BOOL-AN: A method for comparative sequence analysis and phylogenetic reconstruction

A novel discrete mathematical approach is proposed as an additional tool for molecular systematics which does not require prior statistical assumptions concerning the evolutionary process. The method is based on algorithms generating mathematical representations directly from DNA/RNA or protein sequences, followed by the output of numerical (scalar or vector) and visual characteristics (graphs). The binary encoded sequence information is transformed into a compact analytical form, called the Iterative Canonical Form (or ICF) of Boolean functions, which can then be used as a generalized molecular descriptor. The method provides raw vector data for calculating different distance matrices, which in turn can be analyzed by neighbor-joining or UPGMA to derive a phylogenetic tree, or by principal coordinates analysis to get an ordination scattergram. The new method and the associated software for inferring phylogenetic trees are called the Boolean analysis or BOOL-AN

Starvation-response may not involve Atg1-dependent autophagy induction in non-unikont parasites

Autophagy, the lysosome-mediated self-degradation process, is implicated in survival during starvation in yeast, Dictyostelium and animals. In these eukaryotic taxa (collectively called Unikonts), autophagy is induced primarily through the Atg1/ULK1 complex in response to nutrient depletion. Autophagy has also been well-studied in non-unikont parasites, such as Trypanosoma and Plasmodium, and found important in their life-cycle transitions. However, how autophagy is induced in non-unikonts remains largely unrevealed. Using a bioinformatics approach, we examined the presence of Atg1 and of its complex in the genomes of 40 non-unikonts. We found that these genomes do not encode typical Atg1 proteins: BLAST and HMMER queries matched only with the kinase domain of Atg1, while other segments responsible for regulation and protein-binding were missing. Non-unikonts also lacked other components of the Atg1-inducing complex. Orthologs of an alternative autophagy inducer, Atg6 were found only in the half of the species, indicating that the other half may possess other inducing mechanisms. As key autophagy genes have differential expression patterns during life-cycle, we raise the possibility that autophagy in these protists is induced mainly at the post-transcriptional level. Understanding Atg1-independent autophagy induction mechanisms in these parasites may lead to novel pharmacological interventions, not affecting human Atg1-dependent autophagy

The C. elegans Hox gene ceh-13 regulates cell migration and fusion in a non-colinear way. Implications for the early evolution of Hox clusters

Background: Hox genes play a central role in axial patterning during animal development. They are clustered in the genome and specify cell fate in sequential domains along the anteroposterior (A-P) body axis in a conserved order that is co-linear with their relative genomic position. In the soil worm Caenorhabditis elegans, this striking rule of co-linearity is broken by the anterior Hox gene ceh-13, which is located between the two middle Hox paralogs, lin-39 and mab-5, within the loosely organized nematode Hox cluster. Despite its evolutionary and developmental significance, the functional consequence of this unusual genomic organization remains unresolved.Results: In this study we have investigated the role of ceh-13 in different developmental processes, and found that its expression and function are not restricted to the anterior body part. We show that ceh-13 affects cell migration and fusion as well as tissue patterning in the middle and posterior body regions too. These data reveal novel roles for ceh-13 in developmental processes known to be under the control of middle Hox paralogs. Consistently, enhanced activity of lin-39 and mab-5 can suppress developmental arrest and morphologic malformation in ceh-13 deficient animals.Conclusion: Our findings presented here show that, unlike other Hox genes in C. elegans which display region-specific accumulation and function along the A-P axis, the expression and functional domain of the anterior Hox paralog ceh-13 extends beyond the anterior region of the worm. Furthermore, ceh-13 and the middle Hox paralogs share several developmental functions. Together, these results suggest the emergence of the middle-group Hox genes from a ceh-13-like primordial Hox ancestor

Az élet keletkezésének és jelenkori modellorganizmusok evolúciójának számítógépes vizsgálata = Computational study of evolution in early life and extant model organisms

Pályázatunk súlyponti témája az élet keletkezésének és korai evolúciójának vizsgálata volt, szimulációs és matematikai modellezés segítségével. Megvizsgáltuk a sejtes szerveződést megelőző felszíni anyagcsere, illetve az RNS-gének megjelenése előtti prebiotikus rendszerek evolúciójának lehetőségeit és korlátait. Tovább finomítottuk a legegyszerűbb sejtes rendszerek absztrakt dinamikájának (chemoton modell) leírását, és foglalkoztunk az RNS-replikátorok másolásának nehézségeivel. Újabb ismeretekkel szolgáltunk a genetikai kód (transzláció) és a komplex anyagcsere evolúciójának lehetséges történetéről és mechanizmusairól. További projektekben foglalkoztunk a replikátorok általános elméletével, a kooperáció, a nyelvkészség és a virulencia evolúciójával, valamint az agyban zajló evolúciós/szelekciós folyamatokkal. | Our research centred on the origin and early evolution of life, with the tools of simulation and mathematical modelling. We studied the potential and limitations of surface metabolism (preceding cellular organisation) and of the evolution of prebiotic systems (preceding RNA genes). We investigated further aspects of the abstract dynamics of the simplest cellular living organisms (chemoton model), and analyzed the difficulties associated with the copying of RNA replicators. We gleaned new insight into the possible evolutionary history and mechanisms of the genetic code (translation) and of complex metabolism. In further projects, we studied the general theory of replicators, the evolution of cooperation, language and virulence, and the evolutionary/selective processes that occur in the brain

