Evolution of natural lifespan variation and molecular strategies of extended lifespan

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan. Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in replicative lifespan across wild yeast isolates, as well as genes, metabolites and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism and mitochondrial function in long-lived strains. Overall, our multi-omic and lifespan analyses across diverse isolates of the same species shows how gene-environment interactions shape cellular processes involved in phenotypic variation such as lifespan.

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Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

Innovation in Aging ◽

10.1093/geroni/igab046.119 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 32-33

Author(s):

Alaattin Kaya

Keyword(s):

Caloric Restriction ◽

Genetic Basis ◽

Epigenetic Landscape ◽

Intermediary Metabolites ◽

Replicative Lifespan ◽

Nad Metabolism ◽

Wild Yeast ◽

Lifespan Variation ◽

Extended Lifespan ◽

Selective Forces

Abstract To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness.

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Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

10.1101/2020.11.09.374488 ◽

2020 ◽

Author(s):

Alaattin Kaya ◽

Cheryl Zi Jin Phua ◽

Mitchell Lee ◽

Lu Wang ◽

Alexander Tyshkovskiy ◽

...

Keyword(s):

Genetic Basis ◽

Epigenetic Landscape ◽

Intermediary Metabolites ◽

Closely Related Species ◽

Nad Metabolism ◽

Lifespan Variation ◽

Extended Lifespan ◽

Selective Forces ◽

Biology Of Aging ◽

Species Lifespan

ABSTRACTThe question of why and how some species or individuals within a population live longer than others is among the most important questions in the biology of aging. A particularly useful model to understand the genetic basis and selective forces acting on the plasticity of lifespan are closely related species or ecologically diverse individuals of the same species widely different in lifespan. Here, we analyzed 76 diverse wild isolates of two closely related budding yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus and discovered a diversity of natural intra-species lifespan variation. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. We identified sets of genes and metabolites to regulate aging pathways, many of which have not been previously associated with lifespan regulation. We also identified and characterized long-lived strains with elevated intermediary metabolites and differentially regulated genes for NAD metabolism and the control of epigenetic landscape through chromatin silencing. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness. Overall, our study shows how the environment and natural selection interact to shape diversity of lifespan.

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A Chemogenomic Screening of Sulfanilamide-Hypersensitive Saccharomyces cerevisiae Mutants Uncovers ABZ2, the Gene Encoding a Fungal Aminodeoxychorismate Lyase

Eukaryotic Cell ◽

10.1128/ec.00266-07 ◽

2007 ◽

Vol 6 (11) ◽

pp. 2102-2111 ◽

Cited By ~ 21

Author(s):

Javier Botet ◽

Laura Mateos ◽

José L. Revuelta ◽

María A. Santos

Keyword(s):

Large Scale ◽

Phylogenetic Analyses ◽

Open Reading Frames ◽

Gene Encoding ◽

Cellular Processes ◽

Founder Member ◽

Yeast Genes ◽

Vacuole Biogenesis ◽

Reading Frames

ABSTRACT Large-scale phenotypic analyses have proved to be useful strategies in providing functional clues about the uncharacterized yeast genes. We used here a chemogenomic profiling of yeast deletion collections to identify the core of cellular processes challenged by treatment with the p-aminobenzoate/folate antimetabolite sulfanilamide. In addition to sulfanilamide-hypersensitive mutants whose deleted genes can be categorized into a number of groups, including one-carbon related metabolism, vacuole biogenesis and vesicular transport, DNA metabolic and cell cycle processes, and lipid and amino acid metabolism, two uncharacterized open reading frames (YHI9 and YMR289w) were also identified. A detailed characterization of YMR289w revealed that this gene was required for growth in media lacking p-aminobenzoic or folic acid and encoded a 4-amino-4-deoxychorismate lyase, which is the last of the three enzymatic activities required for p-aminobenzoic acid biosynthesis. In light of these results, YMR289w was designated ABZ2, in accordance with the accepted nomenclature. ABZ2 was able to rescue the p-aminobenzoate auxotrophy of an Escherichia coli pabC mutant, thus demonstrating that ABZ2 and pabC are functional homologues. Phylogenetic analyses revealed that Abz2p is the founder member of a new group of fungal 4-amino-4-deoxychorismate lyases that have no significant homology to its bacterial or plant counterparts. Abz2p appeared to form homodimers and dimerization was indispensable for its catalytic activity.

