Primerano - Complex Modes of Inheritance 1+2 Flashcards
What term?
-general term for any genetic change regardless of frequency
Types:
- Single nucleotide variants/polymorphisms (SNV/SNP): one base is changed from ancestral (reference) base
- Insertions and deletions (grouped as “indels’)
- Structural variants (e.g. translocations, rearrangements)
-
Simple tandem repeats (STR)
- Dinucleotide, trinucleotide repeats
- Disease allele detection
- Forensic identification
Variant
_________ diseases are rare and tend to be caused by rare variants; sometimes called ‘private’ variants.
Mendelian diseases
Role of common variants in disease –>
The _______________ hypothesis predicts that common variants in human populations will confer risk to a given disease.
- ex. APOE €4 in Alzheimer’s disease and IL23R in Crohn’s disease
- Growing evidence for the competing hypothesis (rare variants at multiple loci)
Common disease-common variant (CDCV) Hypothesis
___________ is a variant allele that is present in greater than one percent of the allelic population. Just speaks to its frequency.
- Some incorrectly use the term to connote a benign mutation.
Polymorphism
What type of inheritance?
- Single gene determines phenotype regardless of other genes or environmental influences.
- Inheritance pattern is “Mendelian” (AD, AR, X-linked, Mitochondrial)
-
Presence of one allele (or genotype) gives a particular phenotype, while another allele results in a second phenotype
- Some alleles are neutral (benign) or beneficial
- Other alleles that are harmful to gene expression
Monogenic inheritance
What term?
-Configuration of alleles at a given locus
- Genetic locus that has two different alleles is said to be heterozygous.
-
Heterozygosity can mean either:
- presence of a wild type and a mutant allele or,
- the presence of two different mutant alleles.
- Term heteroallelic is used if two defective alleles are present; two different mutations both in the same gene at diff positions.
(Aka: compound heterozygote)
Allelic Constitution
What occurs when there are different alleles at the same locus (gene) which give rise to the same or similar disease?
Allelic Heterogeneity
What disorder? Example of?
- Autosomal recessive disorder
- Defects in CFTR gene lead to failed Cl- transport
-
Pancreatic Insufficient (PI) type (ΔF508 homozygotes –> severe form)
- 85% of all cases
- Have chronic lung disease and defect in synthesis of pancreatic enzymes
-
ΔF508 mutation in CFTR (~70% of all PATHOGENIC alleles in U.S.)
- 3bp deletion = loss of single phe residue at position 50
Cystic Fibrosis, Allelic Heterogeneity
What is the prognosis of the Pancreatic sufficient (PS) type of Cystic Fibrosis?
- 15% of all cases
- Have some pancreatic function
Better prognosis than PI type
**Severity of the disease (+ management) depends on genotype.
Example:
- Patients _________for the ΔF508 allele have the PI form
- Those with a “milder” allele (compound heterozygotes, e.g. 455 Ala –> Glu) + the ΔF508 allele have the less severe PS form of the disease.
Homoallelic
Cystic Fibrosis - variations:
- +/+ –> __________
- F508/ + (HETEROZYGOTE) –>___________
- F508/F508 (HOMOALLELIC) —> __________
- F508/455 (HETEROALLELIC) —>______________
- Homozygous normal
- Normal carrier
- PI form
- Less severe form, PS
What disorder? Example of?
- X-linked recessive, DMD gene
-
_________ FORM (BMD): In frame deletions, less severe disease, normal life span.
- Some protein is detectable in myocytes by immune fluorescence
-
_________ FORM (DMD): OUT OF FRAME DELETIONS in DMD GENE.
- No protein can be detected by immune fluorescence.
- Impaired respiratory function –> life threatening
- Dystrophin: required for assembly of synaptic junction
Muscular dystrophy, Allelic Heterogeneity
Becker Form (BMD)
Duchenne Form (DMD)
What term?
- Genes at different loci (genes) that cause the same or similar disease.
