scholarly journals Network and Evolutionary Analysis of Human Epigenetic Regulators to Unravel Disease Associations

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1457
Author(s):  
Shinji Ohsawa ◽  
Toshiaki Umemura ◽  
Tomoyoshi Terada ◽  
Yoshinori Muto
Keyword(s):  
Positive Selection ◽  
Developmental Stages ◽  
Age Distribution ◽  
System Level ◽  
Disease Genes ◽  
Evolutionary Analysis ◽  
Distribution Analysis ◽  
Cancer Disease ◽  
High Tendency ◽  
Epigenetic Regulators

We carried out a system-level analysis of epigenetic regulators (ERs) and detailed the protein–protein interaction (PPI) network characteristics of disease-associated ERs. We found that most diseases associated with ERs can be clustered into two large groups, cancer diseases and developmental diseases. ER genes formed a highly interconnected PPI subnetwork, indicating a high tendency to interact and agglomerate with one another. We used the disease module detection (DIAMOnD) algorithm to expand the PPI subnetworks into a comprehensive cancer disease ER network (CDEN) and developmental disease ER network (DDEN). Using the transcriptome from early mouse developmental stages, we identified the gene co-expression modules significantly enriched for the CDEN and DDEN gene sets, which indicated the stage-dependent roles of ER-related disease genes during early embryonic development. The evolutionary rate and phylogenetic age distribution analysis indicated that the evolution of CDEN and DDEN genes was mostly constrained, and these genes exhibited older evolutionary age. Our analysis of human polymorphism data revealed that genes belonging to DDEN and Seed-DDEN were more likely to show signs of recent positive selection in human history. This finding suggests a potential association between positive selection of ERs and risk of developmental diseases through the mechanism of antagonistic pleiotropy.

scholarly journals Genome wide analysis of kinesin gene family in Citrullus lanatus reveals an essential role in early fruit development

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shujuan Tian ◽  
Jiao Jiang ◽  
Guo-qi Xu ◽  
Tan Wang ◽  
Qiyan Liu ◽  
...  
Keyword(s):  
Gene Family ◽  
Plant Hormones ◽  
Fruit Development ◽  
Developmental Stages ◽  
Profile Analysis ◽  
Citrullus Lanatus ◽  
Binding Motif ◽  
Distribution Analysis ◽  
Motif Analysis ◽  
Expression Profile Analysis

Abstract Background Kinesin (KIN) as a motor protein is a versatile nano-machine and involved in diverse essential processes in plant growth and development. However, the kinesin gene family has not been identified in watermelon, a valued and nutritious fruit, and yet their functions have not been characterized. Especially, their involvement in early fruit development, which directly determines the size, shape, yield and quality of the watermelon fruit, remains unclear. Results In this study, we performed a whole-genome investigation and comprehensive analysis of kinesin genes in C. lanatus. In total, 48 kinesins were identified and categorized into 10 kinesin subfamilies groups based on phylogenetic analysis. Their uneven distribution on 11 chromosomes was revealed by distribution analysis. Conserved motif analysis showed that the ATP-binding motif of kinesins was conserved within all subfamilies, but not the microtubule-binding motif. 10 segmental duplication pairs genes were detected by the syntenic and phylogenetic approaches, which showed the expansion of the kinesin gene family in C. lanatus genome during evolution. Moreover, 5 ClKINs genes are specifically and abundantly expressed in early fruit developmental stages according to comprehensive expression profile analysis, implying their critical regulatory roles during early fruit development. Our data also demonstrated that the majority of kinesin genes were responsive to plant hormones, revealing their potential involvement in the signaling pathways of plant hormones. Conclusions Kinesin gene family in watermelon was comprehensively analyzed in this study, which establishes a foundation for further functional investigation of C. lanatus kinesin genes and provides novel insights into their biological functions. In addition, these results also provide useful information for understanding the relationship between plant hormone and kinesin genes in C. lanatus.

scholarly journals Evolutionary analysis of vision genes identifies potential drivers of visual differences between giraffe and okapi

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3145 ◽  
Author(s):  
Edson Ishengoma ◽  
Morris Agaba ◽  
Douglas R. Cavener
Keyword(s):  
Positive Selection ◽  
Visual Signal ◽  
Evolutionary Analysis ◽  
Long Distance ◽  
Phenotypic Differences ◽  
Multiple Strategies ◽  
Branch Site ◽  
Signature Of Selection ◽  
Evolutionary Success ◽  
Signatures Of Selection

