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path (genetics) exam 2 Flashcards

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1
Q

SNPs are found in…

A

non-coding regions

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2
Q

what are SNPs?

A

single NT change in DNA seq between individuals

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3
Q

what are the mutations of different parts of the gene?

A

promotor = prevents transcription factors from binding, leads to preventing of transcription and translation
exon = mutation in translation of a protein
5’ UTR = causes mutation in RNA (if the mutation makes an ATG, translation will begin early and make an abnormal protein)

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4
Q

explain transcription

A

RNA poly II will transcribe RNA from template strand
5’ capping, 3’ poly A tail, and splicing
then strand is exported from nucleus to cytoplasm for translation on ribosome

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5
Q

what are the types of RNA poly?

A

I - rRNAs
II - mRNAs and snRNA
III - tRNA and 5S rRNA

RooMmaTe

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6
Q

what is significant about RNA poly II?

A

it is strongly inhibited by alpha-amanitin

poly III is only inhibited by high concentrations

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7
Q

what is the dominant-negative effect?

A

when a mutated allele produces an abnormal/mishapen protein that affects the function of another protein or its own

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8
Q

what are the functions of the different DNA pols?

A

alpha = primers
delta = extending the lagging strand
Epsilon = extending lEading strand

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9
Q

what is the nomenclature for DNA, RNA, and proteins?

A

DNA + RNA –> position of mutation, then what kind of mutation it is

protein = capital letter of protein then location and alteration

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10
Q

what is the nomenclature for introns and exons?

A

intron - list the last NT of exon before donor site, + with number of NT, and alteration
ex: 1614+1 G>C

exon - list first NT after the acceptor site, - with NT in intron BEFORE EXON, and alteration
ex: 1690-2 A>C

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11
Q

mutation rate increases with…

A

paternal age

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12
Q

what is phenotypic heterogeneity?

A

mutations in same gene can cause differnt diseases

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13
Q

what is allelic heterogeneity?

A

one gene, multiple mutations

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14
Q

what is locus heterogeneity?

A

more than one gene on different chromosomes or chromosomal locations

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15
Q

The achondroplasia mutation in FGFR3 is unique in that…

A

it is a gain of function mutation that activates the FGF receptor early, leading the premature limitation of bone proliferation –> achondroplasia

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16
Q

what is heteroplasmy and homoplasmy?

A

heteroplasmy = mix of two or more types of mtDNA in a cell

homoplasmy = mtDNA molecules have the same seq, either normal or mutant

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17
Q

what is the difference between leigh and alpers syndrome?

A

leigh is MTDNA
alpers is NUCLEAR DNA

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18
Q

rett syndrome in ______ is lethal

A

males

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19
Q

what are the types of repeat sequences?

A

true satellite = 14-500 bp, 20-100 kb repeats
minisatellite = 15-100 bp, 1-5 kb repeats
microsatellite = 1-13 bp, 150 times repeats

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20
Q

microsatellite DNA is thought to origina from…

A

backward slippage of growing daughter strand on its template strand during DNA replication

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21
Q

where are the repeats located for triplet repeat diseases?

A

HTD - coding
Fragile X - 5’ UTR, LOF
Myotonic dystrophy I - 3’ UTR
Friedreich ataxia - intron
Myotonic dystrophy II - intron

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22
Q

what is uniparental disomy?

A

inheritance of two copies of a full chromosome from one parent

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23
Q

what are the types of nucleic acid hybridization?

