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1.
Gene ; 727: 144231, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31707000

RESUMO

Autophagy is the cellular process of removal of misfolded or damaged macromolecules and organelles. Experimental studies have demonstrated autophagy as a major mechanism of lifespan extension in long-lived mammals such as bats and mole rat rodents. Moreover, the role of this biological process has been well documented in protection against age-associated diseases and viral infection. However, studies on the molecular adaptive changes of autophagy factors during evolution are scarce. Here, we conducted a bioinformatics study of the molecular evolution of the Lysosomal Associated Membrane Protein 2 (LAMP2), as a rate-limiting factor in the lysosomal degradation stage of autophagy (the communal step of two of autophagy types: macroautophagy and chaperone-mediated). Analyzing LAMP2 across placental mammals, our phylogenetic-based maximum likelihood analyses indicate that the majority of the coding sites undergo purifying selection. However, around 27% of sites display a relaxation of purifying constraints (average ω = 0.42128), among which, 14 particular sites undergo positive selection (ω > 1). These sites are mostly located in the first luminal domain of LAMP2 (N-domain), with a hotspot region in the 135-144 codons interval. Therefore, the N-domain may account for the functional diversity and regulation of LAMP2. In addition, the identified positive selection sites could act as key regulatory sites in the LAMP2 function. On the other hand, testing the rate of evolution in LAMP2 along different clades of placental mammals revealed a relatively relaxed evolution in LAMP2 along megabats' clade. It is not clear yet whether an expedited evolution of LAMP2 in megabats has contributed to their reported up-regulation of autophagy. Finally, our data indicate positive selection sites along the ancestral branch of the clades of rodents, mouse-related rodents, and mole-rats; and suggest the potentially important regulatory role of these sites in LAMP2. Identifying the residues under positive selection, our findings pave the way for future experimental investigations to define how these selective substitutions have functionally affected autophagy.


Assuntos
Eutérios/genética , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Adaptação Biológica/genética , Animais , Autofagia/genética , Sequência Conservada/genética , Eutérios/metabolismo , Evolução Molecular , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Taxa de Mutação , Filogenia , Análise de Sequência de DNA/métodos
2.
BMC Evol Biol ; 19(1): 221, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791244

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are the most widely studied innate immunity receptors responsible for recognition of invading pathogens. Among the TLR family, TLR5 is the only that senses and recognizes flagellin, the major protein of bacterial flagella. TLR5 has been reported to be under overall purifying selection in mammals, with a small proportion of codons under positive selection. However, the variation of substitution rates among major mammalian groups has been neglected. Here, we studied the evolution of TLR5 in mammals, comparing the substitution rates among groups. RESULTS: In this study we analysed the TLR5 substitution rates in Euungulata, Carnivora, Chiroptera, Primata, Rodentia and Lagomorpha, groups. For that, Tajima's relative rate test, Bayesian inference of evolutionary rates and genetic distances were estimated with CODEML's branch model and RELAX. The combined results showed that in the Lagomorpha, Rodentia, Carnivora and Chiroptera lineages TLR5 is evolving at a higher substitution rate. The RELAX analysis further suggested a significant relaxation of selective pressures for the Lagomorpha (K = 0.22, p < 0.01), Rodentia (K = 0.58, p < 0.01) and Chiroptera (K = 0.65, p < 0.01) lineages and for the Carnivora ancestral branches (K = 0.13, p < 0.01). CONCLUSIONS: Our results show that the TLR5 substitution rate is not uniform among mammals. In fact, among the different mammal groups studied, the Lagomorpha, Rodentia, Carnivora and Chiroptera are evolving faster. This evolutionary pattern could be explained by 1) the acquisition of new functions of TLR5 in the groups with higher substitution rate, i.e. TLR5 neofunctionalization, 2) by the beginning of a TLR5 pseudogenization in these groups due to some redundancy between the TLRs genes, or 3) an arms race between TLR5 and species-specific parasites.