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Extended insight into the preponderance of LRRs - a docking & simulation study with members of the TLR1 subfamily

10.1101/592626 ◽

2019 ◽

Author(s):

Debayan Dey ◽

Dipanjana Dhar ◽

Sucharita Das ◽

Aditi Maulik ◽

Soumalee Basu

Keyword(s):

Phylogenetic Analyses ◽

Interleukin 1 ◽

Docking Simulation ◽

Md Simulations ◽

Structural Motif ◽

Cellular Processes ◽

Binding Function ◽

C Terminus ◽

Evolutionarily Conserved ◽

Leucine Rich Repeats

AbstractThe widespread structural motif of Leucine-rich repeats (LRR) constitute the extracellular part of the Toll-like receptor (TLR) family preceded by an intracellular Toll/interleukin-1 receptor (TIR) domain at the C-terminus. The benefit of using LRRs in these pattern recognition receptors (PRR) that are responsible for early detection of pathogens to elicit inflammatory/innate immune response still remains elusive. Phylogenetic analyses (Maximum Likelihood and Bayesian Inference) of nine TLR (TLR 1-9) genes from 36 mammals reconfirmed the existence of two distinct clades, one (TLR1/2/6) for recognizing bacterial cell wall derivatives and another (TLR7/8/9) for various nucleic acids. TLR3, TLR4 and TLR5 showed independent line of evolution. The distinction of the TLR1 subfamily to form heterodimers within its members and the existence of the paralogs TLR1 and TLR6 therein, was appealing enough to carry out further studies with the extracellular recognition domain. Dimerizing and ligand binding residues from the crystal structures of TLR1 and TLR6 were interchanged to generate chimeric proteins. The dimer forming ability of these variants with their common partner, TLR2, were checked before running MD simulations. The chimeras were compared with wild type dimers to find no significant alterations in the overall structure. Finally, interchanged ligands were docked to the variants to ratify reversal of the binding function. Intriguingly, sequence change in substantial numbers, 16 in TLR1 and 18 in TLR6, preserves the native scaffold offered by LRRs. This exercise thus depicts how the LRR motif has been advantageous to be selected as an evolutionarily conserved motif for essential cellular processes.

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Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

International Journal of Molecular Sciences ◽

10.3390/ijms22179322 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9322

Author(s):

Theodora-Christina Kyriakou ◽

Panagiotis Papageorgis ◽

Maria-Ioanna Christodoulou

Keyword(s):

Type 2 Diabetes ◽

Acute Myeloid Leukemia ◽

Whole Blood ◽

Myeloid Leukemia ◽

Expression Patterns ◽

Cellular Processes ◽

Increased Risk ◽

Transcriptomic Changes ◽

Acute Myeloid

Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

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The Type VI Secretion System of Xanthomonas phaseoli pv. manihotis is involved in virulence and in vitro motility

10.21203/rs.3.rs-48039/v2 ◽

2020 ◽

Author(s):

Nathaly Andrea Montenegro Benavides ◽

Alejandro Alvarez Borrero ◽

Mario Luis Arrieta Ortiz ◽

Luis Miguel Rodriguez-R. ◽

David Octavio Botero Rozo ◽

...

Keyword(s):

Gene Knockout ◽

Phylogenetic Analyses ◽

Gene Clusters ◽

Secretion System ◽

Type Vi Secretion System ◽

Cellular Processes ◽

Protein Secretion System ◽

Different Strains

Abstract Background: The type VI protein secretion system (T6SS) is important in diverse cellular processes in Gram-negative bacteria, including interactions with other bacteria and with eukaryotic hosts. In this study we analyze the evolution of the T6SS in the genus Xanthomonas and evaluate its importance of the T6SS for virulence and in vitro motility in Xanthomonas phaseoli pv. manihotis (Xpm), the causal agent of bacterial blight in cassava (Manihot esculenta). We delineate the organization of the T6SS gene clusters in Xanthomonas and then characterize proteins of this secretion system in Xpm strain CIO151. Results: We describe the presence of three different clusters in the genus Xanthomonas that vary in their organization and degree of synteny between species. Using a gene knockout mutagenesis, we also found that vgrG and hcp are required for maximal aggressiveness of Xpm on cassava plants while clpV is important for both motility and maximal aggressiveness. Conclusion: We characterized the T6SS in 15 different strains in Xanthomonas and our phylogenetic analyses suggest that the T6SS might have been acquired by a very ancient event of horizontal gene transfer and maintained through evolution, hinting at their importance for the adaptation of Xanthomonas to their hosts. Finally, we demonstrated that the T6SS of Xpm is functional, and significantly contributes to virulence and motility. This is the first experimental study that demonstrates the role of the T6SS in the Xpm-cassava interaction and the T6SS organization in the genus Xanthomonas.

