L1 Human Genome and Animal Modelling

Question 1

Genome Wide Association Studies

Answer 1

Identification of genes associated with phenotype

Question 2

Monozygotic twin

Answer 2

Epigenome resets early in gestation but each twin accumulates epigenetic changes

Question 3

Human Stem Cells

Answer 3

Genetic manipulations easy

Individualised studies and treatment screening

Question 4

Personalised genomics and personalised health

Answer 4

1. predict disease chance
2. diagnose
3. monitor disease progression
4. personalised treatment

Question 5

Personal genomics - key considerations

Answer 5

1. data interpretation and analysis of “health risk”
2. psychological implications for public
3. benefit of sharing information vs privacy

Question 6

Is society/public ready?

Answer 6

Scientific uncertainty

• genetic counselling
• clinical utility
• hypochondria
• over-burden the health care system

Question 7

Community phenotyping

Answer 7

Integrate doctors, researchers and patients for holistic approach

Increase data for rare diseases across families

potential PRIVACY COST

Question 8

Limitations of humans as genetic models

- 4 points

Answer 8

1. functional in vivo gene manipulations impossible
2. classical inheritance studies slow
3. “controls” fairly limited
4. invasive phenotypic analysis difficult

Question 9

Non-human model systems

Answer 9

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

Question 10

Phylogenetics

Answer 10

evolutionary relationship between species: morphological, molecular (nucleotide, amino acids)

Question 11

Phylogenetic tree

Answer 11

revels accurate evolutionary distances (time) and branching points of common ancestors

Question 12

Phylotypic stage

Answer 12

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”

Question 13

Ethical implications

Answer 13

Key framework for choosing model organism:

1. replacement
2. reduction
3. refinement

whilst maintaining scientific integrity, data must be valid otherwise animals are wasted

Question 14

Replacement

Answer 14

see onenote

substituting living higher animals with insentient material

substituting “higher” with “lower” animals - indication of complexity for intelligence, awareness, feelings

Question 15

Reduction

Answer 15

see onenote

minimising numbers

minimising cumulative impact per animal

Question 16

Refinement

Answer 16

see onenote

process of constant monitoring and adjustment to minimise welfare impact e.g. distress, pain

1. new procedures
2. training for handling
3. environmental enrichment
4. recapitulation of social structure e.g. gender, age, density

Question 17

Relevance vs Suitability

Answer 17

see onenote

Relevance - is the process conserved in humans?

1. evolutionary/genetic distance
2. 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

Question 18

Mouse - mammalian model

Genomic vs proteomic conservation

Answer 18

see onenote

closest genetic model - highest relevance to human genetics

many similar cell, organ and body function

Question 19

Mouse - relevance

Answer 19

see onenote

conserved organs

Question 20

Mouse - embryology

Answer 20

see onenote

development of specific organs

due to ethical and technical constraints, replace with lower vertebrate models if possible

Question 21

Zebrafish

Answer 21

see onenote

large set of genetic tools as a vertebrate but also most distant from humans

many basic vertebrate specific conserved cell types/organs

Question 22

Zebrafish - rapid exo vivo development

Answer 22

see onenote

Can manipulate genetically as they lays eggs

Develops quickly - can within a day, genetically manipulate and visualise what is happening