scholarly journals Genetic control of age-related gene expression and complex traits in the human brain

2017 ◽  
Author(s):  
Trevor Martin ◽  
Hunter B. Fraser
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Genetic Variants ◽  
Complex Traits ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Expression Patterns ◽  
Related Gene ◽  
Age Related

AbstractAge is the primary risk factor for many of the most common human diseases—particularly neurodegenerative diseases—yet we currently have a very limited understanding of how each individual’s genome affects the aging process. Here we introduce a method to map genetic variants associated with age-related gene expression patterns, which we call temporal expression quantitative trait loci (teQTL). We found that these loci are markedly enriched in the human brain and are associated with neurodegenerative diseases such as Alzheimer’s disease and Creutzfeldt-Jakob disease. Examining potential molecular mechanisms, we found that age-related changes in DNA methylation can explain some cis-acting teQTLs, and that trans-acting teQTLs can be mediated by microRNAs. Our results suggest that genetic variants modifying age-related patterns of gene expression, acting through both cis- and trans-acting molecular mechanisms, could play a role in the pathogenesis of diverse neurological diseases.

scholarly journals Core gene identification using gene expression

2020 ◽  
Author(s):  
◽  
Annique Claringbould
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Genetic Code ◽  
Genetic Variants ◽  
Complex Traits ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Altered Level ◽  
Common Genetic Variants

While humans share most of their genetic code with one another, small differences in the DNA can have an impact on an individual’s risk of disease. Common genetic variants exert individually small effects on the development of a disease, but their combined impact is substantial. Although recent research has identified thousands of variants that are associated to complex traits, our understanding of the molecular mechanisms that eventually lead to disease is limited. One way to dive into the molecular changes that result from genetic variation, is to look at changes in gene activity (‘gene expression’). Each cell contains the same genetic code, but genes are only expressed when and where they are required. Research has shown that many disease-associated genetic variants also affect gene expression. Such a change in the expression of a gene can lead to an altered level of the protein it encodes, which in turn can be the start of a dysregulation in the system that can eventually develop into a disease. This thesis describes how gene expression patterns can be used to prioritise and describe the function of trait-relevant genes. The first chapters evaluate methodological considerations for doing gene expression research. Another study covers the systematic linking of genetic variation to gene expression in blood and the last research chapter describes a method for gene prioritisation that leverages the idea that multiple genetic variants converge onto disease-causing genes. These insights can be used to better understand disease and to identify potential drug targets.

scholarly journals Effects of Cutting, Pruning, and Grafting on the Expression of Age-Related Genes in Larix kaempferi

Forests ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 218
Author(s):  
Yao Zhang ◽  
Qiao-Lu Zang ◽  
Li-Wang Qi ◽  
Su-Ying Han ◽  
Wan-Feng Li
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Regular Expression ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Reproductive Development ◽  
Larix Kaempferi ◽  
Clonal Forestry ◽  
Cdna Sequences ◽  
Age Related

Grafting, cutting, and pruning are important horticultural techniques widely used in the establishment of clonal forestry. After the application of these techniques, some properties of the plants change, however, the underlying molecular mechanisms are still unclear. In our previous study, 27 age-related transcripts were found to be expressed differentially between the juvenile vegetative (1- and 2-year-old) and adult reproductive (25- and 50-year-old) phases of Larix kaempferi. Here, we re-analyzed the 27 age-related transcripts, cloned their full-length cDNA sequences, and measured their responses to grafting, cutting, and pruning. After sequence analysis and cloning, 20 transcription factors were obtained and annotated, most of which were associated with reproductive development, and six (LaAGL2-1, LaAGL2-2, LaAGL2-3, LaSOC1-1, LaAGL11, and LaAP2-2) showed regular expression patterns with L. kaempferi aging. Based on the expression patterns of these transcription factors in L. kaempferi trees subjected to grafting, cutting, and pruning, we concluded that (1) cutting and pruning rejuvenate the plants and change their expression, and the effects of cutting on gene expression are detectable within 14 years, although the cutting seedlings are still maturing during these years; (2) within three months after grafting, the rootstock is more sensitive to grafting than the scion and readily becomes mature with the effect of the scion, while the scion is not readily rejuvenated by the effect of the rootstock; and (3) LaAGL2-2 and LaAGL2-3 are more sensitive to grafting, while LaAP2-2 is impervious to it. These findings not only provide potential molecular markers to assess the state of plants but also aid in studies of the molecular mechanisms of rejuvenation.

