Quiz 5 Flashcards
(126 cards)
1
Q
SNV
A
single nucleotide variant
2
Q
SNP
A
single nucleotide polymorphism
3
Q
VUS
A
variation of unknown significance
4
Q
pathogenic variation
A
mutation
5
Q
microsatellites
A
di and trinucleotide repeats important in gene mapping and pathogenesis - sometimes can result in disruption of txn, tln, or protein function
6
Q
somatic vs germline variant
A
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
7
Q
recessive inheritance usually leads to
A
loss of function when get an inherited copy from BOTH parents. half normal abundance is adequate in carrier state
8
Q
gaucher’s disease is an example of
A
autosomal recessive inheritance (anemia, growth retardation, moderate to sever hepatomegaly, moderate to severe splenomegaly)
9
Q
what causes gaucher’s
A
glucocerobroside usually broken down by glucocerebrosidase into glucose and ceramide. in gaucher’s get a build up.
10
Q
how can you do an enzyme activity assay
A
4MU+substrate catalyzed by a specific enzyme to seperate these - concentration of protein alone is proportional to enzyme activity
11
Q
dominant inheritance results in
A
gain of function or loss of function
12
Q
what are subtypes of loss of function
A
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)
13
Q
when do you get male to male transmission
A
dominant inheritance
14
Q
x linked inheritance results in
A
gain of function, loss of function (dominant negative)
15
Q
who is affected in x linked inheritance
A
females less affected, no male to male transmission
16
Q
allelic heterogeneity
A
different variations in one gene can have different effects on phenotype
17
Q
what happens in bone if FGFR3 is constitutively activated
A
get molecular signaling at growth plate
18
Q
achondroplasia (inheritance and mutation)
A
AD inheritance
Mutation causes constitutive activation of FGFR3
19
Q
hypochondroplasia (inheritance and mutation)
A
AD inheritance, mutation also causes activation of FGFR3 but to a lesser extent so phenotype is less affected
20
Q
thanatophoric dysplasia (inheritance and mutation)
A
AD inheritance, mutation also causes activation of FGFR3 but usually not compatible with life
21
Q
genetic or locus heterogeneity
A
mutations in different genes can cause a similar phenotype (EX: many genes affect primary cilia!)
22
Q
bardet biedl syndrom inheritance and mutation
A
Autosomal recessive and associated with multiple genes involved in the primary cilia
23
Q
bardet biedl syndrome clinical features
A
obesity, retinal rod/cone disease, renal disease, plydactyly and brachydactyly, abnormal genitalia, low fertility
24
Q
why is the primary cilia important
A
required for the cell to receive signal and stimuli (hormones, chemokines, growth factors). Important in Wnt and SHH pathways
25
triplet repeat expansions
expansion of a simple sequence repeat
26
disease caused by simple sequence repeats
huntingtons (polyQ) - expansion predominantly in males
27
clinical features huntingtons
progressive movement disorder, dementia, seizures, atrophy of caudate nucleus
28
penetrance options
```
complete (mutation = disease)
incomplete (skips generations)
age related (symptom onset with age)
```
29
anticipation
increased severity in later generations (ex huntingtons where expansion will continue)
30
what is neurofibromatosis caused by
mutation of NF1 gene
31
neurofibromatsosis inheritance
AD, 100 % penetrant
32
clinical features neurofibromatosis
neurofibromas, cafe au lait spots, freckles, bony lesions, optic glioma
33
what does NF1 regulate
RAS signaling. In neurofibromatosis, lose NF1 signaling with increases RAS signaling
34
pleiotropy
gene affects many different tissues
35
how do you get somatic mosaicisms
fertilized zygote doesn't carry mutation, happens spontaneously in one spot and remains clustered
36
proteus syndrome
AKT1 mutation. segmented - only affects specific parts of the body
37
germline mosaicism
germ cell progenitor cells carry mutation, cause risk of recurrence in family
38
what happens with mutations in conserved intron splice donor/acceptor sites
misspliced transcripts
39
ESE
exonic splice enhancer
40
what do mutations in ESE cause
missplicing
41
anticipation
increased disease severity manifesting as earlier age of onset in succeeding generations
42
pleiotropy
one gene influences multiple, seemingly unrelated phenotypic traits.
43
how many newborns have major anomalies
2-3%
44
how many newborns have minor anomalies
15%
45
death percentages attributed to anomalies
20-30% infant deaths
| 30-50% deaths of neonatal period
46
deformation
developmental process is normal but mechanical force alters structure
ex: external forces: oligohydramnios (not enough amniotic fluid) can be secondary to renal hypoplasia
47
ex of deformations
Potter's Facies
| Clubbed Feet
48
disruption
developmental process is NORMAL but interrupted
49
examples and causes of disruption
vascular accident - amniotic band sequence or fetal cocaine exposure, porencephaly
50
malformation
morphological, macroscopic defect from an INTRINSICALLY abnormal developmental process
51
ex of malformation
holoprosencephaly, congenital heart disease, neural tube defect, unilateral cleft lip and palate
52
dysplasia
abnormal microscopic tissue organization and development
53
ex of dysplasia
skeletal or connective tissue dysplasia, ectodermal dysplasias
54
sequence
a series of congenital anomalies derived from a single anomaly - can be part of a syndrome or an isolated event
55
ex of sequence
pierre robin sequence
56
sydnrome
a recognizable pattern of anomalies presumed to be causally related, and NOT a sequence
57
associations
a group of congenital anomalies that co-occur more frequently than expected by chance. these are of unknown etiology.
