Multifactorial Inheritance Flashcards
Multifactorial inheritance is indicated when there is
an increased risk to relatives, but there is no consistent pattern of inheritance within families.
Simple Mendelian diseases are generally _______-gene disorders characterized by inheritance patterns that follow _______ expectations and are discernable by examining _______
single
Mendelian
pedigrees with multiple affected individuals
Complex traits
- Aggregate (cluster) in families
- Do not follow simple Mendelian mode of inheritance
- Likely due to variants in multiple genes and non-genetic factors that may interact
- No simple relationship between genetic variant and trait when looking at the population
Determining the Relative Contribution of Genetic and Environmental Variation
- Need to distinguish between clustering in families due to genetic factors and those due to shared environmental factors
- Twin, adoption, and immigration studies used
- Each measure of genetic contribution needs to be interpreted carefully, but as a group can provide compelling evidence for genetic contribution to trait.
One problem in family studies is that individuals who are genetically related often share a similar
culture and environment
Monozygous (MZ) twins are
identically matched for DNA sequence, age, and gender, and perhaps closely matched for environmental exposures
Dizygous (DZ) twins
on average share 1/2 of their DNA sequences, but may be about as closely matched for other factors as are MZ twins
If it can be assumed that MZ and DZ twins are equally similar with respect to non-inherited factors, then
twins can be used to get an estimate of the relative contribution of genetic vs. environmental variation to the trait
A much higher concordance rate for disease in MZ than DZ twins suggests that
genetic variation contributes to variation in risk more than variation in non-genetic factors
A much higher correlation among MZ compared to DZ twins for a quantitative trait suggests that
genetic variation is relatively more important than variation in non-genetic factors
The Heritability of a trait is
the proportion of total variance in a trait that is due to variation in genes
A high heritability implies
that differences among individuals with respect to a trait such as blood pressure in a population can be attributed to differences in the genetic make-up.
The key to interpreting heritability estimates is to remember that
we’re talking about and describing variation in BOTH genetic factors AND non-genetic factors. If one (alleles or environment) doesn’t demonstrate much variability, then it doesn’t have much potential to explain variability in a trait
Complex traits demonstrate one or more of the following
- Incomplete penetrance:
- Variable expressivity:
- Heterogeneity –
- Presence of phenocopies:
Incomplete penetrance
not everyone with predisposing variant develops disease
Example: Type I diabetes and MHC
Variable expressivity
no two individuals with the same genetic variant have exactly the same disease characteristics
Example: Maturity Onset Diabetes in the Young (MODY)
Heterogeneity
allele and locus: The “same” disease can be caused by different alleles at one location or by alleles at different locations in the genome
Example (allele): Cystic Fibrosis
Example (locus): Alzheimer Disease
Presence of phenocopies
Individuals who have the disease or trait for reasons that are not primarily genetic even though clinical presentation mimics the more genetic version
Example: Thalidomide-induced limb malformation vs. genetically-induced
Implications of Characteristics of Complex Traits
it is very difficult to predict whether or not individuals will develop a certain complex disease or trait, even when you may know something about their family history or their alleles at a certain locus, and it is difficult to identify the genetic variants that might contribute to disease