scholarly journals Molecular inflection points in the aging human brain

2018 ◽  
Author(s):  
Eden Deng
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Aging Process ◽  
Brain Research ◽  
Piecewise Linear ◽  
Human Microglia ◽  
Age Related ◽  
Inflection Points ◽  
Age Dependent

ABSTRACTThe onset of neurodegenerative diseases has been associated with age-dependent changes of gene expression in the brain. Research on age-dependent genes commonly assumes gradual linear relationships between gene expression and aging, failing to identify sudden changes in gene expression that may provide insight into the aging process and its role in neurodegenerative diseases. Here, a piecewise linear regression model is proposed to identify critical inflection points at which aging mechanisms may accelerate. Age-related gene expression data from tissue of four regions of the human brain (frontal cortex, hippocampus, putamen, substantia nigra) and human microglia were analyzed for inflection points. The best piecewise model represented stable expression during younger ages followed by an increase or decrease with age after the inflection point. In brain tissue, genes showing inflection points in expression pattern were enriched for gene ontology terms involved in neurodegenerative diseases. The hippocampus showed the highest proportion of genes with inflection points and the lowest variability in inflection points. These findings suggest that inflection points in gene expression may be used to characterize the aging process in the human brain and may help identify markers for the onset of neurodegenerative diseases.

scholarly journals Molecular mechanisms of cell death in neurological diseases

2021 ◽  
Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Response To Therapy ◽  
Signalling Cascades ◽  
The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

scholarly journals Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1611
Author(s):  
Nur Fathiah Abdul Abdul Sani ◽  
Ahmad Imran Zaydi Amir Amir Hamzah ◽  
Zulzikry Hafiz Abu Abu Bakar ◽  
Yasmin Anum Mohd Mohd Yusof ◽  
Suzana Makpol ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Cognitive Aging ◽  
Successful Aging ◽  
Expression Patterns ◽  
Age Groups ◽  
Genetic Network ◽  
Cross Sectional ◽  
Age Related ◽  
Age Related Cognitive Decline

The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult’s susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.

scholarly journals Cryopreservation of microglia enables single-cell RNA sequencing with minimal effects on disease-related gene expression patterns

iScience ◽  
2021 ◽  
Vol 24 (4) ◽  
pp. 102357
Author(s):  
Brenda Morsey ◽  
Meng Niu ◽  
Shetty Ravi Dyavar ◽  
Courtney V. Fletcher ◽  
Benjamin G. Lamberty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Related Gene ◽  
Single Cell Rna Sequencing ◽  
Disease Related Gene

scholarly journals A transcriptome-wide Mendelian randomization study to uncover tissue-dependent regulatory mechanisms across the human phenome

2019 ◽  
Author(s):  
Tom G Richardson ◽  
Gibran Hemani ◽  
Tom R Gaunt ◽  
Caroline L Relton ◽  
George Davey Smith
Keyword(s):  
Gene Expression ◽  
Genetic Variants ◽  
Complex Traits ◽  
Mendelian Randomization ◽  
Drug Repositioning ◽  
Association Studies ◽  
Thyroid Tissue ◽  
Genome Wide Association Studies ◽  
Tissue Specific ◽  
Genome Wide

AbstractBackgroundDeveloping insight into tissue-specific transcriptional mechanisms can help improve our understanding of how genetic variants exert their effects on complex traits and disease. By applying the principles of Mendelian randomization, we have undertaken a systematic analysis to evaluate transcriptome-wide associations between gene expression across 48 different tissue types and 395 complex traits.ResultsOverall, we identified 100,025 gene-trait associations based on conventional genome-wide corrections (P < 5 × 10−08) that also provided evidence of genetic colocalization. These results indicated that genetic variants which influence gene expression levels in multiple tissues are more likely to influence multiple complex traits. We identified many examples of tissue-specific effects, such as genetically-predicted TPO, NR3C2 and SPATA13 expression only associating with thyroid disease in thyroid tissue. Additionally, FBN2 expression was associated with both cardiovascular and lung function traits, but only when analysed in heart and lung tissue respectively.We also demonstrate that conducting phenome-wide evaluations of our results can help flag adverse on-target side effects for therapeutic intervention, as well as propose drug repositioning opportunities. Moreover, we find that exploring the tissue-dependency of associations identified by genome-wide association studies (GWAS) can help elucidate the causal genes and tissues responsible for effects, as well as uncover putative novel associations.ConclusionsThe atlas of tissue-dependent associations we have constructed should prove extremely valuable to future studies investigating the genetic determinants of complex disease. The follow-up analyses we have performed in this study are merely a guide for future research. Conducting similar evaluations can be undertaken systematically at http://mrcieu.mrsoftware.org/Tissue_MR_atlas/.