BackgroundThe capacity of visually oriented species to perceive and respond to visual signal is integral to their evolutionary success. Giraffes are closely related to okapi, but the two species have broad range of phenotypic differences including their visual capacities. Vision studies rank giraffe’s visual acuity higher than all other artiodactyls despite sharing similar vision ecological determinants with many of them. The extent to which the giraffe’s unique visual capacity and its difference with okapi is reflected by changes in their vision genes is not understood.MethodsThe recent availability of giraffe and okapi genomes provided opportunity to identify giraffe and okapi vision genes. Multiple strategies were employed to identify thirty-six candidate mammalian vision genes in giraffe and okapi genomes. Quantification of selection pressure was performed by a combination of branch-site tests of positive selection and clade models of selection divergence through comparing giraffe and okapi vision genes and orthologous sequences from other mammals.ResultsSignatures of selection were identified in key genes that could potentially underlie giraffe and okapi visual adaptations. Importantly, some genes that contribute to optical transparency of the eye and those that are critical in light signaling pathway were found to show signatures of adaptive evolution or selection divergence. Comparison between giraffe and other ruminants identifies significant selection divergence inCRYAAandOPN1LW. Significant selection divergence was identified inSAGwhile positive selection was detected inLUMwhen okapi is compared with ruminants and other mammals. Sequence analysis ofOPN1LWshowed that at least one of the sites known to affect spectral sensitivity of the red pigment is uniquely divergent between giraffe and other ruminants.DiscussionBy taking a systemic approach to gene function in vision, the results provide the first molecular clues associated with giraffe and okapi vision adaptations. At least some of the genes that exhibit signature of selection may reflect adaptive response to differences in giraffe and okapi habitat. We hypothesize that requirement for long distance vision associated with predation and communication with conspecifics likely played an important role in the adaptive pressure on giraffe vision genes.

scholarly journals Integrated structural and evolutionary analysis reveals common mechanisms underlying adaptive evolution in mammals

2020 ◽  
Vol 117 (11) ◽  
pp. 5977-5986 ◽  
Author(s):  
Greg Slodkowicz ◽  
Nick Goldman
Keyword(s):  
Positive Selection ◽  
Adaptive Evolution ◽  
Evolutionary Biology ◽  
Molecular Mechanisms ◽  
Structural Information ◽  
Protein Structures ◽  
Unexpected Finding ◽  
Evolutionary Analysis ◽  
Genomic Scale ◽  
Evolution Of Mammals

Understanding the molecular basis of adaptation to the environment is a central question in evolutionary biology, yet linking detected signatures of positive selection to molecular mechanisms remains challenging. Here we demonstrate that combining sequence-based phylogenetic methods with structural information assists in making such mechanistic interpretations on a genomic scale. Our integrative analysis shows that positively selected sites tend to colocalize on protein structures and that positively selected clusters are found in functionally important regions of proteins, indicating that positive selection can contravene the well-known principle of evolutionary conservation of functionally important regions. This unexpected finding, along with our discovery that positive selection acts on structural clusters, opens previously unexplored strategies for the development of better models of protein evolution. Remarkably, proteins where we detect the strongest evidence of clustering belong to just two functional groups: Components of immune response and metabolic enzymes. This gives a coherent picture of pathogens and xenobiotics as important drivers of adaptive evolution of mammals.

Genome-wide identification and expression analysis of aquaporin gene family related to abiotic stress in watermelon

Genome ◽  
2019 ◽  
Vol 62 (10) ◽  
pp. 643-656 ◽  
Author(s):  
Yong Zhou ◽  
Junjie Tao ◽  
Golam Jalal Ahammed ◽  
Jingwen Li ◽  
Youxin Yang
Keyword(s):  
Expression Analysis ◽  
Developmental Stages ◽  
Plant Responses ◽  
Distribution Analysis ◽  
Cis Elements ◽  
Promoter Regions ◽  
Specific Expression ◽  
Promoter Sequences ◽  
Genome Wide ◽  
Aquaporin Gene

