Mendelian Inheritance Flashcards
Mendel’s first law?
Law of segregation: At meiosis each allele (2) of a single gene separates into different gametes –> 50:50 ratio
Mendel’s second law?
Law of independent assortment: At meiosis, the segregation of each pair of alleles in 2 more genes is independent –> each 50:50 ratio
Two components of heredity that Mendel’s laws explain?
- How alleles at a single locus segregate independently at meiosis
- How separate loci (separate genes) also segregate independently
Genotype
refers to the molecular sequence of an individual’s DNA
Phenotype
refers to the observable expression of a genotype - morphological - clinical - cellular - biochemical (depends on your measurement method)
Inheritance pattern: In classic Mendelian how many genes are we looking at
1
In classic Mendelian disorders, what two features are we looking for to describe a disorder?
Whether it is dominant or recessive
Whether the chromosomal locus is on an autosome or a sex chromosome
Are dominance and recessiveness intrinsic properties of a given allele?
No! Dominance and recessivity are not properties instrinsic to a particular allele, but refer to the relationship of one allele to the corresponding allele on the homologous chromosome
What makes a trait dominant?
If it is expressed in the heterozygous state –> one mustant allele yields disease
What makes a trait recessive?
If it is expressed ONLY in teh homozygous or compound heterozygous state (both alleles must be mutant to yield disease)
What is compound heterozygous
Both alleles are mutant but not the same mutation (ie neither is WT)
What are codominant traits?
Traits are codominant if both traits (Alleles) are expressed in the heterozygous state
When the heterozygous phenotype is intermediate between the two homozygous pehnotypes, what do we call it?
The terms
Semi-dominant or
Incomplete dominant
What about when the homozygote is more severe than the heterzygote of a dominant mutation?
In theory a truly dominant trait would be expressed equally in heterozygotes adn homozygotes; this is rarely the case as the homozygous (mutant) forms are typically more severe. However, the term “dominant” is still widely used to refer to most (if not all) cases where the disease is present in the heterozygote (irrespective of the severity of the homozygote)
Inheritance Patterns: autosomal dominant
Does it skip generations?
No…phenotype sually appears in every generation, each affected person having an affected parent
Inheritance Patterns: autosomal dominant
What is the risk of a child of an affected parent inheriting the trait?
50% risk (assuming other parent WT )
Inheritance Patterns: autosomal dominant - what can we say about phenotypically normal parent?
Phenotypically normal parents do not transmit the phenotype to their children.
Inheritance patterns: autosomal dominant
Sex?
Males adn females are equally likely to transmit phenotype to children of either sex - in particular, male to male transmission can occur, and males can have unaffected daughters
Charateristics of X-linked recessive inheritance
Is the incidence different in sexes?
Yes, the incidence of the trait is much higher in males than in females
X-linked recessive characteristics
Heterozygous females?
usually unaffected, but some may express the condition with variable severity as determined by the pattern of X inactivation
Characteristics of X linked recessive
What happens to daughters of affected men?
The gene responsible for the condition is transmitted from an affected man to all his daughters. Any of his daughters sons has a 50% chance of inheriting it
Characteristics of X linked recessive
Father to son transmission
Not possible!
The mutant allele is never transmitted directly from father to son, but is transmitted by an affected male to ALL is daughters
Characteristics of X linked recessive
Mutant allele and female family
The mutant allele may be transmitted through a series of carrier females; if so, the affected males in a kindred are related through females
Characteristic of X linked recessive
Isolated cases
A significant proprotion are due to due mutations
Characteristics of X linked dominant inheritance
Affected male progeny?
Affected males with normal mates have no affected sons and no normal daughters
Characteristics of X linked dominant inheritance
Female carrier progeny?
Both male and female offspring of female carriers have a 50% risk for inheriting the phenotype. The pedigree pattern is similar to that seen with autosomal dominant inheritance
Characteristics of X linked dominant inheritance
frequency in females vs males?
Affected females are approximately twice as common as affected males, but affected females typically have milder (although variable) expression of the phenotype
Characteristics of autosomal recessive
Where is it usually seen in family tree?
An autosomal recessive phenotype, if not isolated, is usually only seen in the sibship of the proband, and not in parents, offspring, or other relatives
Characteristics of autosomal recessive
males vs females?
For most autosomal recessive diseases, males and females are equally likely to be affected
Characteristics of autosomal recessive
parents of affected child?
The parents of an affected child are asymptomatic carriers of mutant alleles
Characteristics of autosomal recessive
what makes more likely?
if the parents are consanguineous -
Characteristics of autosomal recessive
recurrence risk
1/4
Metabolic disorders are frequently ________________ (mode of inheritance)
Recessive
Metabolic disorders are due to (most common cause)
due to deficiencies of protein (often enzyme) in biochemical pathways.
Wilson’s disease
example of autosomal recessive metabolic disorder - copper metabolism
Wilson’s disease - clinical
liver disease (cirrhosis) neurological problems
Wilson’s disease clinical give away?
Kayser Fleischer rings - copper around cornea
Semi-dominant?
When the heterozygous phenotype is intermediate between the two homozygous phenotypes
Mitochondrial inheritance
Non-mendelian inheritance -
matrilineal
mom has it –> all offspring
dad has it –> no offspring
Penetrance
The fraction of individuals with a trait (disease) genotype who show ANY manifestation of the disease
Age dependent penetrance
The likelihood of manifesting the disease in mutation carriers is dependent on age. Observed in many adult onset conditions
Expressivity
The degree to which a trait is expressed in an individual (severity)
What helps explain variable expressivity?
sex influence
genetic modifiers
environment
stochastic effects
Stochastic effects
random effects - can influence the expression of phenotypes
Sex Influence
Phenotypic expression is dependent on individuals sex (e.g. gout is more common in males than premenopausal females)
Sex limitation
Occurs if only one sex can express phenotype (e.g. unicornuate uterus)
Environmental factors
Some environmental factors can affect the expression of Mendelian genes - disease may only manifest in individuals if particular environmental factors are present
In acute intermittent porphyria, episodes of abdominal pain and psychiatric illness are dependent on exposures (alcohol, medications) this is an example of what?
Environmental factors (threats to mendel)
Modifier genes
Genetic factors outside of teh genetic locus causing a disease can be important for the expression of Mendelian diseases
Phenocopies
Diseases (Traits) that are due to non-genetic factors. Example: A thyroid cancer due to radiation exposure cannot always be distinguished from a thyroid cancer due to mutations in RET gene
Pleiotropy
Used to describe multiple different phenotypic effects due to mutations in a single gene. Often used, when the phenotypes are seemingly unrelated and/or in multiple different tissues.
NF type I leads to cafe au lait, neurofibromas, hammartomas, abnormal freckling, and learnign difficulties - this is an example of?
Pleiotropy
Threat to Mendelian Inheritance (10)
Penetrance Age dependent penetrance Expressivity Sex Influence Sex Limitation Environmental factors Stochastic effects Modifier genes Phenocopies Pleiotropy