Targeted interplay between bacterial pathogens and host autophagy

Due to the critical role played by autophagy in pathogen clearance, pathogens have developed diverse strategies to subvert autophagy. Despite previous key findings of bacteria-autophagy interplay, a systems level insight into selective targeting by the host and autophagy modulation by the pathogens is lacking. We predicted potential interactions between human autophagy proteins and effector proteins from 56 pathogenic bacterial species by identifying bacterial proteins predicted to have recognition motifs for selective autophagy receptors p62/NDP52 and LC3. Conversely, using structure-based interaction prediction methods, we identified bacterial effector proteins that could putatively modify core autophagy components. Our analysis revealed that autophagy receptors in general potentially target mostly genus specific proteins, and not those present in multiple genera. We also show that the complementarity between the predicted p62 and NDP52 targets, which has been shown for Salmonella, Listeria and Shigella, could be observed across other pathogens. Using literature evidence, we hypothesize that this complementarity potentially leave the host more susceptible to chronic infections upon the mutation of one of the autophagy receptors. To check any bias caused by our pathogenic protein selection criteria, control analysis using proteins derived from entero-toxigenic and non-toxigenic Bacillus outer membrane vesicles indicated that autophagy targets pathogenic proteins rather than non-pathogenic ones. We also observed a pathogen specific pattern as to which autophagy phase could be modulated by specific genera. We found intriguing examples of bacterial proteins which could modulate autophagy, and in turn capable of being targeted by the autophagy receptors and LC3 as a host defence mechanism. To demonstrate the validity of our predictions, we confirmed experimentally with in vitro Salmonella invasion assays the bi-directional interactions underlying the interplay between a Salmonella protease, YhjJ and autophagy. Our comparative meta-analysis points out key commonalities and differences in how pathogens could affect autophagy and how autophagy potentially recognises these pathogenic effectors

Discovering cooperative biomarkers for heterogeneous complex disease diagnoses

Biomarkers with high reproducibility and accurate prediction performance can contribute to comprehending the underlying pathogenesis of related complex diseases and further facilitate disease diagnosis and therapy. Techniques integrating gene expression profiles and biological networks for the identification of network-based disease biomarkers are receiving increasing interest. The biomarkers for heterogeneous diseases often exhibit strong cooperative effects, which implies that a set of genes may achieve more accurate outcome prediction than any single gene. In this study, we evaluated various biomarker identification methods that consider gene cooperative effects implicitly or explicitly, and proposed the gene cooperation network to explicitly model the cooperative effects of gene combinations. The gene cooperation network- enhanced method, named as MarkRank, achieves superior performance compared with traditional biomarker identification methods in both simulation studies and real data sets. The biomarkers identified by MarkRank not only have a better prediction accuracy but also have stronger topological relationships in the biological network and exhibit high specificity associated with the related diseases. Furthermore, the top genes identified by MarkRank involve crucial biological processes of related diseases and give a good prioritization for known disease genes. In conclusion, MarkRank suggests that explicit modeling of gene cooperative effects can greatly improve biomarker identification for complex diseases, especially for diseases with high heterogeneity

A Single Early Introduction Governed Viral Diversity in the Second Wave of SARS-CoV-2 Epidemic in Hungary

Retrospective evaluation of past waves of the SARS-CoV-2 epidemic is key for designing optimal interventions against future waves and novel pandemics. Here we report on analysing genome sequences of SARS-CoV-2 from the first two waves of the epidemic in 2020 in Hungary, mirroring a suppression and a mitigation strategy, respectively. Our analysis reveals that the two waves markedly differed in viral diversity and transmission patterns. Specifically, unlike in several European areas or in the USA, we have found no evidence for early introduction and cryptic transmission of the virus in the first wave of the pandemic in Hungary. Despite the introduction of multiple viral lineages, extensive community spread was prevented by a timely national lockdown in March 2020. In sharp contrast, the majority of the cases in the much larger second wave can be linked to a single transmission lineage of the pan-European B.1.160 variant. This lineage was introduced unexpectedly early, followed by a two-month-long cryptic transmission before a soar of detected cases in September 2020. Epidemic analysis has revealed that the dominance of this lineage in the second wave was not associated with an intrinsic transmission advantage. This finding is further supported by the rapid replacement of B.1.160 by the alpha variant (B.1.1.7) that launched the third wave of the epidemic in February 2021. Overall, these results illustrate how the founder effect in combination with cryptic transmission, instead of repeated international introductions or higher transmissibility, can govern viral diversity