Floral Morphogenesis: Stochastic Explorations of a Gene Network Epigenetic Landscape

In contrast to the classical view of development as a preprogrammed and deterministic process, recent studies have demonstrated that stochastic perturbations of highly non-linear systems may underlie the emergence and stability of biological patterns. Herein, we address the question of whether noise contributes to the generation of the stereotypical temporal pattern in gene expression during flower development. We modeled the regulatory network of organ identity genes in the Arabidopsis thaliana flower as a stochastic system. This network has previously been shown to converge to ten fixed-point attractors, each with gene expression arrays that characterize inflorescence cells and primordial cells of sepals, petals, stamens, and carpels. The network used is binary, and the logical rules that govern its dynamics are grounded in experimental evidence. We introduced different levels of uncertainty in the updating rules of the network. Interestingly, for a level of noise of around 0.5–10%, the system exhibited a sequence of transitions among attractors that mimics the sequence of gene activation configurations observed in real flowers. We also implemented the gene regulatory network as a continuous system using the Glass model of differential equations, that can be considered as a first approximation of kinetic-reaction equations, but which are not necessarily equivalent to the Boolean model. Interestingly, the Glass dynamics recover a temporal sequence of attractors, that is qualitatively similar, although not identical, to that obtained using the Boolean model. Thus, time ordering in the emergence of cell-fate patterns is not an artifact of synchronous updating in the Boolean model. Therefore, our model provides a novel explanation for the emergence and robustness of the ubiquitous temporal pattern of floral organ specification. It also constitutes a new approach to understanding morphogenesis, providing predictions on the population dynamics of cells with different genetic configurations during development

Parallel evolution of amphioxus and vertebrate small-scale gene duplications

Background: Amphioxus are non-vertebrate chordates characterized by a slow morphological and molecular evolution. They share the basic chordate body-plan and genome organization with vertebrates but lack their 2R whole-genome duplications and their developmental complexity. For these reasons, amphioxus are frequently used as an outgroup to study vertebrate genome evolution and Evo-Devo. Aside from whole-genome duplications, genes continuously duplicate on a smaller scale. Smallscale duplicated genes can be found in both amphioxus and vertebrate genomes, while only the vertebrate genomes have duplicated genes product of their 2R wholegenome duplications. Here, we explore the history of small-scale gene duplications in the amphioxus lineage and compare it to small- and large-scale gene duplication history in vertebrates. Results: We present a study of the European amphioxus (Branchiostoma lanceolatum) gene duplications thanks to a new, high-quality genome reference. We fnd that, despite its overall slow molecular evolution, the amphioxus lineage has had a history of small-scale duplications similar to the one observed in vertebrates. We fnd parallel gene duplication profles between amphioxus and vertebrates and conserved func‑tional constraints in gene duplication. Moreover, amphioxus gene duplicates show lev‑ els of expression and patterns of functional specialization similar to the ones observed in vertebrate duplicated genes. We also fnd strong conservation of gene synteny between two distant amphioxus species, B. lanceolatum and B. foridae, with two major chromosomal rearrangements. Conclusions: In contrast to their slower molecular and morphological evolution, amphioxus' small-scale gene duplication history resembles that of the vertebrate line‑age both in quantitative and in functional terms

Criticality, adaptability and early-warning signals in time series in a discrete quasispecies model

