C6 Searching for genetic clues

Question 1

What does genetics offer

Answer 1

• Risk prediction
• Better prevention
• Novel treatment
• Personalised treatment

Question 2

Contemporary strategies to search for genetic basis of CVD

Answer 2

1. Genome-wide mapping
   
   • Searching across genome for points associated with CV disease
2. Fine-mapping
   
   • Focus on a particular area → using a more dense marker to pinpoint where signal is coming from (~1000-10000bp)
3. Identification of functional candidate alleles
   
   • (Few thousand bp) → range of variance within sequence associated with CV disease
4. Testing of candidate alleles in living systems
   
   • Molecular biology state → to physiological state
   • From in vitro to in vivo (effects may not translate)
5. Contribution by candidate alleles to phenotype variation
   
   • How much it contributes to the overall CV condition (It usually has polygenic involvement)

Question 3

Contemporary tools used

Answer 3

1. Linkage mapping (in families)
2. LD (linkage disequilibrium) mapping (in broad population)
3. Transcriptomics
4. Proteomics
5. Computational biology
   
   • Recognises pattern and sequences in genetic data
6. Systems biology (physiology)

Question 4

The human genome

Answer 4

• 2.85billion nucleotides
• 20-25k genes (make up 2% of genome)
• Rest 98% compromises of:
  
  • non-coding DNA & RNA
  • Segmental duplication/deletion

Question 5

Genome variation

Answer 5

• Changes in protein function (involved in coding regions)
• Changes in RNA expression (involved in non-coding regions)
  
  • Due to:
    
    • Genes
    • Non-coding RNA (orchestrates the biological rhythms that we experience)
    • Epigenetic marks (from env factors)

Question 6

Genome maps

Answer 6

• Most common maps used involves lots of markers - some in LD with causative variants
  
  • Represent variants found in our population
  • Average bp differences b/w people, 1/1000bp differs

Question 7

What is linkage disequilibrium (LD)

Answer 7

• The marker and the cause of variance is co-inherited
• Likelihood of separation of marker & cause of variant during linkage is low

Question 8

What is the most common DNA variant

Answer 8

• SNPs are the most common DNA variants
  
  • Average frequency of transition (mutation) of bp ~11%
  • ~12 SNP per gene
    
    • 6 will be in coding regions, 3 will be altering protein sequence (non-synonymous)
    • 6 in perigenetic region → cause changes in gene expression of splicing

Question 9

What is association analysis

Answer 9

• Compare groups of interest in populations rather than restricted in families
• Allows comparison of diseases which are not discretely black or white (i.e. able to compare hypertension)

Question 10

What is missing heritability?

Answer 10

• All genes found accounts for only 5% of heritability

Question 11

What may the missing heritability be due to?

Answer 11

• Gene-gene interaction (epistasis)
  
  • When genes interact → may have addition/synergistic effects
• Gene-env interaction (epigenetics)
• Rare coding variants
  
  • May be missed when using SNPs GWAS for analysis
• Inflated heritability
  
  • Heritability is taken at a snapshot → Does not take into account the env which may change over time

Question 12

Ancient mutation

Answer 12

• Ancient mutation → From the top of the chain of the ancestory
  
  • everyone will have the variant

Question 13

Modern mutation

Answer 13

• Modern mutation → only that specific portion of people will have that variant (localised, infrequent)
  
  • Problem → difference in genetic marker may be mistaken for heritability of BP (but in reality, that pop may just have a high salt diet) → causes inflated heritability

Question 14

Are genetic markers the only solution?

Answer 14

• If we can find the physiological basis for these causes → we can target the diseases without the genetic markers
• By targeting that, you target a much larger range of causes in one go