WEEK 8: COMPLEX DISEASES I Flashcards
What are the 3 main categories for non-mendelian characters/inheritance?
- Extranuclear/maternal inheritance (mitochondrial diseases)
- Parental inheritance (IMPRITING)
- Complex (Polygenic) diseases most of the 3 lectures
How many proteins does mitochondrial DNA code for?
13
Does mitochondria also code for tRNA?
- YES!
What are three features of mitochondrial maternal inheritence?
- Extranuclear
- Cytpolasmic
- Uni-parental (mitochondria from sperm discarded)
What are two examples of mitochondria diseases and what would a pedigree look like?
- LHON–> Leber’s Hereditary Optic Neuropathy
- Leigh Syndrome
- Pedigree would have males and females affected BUT only offspring from affected mother will be affected (i.e. father can inherit it but can’t pass it on)
What is Heteroplasmy?
- Mixed population of normal and mutant genes
Can heteroplasmy be inherited from mother to child?
- YES
Can heteroplasmy be tissue specific and evolve with time?
- YES
What effect does heteroplasmy have on the genotype/phenotype relationship?
- It complicates it!
- Extremely variable (complex) presentation
If an affected woman is heteroplasmic, what would ocur in the offspring in terms of what they would inherit and the phenotype?
- Offspring will inherit BOTH the mutant and normal mtDNA
- This results in the phenotype of the offspring showing HETEROGENEITY from SEVERE–> WT manifestations
What is the difference between Chron’s Disease and Ulcerative Colitis?
- Chron’s can affect ANY portion of the GI tract (from mouth–> anus)
- Ulcerative Colitis is ONLY IN THE COLON and is PROGRESSIVE into the whole colon
What are monogenic diseases?
- There is a DIRECT relationship b/w disease gene and disease status
- The genotype and phenotype CLOSELY CORRELATE–> High penetrance
- The Mutations cause the disease 1 disease, 1 gene
What are polygenic diseases?
- Show STRONG GENETIC PREDISPOSITION but individual genes only MARGINALLY affect disease status
- Genotype and phenotype POORLY CORRELATE–> Low penetrance
- Polymorphisms PREDISPOSE to the disease –> 1 disease, many genes
Which database is mainly used for monogenic diseases and how many approx.. does it contain?
- OMIM –> Approx. 7000 diseases
Which database is mainly used for polygenic diseases and how many associations does it approx.. have ?
- GWAS (genome Wide Association Studies) Catalog
- Approx >150 000 associations
What plays the most important role in the threshold zone for complex diseases?
- The environment
What is the phenotype a result of in complex diseases?
- The result of the SUM of all genes/alleles each with a TINY contribution to risk
What is the strongest risk factor in complex diseases?
- THE ENVIRONMENT e.g. Graph shows that the incidence of IBD tripled –> genes DO NOT evolve that quickly
- thus can’t be explained in genetics so must be from environment
WHICH TWO METHODS WERE COMPLEX DISEASES CLASICALLY FIRST DEMONSTRATED BY?
- Family Studies (Clustering)
2. Twin Studies (Concordance)
What is the formula for the risk ratio (lambda R)?
- Disease prevalence in relatives R of probands/disease prevalence in population
What does a risk ratio of more than 1 indicate?
- There is an increased risk in the family compared to the population
What is the risk ratio involved in?
- Familial Clustering
What does lamba R increase with? (2 things)
- Increasing genetic contribution
- DECREASING population prevalence
Does a rare disease have a higher or lower lambdaR?
- LOWER