58
FAS
fetal alcohol syndrome caused by the fetus being exposed to alcohol
59
teratogen
exposure during pregnancy that has a harmful effect on the developing fetus
60
ex of teratogens
maternal phenylketonuria (PKU), maternal diabetes, TORCH infections, anticonvulsants, retinoic acid embryopathy
61
what is more common, cleft lip and palate or cleft lip alone
CLP more common, more frequent in mailes
62
what causes Van Der Woude
AD dominant mutations in interferon regulatory factor IRF6 - lip pits and cleft lip, palate
63
IRF6 mutation
Van der Woude (lip pits, CLP CLA)
64
what typically causes developmental disorders
txn factors (25-35%)
enzymes (19%)
structural proteins (18%)
receptors (9%)
65
what is homeobox (HOX) involved in
patterining (anterior, posterior, head, tail)
66
unmethylated genes are usually (active vs inactive)
active
67
methylated genes are usually
repressed
68
MOST CpG dinucleotides are
methylated (repressed)
69
anhidrotic ectodermal dysplasia in heterozygous woman caused by
mutation in EDA gene
70
praeder willi and angelman syndrome are caused by
mutation in proximal chr15 - same mutation with different outcomes depending on maternal/paternal because imprinted
71
agouti encodes for
yellow pigment hair color gene
72
what does normal agouti expression give
brown coat (yellow coat is when agouti is turned ON and you also get tumors)
73
insulin like growth factor affected by
reduced methylation at promoter in individuals who conceived during the famine
74
x chromosome modification is a mechanism of
dosage compensation
75
pharmacogenetics
study of drug response in relation to genetic variation in specific candidate genes
76
pharmacogenomics
study of drug response in relation to genetic variation in the entire genome
77
pharmocokinetics implications (PK)
```
ADME
A: Absorption
D: Distribution
M: Metabolism
E: Elimination
```
78
pharmacodynamics (PD) implications
```
receptor interactions
ion channel interactions
enzyme interactions
signaling pathway interactions
immune system interactions
```
79
what genes are responsible for metabolism of a lot of medications
P450 (CYP2C9, CYP2C19, CYP2D6)
80
what are CYP450s
a large diverse superfamily of hemoproteins that catalyze hydroxylation and other metabolic reactions. MAJOR ENZYMES involved in drug metabolism and bioactivation
81
what gene metabolies 20-25% of all medications
CYP2D6
82
what is VKORC1 associated with
warfarin dose requirements
83
what is warfarin used for
widely used anticoagulant for prevention of thrombosis and embolism
84
what is the mechanism of warfarin
impairs synthesis of vitamin K dependent clotting factors
85
why is use of warfarin complicated clinically
wide individual differences in drug response, narrow therapeutic range, high risk of bleeding or stroke
86
LOOK AT WARFARIN PATHWAY
?
87
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
88
what is a common tx for patients with acute coronary syndromes or undergoing percutaneous interventions
clopidogrel (plavix) and aspirin
89
variable response in plavix (clopidogrel) due to PK and PD
PK: metabolites
PD: ex vivo platelet aggregation
90
LOOK AT CLOPIDOGREL (PLAVIX PATHWAY
?
91
where are plavix and warfarin absorbed and metabolized
absorbed in intestine, metabolized in the liver
92
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
93
what gene is involved in active AND inactive pathway in plavix
CYP2C19
94
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
95
karyotype
arranging chromosomes into pairs
96
protein coding genes comprise what percentage of DNA
1.5%
97
conserved region of DNA through evolution
2-5%, suggests functionality. Many probably regulatory elements
98
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)
99
microarray
fluorescently labeled DNA is hybridized to an array of probes on a glass slide that bind either normal or variant DNA
100
microarray comparative genomic hybridization
use control and test DNA - two different fluorescent dyes but hybridize them together on same slide
101
why can DNA polymerase get confused at tandem repeat areas
because these dinucleotide repeats can form a strong secondary structure
102
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
103
salivary amylase
large tandem repeat area that contains entire gene
104
CCL3L1
copy number inversely correlates with susceptibility to HIV infection
105
allele frequence
proportion of CHROMOSOMES in a population carrying a particular allele at some locus
106
genotype frequency
proportion of individuals in a population with a particular genotype at some locus
107
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
108
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.
109
HW law
p^2 + 2pq + q^2=1
P+Q = 1
All allelic frequencies will remain constant over time if certain conditions are met
110
what causes derivation from HWE expected frequencies
```
Genotyping Errors
Selection
Genetic Drift
Non-random Mating
Population Structure
```
111
deleterious mutations
mutations that increase
mortality or reduce fertility [dominant ones – cannot
escape selection upon first appearance; recessive ones –
can accumulate in a population].
112
does genetic drift produce adaptations
NO - completely random. Some individuals will just by chance leave behind a few more descendents.
113
founder effect
population descended from a few colonists - can have higher proportion of disease in these populations
114
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)
115
non random mating (inbreeding) can cause evolution of
subpopulations
116
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.
117
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
118
AIM
ancestry informative markers. set of polymorphisms which exhibit substantially difference frequencies between populations from different geographical regions.
119
linkage disequilibrium (LD) description
non random association of alleles at two or more loci
120
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.
121
D and r^2 = 0
typing one SNP provides no info on other
122
D or r^2 >0.8
two SNPs are in LD - typing one provides information on others
123
what will have more linkage equilibriums, new or old populations>
new, isolated populations
124
what does array CGH provide
genome wide view of copy number variations
125
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
126
what is FISH useful for
deletion or duplication of genomic regions too small to be detected by karyotype analysis
