Quiz 5 Flashcards
SNV
single nucleotide variant
SNP
single nucleotide polymorphism
VUS
variation of unknown significance
pathogenic variation
mutation
microsatellites
di and trinucleotide repeats important in gene mapping and pathogenesis - sometimes can result in disruption of txn, tln, or protein function
somatic vs germline variant
SOMATIC: mutation occured AFTER fertilization so not in all cells in the body, can be tissue or organ specific
GERMLINE: mutation occurred before fertilization so generally in every cell in body incl. spermatocytes and ooctyes
recessive inheritance usually leads to
loss of function when get an inherited copy from BOTH parents. half normal abundance is adequate in carrier state
gaucher’s disease is an example of
autosomal recessive inheritance (anemia, growth retardation, moderate to sever hepatomegaly, moderate to severe splenomegaly)
what causes gaucher’s
glucocerobroside usually broken down by glucocerebrosidase into glucose and ceramide. in gaucher’s get a build up.
how can you do an enzyme activity assay
4MU+substrate catalyzed by a specific enzyme to seperate these - concentration of protein alone is proportional to enzyme activity
dominant inheritance results in
gain of function or loss of function
what are subtypes of loss of function
haploinsufficiency: one copy of the gene is enough (this is opposite of dominant)
dominant negative: one copy of gene messes up all the others (collagen)
when do you get male to male transmission
dominant inheritance
x linked inheritance results in
gain of function, loss of function (dominant negative)
who is affected in x linked inheritance
females less affected, no male to male transmission
allelic heterogeneity
different variations in one gene can have different effects on phenotype
what happens in bone if FGFR3 is constitutively activated
get molecular signaling at growth plate
achondroplasia (inheritance and mutation)
AD inheritance
Mutation causes constitutive activation of FGFR3
hypochondroplasia (inheritance and mutation)
AD inheritance, mutation also causes activation of FGFR3 but to a lesser extent so phenotype is less affected
thanatophoric dysplasia (inheritance and mutation)
AD inheritance, mutation also causes activation of FGFR3 but usually not compatible with life
genetic or locus heterogeneity
mutations in different genes can cause a similar phenotype (EX: many genes affect primary cilia!)
bardet biedl syndrom inheritance and mutation
Autosomal recessive and associated with multiple genes involved in the primary cilia
bardet biedl syndrome clinical features
obesity, retinal rod/cone disease, renal disease, plydactyly and brachydactyly, abnormal genitalia, low fertility
why is the primary cilia important
required for the cell to receive signal and stimuli (hormones, chemokines, growth factors). Important in Wnt and SHH pathways
triplet repeat expansions
expansion of a simple sequence repeat
disease caused by simple sequence repeats
huntingtons (polyQ) - expansion predominantly in males
clinical features huntingtons
progressive movement disorder, dementia, seizures, atrophy of caudate nucleus
penetrance options
complete (mutation = disease) incomplete (skips generations) age related (symptom onset with age)
anticipation
increased severity in later generations (ex huntingtons where expansion will continue)
what is neurofibromatosis caused by
mutation of NF1 gene
neurofibromatsosis inheritance
AD, 100 % penetrant
clinical features neurofibromatosis
neurofibromas, cafe au lait spots, freckles, bony lesions, optic glioma
what does NF1 regulate
RAS signaling. In neurofibromatosis, lose NF1 signaling with increases RAS signaling
pleiotropy
gene affects many different tissues
how do you get somatic mosaicisms
fertilized zygote doesn’t carry mutation, happens spontaneously in one spot and remains clustered
proteus syndrome
AKT1 mutation. segmented - only affects specific parts of the body
germline mosaicism
germ cell progenitor cells carry mutation, cause risk of recurrence in family
what happens with mutations in conserved intron splice donor/acceptor sites
misspliced transcripts
ESE
exonic splice enhancer
what do mutations in ESE cause
missplicing
anticipation
increased disease severity manifesting as earlier age of onset in succeeding generations
pleiotropy
one gene influences multiple, seemingly unrelated phenotypic traits.
