using the Bayesian Markov chain Monte Carlo method with a Bayesian skyline coalescent model. Additionally, an in vitro model was performed with consecutive passages of the 'Challenge' strain (a virulent field strain) and NADL2 strain (a vaccine strain) in a PK-15 cell line supplemented with polyclonal antibodies raised against the vaccine strain. A decrease in genetic diversity was observed in the presence of antibodies in vitro or after vaccination (as estimated by the in silico model). We hypothesized that the antibodies induced a selective pressure that may reduce the incidence of neutral selection, which should play a major role in the emergence of new mutations. In this scenario, vaccine failures and non-vaccinated populations (e.g. wild boars) may have an important impact in the emergence of new phenotypes.

Finalism in Darwinian and Lamarckian Evolution: Lessons from Epigenetics and Developmental Biology

Finalist (teleological) implications have been described for both Darwinian and Lamarckian theories, even though finalism appears to be more commonly associated with Lamarckism. Biologists have focused on finding final causes to explain evolutionary novelties through, for example, applying the “what for?” question to address experimental observations. Now epigenetics, together with developmental biology, may allow us to focus on the efficient causes leading to evolutionary change, asking the “how?” question, considering environmental influences as inducers of genomic change. This is a whole under-studied dimension in evolutionary studies. In this paper, I discuss how epigenetics and developmental biology can help integrate two important ways in which the environment affects evolution: through inducing or through restricting the emergence of new phenotypes. I also discuss which aspects of both theories should be reconsidered in the face of current knowledge in epigenetics and where the emphasis of evolutionary experiments should be placed. Important goals of evolution related epigenetic studies should be: (i) to experimentally consider the separation among the origin of characters in a lineage and its further fixation, in order to address these processes in a proper dimension, (ii) to build the cause-effect relation between the factors inducing epigenetic changes and consequent changes in population parameters, and (iii) to consider that the arising of new characters is modulated by physiological and developmental constraints, and that this process is not related to a purpose or focused to solve an ecological, physiological or evolutionary challenge.

Editorial [Hot Topic: Evolutionary Systems Biology (Guest Editor: Jianying Gu)

Systems biology has a long history as a theoretical framework in biology, positing that cellular systems possess emergent properties that can only be explained by the interactions among the components of an organism rather than by any individual component in itself. With the advent of the genomic era, data sets encompassing systems-wide measurements of gene complements, transcription, and protein expression are becoming available. Thoughtful integration of these data can lead to a systems-level understanding of the components and dynamics of cellular machineries and the development of practical methods for inferring and constructing network models of these interactions is well under way. As the creation of plausible network models of cellular systems becomes possible, comparison of systems in an evolutionary light promises to reveal the evolutionary forces that shape these systems. Systems are dynamic and selectable, that is, they respond to pressures brought to bear by changes in their environment. Therefore, the application of the methods of evolutionary biology within a systems biology framework can aid in identifying the concerted changes that drive the emergence of new phenotypes. A better understanding of systems evolution will greatly advance our knowledge about the complexity of gene regulation and help identify new therapeutic targets for effective treatment of various diseases. This special issue of Current Genomics is intended to provide a forum for researchers to share their experiences on all aspects of genome and systems evolution. This issue includes a review article discussing about the proteomics techniques that are capable of generating high quality data for systems biology research: Chen et al. reviewed recent advances in proteolysis, a key procedure prior to mass spectrometry and peptide mapping in proteomic studies of gene function. They showed that the proteolysis strategies can be accelerated by various electromagnetic waves, such as microwave-accelerated protein digestion, infrared-assisted proteolysis, ultraviolet-enhanced protein digestion, laser-assisted proteolysis, and future prospects. This issue also includes two review articles with a special emphasis on the systems biology of bacteria, ideal model organisms for evolutionary analyses of genome plasticity and adaptive phenotypes. Tang's review is focused on microbial metabolomics, which involves fast, high throughput characterization of the metabolite complements of a microorganism, and thus summarizes the global outcome of the interplay between the developmental processes and the environment. Selected topics illustrate the impact of metabolomics on the understanding of systems microbiology. Zhou et al. provide an overview of the recent advances in Streptomyces biology that have been driven by high throughput technologies. The omics based studies have revolutionized the understanding of system control and regulation dynamics of this group of bacterial of medicinal and industrial importance. Evolutionary systems biology approaches have also been applied to biomedical studies. Cai et al. provide a phylogenomic overview of the origin, distribution, diversity, and evolution of malarial proteases, a class of promising therapeutic targets for combating this devastating infectious disease that is responsible for over 1 million deaths yearly. Klemcke et al. introduce a novel physiogenomic approach to the study of hemorraghic shock, a major cause of death throughout the world. Their findings in heritable quantitative trait loci, as well as potential epigenetic mechanisms that might influence survival time after severe hemorrhage, may lead to the improvement in survival of traumatic hemorrhage and provide knowledge of genetically-informed personalized treatments. Overall, these reviews provide a fascinating survey of the combination of systems thinking and evolutionary analysis across the biological spectrum. As modeling approaches improve and as more data from more species become available, the study of systems evolution will clarify the links among the genotype, the phenotype and the selective pressures arising from the organism’s place in the environment. As an emerging field in the post genomic era, evolutionary systems biology promises to make profound contributions to our understanding of life.

