Mendelism and Sequencing - Dr. Markie Flashcards
Mitochondrial Inheritance
- Inherited from a single gene
- Matrilineal - cytoplasmic inheritance
- Both males and females are affected
- Variable expressivity and incomplete penetrance (a consequence of heteroplasmy)
- Predominant phenotypes are muscular, retinal, and hearing
Homozygosity
two identical alleles at a (disomic) genetic locus
Heterozygosity
two distinguishable alleles at a (disomic) genetic locus
Hemizygosity
the presence of only one allele
ex. monosomy – loci on the X and Y chromosomes in males are monosomic
a large or small deletion can cause hemizygosity - may be unaware b/c its benign
Compound heterozygosity
two different recessive alleles for the same gene. Inheritance of both cause genetic disease state but they are heterozygous b/c alleles are different.
Codominance
both traits can be present in the same individual when heterozygous
Ex. ABO blood system – AB phenotype
Red Flower + White flower == Red and white flower)
Partial Dominance
The heterozygote demonstrates a phenotype intermediate between the two homozygotes
examples
* Achondroplasia - classical “dominance” inheritance of short stature. Very rare homozygotes – more severe skeletal abnormalities with early death due to respiratory difficulties
* Red flower + white flower = pink
Mendel’s First Law –
Law of Segregation
only one of the two gene copies present in an organism is distributed to each gamete (egg or sperm cell) that it makes, and the allocation of the gene copies is random
De novo mutation
New mutation
* A child suddenly gets a dominant disorder that parents don’t have
* Need to consider recurrence risk but different types carry different risk
Types of de novo mutations:
* Gametic Mutation
* Somatic Mutation
* Gonadal Mutation
Gametic Mutation
- Occurs during meiosis in formation of single sperm or egg (Parents)
- Recurrance risk is extremely low for next child
- But - the affected person’s child will have a 1 in 2 risk
Somatic Mosaic
- Occurs post-conception in developing embryo (mosaic b/c not all cells will inherit it)
- Recurrence risk is extremely low for original couple
- Risk to affected person’s children is unpredictable as it depends on is mutation occured early enough to affect germ cells
- Some cells will have the gene and others won’t – there is a threshold for how many cells have the disorder = phenotype
Gonadal Mosaic
- Parent sustained a mutation during development that contributed to germ cells
- Essentally the child of somatic or gametic mutation becomes parent
- This parent may not actually show the disorder b/c low ratio of mutated cells cannot reach threshold
- Recurrance risk depends on the proportion of cells in the gonad affected
- The risk to a second child is unpredictable but risk to grandchild is predictable
Pleiotropism
- Multiple effects of a single gene - seemingly unconnected
- Underlines our limited understanding of molecular biology
- Many genes/proteins are “multi-functional” – more than one pathway, multiple functional domains, or complete function yet to be described
Variable Expression
- Describes changes in the severity of a disorder
- Variation in the severity/age of onset
- Almost all inherited disorders show this to some extent
- Suggests the influence of other factors (genetic, environmental or random) on the development of the disorder - but not well understood
Differences within families - may have different underlying factors
Differences between families - suggests it is allelic
Anticipation
Special kind of variable expression
* Some disorders manifest more severely with each generation
* For many years it was rationalized as ascertainment bias – severe cases are presented to physicians and parents are found to have milder cases
* Still difficult to seperate ascertainment bias from anticipation in many disorders
Mechanism was identified in triplet repeat expansion disorders
* Effects protein or expression of gene
* Severity/age of onset is determined by length of repeat
* Repeat length unstable, tends to expand
Penetrance
- Probability that a person with appropriate genotype will manifest the phenotype
- Single genes predispose to some disorders but may not be the only factors (ex. modifying genes, environment, chance)
Penetrance = 1 (everyone who inherits gene gets disorder = complete penetrance)
Penetrance = 0.5 (50% of those who inherit the gene get the disorder = incomplete penetrance)
Incomplete Penetrance
Not all those who inherit a gene inherit the disorder
* Can complicate determination of mode of inheritance and diagnosis
* Most evident in dominant disorders, applicable to recessive disorders but harder to identify
* May be related to age or sex
Ex. inherited breast cancer (men have less breast tissue – less chance of inheriting
This can be relative or absolute (mainly affect women vs only affects women)
BUT NOT X OR Y LINKED – Only that your underlying biology effects risk — Disorders affecting primary or secondary sex characteristics
Imprinting
Parent of Origin Effect
– special kind of incomplete penetrance
* a minority of genes are silenced during gametogenesis in one parent or another
* For these genes we are functionally hemizygous b/c we only express one allele
* maternal and paternal imprinting
* If the allele that expressed has a mutation that leads to a non functioning allele and can often be genetically lethal
* Imprinting may be relaxed in some tissues
* Imprinted genes are not common
* Often arrise from de novo mutation b/c of genetic lethality
