scholarly journals Natural variation in stochastic photoreceptor specification and color preference in Drosophila

2017 ◽  
Author(s):  
Caitlin Anderson ◽  
India Reiss ◽  
Cyrus Zhou ◽  
Annie Cho ◽  
Haziq Siddiqi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Natural Variation ◽  
Genome Wide Association Study ◽  
Vision System ◽  
Cell Types ◽  
Color Preference ◽  
A Genome ◽  
Stochastic Expression ◽  
Fly Eye ◽  
And Function

AbstractEach individual perceives the world in a unique way, but little is known about the genetic basis of variation in sensory perception. Here we investigated natural variation in the development and function of the color vision system of Drosophila. In the fly eye, the random mosaic of color-detecting R7 photoreceptor subtypes is determined by stochastic expression of the transcription factor Spineless (Ss). Individual R7s randomly choose between SsON or SsOFF fates at a ratio of 65:35, resulting in unique patterns but consistent proportions of cell types across genetically identical retinas. In a genome wide association study, we identified a naturally occurring insertion in a regulatory DNA element in the ss gene that lowers the ratio of SsON to SsOFF cells. This change in photoreceptor fates shifts the innate color preference of flies from green to blue. The genetic variant increases the binding affinity for Klumpfuss (Klu), a zinc finger transcriptional repressor that regulates ss expression. Klu is expressed at intermediate levels to determine the normal ratio of SsON to SsOFF cells. Thus, binding site affinity and transcription factor levels are finely tuned to regulate stochastic on/off gene expression, setting the ratio of alternative cell fates and ultimately determining color preference.

scholarly journals Natural variation in stochastic photoreceptor specification and color preference in Drosophila

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Caitlin Anderson ◽  
India Reiss ◽  
Cyrus Zhou ◽  
Annie Cho ◽  
Haziq Siddiqi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Genome Wide Association Study ◽  
Color Preference ◽  
Naturally Occurring ◽  
Genome Wide ◽  
A Genome ◽  
Stochastic Expression ◽  
Normal Ratio ◽  
Fly Eye ◽  
Regulatory Dna

Each individual perceives the world in a unique way, but little is known about the genetic basis of variation in sensory perception. In the fly eye, the random mosaic of color-detecting R7 photoreceptor subtypes is determined by stochastic on/off expression of the transcription factor Spineless (Ss). In a genome-wide association study, we identified a naturally occurring insertion in a regulatory DNA element in ss that lowers the ratio of SsON to SsOFF cells. This change in photoreceptor fates shifts the innate color preference of flies from green to blue. The genetic variant increases the binding affinity for Klumpfuss (Klu), a zinc finger transcriptional repressor that regulates ss expression. Klu is expressed at intermediate levels to determine the normal ratio of SsON to SsOFF cells. Thus, binding site affinity and transcription factor levels are finely tuned to regulate stochastic expression, setting the ratio of alternative fates and ultimately determining color preference.

scholarly journals Development of a CRISPR-SaCas9 system for projection- and function-specific gene editing in the rat brain

2020 ◽  
Vol 6 (12) ◽  
pp. eaay6687 ◽  
Author(s):  
Haojie Sun ◽  
Su Fu ◽  
Shuang Cui ◽  
Xiangsha Yin ◽  
Xiaoyan Sun ◽  
...  
Keyword(s):  
Rat Brain ◽  
Gene Editing ◽  
High Efficiency ◽  
Protein A ◽  
Cell Types ◽  
Cell Labeling ◽  
Specific Gene ◽  
Creb Binding Protein ◽  
A Genome ◽  
And Function

