Biochemsitry: Genetics Flashcards
How can you study a gene deletion that causes embryonic death before and after the death of the embryo?
By using the Cre-lox system
- inducibly manipulates genes into activating at specific development points in an embryo
Difference between constitutive and conditional expression of a gene when using gene modification tools?
Randomly inserting a new gene or deleting an old gene = constitutive expression
Targeting a specific area for a new gene or deleting a gene = conditional expression
RNA interference
The process of small non-coding RNA binding to mRNA making it unreadable and inhibiting gene expression
- MiRNA and siRNA do this
- Viruses typically use siRNA to target specific mRNA and disabling them to prevent being seen by the immune system
- cancers can be formed by abnormal expression of MiRNA on tumor suppressor genes (ie. p53). They are hairpin like structures that bind to mRNA and prevent it from being read
Codominance
both alleles contribute to the phenotype of a heterozygote
- the heterozygote has a unique phenotype to the autosomal dominant phenotype
- examples: blood types, HLA groups, a1-antitrypsin deficency magnitude*
Variable expressivity
Patients with the same gene type can have different phenotypes
- autosomal dominant/recessive have multiple phenotypes
*examples: any disease which shows varying degrees or severity that is not codominant *
Incomplete penetrance
Possessing a mutant genotype does not guarantee expression of the mutant phenotype
Expression of phenotype = % of penetrance in the specific disorder (x) probability of inheriting the genotype = risk of expression
examples: mutations in BRCA1 (primary breast cancer gene) does not always produce breast cancer
Pleiotropy
One gene contributes to multiple phenotypes
- one gene can produce multiple different affects, not just 1 effect
Examples: Phenylketonuria (PKU) manifests as light skin, mental retardation and body odor.
Anticipation
Increase3d severity or earlier onset of a disease in succeeding generations
- the disease shows earlier in successive generations as it is passed on
Examples: Huntington’s disease
Loss of heterozygosity
If a mutation develops or is inherited in cancer genes , the complimentary allele must be deleted/mutated before cancer initiates
- having 1 mutated Allele in cancer genes cannot produce cancer, you must have 2 (heterozygote is the exact same as autosomal dominant)
- exception to this rule is oncogenes (mutated oncogenes only need 1 mutated Allele)*
- examples: retinoblastoma, “two-hit hypothesis”, lynch syndrome
Dominant negative mutation
A mutation in 1 allele (heterozygote) produces an autosomal dominant effect for theta gene
- heterozygotes for a dominant negative mutation act as a separate autosomal dominant disorder
Examples: p53 suppressor proteins
Linkage disequilibrium
Alleles that are linked at two or more loci tend to appear with sporadic frequencies among different families /
Somatic Mosaicism
Mutations in mitotic errors in multiple different somatic cell lines that results in multiple different genetic compositions all coexisting at the same time in 1 individual and all are express individual phenotypes at the same time
- if the disease shows mosaicism and is seen in the family, it is most likely this genetic course*
Gonadal mosaicism
Germ line mutations in both egg and sperm cells that produces genetically distention cell lines in the same person and expression distinct individual phenotypes at the same time
- if there is disease that is expressing mosaicism and the family DOES NOT have it, it is most likely this genetic pattern*
Locus heterogeneity
Mutations at different loci can produce a similar phenotype
- a mutant phenotype can be produced by multiple different mutated genotypes
Examples: albinosim
Allelic heterogeneity
Different mutations at the same locus produce the exact phenotype
- the phenotype depends on the loci mutation site, not the specific mutation
Examples: B-thalassemia
Heteroplasmy
Mutated mtDNA results in variable expression of mitochondrial inherited diseases
- if any mutant mtDNA is found in the mother, regardless of how much normal mtDNA there is a chance of passing on a genetic mutation
Examples: any mtDNA disorder is passed down by the mother to all children, regardless of father
Uniparental disomy
Offspring receives 2 copies of a chromsome form the same parent and 0 form the other (is always 2 copies thought, never seen in trisomy/heterosomy conditions)
- if the patient has a heterozygous composition for that chromosome composition = type 1 meiosis error
- if patient has a homozygous (IsodIosmy composition for that chromosome composition = type 2 meiosis error
- IsodIosmy is always considered when a patient expresses a recessive disorder in which on 1 parent is a carrier (not expressing it)
Examples: prader-willi and angelman syndrome
Examples:
Hardy-Weinberg genetics
P + q = 1
- p and q = frequency of a dominant and a recessive alleles for a chromosome respectively
P2 + 2pq + q2 = 1
- p2 = frequency of a homozygous dominant allele composition
- q2 = frequency of a homozygous recessive allele composition
- 2pq = frequency of a heterozygous allele composition
Hardy-Weinberg law assumptions
No mutation occurs at the locus
Natural selection is not occurring
Completely random mating
No net migration
Large population
if all rules are met, then the population alleles can be calculated using the 2 hardy-Weinberg equations and the values of p and q remain constant through generations
Imprinting
One copy of a gene (maternal or paternal) is silenced via methylation, the other other is the only one expressed
Two main disorders with this
- Prader-Willi syndrome and AngelMann syndrome
Prayer-willi syndrome
Maternal allele is silenced, disease occurs when the paternal allele from chromosome 15 is deleted or mutated (no gene expression at this point)
- *25% of cases can also be seen in maternal uniparental disomy occurs and then is silenced
Signs/symptoms
- hyperphagia
