Week 7- Cormeir Flashcards
Penetrance
probability that a mutant gene will have a phenotypic epxression
Reduce penetrance
when people with the mutant gene don’t always show the disease phenotype
Expressivity
the severity of expression of phenotype among individuals witht he same disease causing genotype
Variable Expressivity
when the severity of the disease differs in people who have the same genotype
NF1
Neurofibromatosis
Autosomal dominant
Nervous system disease
100% penetrance (mutant always shows some phenotype)
Variable expressivity (some phenotypes are worse than others, nodules vs. tumors)- due to different mutations in the NF1 gene
Allelic heterogeneity
mutations are along a continum of severity, depending on which mutation you have determines the severity of the phenoytpe (example is CF and PKU)
Common in compound heterozygotes (particular combination of mutant alleles can have large impact on severity)
Locus Heterogeneity
same phenotypes are caused by mutations in DIFFERENT GENES (ex: rentinis pigmentosa)
Sex influenced autosomal recessive disorders
-autosomal recessive
-both sexes develop the disease, one sex has a significantly higher frequency (trait seen MORE in one sex than the other)
Ex: hemochromatosis
Sex-limited phenotypes
- autosomal dominant
- trait is seen ONLY in one sex, required direct evidence of father-son transmission or mapping of causative genes to an autosome (to distinguish from X-linked)
CFTR
- Cysitic fibrosis gene
- autosomal recessive
- Show allelic heterogeneity, mutations can be ordered along a continuum of severity.
- DNA analysis, shows most common mutation is delta f 508
PKU
- Phenylalanineketonuria
- mutations in phenylalanine hydroxylase gene
- example of allelic heterogeneity
- different alleles of PAH caused by different mutations, result in varying severity
hyperphenylalanemias
(includes PKU) -example of locus heterogeneity
-mutations in 5 different genes can cause hyperphenylalaninemias
Retinitis pigmentosa
example of locus heterogeneity
-70 genetic diseases causes retinitis pigmentosa
phenotypic heterogeneity
when mutations in the same gene cause completely different diseases
Ex: RET gene that encodes tyrosine kinase (one mutation will cause hirschsprung disease, another causes inherited cancer of the thryoid and adrenal glands)
Hemochromatosis
- iron metabolism disorder,
- ex of sex influenced autosomal recessive
- most often seen in men (reduced penetrance)
Tay-Sachs
lysosomal storage disease, fatal in early childhoood.
- Example of inbreeding (consanguinity at population level) due to cultural /geo/ religious isolation
- most common in Asheknasi jews
- biochemical abnormality in carrier, increase in
Achondroplasia
Incomplete dominant skeletal disorder (short-limbed dwarf with big head)
Example: homozygotes tend to show a more severe pheotype, example of increased function
incomplete dominance
disease is more sever in homozygotes
codominance
two different alleles are expressed together. (ABO blood groups)
hemophilia A
X-linked recessive disorder caused by mutations in the coagulation factor VIII gene
X-inactivation
one pair of X chromosomes is randomly inactivated in each somatic cell.
- equalizes gene dosage
- roughly half of the cells in a tissue in females the wild type will be expressed = mosaicism
Duchennes Muscular Dystrophy (MDM)
x-linked recessive, women show mosaicism, can be detected with immunostaining.