A genome editing technique based on the clustered regularly interspaced short palindromic repeats (CRISPR)–associated endonuclease Cas9 enables efficient modification of genes in various cell types, including neurons. However, neuronal ensembles even in the same brain region are not anatomically or functionally uniform but divide into distinct subpopulations. Such heterogeneity requires gene editing in specific neuronal populations. We developed a CRISPR-SaCas9 system–based technique, and its combined application with anterograde/retrograde AAV vectors and activity-dependent cell-labeling techniques achieved projection- and function-specific gene editing in the rat brain. As a proof-of-principle application, we knocked down the cbp (CREB-binding protein), a sample target gene, in specific neuronal subpopulations in the medial prefrontal cortex, and demonstrated the significance of the projection- and function-specific CRISPR-SaCas9 system in revealing neuronal and circuit basis of memory. The high efficiency and specificity of our projection- and function-specific CRISPR-SaCas9 system could be widely applied in neural circuitry studies.

scholarly journals The Genetic Basis of Natural Variation in Drosophila melanogaster Immune Defense against Enterococcus faecalis

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 234 ◽  
Author(s):  
Joanne R Chapman ◽  
Maureen A Dowell ◽  
Rosanna Chan ◽  
Robert L Unckless
Keyword(s):  
Drosophila Melanogaster ◽  
Enterococcus Faecalis ◽  
Natural Variation ◽  
Genetic Basis ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Immune Defense ◽  
Nucleotide Polymorphisms ◽  
Disease Response ◽  
A Genome

Dissecting the genetic basis of natural variation in disease response in hosts provides insights into the coevolutionary dynamics of host-pathogen interactions. Here, a genome-wide association study of Drosophila melanogaster survival after infection with the Gram-positive entomopathogenic bacterium Enterococcus faecalis is reported. There was considerable variation in defense against E. faecalis infection among inbred lines of the Drosophila Genetics Reference Panel. We identified single nucleotide polymorphisms associated with six genes with a significant (p < 10−08, corresponding to a false discovery rate of 2.4%) association with survival, none of which were canonical immune genes. To validate the role of these genes in immune defense, their expression was knocked-down using RNAi and survival of infected hosts was followed, which confirmed a role for the genes krishah and S6k in immune defense. We further identified a putative role for the Bomanin gene BomBc1 (also known as IM23), in E. faecalis infection response. This study adds to the growing set of association studies for infection in Drosophila melanogaster and suggests that the genetic causes of variation in immune defense differ for different pathogens.

scholarly journals Tau in the Pathophysiology of Parkinson’s Disease

2021 ◽  
Author(s):  
Lina Pan ◽  
Lanxia Meng ◽  
Mingyang He ◽  
Zhentao Zhang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genome Wide Association Study ◽  
Lewy Bodies ◽  
Current Evidence ◽  
Gene Encoding ◽  
Passive Element ◽  
Genome Wide ◽  
A Genome ◽  
And Function

AbstractThe pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau’s involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.

scholarly journals Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project

2020 ◽  
Author(s):  
E.A. Lopera-Maya ◽  
A. Kurilshikov ◽  
A. van der Graaf ◽  
S. Hu ◽  
S. Andreu-Sánchez ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Genome Wide Association Study ◽  
Strongly Correlated ◽  
Microbial Composition ◽  
Host Genetics ◽  
Secretor Status ◽  
Genome Wide ◽  
A Genome ◽  
And Function ◽  
Larger Sample

AbstractHost genetics are known to influence the gut microbiome, yet their role remains poorly understood. To robustly characterize these effects, we performed a genome-wide association study of 207 taxa and 205 pathways representing microbial composition and function within the Dutch Microbiome Project, a population cohort of 7,738 individuals from the northern Netherlands. Two robust, study-wide significant (p<1.89×10−10) signals near the LCT and ABO genes were found to affect multiple microbial taxa and pathways, and were replicated in two independent cohorts. The LCT locus associations were modulated by lactose intake, while those at ABO reflected participant secretor status determined by FUT2 genotype. Eighteen other loci showed suggestive evidence (p<5×10−8) of association with microbial taxa and pathways. At a more lenient threshold, the number of loci identified strongly correlated with trait heritability, suggesting that much larger sample sizes are needed to elucidate the remaining effects of host genetics on the gut microbiome.

