Principles of Genetic Inheritance Flashcards
How do you analyze a pedigree?
Read the proband. It will give you the generation (II,II,III,…) and then a number. Count from the left to this number.
How many alleles are required for expression if it is autosomal dominant?
Only 1 allele (Aa would show).
In what generations is the trait expected in autosomal inheritance?
In every generation. Recurrent risk is 50%.
How many alleles are required for expression in autosomal recessive?
2 copies of a mutant allele (gene) is needed to influence the phenotype. aa=show. Aa=carrier, does not display phenotype.
What is lyonization?
The inactivation of an X chromosome. One of the two X chromosomes in every female cell is randomly inactivated early in embryonic development.
Do unaffected males transmit an X-linked recessive gene.
No. They are not carriers, so they cannot transmit the trait.
If you are a female, you got your X chromosome from your mother. What chromosome do you get from your father?
X chromosome.
If you are a male, you got your X chromosome from your mother. What chromosome do you get from your father?
Y chromosome.
In X-linked recessive, why are all daughters of affected males heterozygous carriers?
-X (from mom)
-X (from dad, with the disease)
Dads disease on the X is recessive. You are “saved” by your moms X chromosome, but still a heterozygous carrier. Since you are a carrier, you can transmit this disease allele to 50% of sons and 50% of daughters.
Do fathers ever transmit their X-linked recessive disease to sons?
No. Sons get X from mom and Y from dad so they never get the diseased X from dad. Only the daughter could because dad gives daughter his X.
What is unique about mtDNA and its repair?
mtDNA does not have any introns. mtDNA is inherited only through the maternal line. The mutation rate is 10x higher than nDNA. There are no repair mechanisms. Damage from free O2 from Oxphos.
If there is a mitochondrial disease, how many of her progeny get it?
All of them because mtDNA is inherited only through the maternal line.
At cell division, mitochondria aren’t distributed equally…how does this affect disease?
When the level of mutant mitochondria exceeds a certain threshold, say 80%, the cell expresses dysfunction. If you have an intermediate amount of mutation, you have mild mitochondrial disease.
What mitochondrial disorder is caused by one of 3 point mutations affecting NADH dehydrogenase?
Lebers hereditary optic neuropathy (LHON). Causes degeneration of retinal ganglion cells (RGCs) because they are starved of energy and cant send signals to brain. Causes acute or subacute loss of central vision in early teens or 20s.
Where is lysine needed in oxphos?
Lysine is required for cytochrome-C oxidase function
Myoclonic epilepsy and ragged red fibers (MERRF) is caused by ___?
MERRF is caused by a mutation in the gene encoding for tRNA for lysince, which disrupts the synthesis of cytochrome-c oxidase.
Sx or MERRF
Ataxia and seizure. Large variability in presentation due to heteroplasmy.
Most commonly inherited mitochondrial disorder
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Affects many body systems
What causes MELAS?
A single point mutation resulting in lactic acid buildup due to the inability to utilize pyruvate.
example of X-linked dominant disorder
Hypophosphatemia.
Define euploid
Cells with the normal number of chromosomes
Define polyploidy
Cells contain a complete set of extra chromosomes. Often seen in plants.
Define aneuploidy
Cells have a missing or an additional individual chromosome. Trisomy, monosomy.
What are the 4 types of chromosomal mutations?
Inversion
Deletion
Duplication
Translocation
What are the 2 types of translocation mutations
- Reciprocal: Exchange of material between nonhomologous chromosomes
- Robertsonian: The long arms of two chromosomes are combines. The short arms are lost.
What does karyotyping lack?
It lacks information at the molecular level. But it is the gold standard used in identifying several chromosomal abnormalities associated w/ genetic disorders.
What are the 2 syndromes associated w/ a deletion within the chromosome 15 region?
Prader-Willi and Angelman Syndromes. The phenotype depends on if the deletion is on the maternal or the maternal chromosome.
Paternal: Prader-Willi
Maternal: Angelman
How does the variability of X numbers influence Klinefelters syndrome?
The more X (48 XXXY, 49 XXXXY) the more severe the symptoms.
Sx of Trisomy 18
Edwards Syndrome (47, XX +18) Microencephaly, prominent occiput, low set ears, smallmouth and jaw, cleft lip/palate, overlapped fingers
Sx of Trisomy 13
Patau Syndrome (47, XX +13) Severe developmental abnormalities, heart and kidney abnormalities, CNS dysfunction, cleft lip, microcephaly.
What does 100% penetrance mean
The frequency in which a gene manifests itself. Ex. Retinoblastoma: phenotype occurs in 90% of individuals so there is a 90% penetrance.
Examples of variable expressivity?
Neurofibromatosis
Marfan Syndrome
What disease is associated with locus heterogeneity
Osteogenesis imperfecta. Locus heterogeneity is when a single disorder, trait, or pattern of traits is caused by mutations in genes at different chromosomal loci. Only 1 mutant locus is needed for phenotype expressivity.
Independence
the occurrence of 1 does not affect the probability of occurrence of another. Ex. having a first child boy, second child girl. It’s always 50/50.
Multiplication Rule
the probability of a given outcome in multiple trials is the product of the probabilities of each trial outcome
Probability of producing 3 girls: 1/2x1/2x1/2=1/8
Addition Rule
probability of either one outcome or another is the sum of the two probabilities
Probability of producing either 3 girls or 3 boys: 1/8 + 1/8 = 1/4
Hardy-Weinberg Equation
p^2+2pq+q^2 = 1
What kind of disorder is more likely with consanguineous mating?
Autosomal recessive disorders
Polygenic
Traits in which variations are thought to be caused by the combined effects of multiple genes
Multifactorial
When environmental factors cause variations in the trait
What is the threshold of liability?
Occurs in multifactorial resistance. It must be crossed before the disease is expressed.
How is sex related to multifactorial resistance?
The least affected sex has a HIGHER risk threshold ( you must have more additive factors than the more affected sex) and transmits the condition more often to the more affected sex because they have a LOWER risk threshold (need fewer factors to show disease)
Is pyloric stenosis more common in males or females?
Males. They need fewer risk genes to show disease.
What is recurrence risk?
The risk of multifactorial diseases recurring. It differs in populations because gene frequencies and environmental factors differ.
When is recurrence risk higher?
- More than one family member affected
- If the expression of disease in the proband is more severe
- If the proband is of the less commonly affected sex