The plant aquaporins (AQPs) are highly conserved integral membrane proteins that participate in multiple developmental processes and responses to various stresses. In this study, a total of 35 AQP genes were identified in the watermelon genome. The phylogenetic analysis showed that these AQPs can be divided into five types, including 16 plasma membrane intrinsic proteins (PIPs), eight tonoplast intrinsic proteins (TIPs), eight nodulin 26-like intrinsic proteins (NIPs), two small basic intrinsic proteins (SIPs), and one uncategorized X intrinsic protein (XIP). A number of cis-elements related to plant responses to hormones and stresses were detected in the promoter sequences of ClAQP genes. Chromosome distribution analysis revealed that the genes are unevenly distributed on eight chromosomes, with chromosomes 1 and 4 possessing the most genes. Expression analysis at different developmental stages in flesh and rind indicated that most of ClAQPs have tissue-specific expression. Meanwhile, some other AQP genes showed differential expression in response to cold, salt, and ABA treatments, which is consistent with the organization of the stress-responsive cis-elements detected in the promoter regions. Our results lay a foundation for understanding the specific functions of ClAQP genes to help the genetic improvement of watermelon.

scholarly journals Characterizing the Diverse Mutational Pathways Associated with R5-Tropic Maraviroc Resistance: HIV-1 That Uses the Drug-Bound CCR5 Coreceptor

2015 ◽  
Vol 89 (22) ◽  
pp. 11457-11472 ◽  
Author(s):  
Xiaowei Jiang ◽  
Felix Feyertag ◽  
Conor J. Meehan ◽  
Grace P. McCormack ◽  
Simon A. Travers ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Failure ◽  
Positive Selection ◽  
Antiretroviral Drugs ◽  
Viral Population ◽  
Cell Protein ◽  
V3 Loop ◽  
Evolutionary Analysis ◽  
Resistance Pathway ◽  
Hiv 1

ABSTRACTEntry inhibitors represent a potent class of antiretroviral drugs that target a host cell protein, CCR5, an HIV-1 entry coreceptor, and not viral protein. Lack of sensitivity can occur due to preexisting virus that uses the CXCR4 coreceptor, while true resistance occurs through viral adaptation to use a drug-bound CCR5 coreceptor. To understand this R5 resistance pathway, we analyzed >500 envelope protein sequences and phenotypes from viruses of 20 patients from the clinical trials MOTIVATE 1 and 2, in which treatment-experienced patients received maraviroc plus optimized background therapy. The resistant viral population was phylogenetically distinct and associated with a genetic bottleneck in each patient, consistent withde novoemergence of resistance. Recombination analysis showed that the C2-V3-C3 region tends to genotypically correspond to the recombinant's phenotype, indicating its primary importance in conferring resistance. Between patients, there was a notable lack of commonality in the specific sites conferring resistance, confirming the unusual nature of R5-tropic resistance. We used coevolutionary and positive-selection analyses to characterize the genotypic determinants of resistance and found that (i) there are complicated covariation networks, indicating frequent coevolutionary/compensatory changes in the context of protein structure; (ii) covarying sites under positive selection are enriched in resistant viruses; (iii) CD4 binding sites form part of a unique covariation network independent of the V3 loop; and (iv) the covariation network formed between the V3 loop and other regions of gp120 and gp41 intersects sites involved in glycosylation and protein secretion. These results demonstrate that while envelope sequence mutations are the key to conferring maraviroc resistance, the specific changes involved are context dependent and thus inherently unpredictable.IMPORTANCEThe entry inhibitor drug maraviroc makes the cell coreceptor CCR5 unavailable for use by HIV-1 and is now used in combination antiretroviral therapy. Treatment failure with drug-resistant virus is particularly interesting because it tends to be rare, with lack of sensitivity usually associated with the presence of CXCR4-using virus (CXCR4 is the main alternative coreceptor HIV-1 uses, in addition to CD4). We analyzed envelope sequences from HIV-1, obtained from 20 patients who enrolled in maraviroc clinical trials and experienced treatment failure, without detection of CXCR4-using virus. Evolutionary analysis was employed to identify molecular changes that confer maraviroc resistance. We found that in these individuals, resistant viruses form a distinct population that evolved once and was successful as a result of drug pressure. Further evolutionary analysis placed the complex network of interdependent mutational changes into functional groups that help explain the impediments to the emergence of maraviroc-associated R5 drug resistance.