scholarly journals A rare missense mutation inMYH6confers high risk of coarctation of the aorta

2017 ◽  
Author(s):  
Thorsteinn Bjornsson ◽  
Rosa B. Thorolfsdottir ◽  
Gardar Sveinbjornsson ◽  
Patrick Sulem ◽  
Gudmundur L. Norddahl ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Genome Wide Association Study ◽  
Cardiac Development ◽  
Heart Defects ◽  
Coarctation Of The Aorta ◽  
Population Level ◽  
Genome Wide ◽  
Cardiac Syndrome ◽  
A Genome ◽  
And Function

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp inMYH6(odds ratio (OR) = 44.2,P= 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF)2. These findings suggest that p.Arg721Trp inMYH6causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.

scholarly journals A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease

2017 ◽  
Author(s):  
Kuan-lin Huang ◽  
Edoardo Marcora ◽  
Anna A Pimenova ◽  
Antonio F Di Narzo ◽  
Manav Kapoor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Age At Onset ◽  
Myeloid Cell ◽  
Cell Types ◽  
A Genome ◽  
Monocytes And Macrophages ◽  
And Function

AbstractA genome-wide survival analysis of 14,406 Alzheimer’s disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and fourteen novel loci associated with age at onset. LD score regression of 220 cell types implicated regulation of myeloid gene expression in AD risk. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affect the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

scholarly journals Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

2019 ◽  
Author(s):  
Qin Huang ◽  
Ken Y. Chan ◽  
Isabelle G. Tobey ◽  
Yujia Alina Chan ◽  
Tim Poterba ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Neurological Diseases ◽  
Cell Types ◽  
Mouse Strains ◽  
Adeno Associated Virus ◽  
Genome Wide ◽  
A Genome ◽  
Gene Therapy Vectors ◽  
Different Cell Types ◽  
Mouse Central Nervous System

The engineered AAV-PHP.B family of adeno-associated virus efficiently delivers genes throughout the mouse central nervous system. To guide their application across disease models, and to inspire the development of translational gene therapy vectors useful for targeting neurological diseases in humans, we sought to elucidate the host factors responsible for the CNS tropism of AAV-PHP.B vectors. Leveraging CNS tropism differences across mouse strains, we conducted a genome-wide association study, and rapidly identified and verified LY6A as an essential receptor for the AAV-PHP.B vectors in brain endothelial cells. Importantly, this newly discovered mode of AAV binding and transduction is independent of other known AAV receptors and can be imported into different cell types to confer enhanced transduction by the AAV-PHP.B vectors.

scholarly journals Identification of 13 independent genetic loci associated with cognitive resilience in healthy aging in 330,097 individuals in the UK Biobank

2021 ◽  
Author(s):  
Joan Fitzgerald ◽  
Laura Fahey ◽  
Laurena Holleran ◽  
Pilib Ó Broin ◽  
Gary Donohoe ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Genome Wide Association Study ◽  
Cell Types ◽  
Brain Regions ◽  
Specific Cell ◽  
Uk Biobank ◽  
Negative Effects ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

AbstractCognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. Here we employed a proxy phenotype approach to create a longitudinal cognitive resilience phenotype using past education years and current processing speed, reflecting an average time span of 40 years, in 330,097 individuals from the UK Biobank. A genome-wide association study identified 13 independent genome-wide significant loci that implicate 33 genes. A portion of resilience’s genetic signal is distinct from the genetics of intelligence. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59×10−8) and glutamatergic neurons (P=6.98×10−6) in the cortex. Gene-set analyses implicated the biological process “neuron differentiation” (P=9.7×10−7) and the cellular component “synaptic part” (P=2.14×10−6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience.

Sign in / Sign up

Export Citation Format

Share Document