- new mutations occur, because males often die before they can reproduce (strong selective pressure against disease gene but still happens)
- Serum creatine kinase levels increases in female gene carriers
manifesting heterozygotes
female heterozygotes for an X-linked recessive disease demonstrate a disease phenotype
Rett Sydrome
X-linked dominant with male lethality, neurosymptoms in female hterozygous children. Hemizygosity in males results in prenatal lethyality
Male-limited precocious puberty
sex limited autosomal dominant, mutaiton in luteinizing hormone receptor that causes puberty at very early age
RFLP
restriction fragment length polymorphism
- allelic variant that abolishes or generates a restriction endonuclease recognition site or changes the size of an RFLP (insertion or deletion)
- *RE are methylation-sensitive so restriction enzyme site can be lost due to hypermethylation
haplotype
combination of alleles, loci, or markers on the same chromosome. (commonly refers to groups of nearby alleles that are inherited together)
Prader Willi
- Maternally imprinted
- Random mutation in paternal chromosome causes PW disease (however would not get Angelman because that is paternally imprinted)
Angelman Syndrome
- paternally imprinted
- random mutation in maternal chromosomes causes angelmans disease, however you would not get prader willi (because this is maternally imprinted)
BCR-ABL
- Philadelphia chromosme in chronic myelogenous leukemia (CML)
- B cell receptor, abelson tyrosine kinase
- 9:22 translocation
- amplifys oncogene
- gene fusion
- example of chromosomal instability
- CML can be treated with Gleevec that blocks the ATP binding site of BCR-ABL protein
Downs Syndrome
KNOW LABS
- trisomy 21 (aneuploidy)
- 5 miRNAs overexpressed
- increase rate in women of 45
- LABS in maternal serum: increased= BHCG and inhibin A
- increased gene dosage
alpha1- antitrypsin (alpha-AT)
-example of ecogenetics (genetic variation that lead to susceptibility of environmental agents)
serum protein that inhibits leukocyte elastase
-Leukocyte elastase can damage lung if not down-regulated
-5 aelles differ in amount of protein
-people with ZZ genotype make 15% of normal protein
-kills of smokers quicker if you have ZZ
Heterozygous advantage
deleterious allele that is maintained in a population because when heterozygous it increased reproductive fitness
- B-globin locus- sickle cell trait
- B-s homozgous = sickle cell anemia
- novel function
mitochondrial disease
affected fathers cannot pass on!!!
Linkage equilbrium and disequilibrium
equilibrium- when frequency of biomarker is associated equally with both alleles A and a
disquilibrium- when frequncies of disease is associated more with one of the biomarker alleles
Sib-Pair Analysis
identical by state- # of alleles that are the same between siblings
identical by descent- # of alleles shared allleles that came from the same parent
Example- Hirschsprung disease is indetical by descent
Cancer stem cell hypothesis
subpopulation of CSC that allows for residual growth and repopulation after all the differentiated cells have been killed by surgery/ chemotherapy
- clincally shows why some recurrs
- drugs designed to kill proliferatied cells would not be able to kill CSC because CSC use Wnt/catenin pathway that is not targeted by drugs
Clonal evolution hypothesis
every tumor cell is equally capable of initiating neoplastic growth- genetic and epigenetic changes occur over time in individual cancer cell that allow selective advantage
Sporadic vs. Inherited cancer
sporadic - required 2 mutations
inherited - only requires 1 mutation (ex. retinoblastoma gene)
Genomic instability
Microinstability vs. Chromosomal instability (examples)
Microinstability - defects in mismatch repair or nuclear excision repair (MLH1 most common in mismatch repair, see early onset of cancers, colon cancer!)
Chromosomal instability- defects in genes that control chromatin condensation, chromatid seperation and mitotic events. (BCR-ABL translocation between chromosome 9 and 22 = CML)
Colon cancer
APC mutation in CRC is classic tumor suppressor gene.
APC regulates cellular level of beta-catenin –> loss of APC results in uncontrolled activation of beta-catenin that drives cell cycle forward.
** requires multile mutations in sequential steps: APC-dependent cancers must loose APC first
3 complications to treating monogenic disorders
- gene may not have been identified
- fetal damage may occur prior to diagnosis
- more severe clinical phenotypes are less amenable to intervention
Retrovirus (+ and -)
limitations: only transduces dividing cells, intergretation might cause oncogenesis
Advantage: persistent gene transfer in dividing cells
Lentivirus (+ and -)
Limitations: may cause oncogenesis (can revert back to HIV)
Advantages: persistent gene transfer in most tissues
HSV-1 (+ and -)
Limitations: inflammatory, usually only expresses in neurons
Advantages: large packaging capacity, strong tropism for neurons
AAV (+ and -)
Limits: small packaging capacity
Advantages: non-inflammatory, non pathogenic, can infect dividing and non-dividing cells
**now preferred viral vector for clinical trials
Adenovirus (+ and -)
Limits: large inflammatory response, doesn’t integrate into genome so expression is transient
Advantage: very good at infecting most tissues, high titres, high efficiency of infection, can accommodate large genes (p53, Rb)
Non-viral vectors (+ and -)
advantages: lack biological risk, potential is unlimited
disadvantages: not very successful, DNA tends to get degraded in lysosomes and not translocated to the nucleus
Gaucher Disease
lysosomal storage disease = successful treatment with protein treatment
cytotoxic
kils rapidly dividing cells