Assuntos
Evolução Molecular , Mamíferos/genética , Receptor 5 Toll-Like/genética , Animais , Teorema de Bayes , Códon , Flagelina/metabolismo , Humanos , Imunidade Inata , Mamíferos/imunologia , Filogenia , Especificidade da Espécie , Receptor 5 Toll-Like/química , Receptor 5 Toll-Like/imunologia
3.
BMC Bioinformatics ; 20(Suppl 24): 596, 2019 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-31861975

RESUMO

BACKGROUND: Adenosine-to-inosine RNA editing can markedly diversify the transcriptome, leading to a variety of critical molecular and biological processes in mammals. Over the past several years, researchers have developed several new pipelines and software packages to identify RNA editing sites with a focus on downstream statistical analysis and functional interpretation. RESULTS: Here, we developed a user-friendly public webserver named MIRIA that integrates statistics and visualization techniques to facilitate the comprehensive analysis of RNA editing sites data identified by the pipelines and software packages. MIRIA is unique in that provides several analytical functions, including RNA editing type statistics, genomic feature annotations, editing level statistics, genome-wide distribution of RNA editing sites, tissue-specific analysis and conservation analysis. We collected high-throughput RNA sequencing (RNA-seq) data from eight tissues across seven species as the experimental data for MIRIA and constructed an example result page. CONCLUSION: MIRIA provides both visualization and analysis of mammal RNA editing data for experimental biologists who are interested in revealing the functions of RNA editing sites. MIRIA is freely available at https://mammal.deepomics.org.


Assuntos
Mamíferos , Edição de RNA , Análise de Sequência de RNA , Transcriptoma , Animais , Genoma , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mamíferos/genética , RNA/genética , Análise de Sequência de RNA/métodos
4.
PLoS Genet ; 15(11): e1008478, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693685

RESUMO

Circadian rhythms allow animals to coordinate behavioral and physiological processes with respect to one another and to synchronize these processes to external environmental cycles. In most animals, circadian rhythms are produced by core clock neurons in the brain that generate and transmit time-of-day signals to downstream tissues, driving overt rhythms. The neuronal pathways controlling clock outputs, however, are not well understood. Furthermore, it is unclear how the central clock modulates multiple distinct circadian outputs. Identifying the cellular components and neuronal circuitry underlying circadian regulation is increasingly recognized as a critical step in the effort to address health pathologies linked to circadian disruption, including heart disease and metabolic disorders. Here, building on the conserved components of circadian and metabolic systems in mammals and Drosophila melanogaster, we used a recently developed feeding monitor to characterize the contribution to circadian feeding rhythms of two key neuronal populations in the Drosophila pars intercerebralis (PI), which is functionally homologous to the mammalian hypothalamus. We demonstrate that thermogenetic manipulations of PI neurons expressing the neuropeptide SIFamide (SIFa) as well as mutations of the SIFa gene degrade feeding:fasting rhythms. In contrast, manipulations of a nearby population of PI neurons that express the Drosophila insulin-like peptides (DILPs) affect total food consumption but leave feeding rhythms intact. The distinct contribution of these two PI cell populations to feeding is accompanied by vastly different neuronal connectivity as determined by trans-Tango synaptic mapping. These results for the first time identify a non-clock cell neuronal population in Drosophila that regulates feeding rhythms and furthermore demonstrate dissociable control of circadian and homeostatic aspects of feeding regulation by molecularly-defined neurons in a putative circadian output hub.