how many newborns have major anomalies
2-3%
how many newborns have minor anomalies
15%
death percentages attributed to anomalies
20-30% infant deaths
30-50% deaths of neonatal period
deformation
developmental process is normal but mechanical force alters structure
ex: external forces: oligohydramnios (not enough amniotic fluid) can be secondary to renal hypoplasia
ex of deformations
Potter’s Facies
Clubbed Feet
disruption
developmental process is NORMAL but interrupted
examples and causes of disruption
vascular accident - amniotic band sequence or fetal cocaine exposure, porencephaly
malformation
morphological, macroscopic defect from an INTRINSICALLY abnormal developmental process
ex of malformation
holoprosencephaly, congenital heart disease, neural tube defect, unilateral cleft lip and palate
dysplasia
abnormal microscopic tissue organization and development
ex of dysplasia
skeletal or connective tissue dysplasia, ectodermal dysplasias
sequence
a series of congenital anomalies derived from a single anomaly - can be part of a syndrome or an isolated event
ex of sequence
pierre robin sequence
sydnrome
a recognizable pattern of anomalies presumed to be causally related, and NOT a sequence
associations
a group of congenital anomalies that co-occur more frequently than expected by chance. these are of unknown etiology.
FAS
fetal alcohol syndrome caused by the fetus being exposed to alcohol
teratogen
exposure during pregnancy that has a harmful effect on the developing fetus
ex of teratogens
maternal phenylketonuria (PKU), maternal diabetes, TORCH infections, anticonvulsants, retinoic acid embryopathy
what is more common, cleft lip and palate or cleft lip alone
CLP more common, more frequent in mailes
what causes Van Der Woude
AD dominant mutations in interferon regulatory factor IRF6 - lip pits and cleft lip, palate
IRF6 mutation
Van der Woude (lip pits, CLP CLA)
what typically causes developmental disorders
txn factors (25-35%)
enzymes (19%)
structural proteins (18%)
receptors (9%)
what is homeobox (HOX) involved in
patterining (anterior, posterior, head, tail)
unmethylated genes are usually (active vs inactive)
active
methylated genes are usually
repressed
MOST CpG dinucleotides are
methylated (repressed)
anhidrotic ectodermal dysplasia in heterozygous woman caused by
mutation in EDA gene
praeder willi and angelman syndrome are caused by
mutation in proximal chr15 - same mutation with different outcomes depending on maternal/paternal because imprinted
agouti encodes for
yellow pigment hair color gene
what does normal agouti expression give
brown coat (yellow coat is when agouti is turned ON and you also get tumors)
insulin like growth factor affected by
reduced methylation at promoter in individuals who conceived during the famine
x chromosome modification is a mechanism of
dosage compensation
pharmacogenetics
study of drug response in relation to genetic variation in specific candidate genes
pharmacogenomics
study of drug response in relation to genetic variation in the entire genome
pharmocokinetics implications (PK)
ADME A: Absorption D: Distribution M: Metabolism E: Elimination
pharmacodynamics (PD) implications
receptor interactions ion channel interactions enzyme interactions signaling pathway interactions immune system interactions
what genes are responsible for metabolism of a lot of medications
P450 (CYP2C9, CYP2C19, CYP2D6)
what are CYP450s
a large diverse superfamily of hemoproteins that catalyze hydroxylation and other metabolic reactions. MAJOR ENZYMES involved in drug metabolism and bioactivation
what gene metabolies 20-25% of all medications
CYP2D6
what is VKORC1 associated with
warfarin dose requirements
what is warfarin used for
widely used anticoagulant for prevention of thrombosis and embolism
what is the mechanism of warfarin
impairs synthesis of vitamin K dependent clotting factors
why is use of warfarin complicated clinically
wide individual differences in drug response, narrow therapeutic range, high risk of bleeding or stroke
LOOK AT WARFARIN PATHWAY
?
what is warfarin’s target
VKORC1 which is important in vitamin K reduction cycle and is necessary for clotting factors to become carboxylated so they can continue in clotting cascade
what is a common tx for patients with acute coronary syndromes or undergoing percutaneous interventions
clopidogrel (plavix) and aspirin
variable response in plavix (clopidogrel) due to PK and PD
PK: metabolites
PD: ex vivo platelet aggregation
LOOK AT CLOPIDOGREL (PLAVIX PATHWAY
?