Complex systems from different fields of knowledge often do not allow a mathematical description or modeling, because of their intricate structure composed of numerous interacting components. As an alternative approach, it is possible to study the way in which observables associated with the system fluctuate in time. These time series may provide valuable information about the underlying dynamics. It has been suggested that complex dynamic systems, ranging from ecosystems to financial markets and the climate, produce generic early-warning signals at the >tipping points,> where they announce a sudden shift toward a different dynamical regime, such as a population extinction, a systemic market crash, or abrupt shifts in the weather. On the other hand, the framework of Self-Organized Criticality (SOC), suggests that some complex systems, such as life itself, may spontaneously converge toward a critical point. As a particular example, the quasispecies model suggests that RNA viruses self-organize their mutation rate near the error-catastrophe threshold, where robustness and evolvability are balanced in such a way that survival is optimized. In this paper, we study the time series associated to a classical discrete quasispecies model for different mutation rates, and identify early-warning signals for critical mutation rates near the error-catastrophe threshold, such as irregularities in the kurtosis and a significant increase in the autocorrelation range, reminiscent of 1/f noise. In the present context, we find that the early-warning signals, rather than broadcasting the collapse of the system, are the fingerprint of survival optimization. © 2013 Higher Education Press and Springer-Verlag Berlin Heidelberg.We acknowledge financial support from CONACYT (grants CB-2011-01-167441, CB-2010-01-155663 and I010/266/2011/C-410-11) and PAPIIT-DGAPA (grant IN114411). This work was partly funded by the project FP7-PEOPLE-2009-IRSES-247541-MATSI-QEL. R.F. acknowledges financial support from the Instituto Nacional de Geriatría (project DI-PI-002/2012).Peer Reviewe

Effect of collapsed duplications on diversity estimates: what to expect

The study of segmental duplications (SDs) and copy-number variants (CNVs) is of great importance in the fields of genomics and evolution. However, SDs and CNVs are usually excluded from genome-wide scans for natural selection. Because of high identity between copies, SDs and CNVs that are not included in reference genomes are prone to be collapsed-that is, mistakenly aligned to the same region-when aligning sequence data from single individuals to the reference. Such collapsed duplications are additionally challenging because concerted evolution between duplications alters their site frequency spectrum and linkage disequilibrium patterns. To investigate the potential effect of collapsed duplications upon natural selection scans we obtained expectations for four summary statistics from simulations of duplications evolving under a range of interlocus gene conversion and crossover rates. We confirm that summary statistics traditionally used to detect the action of natural selection on DNA sequences cannot be applied to SDs and CNVs since in some cases values for known duplications mimic selective signatures. As a proof of concept of the pervasiveness of collapsed duplications, we analyzed data from the 1,000 Genomes Project. We find that, within regions identified as variable in copy number, diversity between individuals with the duplication is consistently higher than between individuals without the duplication. Furthermore, the frequency of single nucleotide variants (SNVs) deviating from Hardy-Weinberg Equilibrium is higher in individuals with the duplication, which strongly suggests that higher diversity is a consequence of collapsed duplications and incorrect evaluation of SNVs within these CNV regions.This work has been supported by Ministerio de Ciencia e Innovación, Spain (BFU2015-68649-P, MINECO/FEDER, UE), the Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866), the Spanish National Institute of Bioinformatics (PT13/0001/0026) of the Instituto de Salud Carlos III, grant MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to UPF’s Department of Experimental and Health Sciences; a grant to D.A.H. from Conacyt; and by the Fondo Europeo de Desarrollo Regional (FEDER) and the Fondo Social Europeo (FSE)

Expression of cell-wall related genes is highly variable and correlates with sepal morphology

Control of organ morphology is a fundamental feature of living organisms. There is, however, observable variation in organ size and shape within a given genotype. Taking the sepal of Arabidopsis as a model, we investigated whether we can use variability of gene expression alongside variability of organ morphology to identify gene regulatory networks potentially involved in organ size and shape determination. We produced a dataset composed of morphological parameters and genome-wide transcriptome obtained from 27 individual sepals from wild-type plants with nearly identical genetic backgrounds, environment, and developmental stage. Sepals exhibited appreciable variability in both morphology and transcriptome, with response to stimulus genes and cell-wall related genes displaying high variability in expression. We additionally identified five modules of co-expressed genes which correlated significantly with morphology, revealing biologically relevant gene regulatory networks. Interestingly, cell-wall related genes were overrepresented in two of the top three modules. Overall, our work highlights the benefit of using coupled variation in gene expression and phenotype in wild-type plants to shed light on the mechanisms underlying organ size and shape determination. Although causality between gene expression and sepal morphology has not been established, our approach opens the way to informed analysis for mutant characterization and functional studies