scholarly journals The fog of genetics: Known unknowns and unknown unknowns in the genetics of complex traits and diseases

2019 ◽  
Author(s):  
João Pedro de Magalhães ◽  
Jingwei Wang
Keyword(s):  
Genetic Variability ◽  
Genetic Variants ◽  
Genetic Information ◽  
Complex Traits ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Genetic Associations ◽  
Missing Heritability ◽  
Genome Space ◽  
Known Unknowns

AbstractAssociating genetic variants with phenotypes is not only important to understand the underlying biology but also to identify potential drug targets for treating diseases. It is widely accepted that for most complex traits many associations remain to be discovered, the so-called “missing heritability.” Yet missing heritability can be estimated, it is a known unknown, and we argue is only a fraction of the unknowns in genetics. The majority of possible genetic variants in the genome space are either too rare to be detected or even entirely absent from populations, and therefore do not contribute to estimates of phenotypic or genetic variability. We call these unknown unknowns in genetics the “fog of genetics.” Using data from the 1000 Genomes Project we then show that larger genes with greater genetic diversity are more likely to be associated with human traits, demonstrating that genetic associations are biased towards particular types of genes and that the genetic information we are lacking about traits and diseases is potentially immense. Our results and model have multiple implications for how genetic variability is perceived to influence complex traits, provide insights on molecular mechanisms of disease and for drug discovery efforts based on genetic information.

scholarly journals An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity

2020 ◽  
Author(s):  
María Teruel ◽  
Guillermo Barturen ◽  
Manuel Martínez-Bueno ◽  
Miguel Barroso ◽  
Olivia Castelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Sjögren’S Syndrome ◽  
Genetic Variants ◽  
Sjögren's Syndrome ◽  
Expression Patterns ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Regulatory Function ◽  
Sjögren‘S Syndrome

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

scholarly journals A review on the influence of dietary immunobiotics on the performance, intestinal morphology and immune-related gene expression in post-hatched broiler chicks

2020 ◽  
Vol 5 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Asad A. Khaskheli ◽  
Muhammad I. Khaskheli ◽  
Allah J. Khaskheli ◽  
Arshad A. Khaskheli
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Functional Foods ◽  
Molecular Mechanisms ◽  
Intestinal Morphology ◽  
Lymphoid Tissues ◽  
Broiler Chicks ◽  
Related Gene ◽  
Current Review ◽  
Immune Related Gene

The use of antibiotics in the broiler industry is continuously increasing for promoting growth performance, improving the edible meat yield, and preventing microbial infections in the chicks. Due to the extreme misuse of antibiotics, antimicrobial resistance is developing among the broilers and simultaneously to their consumers. Keeping in view these facts current review was planned to understand the effect of different dietary immunobiotics on the performance, intestinal morphology, and immune-related gene expression in post-hatched broiler chicks. The review of the literature indicated that the application of immunobiotics as functional foods and its biological value have been reported by many scientists worldwide. In addition, to develop immunologically functional foods, immunobiotics also help in regulating intestinal immunity. The current review further explored that the immunobiotics regulate intestinal immune homeostasis, cellular and molecular mechanisms. It was also interesting to note that immunobiotics concerning microorganisms stimulate the activation of mucosal immunity in the Gut Associated Lymphoid Tissues (GALT). In vitro studies on the toll-like receptor (TLR) 2-transfected cells showed that immunobiotics can potentially be used to enhance the immune system in the GALT. Keeping in view reviewed studies on immunobiotics it could be concluded that immunobiotics positively influence the performance, intestinal morphology, and immune-related gene expression in post-hatch chicks. They could be used as the best alternative to antibiotics. Keywords: Gut Associated Lymphoid Tissues; Immune system; Prebiotics; Receptors. 

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