- Contrast to allelic heterogeneity
Locus Heterogeneity
Example of?
PKU results from failure to convert phenylalanine to tyrosine.
- 97% of all PKU have defects in _______________________ (enzyme)
- 3% have defects in other loci.
-
Type I: gene for PAH
Diet: Restrict phe + provide tyrosine -
Type II: gene for BH4 reductase
Diet: Restrict phe + provide L-DOPA + 5HT (Precursors to neurotransmitters) -
Type III: gene for biopterin synthesis
Diet: Restrict phe +provide L-DOPA + 5HT (Precursors to neurotransmitters)
Locus Heterogeneity; phenylalanine hydroxylase (PAH)
BH4 is cofactor that serves as a reducing agent in phenylalanine hydroxylase reaction
- What other biosynthetic reactions does BH4 participate in?
- Phenylalanine to Tyrosine (Phenylalanine hydroxylase enzyme)
- Tyrosine to L-DOPA (Tyr hydrolylase)
- Tryptophan to 5-OH trp –> Serotonin (Trp Hydroxylase)
Practice Problem: Set up Punnett Square - What would the Gametes be?
Mating between Type I and Type III PKU Patients
Assume Mom is Type 1 = PAH Homozygous mutant and BH4 synthesis homozygous normal
Assume Dad is Type 3 = PAH homozygous normal and BH4 synthesis homozygous mutant
Mom = p/p, B/B
Dad = P/P, b/b
Gametes = p/B and P/b
What type of inheritance?
- 37 genes involved in ox-phosphorylation, rRNAs and tRNAs
- Disruption of energy production is pleiotropic (affects many organs)
- >100 point mutations + >100 rearrangements
-
Maternal only inheritance*****
- Mom to all offspring*****
- Dad to no offspring
Mitochondrial inheritance
What term?
- Explains the phenotypic variation among affected offspring within the same family
____________: mixture of mitochondrial genomes, some wild type and some mutant
Replicative Segregation
Heteroplasmy
______________: one gene with multiple alleles that give rise to same/similar disease
______________: one of several genes (with or without multiple alleles) that give rise to the same/similar disease.
____________ = monogenic inheritance***
Everything else = Complex mode of inheritance
- Polygenic
- Multifactorial
Allelic Heterogeneity
Locus Heterogeneity
Mendelian
What term?
Two or more genes (gene products) interact to render the actual phenotype (no environmental effects).
- Genetic background refers to all other genes that influence the action of the gene in question.
- Genetic phenomena that arise from gene-gene interactions
- Sex influenced traits (autosomal defect)
- Incomplete penetrance
- Variable expressivity
Polygenic Inheritance
What is the probability of manifesting a trait given the presence of a (defective) allele?
- This is an “either or” phenomenon.
- A target gene and modifier gene determine the phenotypic outcome
- Not to be confused with variable expressivity
Penetrance
Incomplete penetrance is found *only in __________ modes of inheritance.
- Looks like a combination of both recessive and dominant
- Disease “skips” a generation**
- Phenotypic normal may have disease allele and pass it on
Dominant
If CF locus is homozygous mutant, then child has 100% chance of developing CF disease. CF is said to be _________.
- Regardless of genetic background
Completely penetrant
Huntington’s Disease
- Autosomal dominant neuro-degenerative disease
- If you receive the disease allele, you develop the disease at some point.
- HD is 100% ________ with variable age on onset.
Image: 50% of defective allele carriers are affected by age 34. 90% are affected by age 70.
Penetrant
Example of what?
Polydactyly
- Autosomal dominant
- Not all family members with disease allele get extra digit
- 7p13
Incomplete penetrance
What is the formula to calculate penetrance?
= # with affected phenotype / # with affected genotype (carriers included)
Example of what type of inheritance?
Retinitis pigmentosa
- Two unlinked genes (peripherin and ROM1) encode photoreceptor proteins. Retinal degeneration affects rod photoreceptors.
- Patients heterozygous at either (but not both) loci are normal.