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The Type VI Secretion System of Xanthomonas Phaseoli pv. Manihotis is Involved in Virulence and in vitro Motility

10.21203/rs.3.rs-48039/v1 ◽

2020 ◽

Author(s):

Nathaly Andrea Montenegro Benavides ◽

Alejandro Alvarez Borrero ◽

Mario Luis Arrieta Ortiz ◽

Luis Miguel Rodriguez-R. ◽

David Octavio Botero Rozo ◽

...

Keyword(s):

Gene Knockout ◽

Phylogenetic Analyses ◽

Gene Clusters ◽

Secretion System ◽

Type Vi Secretion System ◽

In Vitro Motility ◽

Cellular Processes ◽

Protein Secretion System ◽

Different Strains

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An -omics Perspective on Marine Invertebrate Larvae

10.1093/oso/9780198786962.003.0019 ◽

2018 ◽

Cited By ~ 3

Keyword(s):

Large Scale ◽

Natural Variation ◽

Molecular Mechanisms ◽

Marine Invertebrate ◽

Life History Evolution ◽

Molecular Approaches ◽

Fine Detail ◽

Technological Advances ◽

Gene Environment ◽

Invertebrate Larvae

The diverse phenotypes exhibited by marine invertebrate larvae are the result of complex gene-environment interactions. Recently, technological advances in molecular biology have enabled large-scale -omics approaches, which can provide a global overview of the molecular mechanisms that shape the larval genotype-phenotype landscape. -omics approaches are facilitating our understanding of larval development and life history evolution, larval response to environmental stress, the larval microbiome, larval physiology and feeding, and larval behavior. These large-scale molecular approaches are even more effective when combined with large-scale environmental monitoring and phenotypic measurements. Current -omics approaches to studying larvae can be improved by the addition of functional genetic analyses and the reporting of natural variation in gene expression between individuals and populations. Systems-level approaches that combine multiple -omics techniques will allow us to explore in fine detail the interactions of environmental and genotypic influences on larval phenotype.

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Ancient complement and lineage-specific evolution of the Sec7 ARF GEF proteins in eukaryotes

Molecular Biology of the Cell ◽

10.1091/mbc.e19-01-0073 ◽

2019 ◽

Vol 30 (15) ◽

pp. 1846-1863 ◽

Cited By ~ 5

Author(s):

Shweta V. Pipaliya ◽

Alexander Schlacht ◽

Christen M. Klinger ◽

Richard A. Kahn ◽

Joel Dacks

Keyword(s):

Membrane Trafficking ◽

Protein Function ◽

Phylogenetic Analyses ◽

Guanine Nucleotide Exchange Factors ◽

Nucleotide Exchange ◽

Cellular Processes ◽

Guanine Nucleotide Exchange ◽

Nucleotide Exchange Factors ◽

Gtpase Activating Proteins ◽

Functionally Diverse

Guanine nucleotide exchange factors (GEFs) are the initiators of signaling by every regulatory GTPase, which in turn act to regulate a wide array of essential cellular processes. To date, each family of GTPases is activated by distinct families of GEFs. Bidirectional membrane trafficking is regulated by ADP-ribosylation factor (ARF) GTPases and the development throughout eukaryotic evolution of increasingly complex systems of such traffic required the acquisition of a functionally diverse cohort of ARF GEFs to control it. We performed phylogenetic analyses of ARF GEFs in eukaryotes, defined by the presence of the Sec7 domain, and found three subfamilies (BIG, GBF1, and cytohesins) to have been present in the ancestor of all eukaryotes. The four other subfamilies (EFA6/PSD, IQSEC7/BRAG, FBX8, and TBS) are opisthokont, holozoan, metazoan, and alveolate/haptophyte specific, respectively, and each is derived from cytohesins. We also identified a cytohesin-derived subfamily, termed ankyrin repeat-containing cytohesin, that independently evolved in amoebozoans and members of the SAR and haptophyte clades. Building on evolutionary data for the ARF family GTPases and their GTPase-activating proteins allowed the generation of hypotheses about ARF GEF protein function(s) as well as a better understanding of the origins and evolution of cellular complexity in eukaryotes.

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Transcriptomic Changes Related to Cellular Processes with Particular Emphasis on Cell Activation in Lysosomal Storage Diseases from the Group of Mucopolysaccharidoses

International Journal of Molecular Sciences ◽

10.3390/ijms21093194 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3194 ◽

Cited By ~ 3

Author(s):

Estera Rintz ◽

Lidia Gaffke ◽

Magdalena Podlacha ◽

Joanna Brokowska ◽

Zuzanna Cyske ◽

...

Keyword(s):

Cell Activation ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Lysosomal Storage Diseases ◽

Lysosomal Storage ◽

Storage Diseases ◽

Monogenic Disorders ◽

Cellular Processes ◽

Transcriptomic Changes ◽

Molecular Pathomechanisms

Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.

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