Assuntos
Relógios Circadianos/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Proteínas Circadianas Period/genética , Animais , Animais Geneticamente Modificados , Encéfalo/fisiologia , Ritmo Circadiano/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Jejum , Hipotálamo/metabolismo , Mamíferos/genética , Mamíferos/fisiologia , Neuroglia/fisiologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo
5.
BMC Evol Biol ; 19(1): 203, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694538

RESUMO

BACKGROUND: The flood of genomic data to help build and date the tree of life requires automation at several critical junctures, most importantly during sequence assembly and alignment. It is widely appreciated that automated alignment protocols can yield inaccuracies, but the relative impact of various sources error on phylogenomic analysis is not yet known. This study employs an updated mammal data set of 5162 coding loci sampled from 90 species to evaluate the effects of alignment uncertainty, substitution models, and fossil priors on gene tree, species tree, and divergence time estimation. Additionally, a novel coalescent likelihood ratio test is introduced for comparing competing species trees against a given set of gene trees. RESULTS: The aligned DNA sequences of 5162 loci from 90 species were trimmed and filtered using trimAL and two filtering protocols. The final dataset contains 4 sets of alignments - before trimming, after trimming, filtered by a recently proposed pipeline, and further filtered by comparing ML gene trees for each locus with the concatenation tree. Our analyses suggest that the average discordance among the coalescent trees is significantly smaller than that among the concatenation trees estimated from the 4 sets of alignments or with different substitution models. There is no significant difference among the divergence times estimated with different substitution models. However, the divergence dates estimated from the alignments after trimming are more recent than those estimated from the alignments before trimming. CONCLUSIONS: Our results highlight that alignment uncertainty of the updated mammal data set and the choice of substitution models have little impact on tree topologies yielded by coalescent methods for species tree estimation, whereas they are more influential on the trees made by concatenation. Given the choice of calibration scheme and clock models, divergence time estimates are robust to the choice of substitution models, but removing alignments deemed problematic by trimming algorithms can lead to more recent dates. Although the fossil prior is important in divergence time estimation, Bayesian estimates of divergence times in this data set are driven primarily by the sequence data.


Assuntos
Mamíferos/classificação , Mamíferos/genética , Filogenia , Algoritmos , Animais , Teorema de Bayes , Simulação por Computador , Fósseis , Genoma , Modelos Genéticos , Incerteza
6.
Nat Commun ; 10(1): 4327, 2019 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-31548547

RESUMO

Synthetic RNA-based genetic devices dynamically control a wide range of gene-regulatory processes across diverse cell types. However, the limited throughput of quantitative assays in mammalian cells has hindered fast iteration and interrogation of sequence space needed to identify new RNA devices. Here we report developing a quantitative, rapid and high-throughput mammalian cell-based RNA-Seq assay to efficiently engineer RNA devices. We identify new ribozyme-based RNA devices that respond to theophylline, hypoxanthine, cyclic-di-GMP, and folinic acid from libraries of ~22,700 sequences in total. The small molecule responsive devices exhibit low basal expression and high activation ratios, significantly expanding our toolset of highly functional ribozyme switches. The large datasets obtained further provide conserved sequence and structure motifs that may be used for rationally guided design. The RNA-Seq approach offers a generally applicable strategy for developing broad classes of RNA devices, thereby advancing the engineering of genetic devices for mammalian systems.


Assuntos
Mamíferos/genética , RNA Catalítico/química , Biologia Sintética/métodos , Animais , Redes Reguladoras de Genes , Engenharia Genética , Células HEK293 , Humanos , Motivos de Nucleotídeos , RNA Catalítico/metabolismo , RNA Catalítico/fisiologia
7.
Int J Mol Sci ; 20(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533246

RESUMO

Cellular, organ, and whole animal physiology show temporal variation predominantly featuring 24-h (circadian) periodicity. Time-course mRNA gene expression profiling in mouse liver showed two subsets of genes oscillating at the second (12-h) and third (8-h) harmonic of the prime (24-h) frequency. The aim of our study was to identify specific genomic, proteomic, and functional properties of ultradian and circadian subsets. We found hallmarks of the three oscillating gene subsets, including different (i) functional annotation, (ii) proteomic and electrochemical features, and (iii) transcription factor binding motifs in upstream regions of 8-h and 12-h oscillating genes that seemingly allow the link of the ultradian gene sets to a known circadian network. Our multifaceted bioinformatics analysis of circadian and ultradian genes suggests that the different rhythmicity of gene expression impacts physiological outcomes and may be related to transcriptional, translational and post-translational dynamics, as well as to phylogenetic and evolutionary components.