- Patients heterozygous at both peripherin and ROM1 develop RP.
True Polygenic Inheritance
Fact:
For polygenic modes (like incomplete penetrance), two or more genes determine the phenotypic outcome.
In a few cases, monogenic allelic heterogeneity (caused by genomic instability) provides a better explanation for observed variation –> FRAGILE X SYNDOME
What syndrome?
The second most common cause of intellectual disability and most common hereditary form of mental retardation.
- Cytology: Cells cultured from these patients have a secondary constriction on X chromosome which is the site of frequent breakage.
- This site fails to condense during metaphase.
- X-linked dominant trait with incomplete penetrance - probability of being affected increases over generations
- Details:
- Affected males: 1 in 1250
- Affected males: moderate intellectual disability, large heads, large protruding ears, stubby hands, prominent jaw.
- Language development is delayed.
- Some overlap with autism spectrum (inattention, hyperactivity)
Fragile X syndrome
Carrier females of Fragile X syndrome are rarely physically dysmorphic but do show variable learning ability.
- Some female carriers are affected in that they tend to be shy and show some learning disorders.
- Since female carriers have an affected phenotype, we say that Fragile X is a dominant trait.
- Phenotypic variation in females can be due to _______.
Biased Lionization (depending upon which X chromosome is converted to a barr body)
Fragile X Mode of Transmission:
- Phenotypically normal man who passes the disease allele on to his daughters and his grandsons is called a ___________
- Brothers of this NTM have a 9% risk of being affected
- ___________ have higher chance of being affected than brothers.
- The risk of the granddaughters and great-granddaughters being affected also increases from 5% (sister affected in gen II) to 17% and 20% in gen IV.
- Nonpenetrant Transmitting Male (NTM) -> II-3 on image
- Grandsons and great-grandsons
Fragile X Mode of Transmission
Position in the pedigree (generation) in part determines the risk of developing the syndrome.
This is known as the _________.
Sherman paradox
Molecular Basis of the Sherman Paradox:
- Multiple CGG trinucleotide repeats are present in the 5’ noncoding region of fragile X gene (FMR1).
- Phenotypically normal males and females have less than _________.
- NTMs and carrier females have variant alleles with between 50 and 200 repeats called ___________
- If >200 repeats, the individuals will develop Fragile X Syndrome.
- Normal alleles and premutation alleles allow synthesis of functional _______ gene product and normal mental development ensues.
- 50 repeats
- Premutation alleles
- Functional FMR1 gene product
Why are the offspring of III-3 at greater risk than offspring of I-2?
Length of repeat is greater in III-3.
NOTE:
- NTMs are said to be nonpenetrant because they have a “defective” allele but do not express the phenotype.
- This is a slight twist on accepted meaning of penetrance, because premutation allele is not truly defective since it encodes a normal FMR1 product.
- But it does confer increased probability of expansion to the “full” mutation.
Southern blot analysis provides the length of the triplet expansion in based pairs of the FMR1 promoter.
Predict the phenotype of each of the seven patients in the graphical PCR representation.
Each band represents an allele at the FMR1 locus.
Each column represents an individual’s genotype.
Male 1: Normal
Female 2: 1 Normal Allele, 1 Premutation Allele = Normal, risk for offspring
Male 3: 1 Premutation Allele = Normal
Female 4: (Somatic Mosaicism) 2 Premutation Alleles = Normal probably
Male 5: Full Mutation Alleles (Somatic events) = Fragile X Syndrome
Female 6: 1 Normal Allele, 1 Full Mutation = Fragile X syndrome symptoms
Male 7: 1 Premutation and 1 Full Mutation = Fragile X Syndrome likely
What term?
-refers to the apparent worsening of a disease over several generations.