- obesity
- mental retardation
- hypogonadism
- hypotonia
“ Prader has no Dad” (paternal deletion)
AngelMann syndrome
Paternal allele UBE3A on chromosome 15 is silenced and the maternal allele is deleted or mutated
- * 5% of cases occurs due to paternal uniparental disomy (and then are silenced or mutated)
Symptoms: “set SAIL for angel island”
- Seizures (chronic and often not treatable)
- Ataxia
- Intellectual disabilities
- Laughter out of place (joker laugh)
“MDs are angels” (Maternal Deletion)
Differences between homozygous dominant and recessive disorders
Dominant
- usually structural genes are affected
- usually presents with pleiotropic effects
- usually less severe
- moderate-late onset
- DOES NOT skip generations
Recessive
- usually enzyme disorders
- DOES SKIP GENERATIONS
- more severe
- very early onset
- more common in consanguineous families
X-linked recessive inheritance
Must express the recessive genotype “X” in order to get the disease
- very rare in females since they need to be homozygous recessive to have disease
- a father CANNOT pass on to a son (it can only be the mother)
- more common in males since they only need 1 recessive x from the mother instead fo 2
- heterozygous mothers chance of passing to son = 50% always
- skips generations often
X-linked dominant inheritance
Must express at least 1 dominant “X” allele for the gene in order to express phenotype
- since it is dominant, there is usually no “carriers”
- fathers CANNOT pas to sons, only mothers can
- if the father has the dominant allele, will pass to daughters 100% of the time (since they only have 1 “X” to pass along).
- heterozygous mothers have a 50% chance to pass to all children regardless of sex
- does not usually skip generations (but still can)
Mitochondrial inheritance
Infected mother always passes down infected mtDNA to all children 100% of the time
- the only thing that varies is the degree of severity of the diseases expression (heteroplasmy pattern)
Lebar hereditary optic neuropathy
MtDNA disorder in which optic neuronal cells spontaneously undergo apoptosis
- results in subacute bilateral vision loss in teens/young adults and is almost always Permanent
- 90% of affected population are males
Cystic fibrosis
most lethal genetic disorder in Caucasian populations
Autosomal recessive disorder that results in a defective CFTR gene on chromosome 7
- also often shows deletion of Phe508 gene as well
- usually results in ATP-gated chloride channels being misfolded while formed and is retained in the rough endoplasmic reticulum instead of being transported to the cell membrane
CFTR gene encodes for ATP-gated chloride channels that secrete chloride in lungs/GI and reabsorption in sweat glands.
- results in decreased chloride ion secretion and retention of water and sodium as a secondary effect in the lungs/GI tissues
- also results in increased chloride ion concentration in sweat
- causes abnormally salty sweat and thick mucus in GI/lungs (recurrent infections)
Symptoms:
- recurrent GI/lung infections (especially S.aureus and P.aeruginosa)
- salty sweat
- opacification of sinuses on imaging
- pancreatic insufficiency
- malabsorption of fat (fatty stools)
- fat soluble vitamin deficiencies (A/D/E/K)
- liver disease
- meconium ileus in newborns
- infertility in men and sub fertility in women
- nasal polyps
- clubbing of nails
Diagnosis
- chloride levels in sweat and immunoreactive trypsinogen
Treatment:
- lumacaftor/ivacaftor (improves chloride channel production and depositing on cell membranes)
- z-pack for infections
- ibuprofen 1x PO to slow disease progression
- hypertonic saline to loosen up mucus
- albuterol for lung issues
Duchenne muscular dystrophy
X-linked recessive disorder that produces a frameshift or nonsense mutation in dystrophin genes (DMD)
- *is the largest muscular gene so can rarely present sometimes as a spontaneous mutation
- loss of or truncated dystrophin results in myonecrosis due to inability to anchor muscle fibers to Z-discs
- onset is usually around 5 years of age
Symptoms:
- muscle weakness in the pelvic and hurdle muscles first (then spreads peripherally the further along the disease course)
- pseudohypertrophy of the calf muscles (muscles are actually being replaced with fat so is actually hypotropic but appears hypertrophic)
- thigh atrophy and increased loridosis
- waddling gait
- (+) gowers sign (must use hands to help stand up when laying on floor)
- dilated cardiomyopathy (chronic and is the leading cause of death)
Becker muscular dystrophy
X-linked recessive disorder that results in a non-frameshift mutation of dystrophin (less severe duchennes)
- onset is later in life (around 20ish)
- similar symptoms to duchennes except less severe and can usually live with symptoms as long as managed properly
Myotonic dystrophy
Autosomal dominant disorder that results in excessive CTG trinucleotide reports expansions in the DMPK genes
- abnormal expression of myotonin protein kinase
Symptoms:
- diffuse muscle wasting
- myotonia (difficulty flexing and extending)
- cataracts
- testicular atrophy
- frontal balding
- arrthymias
Rest syndrome
Sporadic de novo mutations of the MECP2 gene on the X chromosome
- almost exclusively seen in females (males 95% of the time die in uterus if they have this)
Symptoms
- manifest around 1-4 yrs old
- regressing (RETTurn) in: motor, verbal, cognition controls
- ataxia
- seizures
- growth failure
- hand wringing sporadically
Fragile X syndrome
most common inherited cause of mental retardation (misnomer is down-syndrome but this is most common GENETIC disorder, not inheritance)
X-linked dominant disorder which produces a CGG trinucleotide expansion in the FMR1 gene which leads to hypermethylation of the gene and ultimately little expression
Symptoms:
- post-pubertal macroochidism (enlarged testicles)
- long face with large jaw
- large exerted ears
- autism
- MVP (chronic usually and seen later in life)
- hypermobile joints
What are the 4 most common trinucleotide repeat expansion diseases?