Assuntos
Genômica , Mamíferos/genética , Mamíferos/metabolismo , Proteômica , Animais , Sítios de Ligação , Biomarcadores , Mapeamento Cromossômico , Biologia Computacional/métodos , Epigênese Genética , Perfilação da Expressão Gênica , Genômica/métodos , Humanos , Anotação de Sequência Molecular , Filogenia , Regiões Promotoras Genéticas , Proteoma , Proteômica/métodos , Fatores de Tempo , Fatores de Transcrição
8.
PLoS Genet ; 15(9): e1008389, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31525198

RESUMO

Gene expression is subject to stochastic noise, but to what extent and by which means such stochastic variations are coordinated among different genes are unclear. We hypothesize that neighboring genes on the same chromosome co-fluctuate in expression because of their common chromatin dynamics, and verify it at the genomic scale using allele-specific single-cell RNA-sequencing data of mouse cells. Unexpectedly, the co-fluctuation extends to genes that are over 60 million bases apart. We provide evidence that this long-range effect arises in part from chromatin co-accessibilities of linked loci attributable to three-dimensional proximity, which is much closer intra-chromosomally than inter-chromosomally. We further show that genes encoding components of the same protein complex tend to be chromosomally linked, likely resulting from natural selection for intracellular among-component dosage balance. These findings have implications for both the evolution of genome organization and optimal design of synthetic genomes in the face of gene expression noise.


Assuntos
Regulação da Expressão Gênica/genética , Expressão Gênica/genética , Ligação Genética/genética , Animais , Cromatina/genética , Mapeamento Cromossômico/métodos , Cromossomos/genética , Bases de Dados Genéticas , Evolução Molecular , Genoma/genética , Genômica/métodos , Humanos , Mamíferos/genética , Camundongos , Seleção Genética , Processos Estocásticos
9.
Biol Direct ; 14(1): 17, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481097

RESUMO

BACKGROUND: Determining the factors involved in the likelihood of a gene being under adaptive selection is still a challenging goal in Evolutionary Biology. Here, we perform an evolutionary analysis of the human metabolic genes to explore the associations between network structure and the presence and strength of natural selection in the genes whose products are involved in metabolism. Purifying and positive selection are estimated at interspecific (among mammals) and intraspecific (among human populations) levels, and the connections between enzymatic reactions are differentiated between incoming (in-degree) and outgoing (out-degree) links. RESULTS: We confirm that purifying selection has been stronger in highly connected genes. Long-term positive selection has targeted poorly connected enzymes, whereas short-term positive selection has targeted different enzymes depending on whether the selective sweep has reached fixation in the population: genes under a complete selective sweep are poorly connected, whereas those under an incomplete selective sweep have high out-degree connectivity. The last steps of pathways are more conserved due to stronger purifying selection, with long-term positive selection targeting preferentially enzymes that catalyze the first steps. However, short-term positive selection has targeted enzymes that catalyze the last steps in the metabolic network. Strong signals of positive selection have been found for metabolic processes involved in lipid transport and membrane fluidity and permeability. CONCLUSIONS: Our analysis highlights the importance of analyzing the same biological system at different evolutionary timescales to understand the evolution of metabolic genes and of distinguishing between incoming and outgoing links in a metabolic network. Short-term positive selection has targeted enzymes with a different connectivity profile depending on the completeness of the selective sweep, while long-term positive selection has targeted genes with fewer connections that code for enzymes that catalyze the first steps in the network. REVIEWERS: This article was reviewed by Diamantis Sellis and Brandon Invergo.


