L1 Human Genome and Animal Modelling Flashcards
Genome Wide Association Studies
Identification of genes associated with phenotype
Monozygotic twin
Epigenome resets early in gestation but each twin accumulates epigenetic changes
Human Stem Cells
Genetic manipulations easy
Individualised studies and treatment screening
Personalised genomics and personalised health
- predict disease chance
- diagnose
- monitor disease progression
- personalised treatment
Personal genomics - key considerations
- data interpretation and analysis of “health risk”
- psychological implications for public
- benefit of sharing information vs privacy
Is society/public ready?
Scientific uncertainty
- genetic counselling
- clinical utility
- hypochondria
- over-burden the health care system
Community phenotyping
Integrate doctors, researchers and patients for holistic approach
Increase data for rare diseases across families
potential PRIVACY COST
Limitations of humans as genetic models
- 4 points
- functional in vivo gene manipulations impossible
- classical inheritance studies slow
- “controls” fairly limited
- invasive phenotypic analysis difficult
Non-human model systems
Key concepts
- evolutionary and genetic conservation
- Phylotypic stage vs genomic analysis
- ethical implications: Replacement, reduction, refinement
- relevance vs technical suitability of animal models
- genomic vs proteomic conservation
- cell vs organ vs integrated function vs higher order behaviour
Phylogenetics
evolutionary relationship between species: morphological, molecular (nucleotide, amino acids)
Phylogenetic tree
revels accurate evolutionary distances (time) and branching points of common ancestors
Phylotypic stage
See onenote diagram
Early developmental stage of high anatomical similarity
Also shown to be stage of greatest molecular similarity (comparative genomic analysis)
Genetic toolkit - small group of low divergence, highly conserved genes controls development and is studied in “evo-devo”
Ethical implications
Key framework for choosing model organism:
- replacement
- reduction
- refinement
whilst maintaining scientific integrity, data must be valid otherwise animals are wasted
Replacement
see onenote
substituting living higher animals with insentient material
substituting “higher” with “lower” animals - indication of complexity for intelligence, awareness, feelings
Reduction
see onenote
minimising numbers
minimising cumulative impact per animal
Refinement
see onenote
process of constant monitoring and adjustment to minimise welfare impact e.g. distress, pain
- new procedures
- training for handling
- environmental enrichment
- recapitulation of social structure e.g. gender, age, density
Relevance vs Suitability
see onenote
Relevance - is the process conserved in humans?
- evolutionary/genetic distance
- complexity (cellular vs organ or behaviour)
Suitability - what is the most suitable model (e.g. with genetic tools)
KNOW AN EXAMPLE FOR EACH ANIMAL AND BE ABLE TO RANK ANIMALS GIVEN A CATEGORY
Mouse - mammalian model
Genomic vs proteomic conservation
see onenote
closest genetic model - highest relevance to human genetics
many similar cell, organ and body function
Mouse - relevance
see onenote
conserved organs
Mouse - embryology
see onenote
development of specific organs
due to ethical and technical constraints, replace with lower vertebrate models if possible
Zebrafish
see onenote
large set of genetic tools as a vertebrate but also most distant from humans
many basic vertebrate specific conserved cell types/organs
Zebrafish - rapid exo vivo development
see onenote
Can manipulate genetically as they lays eggs
Develops quickly - can within a day, genetically manipulate and visualise what is happening