Huntington’s disease:
- CAG repeat
- autosomal dominant disorder
Myotonic dystrophy:
- CTG repeat
- autosomal dominant disorder
Fragile X syndrome
- CGG repeat
- X-linked dominant disorder
Friedreich ataxia
- GAA repeat
- Autosomal recessive disorder
“ Tri hunting for my fragile cage-fried eggX “
What are the three most clinically relevant autosomal trisomies?
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Palau syndrome (trisomy 13)
Down syndrome
- most common genetic cause of mental retardation*
A genetic disorder that can be inherited or sporadically caused. Produces a trisomy allele on chromosome 21.
- 95% of cases are due to meiosis nondisjunction ( failure of a chromosome paire to separate while undergoing formation
- 4% of cases are due to unbalanced robertsonian translocation between chromosome 14:21
- incidence rates exponentially get larger the older the mother is and if the mother is an alcoholic during pregnancy*
Symptoms
- intellectual disability
- flat facies
- prominent epicanthal folds
- singular palmar crease w/ incurved 5th finger
- duodenal atresia (abnormal narrowing of the duodenum)
- increased chances of Atrioventricual septal defects
- increased chances of early onset Alzheimer’s disease
- increased risk of AML/ALL
5A’s of Down syndrome
- Adavnced maternal age
- Atresia (duodenum)
- Atrioventricular septal defects
- Alzheimer’s disease early onset
- AML/ALL susceptibility
“Drinking age is 21”
Edwards syndrome
A genetic disorder that is sporadically induced. Causes a trisomy in chromosome 18
- usually kills around age 1
Symptoms: “PRINCE-Edward”
Prominent occiput
Rocker-bottom feet (talus is vertical causing feet to look like rocking chair feet)
Intellectual disability
Nondisjunction
Clenched fists produce overlapping fingers
Ears are low-set
- also (+/-) omphalocele and/or myelomeningocele
- (+/-) congenital heart disease
“Election age is 18” (E is for Edwards)
Patau syndrome
A genetic disorder that is sporadically induced. Causes a trisomy in chromosome 13
- usually kills around age 1
- also often produces a defect in fusion of the perch or dial mesoderm (results in diffuse midline defects)
Symptoms
- cleft lip/palate
- cutis aplasia (spot on scalp that is missing skin/bone)
- polycystic kidney disease
- polydactyly (6 or more fingers on a hand)
Genetic markers testing at 1st and 2nd trimester to differentiate between down/Edwards and patau syndromes
1st trimester:
- Down syndrome = increased B-hcG and decreased PAPP-A
- both Edwards and patau show decreases in B-hcG and PAPP-A
2nd trimester
- Down syndrome = increased B-hcG and decreased AFP
- Edwards syndrome = decreased estriol, AFP and B-hcG
- Patau syndrome = normal across the board
Robertsonian translocation
Chromsomal translation most commonly seen between paired chromosomes 21,22,13,14,15
Occurs when the long arms of the 2 paired chromosomes fuse at centromeres and results in loss of short arms of the paired chromosomes
- can lose 1 arm (deadly) or two arms (less deadly and usually benign)
Cri-du-chat syndrome
“Cry of the cat”
Congenital deletion of the short arm on chromosome 5
Symptoms:
- Microcephaly
- intellectual disability
- *high-pitched crying/meowing spontaneously
- prominent epicanthal folds
- ventricular septal defects
Williams syndrome
Congenital micro deletion of the long arm of chromosome 7
includes the elastin gene
Symptoms:
- elf-like facies
- intellectual disabilities
- hypercalcemia
- well-beyond normal aged verbal skills
- extreme friendliness with strangers
- cardiac abnormalities and artery stenosis
“Will Ferrell in Elf”
