What is the main difference between Mendelian traits and complex traits?
Mendelian traits
- easy to study
- single gene (monogenic) with high penetrance
- predictable mode of inheritance
- simple relationship between genotype and phenotype
- e.g. cystic fibrosis
Complex traits
- hard to study
- multiple alleles (polygenic) with low penetrance
- familial clustering but inheritance is not predictable
- complex relationship between genotype and phenotype
- often strongly influenced by the environment
- multifactorial
List some examples of complex traits in human medicine.
- Type 1 and 2 Diabetes
- Cleft lip/palate
- Coronary heart disease
- Asthma
- Alzheimer’s disease
- Neural tube defects
- Crohn’s disease
These complex traits often have a prevalence of approximately 600 per 1000 in the population.
What is heritability?
The proportion of the total phenotypic variance due to genes
H^2 = VG/ VP
H^2 is a value between 0 and 1
Define concordance in the context of twin studies.
Concordance is the probability that if one twin is affected, the other twin is also affected by a trait
A concordance of 1.0 means if one twin is affected, the other is always affected, while a concordance of 0.6 means there is a 60% chance the second twin will also be affected.
What is the formula used to estimate heritability using twin studies?
H^2 = 2(MZ - DZ)
MZ refers to monozygotic twins and DZ refers to dizygotic twins.
True or False: Complex traits can be both discontinuous and continuous.
True
Discontinuous traits are either present or not, while continuous traits show a range of phenotypes.
What does an odds ratio (OR) greater than 1.0 indicate in association studies?
It indicates that the allele gives a higher risk of disease
Conversely, an OR less than 1.0 suggests that the allele is protective.
Describe the role of haplotype blocks in GWAS.
- haplotypes = closely linked SNPs on the same chromosome
- these are often inherited together in haplotype blocks
- the ‘gaps’ between haplotype blocks are preferred sites of crossing over in meiosis
- haplotype blocks are regions without crossing over
- each haplotype block is defined by a small number of tag SNPs
What is the range of heritability estimates for Type 2 Diabetes?
0.4-0.8
This indicates a moderate level of genetic influence on the trait.
How do genetics and environmental influences impact type 2 diabetes?
If one parent is affected = risk factor increases by 15%
If both parents are affected = risk factor increases by 75%
Environment- if BMI >30 = risk factor increases by 20%
What are discontinuous traits?
E.g. gender, blood group, eye colour
Complex traits can be discontinuous or discrete = the trait or disease is either present or not
These cannot be measured across a big range of
What are continuous traits?
E.g. height, blood pressure, serum cholesterol, BMI, crop yield
Complex traits can be quantitative or continuous traits
These can be measured across a broad range shown on a graph where
Mean = the centre of distribution
Variance = the spread of values around the mean
What are the key features of continuous variants?
Properties
- no distinct categories
- no limit on the values
- tends to be quantitative
- shown as a line graph
Examples
- height
- weight
- heart rate
- finger length
- leaf length
Controlled by
A lot of gene and environment = range of phenotypes between 2 extremes
What are the key features of discontinuous traits?
Properties
- distinct categories
- no in-between categories
- tends to be qualitative
- shown as bar graphs
Examples
- tongue rolling
- finger prints
- eye colour
- blood groups
Controlled by
A few genes = limited number of phenotypes with no intermediates
How is the total phenotypic variance calculated?
VP (or VT) = VG + VE
Where VP/VT is total phenotypic variance
VG is genetic variance
VE is environmental variance
What does heritability show?
High heritability (near to 1) means that genetic differences in the population explain a high proportion of the phenotypic variation
If a trait has high heritability, it will be easier to identify genetic variants associated with the trait than with a trait with low heritability
Why should disease-associated alleles be common?
- alleles that were advantageous or neutral in the past may confer disease susceptibility in modern societies (‘thrifty gene’)
- disease causing alleles can be maintained at high frequency by balancing selection
- late onset diseases have little effect on fitness (weak purifying selection)
What is the odds ratio (OR) used for?
Used to calculate the probability of association between each SNP and the disease
An OR > 1.0 means the allele gives higher risk of disease
An OR < 1.0 means the allele is protective
What does GWAS teach about human disease genetics?
- majority disease-associated variants confer a small increased risk of disease (OR of over 1)
- over 90% of variants are in non-coding DNA and it can be difficult to identify the causal variants associated
- GWAS generates new biological hypotheses about the causes of disease
- requires studies of rare SNPs and other types of DNA sequence variations to understand complex traits