Assuntos
Evolução Molecular , Mamíferos/genética , Redes e Vias Metabólicas/genética , Seleção Genética , Animais , Humanos , Mamíferos/metabolismo
10.
PLoS Genet ; 15(9): e1008333, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31537017

RESUMO

In mammals, dosage compensation of sex chromosomal genes between females (XX) and males (XY) is achieved through X-chromosome inactivation (XCI). The X-linked X-inactive-specific transcript (Xist) long noncoding RNA is indispensable for XCI and initiates the process early during development by spreading in cis across the X chromosome from which it is transcribed. During XCI, Xist RNA triggers gene silencing, recruits a plethora of chromatin modifying factors, and drives a major structural reorganization of the X chromosome. Here, we review our knowledge of the multitude of epigenetic events orchestrated by Xist RNA to allow female mammals to survive through embryonic development by establishing and maintaining proper dosage compensation. In particular, we focus on recent studies characterizing the interaction partners of Xist RNA, and we discuss how they have affected the field by addressing long-standing controversies or by giving rise to new research perspectives that are currently being explored. This review is dedicated to the memory of Denise Barlow, pioneer of genomic imprinting and functional long noncoding RNAs (lncRNAs), whose work has revolutionized the epigenetics field and continues to inspire generations of scientists.


Assuntos
Compensação de Dosagem (Genética)/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Compensação de Dosagem (Genética)/fisiologia , Epigênese Genética/genética , Feminino , Inativação Gênica/fisiologia , Humanos , Masculino , Mamíferos/genética , RNA Longo não Codificante/fisiologia , Cromossomo X/genética , Inativação do Cromossomo X/genética
11.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514326

RESUMO

In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian leptin and TNF is limited and they are absent or lowly expressed in adipose, respectively. Employing radiation-hybrid mapping and FISH-TSA, we mapped TNF and its syntenic genes to chicken chromosome 16 within the major histocompatibility complex (MHC) region. This mapping position suggests that avian TNF has a role in regulating immune response. To test its possible interaction with leptin within the immune system and beyond, we compared the transcription patterns of TNF, leptin and their cognate receptors obtained by meta-analysis of GenBank RNA-seq data. While expression of leptin and its receptor (LEPR) were detected in the brain and digestive tract, TNF and its receptor mRNAs were primarily found in viral-infected and LPS-treated leukocytes. We confirmed leptin expression in the duodenum by immunohistochemistry staining. Altogether, we suggest that whereas leptin and TNF interact as adipokines in mammals, in birds, they have distinct roles. Thus, the interaction between leptin and TNF may be unique to mammals.


Assuntos
Galinhas/genética , Mapeamento Cromossômico , Digestão , Regulação da Expressão Gênica , Leptina/genética , Mamíferos/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Galinhas/metabolismo , Duodeno/metabolismo , Feminino , Leptina/metabolismo , Metáfase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Mapeamento de Híbridos Radioativos , Receptores para Leptina/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Sintenia/genética , Fator de Necrose Tumoral alfa/genética
12.
Vet Res Commun ; 43(4): 203-214, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31410631

RESUMO

The interferon-induced transmembrane protein 3 (IFITM3) gene is classified as a small interferon-stimulated gene and is associated with a broad spectrum of antiviral functions against several fatal enveloped viruses, including influenza A viruses (IAVs). The rs12252 single nucleotide polymorphism (SNP) of the IFITM3 gene in humans was associated with susceptibility to H1N1 influenza in a 2009 pandemic. In addition, overexpression of the IFITM3 protein potently inhibits the highly pathogenic avian influenza H5N1 virus in ducks and chickens. Although chickens are a major host of influenza viruses and the IFITM3 gene participates in the host antiviral system, studies on chicken IFITM3 gene are very rare. To investigate the genetic characteristics of the chicken IFITM3 gene, we performed direct sequencing and alignment in 108 Dekalb White and 72 Ross breeds. We also investigated the genotype and haplotype frequencies and linkage disequilibrium of the IFITM3 gene polymorphisms and evaluated whether the non-synonymous SNPs are deleterious. We found significantly different genotype, allele and haplotypes frequencies between two chicken breeds, Dekalb White and Ross. Furthermore, we compared and analyzed the promoter structure of the chicken IFITM3 gene with that of several species. We found that birds have a long C-terminal domain and inverted topology of the IFITM3 protein compared to mammals. We also identified fourteen genetic polymorphisms in the chicken IFITM3 gene. L100 M and N125H were predicted as 'probably damaging' and L100 M can alter the length of its conserved intracellular loop (CIL). Furthermore, chickens, but not mammals, contain CpG islands (CGIs) in this promoter region.