Examples:
- Huntington Disease (dec in age of onset)
- Myotonic Dystrophy (Inc in disease severity)
- Fragile X (inc in penetrance)
-may also stem from _____________ bias (mildly affected individuals may escape detection and give rise to artifically low penetrance in an older genetration d/t lack of clinical skills, etc)
Anticipation
ascertainment bias
What is the trinucleotide repeat in Huntington’s Disease?
Inverse relationship between repeat length and age of onset.
CAG.
What condition?
- anticipation (repeat expansion accounts for the phenotypic worsening over generations
- AD, characterized by myotonia, ptosis, cataracts, hypogonadism, frontal balding, ECG changes
- defect in 1 form is an amplified trinucleotide repeat in the 3’ untranslated region of a protein kinase gene on Chr 19
Myotonic Dystrophy
FYI: Triplet Expansion in Myotonic Dystrophy
What term?
-range of phenotypic manifestations of same genetic disorder (or of same genotype)
While penetrance refers to the presence or absence of any effect of a gene,
__________ refers to the type or degree of manifestation of a gene that is a penetrant.
Variable expressivity
expressivity
What condition?
- exhibits variability expressivity
- AD, neurocutaneous disorder
-NF1 gene
- mild cases: Cafe au lait spots (light brown in color) + benign neurofibromas
- severe cases: disfiguring neurofibromas and malignant tumors (eye, brain, spinal cord), intellectual disabiity and/or speech impediment can be present.
Neurofibromatosis (NF1)
FACT: variability expressivity is a polygenic inheritance phenomenon.
Variable phenotype even in those with the same NF1 mutation so we believe there must be other factors (probably genes) involved in determining the clinical manifestations.
What term?
- a gamete disomic for a given chromosome will fertilze one which is nullisomic for the same chromosome
- resulting zygote will have a euploid chromosome number but 2 chromosomes from the same parent (i.e. 2 maternal chromosome 15s)
Uniparental Disomy
What term?
- some genes are activated or inactivated in a sex (gamete)-specific manner
- follows that uniparental disomy could lead to a gene being present in either 2 active or inactive doses
- functional imbalance and phenotype depends on the “parent of origin”
Genomic Imprinting
Name Condition.
- obesity, hyperphagia
- intellectual disability
- hypogonadism
- small hands/feet
-ONLY MATERNAL 15q information
Prader-Willi Syndrome
Name Condition.
- severe intellectual disability
- spasticity
- seizures
-ONLY PATERNAL 15q information
Angelman Syndrome
What condition results from inheritance of pair of maternal Chr 15s and no paternal 15s (~30%)? Can also result from deletions in the gene.
What condition which is phenotypically distinct resulting from the inheritance of pair of paternal chromosome 15s and no materal 15s (~7%)? Can also result form deletions in gene.
Prader-Willi (2 Maternal)
Angelman Syndrome (2 paternal)
What term?
environmental and genetic factors combine to produce a phenotype
-most human traits/disorders fall in to this category
Ex: height, intelligence, weight and susceptibility to CV disease, cancer and some forms of Alzheimer’s disease, autism, behavioral disorders
Multifactorial Inheritance
Fact: Continuous Multifactorial Traits
- many physical and behavioral traits have a continuous spectrum of phenotypes (height, weight, BP, IQ)
- referred to as quantitative traits bc measurable and varies across indiv. in a population
- can be explained by multifactorial inheritance
What term?
a number of complex human diseases do NOT occur as continuous traits in a bell-shaped distribution
instead either fully present or absent in an individual
only when a certain threshold is reached will the disease phenotype manifest itself
-can be sex dependent
X Axis: liability
Y Axis: number of people with x amt of liability
Threshold or dichotomous (either/or) traits
These are all examples of what type/category of human diseases?
- neural tube defects
- cleft lip/palate
- CV Disease genotype of individual (family history of MI) + environmental factors (cig smoking, stress, diet)
- Lung disease w/alpha-1 Antitrypsin deficiency is determined by smoking and mutations in the alpha-1 antitrypsin gene
Threshold Human Diseases
4 Key Features of Multifactorial Diseases
- Family studies suggest inherited condition by measuring _____________. But there is NO distinctive Mendelian pattern of inheritance.
