scholarly journals In-Frame Indel Mutations in the Genome of the Blind Mexican Cavefish, Astyanax mexicanus

2019 ◽  
Vol 11 (9) ◽  
pp. 2563-2573 ◽  
Author(s):  
Daniel Berning ◽  
Hannah Adams ◽  
Heidi Luc ◽  
Joshua B Gross
Keyword(s):  
Vision Loss ◽  
Copy Number Variants ◽  
Model Systems ◽  
Developmental Expression ◽  
Growth Factor Signaling ◽  
Environmental Pressures ◽  
Genetic Changes ◽  
Regressive Evolution ◽  
Astyanax Mexicanus ◽  
A Genome

AbstractOrganisms living in the subterranean biome evolve extreme characteristics including vision loss and sensory expansion. Despite prior work linking certain genes to Mendelian traits, the genetic basis for complex cave-associated traits remains unknown. Moreover, it is unclear if certain forms of genetic variation (e.g., indels, copy number variants) are more common in regressive evolution. Progress in this area has been limited by a lack of suitable natural model systems and genomic resources. In recent years, the Mexican tetra, Astyanax mexicanus, has advanced as a model for cave biology and regressive evolution. Here, we present the results of a genome-wide screen for in-frame indels using alignments of RNA-sequencing reads to the draft cavefish genome. Mutations were discovered in three genes associated with blood physiology (mlf1, plg, and wdr1), two genes associated with growth factor signaling (ghrb, rnf126), one gene linked to collagen defects (mia3), and one gene which may have a global epigenetic impact on gene expression (mki67). With one exception, polymorphisms were shared between Pachón and Tinaja cavefish lineages, and different from the surface-dwelling lineage. We confirmed the presence of mutations using direct Sanger sequencing and discovered remarkably similar developmental expression in both morphs despite substantial coding sequence alterations. Further, three mutated genes mapped near previously established quantitative trait loci associated with jaw size, condition factor, lens size, and neuromast variation. This work reveals previously unappreciated traits evolving in this species under environmental pressures (e.g., blood physiology) and provides insight to genetic changes underlying convergence of organisms evolving in complete darkness.

scholarly journals Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice

2020 ◽  
Vol 9 (7) ◽  
pp. 2242
Author(s):  
Ye Liu ◽  
Kousuke Noda ◽  
Miyuki Murata ◽  
Di Wu ◽  
Atsuhiro Kanda ◽  
...  
Keyword(s):  
Growth Factor ◽  
Choroidal Neovascularization ◽  
Vision Loss ◽  
Growth Factor Receptor ◽  
Neutralizing Antibody ◽  
Age Related Macular Degeneration ◽  
Platelet Derived Growth Factor ◽  
Growth Factor Signaling ◽  
Age Related ◽  
Subretinal Fibrosis

Neovascular age related macular degeneration (nAMD) leads to severe vision loss worldwide and is characterized by the formation of choroidal neovascularization (CNV) and fibrosis. In the current study, we aimed to investigate the effect of blockade for platelet derived growth factor receptor-β (PDGFR-β) on the formation of choroidal neovascularization and fibrosis in the laser-induced CNV model in mice. Firstly, the presence of PDGFR-β in CNV lesions were confirmed. Intravitreal injection of PDGFR-β neutralizing antibody significantly reduced the size of CNV and subretinal fibrosis. Additionally, subretinal hyperreflective material (SHRM), a landmark feature on OCT as a risk factor for subretinal fibrosis formation in nAMD patients was also suppressed by PDGFR-β blockade. Furthermore, pericytes were abundantly recruited to the CNV lesions during CNV formation, however, blockade of PDGFR-β significantly reduced pericyte recruitment. In addition, PDGF-BB stimulation increased the migration of the rat retinal pericyte cell line, R-rPCT1, which was abrogated by the neutralization of PDGFR-β. These results indicate that blockade of PDGFR-β attenuates laser-induced CNV and fibrosis through the inhibition of pericyte migration.

scholarly journals Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals

2019 ◽  
Vol 116 (51) ◽  
pp. 25745-25755 ◽  
Author(s):  
Nicholas R. Casewell ◽  
Daniel Petras ◽  
Daren C. Card ◽  
Vivek Suranse ◽  
Alexis M. Mychajliw ◽  
...  
Keyword(s):  
Serine Proteases ◽  
Prey Capture ◽  
Convincing Evidence ◽  
Model Systems ◽  
Ancestral State ◽  
Origin And Evolution ◽  
Physiological Processes ◽  
A Genome ◽  
Taxonomic Groups

Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find thatKLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.