Crystal structure of an integron gene cassette-associated protein from Vibrio cholerae identifies a cationic drug-binding module.

BackgroundThe direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes.Methodology/Principal FindingsWe report the 1.8 Å crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, such as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators.Conclusions/SignificanceGenetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds.

ON AN INTEGRATIVE THEORETICAL FRAMEWORK FOR THE MOLECULAR NATURAL HISTORY OF VIRAL DISEASES

RNA-virus caused diseases pose a challenging problem for a deep epidemiological comprehension due to the trick nature of the population genetics of such viruses and the sometimes obscure host-parasite relationship at the molecular level. In this article, data presented by other authors is reviewed and speculations based on these are depicted in order to search for patterns that could help the understanding of transmissible diseases mechanisms and the prediction of epidemics trends. Elements that connect parasite, host and epidemiology are presented as polarized interactions with negative or positive trends and a model for the emergence of new phenotypes is also presented based on the quasispecies theory. DOI: http://dx.doi.org/10.17525/vrr.v15i2.44

Hypercomplexity

What is biological complexity? How many sorts exist? Are there levels of complexity? How are they related to one another? How is complexity related to the emergence of new phenotypes? To try to get to grips with these questions, we consider the archetype of a complex biological system, Escherichia coli. We take the position that E. coli has been selected to survive adverse conditions and to grow in favourable ones and that many other complex systems undergo similar selection. We invoke the concept of hyperstructures which constitute a level of organisation intermediate between macromolecules and cells. We also invoke a new concept, competitive coherence, to describe how phenotypes are created by a competition between maintaining a consistent story over time and creating a response that is coherent with respect to both internal and external conditions. We suggest how these concepts lead to parameters suitable for describing the rich form of complexity termed hypercomplexity and we propose a relationship between competitive coherence and emergence.

Environmental signaling and evolutionary change: can exposure of pregnant mammals to environmental estrogens lead to epigenetically induced evolutionary changes in embryos?

DNA methylation is one of the epigenetic and hereditary mechanisms regulating genetic expression in mammalian cells. In this review, we propose how certain natural agents, through their dietary consumption, could induce changes in physiological aspects in mammalian mothers, leading to alterations in DNA methylation patterns of the developing fetus and to the emergence of new phenotypes and evolutionary change. Nevertheless, we hypothesize that this process would require (i) certain key periods in the ontogeny of the organism where the environmental stimuli could produce effects, (ii) particular environmental agents as such stimuli, and (iii) that a genomic persistent change be consequently produced in a population. Depending on the persistence of the environmental stimuli and on whether the affected genes are imprinted genes, induced changes in DNA methylation patterns could become persistent. Moreover, some fragments could be more frequently methylated than others over several generations, leading to biased base change and evolutionary consequences.

The matrix of rat calvarium as transformant of fibroblasts.

Allogeneic transplantation of coarse powders of the rat calvarial matrix to subcutaneous spaces resulted in transformation of fibroblasts to chondroblasts and osteoblasts. The emergence of new phenotypes was quantitated by determination of alkaline phosphatase activity and 45Ca incorporation. A comparison of the matrices from rat calvarium and diaphyseal bone revealed that matrix of the shaft of long bones is more potent as transformant than matrix of the vault of the skull.