Assuntos
Galinhas/genética , Galinhas/imunologia , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Animais , Cruzamento , Sequência Conservada , Ilhas de CpG/genética , Frequência do Gene , Genótipo , Haplótipos , Mamíferos/genética , Regiões Promotoras Genéticas/genética , Inversão de Sequência
13.
An Acad Bras Cienc ; 91(suppl 3): e20190339, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31460595

RESUMO

Genetic drift is the fortuitous occurrence of genetic events that when they become fixed modify the genome of populations. They can take the form of mutations of single nucleotides (SNPs), the insertion or deletion of short sequences (Indels) or the repetitions of short sequences (CNV i.e. copy number variants) or long insertions or deletion (structural modifications). Their frequency is 10-9 to 10-8 depending on the species, or 50 to 100 per birth in humans. The incidence of these de novo mutations is higher when the father is old at conception. It thus appears that genetic drift, which constitutes the initial element of evolution, has a very strong dynamics. Its intervention in the appearance or disappearance of some major phenotypes is complicated by the uncertainties about the genetic mechanisms in heritability which, paradoxically, are only partially understood.


Assuntos
Evolução Molecular , Deriva Genética , Mutação INDEL/genética , Mamíferos/genética , Animais , Humanos , Camundongos , Ratos
14.
Mol Biol Evol ; 36(10): 2195-2204, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31270536

RESUMO

Condensins play a crucial role in the organization of genetic material by compacting and disentangling chromosomes. Based on studies in a few model organisms, the condensins I and II complexes are considered to have distinct functions, with the condensin II complex playing a role in meiosis and somatic pairing of homologous chromosomes in Drosophila. Intriguingly, the Cap-G2 subunit of condensin II is absent in Drosophila melanogaster, and this loss may be related to the high levels of chromosome pairing seen in flies. Here, we find that all three non-SMC subunits of condensin II (Cap-G2, Cap-D3, and Cap-H2) have been repeatedly and independently lost in taxa representing multiple insect orders, with some taxa lacking all three. We also find that all non-Dipteran insects display near-uniform low-pairing levels regardless of their condensin II complex composition, suggesting that some key aspects of genome organization are robust to condensin II subunit losses. Finally, we observe consistent signatures of positive selection in condensin subunits across flies and mammals. These findings suggest that these ancient complexes are far more evolutionarily labile than previously suspected, and are at the crossroads of several forms of genomic conflicts. Our results raise fundamental questions about the specific functions of the two condensin complexes in taxa that have experienced subunit losses, and open the door to further investigations to elucidate the diversity of molecular mechanisms that underlie genome organization across various life forms.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ligação a DNA/genética , Evolução Molecular , Insetos/genética , Complexos Multiproteicos/genética , Animais , Mamíferos/genética , Seleção Genética
15.
Biochem Soc Trans ; 47(4): 997-1003, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31320500

RESUMO

DNA methylation at the fifth position of cytosine is a major epigenetic mark conserved in plants and mammals. Genome-wide DNA methylation patterns are dynamically controlled by integrated activities of establishment, maintenance, and removal. In both plants and mammals, a pattern of global DNA hypomethylation coupled with increased methylation levels at some specific genomic regions arises at specific developmental stages and in certain abnormal cells, such as mammalian aging cells and cancer cells as well as some plant epigenetic mutants. Here we provide an overview of this distinct DNA methylation pattern in mammals and plants, and propose that a methylstat, which is a cis-element responsive to both DNA methylation and active demethylation activities and controlling the transcriptional activity of a key DNA methylation regulator, can help to explain the enigmatic DNA methylation patterns in aging cells and cancer cells.