scholarly journals Association of CNVs with methylation variation

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Xinghua Shi ◽  
Saranya Radhakrishnan ◽  
Jia Wen ◽  
Jin Yun Chen ◽  
Junjie Chen ◽  
...  
Keyword(s):  
Association Studies ◽  
Copy Number Variants ◽  
Cpg Methylation ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Cellular Phenotype ◽  
Genome Wide ◽  
A Genome ◽  
Physical Interactions ◽  
Trait Locus

Abstract Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.

scholarly journals A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

2012 ◽  
Vol 22 (4) ◽  
pp. 816-824 ◽  
Author(s):  
Jade Chapman ◽  
Elliott Rees ◽  
Denise Harold ◽  
Dobril Ivanov ◽  
Amy Gerrish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Copy Number ◽  
Disease Risk ◽  
Copy Number Variants ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Study

scholarly journals Intramolecular phenotypic capacitance in a modular RNA molecule

2015 ◽  
Vol 112 (40) ◽  
pp. 12444-12449 ◽  
Author(s):  
Eric J. Hayden ◽  
Devin P. Bendixsen ◽  
Andreas Wagner
Keyword(s):  
Catalytic Activity ◽  
In Vitro Selection ◽  
Ion Concentration ◽  
Magnesium Ion ◽  
Interacting Protein ◽  
Genetic Changes ◽  
Low Magnesium ◽  
Naturally Occurring ◽  
A Genome

Phenotypic capacitance refers to the ability of a genome to accumulate mutations that are conditionally hidden and only reveal phenotype-altering effects after certain environmental or genetic changes. Capacitance has important implications for the evolution of novel forms and functions, but experimentally studied mechanisms behind capacitance are mostly limited to complex, multicomponent systems often involving several interacting protein molecules. Here we demonstrate phenotypic capacitance within a much simpler system, an individual RNA molecule with catalytic activity (ribozyme). This naturally occurring RNA molecule has a modular structure, where a scaffold module acts as an intramolecular chaperone that facilitates folding of a second catalytic module. Previous studies have shown that the scaffold module is not absolutely required for activity, but dramatically decreases the concentration of magnesium ions required for the formation of an active site. Here, we use an experimental perturbation of magnesium ion concentration that disrupts the folding of certain genetic variants of this ribozyme and use in vitro selection followed by deep sequencing to identify genotypes with altered phenotypes (catalytic activity). We identify multiple conditional mutations that alter the wild-type ribozyme phenotype under a stressful environmental condition of low magnesium ion concentration, but preserve the phenotype under more relaxed conditions. This conditional buffering is confined to the scaffold module, but controls the catalytic phenotype, demonstrating how modularity can enable phenotypic capacitance within a single macromolecule. RNA’s ancient role in life suggests that phenotypic capacitance may have influenced evolution since life’s origins.

scholarly journals Real age prediction from the transcriptome with RAPToR

2021 ◽  
Author(s):  
Romain Bulteau ◽  
Mirko Francesconi
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Time Series Data ◽  
Expression Profiles ◽  
Computational Method ◽  
Model Systems ◽  
Developmental Expression ◽  
Model Organisms ◽  
Series Data ◽  
Developmental Variation

AbstractGenome-wide gene expression profiling is a powerful tool for exploratory analyses, providing a high dimensional picture of the state of a biological system. However, uncontrolled variation among samples can obscure and confound the effect of variables of interest. Uncontrolled developmental variation is often a major source of unknown expression variation in developmental systems. Existing methods to sort samples from transcriptomes require many samples to infer developmental trajectories and only provide a relative pseudo-time.Here we present RAPToR (Real Age Prediction from Transcriptome staging on Reference), a simple computational method to estimate the absolute developmental age of even a single sample from its gene expression with up to minutes precision. We achieve this by staging samples on high-resolution reference developmental expression profiles we build from existing time series data. We implemented RAPToR for the most common animal model systems: nematode, fruit fly, zebrafish, and mouse, and demonstrate application for non-model organisms. We show how developmental variation discovered by RAPToR can be exploited to increase power to detect differential expression and to untangle the signal of perturbations of interest even when it is completely confounded with development. We anticipate our RAPToR post-profiling staging strategy will be especially useful in large scale single organism profiling because it eliminates the need for synchronization or for a tedious and potentially difficult step of accurate staging before profiling.

scholarly journals Evaluation of copy number burden in specific epilepsy types from a genome-wide study of 18,564 subjects