Comparative genomic analysis of a mammalian β-defensin gene cluster

2007 ◽  
Vol 30 (3) ◽  
pp. 213-222 ◽  
Author(s):  
Yashwanth Radhakrishnan ◽  
Mario A. Fares ◽  
Frank S. French ◽  
Susan H. Hall
Keyword(s):  
Positive Selection ◽  
Gene Cluster ◽  
Genomic Analysis ◽  
Urogenital Tract ◽  
Comparative Genomic ◽  
Evolutionary Analysis ◽  
Defensin Gene ◽  
Duplication Events ◽  
Molecular Evolutionary Analysis

Comparative genomic analyses have yielded valuable insights into conserved and divergent aspects of gene function, regulation, and evolution. Herein, we describe the characterization of a mouse β-defensin gene cluster locus on chromosome 2F6. In addition, we present the evolutionary analysis of this cluster and its human, rhesus, and rat orthologs. Expression analysis in mouse revealed the occurrence of defensin cluster transcripts in multiple tissues, with the highest abundance in the urogenital tract. Molecular evolutionary analysis suggests that this cluster originated by a series of duplication events, and by positive selection occurring even after the rodent-primate split. In addition, the constraints analysis showed higher positive selection in rodents than in primates, especially distal to the six-cysteine array. Positive selection in the evolution of these defensins may relate not only to the evolving enhancement of ancestral host defense but also to functional innovations in reproduction. The multiplicity of defensins and their preferential overexpression in the urogenital tract indicate that defensins function in the protection and maintenance of fertility.

scholarly journals Rapid molecular evolution across amniotes of the IIS/TOR network

2015 ◽  
Vol 112 (22) ◽  
pp. 7055-7060 ◽  
Author(s):  
Suzanne E. McGaugh ◽  
Anne M. Bronikowski ◽  
Chih-Horng Kuo ◽  
Dawn M. Reding ◽  
Elizabeth A. Addis ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Positive Selection ◽  
Insulin Receptor ◽  
Metabolic Diseases ◽  
Vital Role ◽  
Evolutionary Rates ◽  
Evolutionary Analysis ◽  
Binding Surface ◽  
Tor Network ◽  
Positively Selected Sites

The insulin/insulin-like signaling and target of rapamycin (IIS/TOR) network regulates lifespan and reproduction, as well as metabolic diseases, cancer, and aging. Despite its vital role in health, comparative analyses of IIS/TOR have been limited to invertebrates and mammals. We conducted an extensive evolutionary analysis of the IIS/TOR network across 66 amniotes with 18 newly generated transcriptomes from nonavian reptiles and additional available genomes/transcriptomes. We uncovered rapid and extensive molecular evolution between reptiles (including birds) and mammals: (i) the IIS/TOR network, including the critical nodes insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K), exhibit divergent evolutionary rates between reptiles and mammals; (ii) compared with a proxy for the rest of the genome, genes of the IIS/TOR extracellular network exhibit exceptionally fast evolutionary rates; and (iii) signatures of positive selection and coevolution of the extracellular network suggest reptile- and mammal-specific interactions between members of the network. In reptiles, positively selected sites cluster on the binding surfaces of insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R), and insulin receptor (INSR); whereas in mammals, positively selected sites clustered on the IGF2 binding surface, suggesting that these hormone-receptor binding affinities are targets of positive selection. Further, contrary to reports that IGF2R binds IGF2 only in marsupial and placental mammals, we found positively selected sites clustered on the hormone binding surface of reptile IGF2R that suggest that IGF2R binds to IGF hormones in diverse taxa and may have evolved in reptiles. These data suggest that key IIS/TOR paralogs have sub- or neofunctionalized between mammals and reptiles and that this network may underlie fundamental life history and physiological differences between these amniote sister clades.

scholarly journals MORC protein family-related signature within human disease and cancer

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Huan Wang ◽  
Ling Zhang ◽  
Qiuhua Luo ◽  
Jia Liu ◽  
Guiling Wang
Keyword(s):  
Cancer Progression ◽  
Coiled Coil ◽  
Diagnostic Tools ◽  
Disease Genes ◽  
Biological Functions ◽  
New Paradigm ◽  
Aberrant Expression ◽  
Domain Structures ◽  
Human Disorders ◽  
Epigenetic Regulators