Assuntos
Envelhecimento/genética , Metilação de DNA , Neoplasias/genética , Plantas/genética , Animais , Desmetilação , Epigênese Genética , Humanos , Mamíferos/genética , Neoplasias/patologia
16.
Gene ; 713: 143975, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302167

RESUMO

Hair is one of the defining characteristics of mammals. The hair shaft has a two-layer structure comprising the cortex, which is the inner layer and is composed of cortical cells, and the cuticle, which is the outermost layer. S100 calcium-binding protein A3 (S100A3) is expressed at high levels in the human hair cuticle. Arginine 51 of S100A3 protein is citrullinated specifically by peptidylarginine deiminase 3 (PAD3), and this citrullination is related to maturation of the cuticle. However, the detailed evolutionary processes of S100A3 and PAD3 during mammalian evolution are unknown. Here, we show that nonsynonymous changes in S100A3 accelerated in the common ancestral branch of mammals, probably as a result of positive selection that returned after the acquisition of hair cuticle-specific function in mammals. Later, pseudogenisation or nonfunctionalisation of S100A3 and PAD3 occurred in some species, such as the cetaceans. Our results show that positive selection and relaxation of the functional constraints of genes played important roles in the evolution of mammalian hair.


Assuntos
Evolução Molecular , Cabelo/química , Mamíferos/genética , Desiminases de Arginina em Proteínas/genética , Proteínas S100/genética , Seleção Genética , Sequência de Aminoácidos , Animais , Filogenia , Homologia de Sequência
17.
Methods Mol Biol ; 1910: 373-397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31278671

RESUMO

Populations evolve as mutations arise in individual organisms and, through hereditary transmission, may become "fixed" (shared by all individuals) in the population. Most mutations are lethal or have negative fitness consequences for the organism. Others have essentially no effect on organismal fitness and can become fixed through the neutral stochastic process known as random drift. However, mutations may also produce a selective advantage that boosts their chances of reaching fixation. Regions of genomes where new mutations are beneficial, rather than neutral or deleterious, tend to evolve more rapidly due to positive selection. Genes involved in immunity and defense are a well-known example; rapid evolution in these genes presumably occurs because new mutations help organisms to prevail in evolutionary "arms races" with pathogens. In recent years genome-wide scans for selection have enlarged our understanding of the genome evolution of various species. In this chapter, we will focus on methods to detect selection on the genome. In particular, we will discuss probabilistic models and how they have changed with the advent of new genome-wide data now available.


Assuntos
Evolução Molecular , Genoma , Seleção Genética , Animais , Códon , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla , Genômica/métodos , Genótipo , Humanos , Mamíferos/genética , Modelos Genéticos , Modelos Estatísticos , Mutação , Filogenia , Polimorfismo Genético , Software , Navegador
18.
BMC Evol Biol ; 19(1): 154, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31345177

RESUMO

BACKGROUND: Genes that encode proteins associated with sperm competition, fertilization, and sexual conflicts of interest are often among the most rapidly evolving parts of animal genomes. One family of sperm-expressed genes (Zp3r, C4bpa) in the mammalian gene cluster called the regulator of complement activation (RCA) encodes proteins that bind eggs and mediate reproductive success, and are therefore expected to show high relative rates of nonsynonymous nucleotide substitution in response to sexual selection in comparison to other genes not involved in gamete binding at fertilization. We tested that working hypothesis by using phylogenetic models of codon evolution to identify episodes of diversifying positive selection. We used a comparative approach to quantify the evidence for episodic diversifying selection acting on RCA genes with known functions in fertilization (and sensitivity to sexual selection), and contrast them with other RCA genes in the same gene family that function in innate immunity (and are not sensitive to sexual selection). RESULTS: We expected but did not find evidence for more episodes of positive selection on Zp3r in Glires (the rodents and lagomorphs) or on C4BPA in Primates, in comparison to other paralogous RCA genes in the same taxon, or in comparison to the same orthologous RCA gene in the other taxon. That result was not unique to RCA genes: we also found little evidence for more episodes of diversifying selection on genes that encode selective sperm-binding molecules in the egg coat or zona pellucida (Zp2, Zp3) in comparison to members of the same gene family that encode structural elements of the egg coat (Zp1, Zp4). Similarly, we found little evidence for episodic diversifying selection acting on two other recently discovered genes (Juno, Izumo1) that encode essential molecules for sperm-egg fusion. CONCLUSIONS: These negative results help to illustrate the importance of a comparative context for this type of codon model analysis. The results may also point to other phylogenetic contexts in which the effects of selection acting on these fertilization proteins might be more readily discovered and documented in mammals and other taxa.


