From mutation to mechanism: deciphering the molecular function of genetic variants linked to human ageing
| Autor: | Joris Deelen, Linda Partridge, Helena M Hinterding, Maarouf Baghdadi |
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| Rok vydání: | 2021 |
| Předmět: |
AcademicSubjects/SCI01140
functional characterisation Aging media_common.quotation_subject In silico Longevity ved/biology.organism_classification_rank.species healthspan Disease Computational biology Biology medicine.disease_cause Biochemistry Genome model organisms 03 medical and health sciences 0302 clinical medicine Genetics medicine Humans Model organism Molecular Biology 030304 developmental biology media_common Review Paper 0303 health sciences Mutation ved/biology Mechanism (biology) genetic variants General Medicine Phenotype Diabetes Mellitus Type 2 Ageing lifespan 030217 neurology & neurosurgery |
| Zdroj: | Briefings in Functional Genomics |
| ISSN: | 2041-2657 2041-2649 |
| Popis: | Many of the leading causes of death in humans, such as cardiovascular disease, type 2 diabetes and Alzheimer’s disease are influenced by biological mechanisms that become dysregulated with increasing age. Hence, by targeting these ageing-related mechanisms, we may be able to improve health in old age. Ageing is partly heritable and genetic studies have been moderately successful in identifying genetic variants associated with ageing-related phenotypes (lifespan, healthspan and longevity). To decipher the mechanisms by which the identified variants influence ageing, studies that focus on their functional validation are vital. In this perspective, we describe the steps that could be taken in the process of functional validation: (1) in silico characterisation using bioinformatic tools; (2) in vitro characterisation using cell lines or organoids; and (3) in vivo characterisation studies using model organisms. For the in vivo characterisation, it is important to focus on translational phenotypes that are indicative of both healthspan and lifespan, such as the frailty index, to inform subsequent intervention studies. The depth of functional validation of a genetic variant depends on its location in the genome and conservation in model organisms. Moreover, some variants may prove to be hard to characterise due to context-dependent effects related to the experimental environment or genetic background. Future efforts to functionally characterise the (newly) identified genetic variants should shed light on the mechanisms underlying ageing and will help in the design of targeted interventions to improve health in old age. |
| Databáze: | OpenAIRE |
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