2019 ◽  
Author(s):  
Lisa-Marie Niestroj ◽  
Daniel P. Howrigan ◽  
Eduardo Perez-Palma ◽  
Elmo Saarentaus ◽  
Peter Nürnberg ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Architecture ◽  
Focal Epilepsy ◽  
Copy Number Variants ◽  
Epileptic Encephalopathy ◽  
Additional Risk ◽  
Genome Wide ◽  
A Genome ◽  
Generalized Epilepsy ◽  
Genome Wide Study

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

scholarly journals Power and limits of selection genome scans on temporal data from a selfing population

2020 ◽  
Author(s):  
Miguel Navascués ◽  
Arnaud Becheler ◽  
Laurène Gay ◽  
Joëlle Ronfort ◽  
Karine Loridon ◽  
...  
Keyword(s):  
Low Frequency ◽  
Genome Scan ◽  
Temporal Data ◽  
Genetic Changes ◽  
Standing Variation ◽  
Power Of The Test ◽  
Contemporary Sample ◽  
A Genome ◽  
Temporal Differentiation ◽  
Historical Recombination

AbstractTracking genetic changes of populations through time allows a more direct study of the evolutionary processes acting on the population than a single contemporary sample. Several statistical methods have been developed to characterize the demography and selection from temporal population genetic data. However, these methods are usually developed under the assumption of outcrossing reproduction and might not be applicable when there is substantial selfing in the population. Here, we focus on a method to detect loci under selection based on a genome scan of temporal differentiation, adapting it to the particularities of selfing populations. Selfing reduces the effective recombination rate and can extend hitch-hiking effects to the whole genome, erasing any local signal of selection on a genome scan. Therefore, selfing is expected to reduce the power of the test. By means of simulations, we evaluate the performance of the method under scenarios of adaptation from new mutations or standing variation at different rates of selfing. We find that the detection of loci under selection in predominantly selfing populations remains challenging even with the adapted method. Still, selective sweeps from standing variation on predominantly selfing populations can leave some signal of selection around the selected site thanks to historical recombination before the sweep. Under this scenario, ancestral advantageous alleles at low frequency leave the strongest local signal, while new advantageous mutations leave no local footprint of the sweep.

scholarly journals Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression

2021 ◽  
Author(s):  
Yiwen Zhu ◽  
Min-Jung Wang ◽  
Katherine M Crawford ◽  
Juan Carlos Ramirez-Tapia ◽  
Alexandre A Lussier ◽  
...  
Keyword(s):  
Animal Studies ◽  
Socioeconomic Disadvantage ◽  
Developmental Expression ◽  
Sensitive Period ◽  
Genetic Pathways ◽  
Gene Set ◽  
Sensitive Periods ◽  
Depression Risk ◽  
Genome Wide ◽  
A Genome

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects in shaping brain structure or function, behavior, and disease risk. Sensitive periods for depression likely arise through a complex interplay of genes and experience, though this possibility has not been explored. We examined the effect of sensitive period-regulating genetic pathways identified in preclinical animal studies, alone and in interaction with socioeconomic disadvantage, a common childhood adversity, on depression risk. Using a translational approach, we: (1) performed gene-set association analyses using summary data from a genome-wide association study of depression (n=807,553) to assess the effects of three gene sets (60 genes) shown in animal studies to regulate sensitive periods; (2) evaluated the developmental expression patterns of these sensitive period-regulating genes using data from BrainSpan (n=31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay by analyzing the combined effect of common variants in sensitive period genes and timing of exposure to socioeconomic disadvantage within a population-based birth cohort (n=6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, six of the 15 genes in this set showed developmentally regulated gene-level expression. A genome-wide polygenic risk score-by-environment analysis showed socioeconomic disadvantage during ages 1-5 years were independently associated with depression risk, but no gene-by-development interactions were found. Genes involved in regulating sensitive periods may be implicated in depression vulnerability and differentially expressed across the life course, though larger studies are needed to identify developmental interplays.

scholarly journals CFH and VIPR2 as susceptibility loci in choroidal thickness and pachychoroid disease central serous chorioretinopathy

2018 ◽  
Vol 115 (24) ◽  
pp. 6261-6266 ◽  
Author(s):  
Yoshikatsu Hosoda ◽  
Munemitsu Yoshikawa ◽  
Masahiro Miyake ◽  
Yasuharu Tabara ◽  
Jeeyun Ahn ◽  
...  
Keyword(s):  
Central Serous Chorioretinopathy ◽  
Choroidal Thickness ◽  
Vision Loss ◽  
Genome Wide Association Study ◽  
Age Related Macular Degeneration ◽  
Common Disease ◽  
Susceptibility Loci ◽  
Case Control Studies ◽  
Age Related ◽  
A Genome

Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10−10 and 6.75 × 10−8, respectively). Case–control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10−5 and 5.14 × 10−5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.

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