Copy number variants and fixed duplications among 198 rhesus macaques (Macaca mulatta)

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes. One commonly used model organism in biomedical research is a species of Old World monkey, the rhesus macaque (Macaca mulatta). When translating biomedical research findings from rhesus macaques to humans, knowledge about the genetic differences between these two species is fundamental. In this study, we focus on copy number variation, which happens as a consequence of large duplication and deletion events in the genome, and which often has been overlooked. Copy number variation is a type of genetic variation which consists of one individual having more copies of a particular genomic region than another individual. We have performed an extensive evaluation of the copy number variants and fixed duplications among the genomes of 198 rhesus macaques and have generated a copy number map of high resolution for this species. We find that the overall pattern of within-species variation is similar to that in humans. However, when comparing specific duplicated regions between rhesus macaques and humans, we do find differences that could potentially have functional consequences. We have identified genes associated with human disease that have different copy number profiles between these two species, and therefore, we suggest avoiding human-centered assumptions in biomedical research conducted with model organisms

Robustness of organ morphology is associated with modules of co-expressed genes related to plant cell wall

Reproducibility in organ size and shape is a fundamental trait of living organisms. Themechanisms underlying such robustness remain, however, to be elucidated. Taking the sepal ofArabidopsis as a model, we investigated whether variability of gene expression plays a role invariation of organ morphology. To address this question, we produced a dataset composed ofboth transcriptomic and morphological information obtained from 27 individual sepals fromwild-type plants. Although nearly identical in their genetic background, environment, anddevelopmental stage, these sepals exhibited appreciable variability in both morphology andtranscriptome. We identified modules of co-expressed genes in sepals, three of whichcorrelated significantly with morphology, revealing biologically relevant gene regulatorynetworks. Interestingly, cell-wall related genes were overrepresented in two of these threemodules. Additionally, we found that highly variable genes were unexpectedly enriched incell-wall related processes. We then analyzed sepal morphology from 16 cell-wall mutants andfound that the more a gene is expressed in wild-type, the more variable the morphology of thecorresponding mutant. Altogether, our work unravels the contribution of cell-wall related genesto the robustness of sepal morphology. More generally, we propose that canalizing traits duringdevelopment could rely on the modulation of highly expressed genes

Temporal sequence of cell-fate attainment patterns under the Glass dynamics with noise.

<p>Maximum relative probability (“Y” axis) of attaining each attractor as a function of iteration number or time (“X” axis). (A) The maxima of the cell-fate curves are attained in a particular sequence in time, which in this case is sepal, petal, stamen, and carpel. Parameters used: dt = 0.01, τ = 1, and Δ<i>t_p</i> = 2.5. (B) When the simulations mimic the Boolean case (dt = 1, τ = 1 and Δ<i>t_p</i> = 1; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003626#s2" target="_blank">Results</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003626#s4" target="_blank">Methods</a>), a temporal pattern identical to that of the Boolean dynamics was obtained, with a sequence of sepal, petal, carpel and stamen. The noise used in both cases was η = 0.03. Although the Boolean and Glass dynamics need not coincide in general, for the case of the <i>A. thaliana</i> GRN, both models provide similar predictions. Simulations show that the order of emergence of the stamen and carpel maxima, as compared to the Boolean model, may depend on the precise values of the kinetic constants.</p

Heat map of the similarity matrix among the ten attractors of the GRN.

<p>A strict consensus phenogram was obtained for the GRN attractors (vectors of zeros and ones) by using the Manhattan distance similarity index (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003626#s4" target="_blank">Methods</a>). This phenogram is shown below the attractors that are ordered along the X and Y axes of the heat map. Attractors that group together had the highest similarity indexes between them (i.e. the lowest Manhattan distance). Color scale: darker colors indicate more similar, while lighter ones indicate more different attractors in the pairs compared.</p