Assuntos
Epistasia Genética , Evolução Molecular , Fertilização/genética , Mamíferos/genética , Animais , Códon/genética , Feminino , Variação Genética , Masculino , Camundongos , Fenótipo , Filogenia , Seleção Genética
19.
Nat Commun ; 10(1): 3274, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332171

RESUMO

Genome-wide studies of DNA replication origins revealed that origins preferentially associate with an Origin G-rich Repeated Element (OGRE), potentially forming G-quadruplexes (G4). Here, we functionally address their requirements for DNA replication initiation in a series of independent approaches. Deletion of the OGRE/G4 sequence strongly decreased the corresponding origin activity. Conversely, the insertion of an OGRE/G4 element created a new replication origin. This element also promoted replication of episomal EBV vectors lacking the viral origin, but not if the OGRE/G4 sequence was deleted. A potent G4 ligand, PhenDC3, stabilized G4s but did not alter the global origin activity. However, a set of new, G4-associated origins was created, whereas suppressed origins were largely G4-free. In vitro Xenopus laevis replication systems showed that OGRE/G4 sequences are involved in the activation of DNA replication, but not in the pre-replication complex formation. Altogether, these results converge to the functional importance of OGRE/G4 elements in DNA replication initiation.


Assuntos
Replicação do DNA/genética , Quadruplex G , Mamíferos/genética , Origem de Replicação/genética , Animais , Células Cultivadas , Vetores Genéticos/genética , Humanos , Camundongos , Mutação , Células NIH 3T3 , Oócitos/metabolismo , Plasmídeos/genética , Xenopus laevis
20.
BMC Evol Biol ; 19(1): 144, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311498

RESUMO

BACKGROUND: Rapid accumulation of vertebrate genome sequences render comparative genomics a powerful approach to study macro-evolutionary events. The assessment of phylogenic relationships between species routinely depends on the analysis of sequence homology at the nucleotide or protein level. RESULTS: We analyzed mRNA GC content, codon usage and divergence of orthologous proteins in 55 vertebrate genomes. Data were visualized in genome-wide landscapes using a sliding window approach. Landscapes of GC content reveal both evolutionary conservation of clustered genes, and lineage-specific changes, so that it was possible to construct a phylogenetic tree that closely matched the classic "tree of life". Landscapes of GC content also strongly correlated to landscapes of amino acid usage: positive correlation with glycine, alanine, arginine and proline and negative correlation with phenylalanine, tyrosine, methionine, isoleucine, asparagine and lysine. Peaks of GC content correlated strongly with increased protein divergence. CONCLUSIONS: Landscapes of base- and amino acid composition of the coding genome opens a new approach in comparative genomics, allowing identification of discrete regions in which protein evolution accelerated over deep evolutionary time. Insight in the evolution of genome structure may spur novel studies assessing the evolutionary benefit of genes in particular genomic regions.


Assuntos
Composição de Bases/genética , Evolução Molecular , Exoma/genética , Proteínas/genética , Vertebrados/genética , Animais , Códon/genética , Genoma , Humanos , Mamíferos/genética , Filogenia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Répteis/genética
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