Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

AbstractThe genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

Download Full-text

The genetic basis of evolutionary change in gene expression levels

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2010.0005 ◽

2010 ◽

Vol 365 (1552) ◽

pp. 2581-2590 ◽

Cited By ~ 44

Author(s):

J. J. Emerson ◽

Wen-Hsiung Li

Keyword(s):

Gene Expression ◽

Genetic Basis ◽

Regulation Of Gene Expression ◽

Specific Expression ◽

Genetic Changes ◽

Expression Variation ◽

Regulatory Variation ◽

Global Mapping ◽

History Of ◽

Trait Locus

The regulation of gene expression is an important determinant of organismal phenotype and evolution. However, the widespread recognition of this fact occurred long after the synthesis of evolution and genetics. Here, we give a brief sketch of thoughts regarding gene regulation in the history of evolution and genetics. We then review the development of genome-wide studies of gene regulatory variation in the context of the location and mode of action of the causative genetic changes. In particular, we review mapping of the genetic basis of expression variation through expression quantitative trait locus studies and measuring the cis / trans component of expression variation in allele-specific expression studies. We conclude by proposing a systematic integration of ideas that combines global mapping studies, cis / trans tests and modern population genetics methodologies, in order to directly estimate the forces acting on regulatory variation within and between species.

Download Full-text

Genetic Regulation of Transcription in the Endometrium in Health and Disease

Frontiers in Reproductive Health ◽

10.3389/frph.2021.795464 ◽

2022 ◽

Vol 3 ◽

Author(s):

Sally Mortlock ◽

Brett McKinnon ◽

Grant W. Montgomery

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Genetic Variation ◽

Menstrual Cycle ◽

Gene Mapping ◽

Genetic Risk ◽

Genetic Regulation ◽

Regulation Of Gene Expression ◽

Genetic Risk Factors ◽

Genetic Effects

The endometrium is a complex and dynamic tissue essential for fertility and implicated in many reproductive disorders. The tissue consists of glandular epithelium and vascularised stroma and is unique because it is constantly shed and regrown with each menstrual cycle, generating up to 10 mm of new mucosa. Consequently, there are marked changes in cell composition and gene expression across the menstrual cycle. Recent evidence shows expression of many genes is influenced by genetic variation between individuals. We and others have reported evidence for genetic effects on hundreds of genes in endometrium. The genetic factors influencing endometrial gene expression are highly correlated with the genetic effects on expression in other reproductive (e.g., in uterus and ovary) and digestive tissues (e.g., salivary gland and stomach), supporting a shared genetic regulation of gene expression in biologically similar tissues. There is also increasing evidence for cell specific genetic effects for some genes. Sample size for studies in endometrium are modest and results from the larger studies of gene expression in blood report genetic effects for a much higher proportion of genes than currently reported for endometrium. There is also emerging evidence for the importance of genetic variation on RNA splicing. Gene mapping studies for common disease, including diseases associated with endometrium, show most variation maps to intergenic regulatory regions. It is likely that genetic risk factors for disease function through modifying the program of cell specific gene expression. The emerging evidence from our gene mapping studies coupled with tissue specific studies, and the GTEx, eQTLGen and EpiMap projects, show we need to expand our understanding of the complex regulation of gene expression. These data also help to link disease genetic risk factors to specific target genes. Combining our data on genetic regulation of gene expression in endometrium, and cell types within the endometrium with gene mapping data for endometriosis and related diseases is beginning to uncover the specific genes and pathways responsible for increased risk of these diseases.

Download Full-text

Festination Correlates with SNCA Polymorphism in Chinese Patients with Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2017/3176805 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Jinhua Zheng ◽

Xinglong Yang ◽

Quanzhen Zhao ◽

Sijia Tian ◽

Hongyan Huang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Logistic Regression ◽

Genetic Basis ◽

Univariate Analysis ◽

Alpha Synuclein ◽

Chinese Patients ◽

Motor Symptom ◽

Consecutive Series ◽

Snca Gene

The genetic basis of festination, a common motor symptom in Parkinson’s disease (PD), remains unclear. Since polymorphism in the alpha-synuclein (SNCA) gene is associated with PD phenotype, we examined whether such polymorphism is also associated with festination. SNCA polymorphisms rs11931074 and rs894278 were genotyped in a consecutive series of 258 patients with PD, of whom 122 (47.3%) suffered festination. Univariate analysis revealed significant differences in genotype and minor allele frequencies at rs11931074 or rs894278 between patients with festination and those without it (all p<0.05). Based on logistic regression, a GG or GT genotype at rs11931074 was associated with higher risk of festination among patients with PD (OR 2.077, 95% CI 1.111–3.883, p=0.022), as was the TT genotype at rs894278 (OR 2.271, 95% CI 1.246–4.139, p=0.007). Therefore, we conclude that festination is associated with polymorphism at rs11931074 or rs894278 among patients with PD.

Download Full-text

Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4+ Effector Memory T Cells

PLoS Genetics ◽

10.1371/journal.pgen.1004404 ◽

2014 ◽

Vol 10 (6) ◽

pp. e1004404 ◽

Cited By ~ 29

Author(s):

Xinli Hu ◽

Hyun Kim ◽

Towfique Raj ◽

Patrick J. Brennan ◽

Gosia Trynka ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Autoimmune Disease ◽

Genetic Basis ◽

Memory T Cells ◽

Regulation Of Gene Expression ◽

Effector Memory ◽

Effector Memory T Cells ◽

Disease Loci

Download Full-text

Linking transcription, RNA polymerase II elongation and alternative splicing

Biochemical Journal ◽

10.1042/bcj20200475 ◽

2020 ◽

Vol 477 (16) ◽

pp. 3091-3104 ◽

Cited By ~ 1

Author(s):

Luciana E. Giono ◽

Alberto R. Kornblihtt

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Rna Polymerase Ii ◽

Environmental Changes ◽

Transcription Elongation ◽

Single Gene ◽

Regulation Of Gene Expression ◽

Regulation Of Transcription ◽

Stepping Stones ◽

Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

Download Full-text