where are plavix and warfarin absorbed and metabolized
absorbed in intestine, metabolized in the liver
what kind of drug is plavix
pro drug because P450 activation steps are what generates the metabolite. THEN it can travel to platelets and bind irreversibly
what gene is involved in active AND inactive pathway in plavix
CYP2C19
what is the issue with *2 carriers in plavix tx
they do not get anticoagulation effects - these individuals have increased risk of death from cardiovascular causes, MI, or stroke compared to non carriers
karyotype
arranging chromosomes into pairs
protein coding genes comprise what percentage of DNA
1.5%
conserved region of DNA through evolution
2-5%, suggests functionality. Many probably regulatory elements
why would there be a specific area of the genome where there aren’t many mutations
because some areas end up in very unregulated development if mutated so wouldnt get passed down (ex: HOX)
microarray
fluorescently labeled DNA is hybridized to an array of probes on a glass slide that bind either normal or variant DNA
microarray comparative genomic hybridization
use control and test DNA - two different fluorescent dyes but hybridize them together on same slide
why can DNA polymerase get confused at tandem repeat areas
because these dinucleotide repeats can form a strong secondary structure
fragile X
get over 200 repeats (50 is max normal) of CGG near FMR1 gene on ChrX. DNA polymerase has trouble replicating here so get pinched off area where genes aren’t being transcibed
salivary amylase
large tandem repeat area that contains entire gene
CCL3L1
copy number inversely correlates with susceptibility to HIV infection
allele frequence
proportion of CHROMOSOMES in a population carrying a particular allele at some locus
genotype frequency
proportion of individuals in a population with a particular genotype at some locus
in HW equilibirum
A,a
P
Q
A,a: alleles at a single locus
p: relative frequency of A
q: relative frequency of a
P+Q=1
things to consider for HW equilibirum
It takes into consideration that population is indefinitely large or large enough to neglect errors, mating in population occurs at random, there is no advantage for any genotype, no migration and new mutations.
HW law
p^2 + 2pq + q^2=1
P+Q = 1
All allelic frequencies will remain constant over time if certain conditions are met
what causes derivation from HWE expected frequencies
Genotyping Errors Selection Genetic Drift Non-random Mating Population Structure
deleterious mutations
mutations that increase
mortality or reduce fertility [dominant ones – cannot
escape selection upon first appearance; recessive ones –
can accumulate in a population].
does genetic drift produce adaptations
NO - completely random. Some individuals will just by chance leave behind a few more descendents.
founder effect
population descended from a few colonists - can have higher proportion of disease in these populations
non random mating due to
mate selection and inbreeding (mates selected from within own communities which results in positive assortative effects on their gene pool)
non random mating (inbreeding) can cause evolution of
subpopulations
HWE issues
assumes sample came from single population, actually may be from 2+ with different allele frequencies. Usually has higher than expected homozygosity and sometimes has false positive associations.
what can happen if cases and controls are not well matched ancestrally
any allele more common in population with increased risk of disease may appear to be associated with that disease, even if it isnt
AIM
ancestry informative markers. set of polymorphisms which exhibit substantially difference frequencies between populations from different geographical regions.
linkage disequilibrium (LD) description
non random association of alleles at two or more loci
D and r^2 in LD
D’ varies from 0 (complete equilibrium) to 1 (complete disequilibrium) *DOES NOT ADEQUATELY ACCOUNT FOR ALLELE FREQUENCIES.
r^2 is correlation between SNPs, preferred measure.
D and r^2 = 0
typing one SNP provides no info on other
D or r^2 >0.8
two SNPs are in LD - typing one provides information on others
what will have more linkage equilibriums, new or old populations>
new, isolated populations
what does array CGH provide
genome wide view of copy number variations
what can array CGH not tell us
cannot detect chromosomal abnormalities that maintain normal copy numbers (balanced translocation, inversion) OR data on repeat rich regions such as centromeres and heterochromatin
what is FISH useful for
deletion or duplication of genomic regions too small to be detected by karyotype analysis