AbstractThe microrchidia (MORC) family of proteins is a highly conserved nuclear protein superfamily, whose members contain common domain structures (GHKL-ATPase, CW-type zinc finger and coiled-coil domain) yet exhibit diverse biological functions. Despite the advancing research in previous decades, much of which focuses on their role as epigenetic regulators and in chromatin remodeling, relatively little is known about the role of MORCs in tumorigenesis and pathogenesis. MORCs were first identified as epigenetic regulators and chromatin remodelers in germ cell development. Currently, MORCs are regarded as disease genes that are involved in various human disorders and oncogenes in cancer progression and are expected to be the important biomarkers for diagnosis and treatment. A new paradigm of expanded MORC family function has raised questions regarding the regulation of MORCs and their biological role at the subcellular level. Here, we systematically review the progress of researching MORC members with respect to their domain architectures, diverse biological functions, and distribution characteristics and discuss the emerging roles of the aberrant expression or mutation of MORC family members in human disorders and cancer development. Furthermore, the illustration of related mechanisms of the MORC family has made MORCs promising targets for developing diagnostic tools and therapeutic treatments for human diseases, including cancers.

scholarly journals Heightened virulence of Yersinia is associated with decreased function of the YopJ protein

2021 ◽  
Author(s):  
Chris A Mares ◽  
Fernando P Lugo ◽  
Mohammad Albataineh ◽  
Beth Goins ◽  
Irene Newton ◽  
...  
Keyword(s):  
Positive Selection ◽  
Sequence Divergence ◽  
Bacterial Pathogenesis ◽  
Effector Protein ◽  
Evolutionary Analysis ◽  
Yersinia Species ◽  
Macrophage Cytotoxicity ◽  
A Minor ◽  
Pathogenic Yersinia

Despite the maintenance of YopP/J alleles throughout the human-pathogenic Yersinia lineage, the benefit of YopP/J-induced phagocyte death for Yersinia pathogenesis in animals is not obvious. To determine how sequence divergence of YopP/J has impacted Yersinia virulence, we examined protein polymorphisms in this Type III secreted effector protein across 17 Yersinia species, and tested the consequences of polymorphism in a murine model of sub-acute systemic yersiniosis. Our evolutionary analysis revealed that codon 177 has been subjected to positive selection - the Y. enterocolitica residue had been altered from a leucine to a phenylalanine in nearly all Y. pseudotuberculosis and Y. pestis strains examined. Despite being a minor change, as both leucine and phenylalanine have hydrophobic side chains, reversion of YopJF177 to the ancestral YopJL177 variant yielded a Y. pseudotuberculosis strain with enhanced cytotoxicity towards macrophages, consistent with previous findings. Surprisingly, expression of YopJF177L in the mildly attenuated ksgA- background rendered the strain completely avirulent in mice. Consistent with this hypothesis that YopJ activity indirectly relates to Yersinia pathogenesis in vivo, ksgA- strains lacking functional YopJ failed to kill macrophages but actually regained virulence in animals. Also, treatment with the anti-apoptosis drug suramin prevented YopJ-mediated macrophage cytotoxicity and enhanced Y. pseudotuberculosis virulence in vivo. Our results demonstrate that Yersinia-induced cell death is detrimental for bacterial pathogenesis in this animal model of illness, and indicate that positive selection has driven YopJ/P and Yersinia evolution towards diminished cytotoxicity and increased virulence, respectively.

scholarly journals A distinct expression profile in the cerebellum and striatum for genes under selection within introgression deserts

2021 ◽  
Author(s):  
Raul Buisan ◽  
Juan Moriano ◽  
Alejandro Andirko ◽  
Cedric Boeckx
Keyword(s):  
Positive Selection ◽  
Evolutionary History ◽  
Developmental Stages ◽  
Homo Sapiens ◽  
Transcriptomic Data ◽  
Functional Differences ◽  
History Of ◽  
Genomic Regions ◽  
Cerebral Neocortex

Analyses of ancient DNA from extinct hominins have provided unique insights into the complex evolutionary history of Homo sapiens, intricately related to that of the Neanderthals and the Denisovans as revealed by several instances of admixture events. These analyses have also allowed the identification of introgression deserts: genomic regions in our species that are depleted of `archaic' haplotypes. The presence of genes like FOXP2 in these deserts has been taken to be suggestive of brain-related functional differences between Homo species. Here, we seek a deeper characterization of these regions, taking into account signals of positive selection in our lineage. Analyzing publicly available transcriptomic data from the human brain at different developmental stages, we found that structures outside the cerebral neocortex, and especially the cerebellum and the striatum at prenatal stages, show the most divergent transcriptomic profiles when considering genes under positive selection within introgression deserts.

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