- The risk to primary family members is the square root of the general population frequency of the disease.
- The risk ___________ (increases, decreases) rapidly for more remote relatives. (Comparison: AD traits only decline by half each degree of separation)
- For traits with sex-dependent liabilities, the recurrence risk is ______ (higher/lower) when the less commonly affected sibling is the proband, presumably bc this proband has a higher level of genetic liability.
- familial aggregation
- decreases
- higher
Name the condition.
slow progression that results in memory loss and alteration of intellectual function and cognitive abilities (i.e. loss of executive function - planning, organizing, strategizing)
-most common form of dementia occurrring after 40
Alzheimer’s Disease (AD)
Alzheimer’s Disease
_______________: found in neurons of cerebral cortex and hippocampus
_______________: within senile plaques are caused by the accumulation of amyloid precursor protein cleavage product (APP Aβ) and other proteins.
________ and ____________ are required for processing of APP.
Mutations in presenilins and APP lead to overproduction of _________ peptide and the early (young) onset forms of the disease.
Neurofibrillary Tangles
Amyloid deposits
Presenilin 1 and Presenillin 2
Aβ42
Fact: APP Processing
Figure 1. Schematic representation of APP processing and role of its products in AD pathology. The proteolytic processing of the large, transmembrane, amyloid precursor protein (APP) occurs in two distinct amyloidogenic and non-amyloidogenic pathways. The amyloidogenic pathway involves the sequential cleavage of APP by an aspartic proteinase, β-secretase, which releases a soluble ectodomain (sAPPβ) and the C-terminal fragment CTF99. This, in turn, is cleaved by another aspartic proteinase, γ-secretase, generating the transcriptional regulator APP intracellular domain (AICD), and releasing the 39–42 amino acid amyloid-β peptide (Aβ). Due to its very high ability to aggregation, Aβ forms dimers, trimers, and higher level oligomers which are toxic to cells and cause neuronal death. Formation of amyloid plaques from Aβ aggregates in complex with other proteins is a hallmark of AD but is considered as a scavenging process. In the non-amyloidogenic pathway APP molecules are cleaved at the α-secretase site within the Aβ-domain releasing a soluble ectodomain sAPPα and the C-terminal fragment CTF83. Proteolytic cleavage of CTF83 by γ-secretase releases AICD and p3 fragment whose functions are still unknown. The AICD fragment produced in the amyloidogenic pathway binds to a stabilizing factor Fe65 and in a complex with other factors (the histone acetyl transferase, Tip60, and a Mediator complex subunit Med12) can act as transcription factor regulating expression of a variety of genes, including an Aβ-degrading enzyme neprilysin. This process was found to be specific to the neuronal APP695 isoform. AICD produced in the non-amyloidogenic pathway and from other APP isoforms (APP751 and APP770) is most likely to be degraded (e.g., by some intracellular proteases, e.g., insulin-degrading enzyme). Soluble APP ectodomains, sAPPα, and sAPPβ, have been shown to have neuroprotective properties.
Alzheimer’s Disease: Locus Heterogeneity
Early onset forms occur before age 60 and are often inherited as AD. Defects occur in ______, ________ & _________.
Late onset forms are more common than early onset; some cases appear to be multifactorial.
A portion of late onset forms “result” from mutations in ______.
APP, Presenilins I & II
apoE
What are the 3 ApoE Alleles in Alzheimer’s Disease?
ApoE protein is known to complex with _____ complexes.
APOE*E2 –> Protective
APOE*E3
APOE*E4 –> 30-50% genetic risk of AD
Aβ42
What Allele combination poses the highest risk for Alzheimer’s Disease?
Not ALL homozygotes develop AD.
Environmental effects: age/head trauma raise risk
social, mental and physical activity reduce risk
So late onset AD is multifactorial and __________ is a risk factor.
ApoE4/ApoE4
ApoE4
