Non Mendelian Inheritance Flashcards
Definition of phenocopies/genetic heterogeneity
Many different alleles/gene variants => 1 phenotype
Definition of incomplete penetrance
Have the genotype associated with the disease but disease phenotype is not expressed
Definition of sib pair analysis
The idea that if a marker is linked to a disease locus, the same marker allele will be inherited by 2 siblings who express disease more often than expected by chance
Definition of syntetic
Whether the genes are on the same chromosome
What is the mode of inheritance for mitochondrial diseases
Is male to female transmission possible? Why?
Matrillineal inheritance
Female => both genders equally
Male => female transmission is not possible
Egg cell contains nuclear DNA and mitochondria
Sperm contains nuclear DNA and mitochondria but only nuclear DNA is passed on
What are the 3 factors that contribute to the expression of a mitochondrial disease
Type of mutation
Amount of abnormal vs normal mitochondria
- heteroplasmy, mix of normal and mutant mitochondria in each cell
- homoplasmy, mitochondria in a cell are all the same
Organ system affected
What is genomic imprinting
What sort of imprinting is considered normal
What are the 2 outcomes if imprinting goes wrong
Certain genes expressed in a parent of origin specific manner
If allele inherited from 1 parent is imprinted => silenced so only maternal allele expressed
Normally, we have 1 active copy of an imprinted gene
-improper imprinting leads to either
2 active copies 2 inactive copes
Describe what has gone wrong in Prader Willi and Angelman Syndrome
Prader Willi
- deletion/mutation in paternal genes
- no active copies of affected genes
Angelman Syndrom
- deletion/mutation in maternal genes
- no active copies of affected genes
Describe what is multifactorial/complex inheritance
Phenotypes that don’t express classic Mendelian inheritance
-single genes cannot explain phenotypic variation
Genes and environment influence traits
What are the 2 main types of complex traits
Describe them
What are the properties of complex inheritance
Polygenic
- +1 genes with small additive effects
- pure polygenic traits are v rare
Multifactorial
- +1 genes and environment
- no Mendelian ratios
Common polymorphisms associated with complex disease have small additive effects
If additive effect is large enough => disease
What is familial aggregation
What can also account for the increased prevalence of a complex disease in families
Families share a larger proportion of their alleles than the general population => higher prevalence of disease with complex inheritance
Non genetic factors may also lead to the expression of the disease as families often share similar environmental exposures
What is concordance and what are the 2 causes of disease concordance
2 individuals both express the disease
Due to
- similar/same alleles
- genetic heterogeneity/phenocopies
What is discordance and what are the 2 causes of disease discordance
Individuals in a family do not all express the disease
Due to
- different alleles found in each individual
- incomplete penetrance
Why is it hard to identify genes/causes of polygenic/multifactorial diseases
Describe the relative concordances of disease in MZ and DZ with monogenic and complex diseases
Incomplete penetrance and phenocopies
MZ have higher concordance in monogenic diseases
Both MZ and DZ have lower concordance for complex diseases
How would you estimate the risk of a disease recurring in a family
What factors lead to a higher risk
Empiric risk
- based on observations within a family
- used to predict recurrence of a trait in a family
Higher risk associated with
- increased severity
- no of affected relatives
- sex
- relatedness to affected individuals
Heritability
- estimates proportion of variation in a population for a multifactorial trait due to genotype
- coefficient of relatedness => proportion of genes relatives share
- higher COR as more closely related people compared
How would you map the genetic cause of a condition
Linkage analysis Association studies/case controls GWAS NGS Detecting large structural variations New approaches to understanding the aetiology of complex diseases on a molecular level
Why would you use linkage analysis to map the genetic causes of a condition
What is the threshold value
Used to identify a region of the genome that contains the causative gene
cM (unit of measure)
The larger the marker, the further they are from each other
Greater than 50 => unlinked
How would you use the affected pedigree method (sib pair analysis) to map the genetic causes of a condition
Linkage analysis of complex polygenic conditions that relies on pairs of family members who are concordant for a trait
-sibling-sibling or parents-sibling pairs used as they share DNA from a direct inherited lineage
How would you use case control studies to map the genetic cause of a condition
See if the trait expressed is associated with a particular genotype
Compare with controls who don’t express the trait
How would you use linkage disequilibrium to map the genetic cause of a condition
See if the presence of a mutated/pathogenic allele is associated with another allele at a specific locus
How would you use GWAS to map the genetic cause of a condition
How much data would you need
What is the downfall of findings in GWAS
Identify large no’s of common variants associated with disease in an assay
Data obtained from many samples to provide statistical confidence needed for disease association
However, associated variants may not directly cause disease
-linkage disequilbrium is possible => more steps needed to identify variant
How would you use NGS to map the genetic cause of a condition
What is the downfall of NGS
By sequencing genomes/exomes, can find causative variants in rare/complex diseases, including detection of potential de novo mutations
NGS effective for common variant identification
-loci selection needed for SNP arrays can limit detection of rare variants occurring at a low frequency in a population
Why would you detect large structural variation to map the genetic cause of a condition
Copy no variants result in abnormal no’s of gene copies
- duplication
- deletions
- inversions
Can predispose to common complex conditions
