multifactorial inheritance Flashcards
simple medelian trait
genetic variant leads to a trait
variable disease progression depends on
other factors besides just genetic variant
different alleles in the same gene associated with varying severity
complex traits explain
multifactoial ineritance.
Many things lead to trait
examples of multifactorial inheritance
- cancer
- type 1/2 diabetes
- alzheimers
- IBD
- schizophrenia
- cleft lip/palate
- hypertension
- asthma
complex traits/Multifactorial inheritance
- complex trait aggregates in family
- do not follow simple mendelian mode of inheritance
- need to distinguish between clustering in families due to genetic facts and those due to shared environmental facts.
- epidemiologic twin, adoption and immigration studies used
- each measure of genetic contribution need to be interpreted carefully, but as the group can provide compelling evidence fro genetic contribution to trait
twin studies: mono vs. dizygotic
mono: share 100% DNA
certain amount of environment
di: share 50% of DNA certain amount of environment
if twins raised together and assume same degree of similar environment, then difference in concordance rate between mono and di likely due to
genetic factors
If twins raised apart and assume had different environments then similarities in trait are likely due to
genetic factors
adoption studies
compare similarity btwn biologic siblings raised apart and adoptive siblings
If biological sib 2 more concordant with biological sibling than adopted sibling, then have evidence for _____ as opposed to _____
genetic component as opposed to environmental component
risk of disease in relatives
risk of disease in siblings of affected/ risk of disease in general population
heritability
h2
proportion of variance in trait that is due to genetic variation
low heritability
less than 50%
high heritability
more than 50%
characteristics of complex traits
- incomplete penetrance
- variable epxressivity
- heterogeneity –allele and locus
- presence of phenocopies
penetrance
relationship between trait and genotype
probability that an individual will develop the trait if they have the genotype
complete penetrance
everyone with pre-disposing genotype will get the trait
incomplete penetrance
some with genotype will not get the trait
susceptibility variants for complex diseases are generally though to have ______
low penetrance
example of incomplete penetrance
type 1 diabetes.
up to 20% of general population has two highest risk haplotypes, but incidence is only 0.4%
variable expressivity
individuales with the same variant do not show precisely the same disease or quantitative phenotype characteristics
example age dependent diabetes
allelic heterogeneity
- different alleles in the same gene result in the same trait
- different alleles in the same gene result in different traits
- ex. cystic fibrosis
- many allele appear to have a very similar clinical progression of the disease
- allele can be grouped into classes; severity of lungs and pancreatic involvement depends on the allele class
locus heterogeneity
- variants in different genes result in very similar clinical presentation
- early onset alzheimer disease
- mutations on 3 different genes all result in identical clinical manifestations of early onset AD
phenocopy
environmentally cause phenotype that mimics the genetic version of the trait
example of phenocopy
thalidomide-induced limb malformation vs. genetically induced
Concordance rates are often used to
compare MZ and DZ twins. A 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.
Implication: A high heritability does not imply that
non-genetic factors are not important. A low heritability does not imply that environment is not important.
incomplete penetrance example
Type 1 diabetes and MHC
variable expressivity example
maturity onset diabetes i the young (MODY)
Variable expressivity means that
no two individuals with the same genetic variant have exactly the same disease characteristics
heterogeneity examples
cyctic fibrosis
alzheimers disease
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
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
examples of phenocopies
Thalidomide-induced limb malformation vs. genetically-induced
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.
example: AD and APOE locus
The role of non-genetic factors in contributing to variation in complex traits will
vary from trait to trait and individual to individual.