A

southern - DNA-DNA
dot - DNA-DNA
northern - RNA-DNA
western - protein-antibody

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24
Q

a SINGLE bp difference in recognition seq will…

A

prevent enzyme from cutting DNA

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25
which types of hybridizations require probes?
southern and northern blots
26
what is the function of ddNT?
terminates a chain randomly
27
what are the next gene results complications?
actionable variants = clear clinical significance that can be observed i nmany other cases variants of unclear significance = unclead clinical significance and never observed before, do not disrupt a gene with a clear functional involve in the disease incidental findings = when you are looking for a gene defect in one disease but end up finding a defect for another
28
which hybridization test uses REs?
Southern blot
29
Describe the process of southern blotting
DNA is first separated by gel electrophoresis DNA is large and must be first digested into smaller fragments with restriction enzymes (RE). The RE will cut the DNA into pieces ranging from very small <100bp to large >50KB. The DNA is loaded onto a gel and fragments are separated by size. To separate the fragments, DNA is negatively charged and will run to the positive pole during electrophoresis. A specific labeled PROBE is used to identify a distinct region. Limitation: The gene or region of interest must be known
30
How does allele specific oligonucleotide hybridization (ASO) work?
1. Take a know gene sequence that differs by a few base pair changes between normal and disease 2. Synthesize 2 oligonucleotides: 1 that is complementary to the mutant and 1 that is complementary to the normal sequence 3. Denature the DNA from the patient, and hybridize it to each oligonucleotide 4. Control DNA will hybridize to the control oligo, and the mutant DNA will hybridize to the mutant oligo
31
what is the HWE?
p^2+2pq+q^2 = 1
32
the frequency of an X-linked disorder in males is directly equal to...
freq of disease allele in population (q) same applies for normal males (p)
33
what are the 5 factors that drive a population OUT of HWE?
non-random mating, migration, population size, genetic drift, and mutation selection balance
34
what is important to note about small population sizes?
they are most susceptible to changes in allele frequency
35
what is the founder effect?
loss of genetic variation when a new colony is established by a small number of individuals from a larger population loss of rare alleles if not represented in founders, but increases frequency if represented
36
if more than one gene governs a trait...
expect to see a bell shaped curve phenotype with continuous variation
37
what is concordance and disconcordance?
concordance - two related individuals in a family have the same disease (do not share same genetic risk factors but share environmental risk factors) disconcordance - one member of a pair of relatives is affected while other is not (same genetic risk factors for a disease but one did not encounter environmental influences)
38
risk of recurrence in 1st degree relative of an affected individual is roughly equal to...
SQUARE ROOT of the general population incidence
39
what is the most common chromosomal abnormality?
aneuploidy it is seen in 5% of all pregnancies
40
explain the separation of homologs and sister chromatids
homologs separate in meiosis I sister chromatids separate in meiosis II
41
what is anaphase lag?
chromosome loss due to delayed movement of chromosome/chromatid during anaphase
42
what are the results of pericentric or paracentric inversion?
pericentric - deletions and duplications paracentric - dicentric or acentric (causes inviable offspring), or normal
43
explain the etiology of aneuploidy
- anaphase lag - non-disjuction failure of HOMOLOGOUS chromosomes to separate in meiosis I failure SISTER chromatids to separate in meiosis II failure of sister chromatids to separate in mitosis
44
ring chromosomes lack...
telomeres this can cause in deletions, problems in meiosis, often associated with instability and mosaicism
45
pericentric inversion in chromosome 1 is responsible for...
male infertility
46
what is a derivative chromosome?
a chromosome that has material from 2 different chromosomes
47
what are robertsonian translocations?
results from fusion of two acrocentric chromosomes (13,14,15,21,22)
48
what happens in balanced translocations with alternate centromeres?
normal and balanced gametes
49
what happens in balanced translocations with adjacent centromeres?
abnormal and unbalanced
50
abnormalities in chromosomes structures arise by breakage, recombo, or exchange which leads to...
deletions of duplications of segments of chromosomes
51
what are the biological causes of DS?
95% due to nondisjunction in meiosis (90% maternal in meiosis 1, 10% paternal in meiosis) 2% mosaic 4% Robertsonian translocation partial trisomy 21
52
what heart defects are common in px with Patau syndrome?
truncus arteriosus and tetralogy of fallot
53
describe DiGeorge syndrome
Cardia issues Abnormal facies (underdeveloped chin, wide set eyes, hooded eyes, enlarged nose tip, asymmetric crying face) Thymic hypoplasia Cleft palate Hypocalcemia (due to hypoplastic thyroid-T cells) 22 q deletion
54
name the parts derived from pharyngeal pouches/arches
PA 1 - auditory tube and tympanic cavity PA 2 - palatine tonsil PA 3 - inf. parathyroid and thymus PA 4-6 - sup. parathyroid and ultimobranchial body
55
what are the key characteristics of each deletion syndrome
DiGeorge - CATCH22 Cri du chat (5p deletion) - cat cry (malformed larynx) Williams-Beuren (7q deletion) - Ellin facies, hypercalcemia, hypercalciuria, hypothyroidism Wolf-Hirschhorn (4p deletion) - Greek helmet nose
56
explain the process of X chromosome inactivation
one X makes the RNA and the other wraps the RNA around it (chromosomes will compete to inactivate) RNA is made from XIC and will eventually inactivate one of the wrapped the X chromosomes randomly
57
if a male has a barr body he has...
2 X chromosomes
58
what are the sex chromosomal disorders?
XXY - Klinfelter XYY - Jacobs XXX - Triple X X0 - Turner
59
what is the difference between karyotyping and FISH?
karyotyping is used to observe when a child has an abnormality or multiple (specific chromosome abnormality) FISH is used when you suspect exactly the child has (detect cryptic and submicroscopic changes)
60
what is FISH? how does it work?
fluorescent in-situ hybridization - Need cells or fixed tissue and a fluorescently-labelled DNA probe - Denature the DNA from the tissue to be single stranded - Hybridize the DNA with the probe and incubate - If the gene is present in the sample, the probe will hybridize to the DNA and we'll see a fluorescent signal
61
what is array based CGH?
detect DNA imbalances capable of genome wide scanning balanced translocations and rearrangements (inversions) CANNOT be resolved by array-based CGH
62
how does array based CGH work?
obtain DNA via CVS, amniocentesis, or fetal blood culture or use it directly label the DNA hybridize to DNA fragments on gene chip DNA fragments on gene chip will scan the whole genome use laser scanner to observe results if only patient DNA hybridize to gene chip = DUPLICATION, if control hybridizes then DELETION
63
compared to karyotyping, CGH has a higher...
abnormality detection rate
64
birth defects normally arise within...
the first trimester
65
what vitamin is needed to prevent spina bifida?
folate (B9)
66
what are the roles of folate?
cofactor for enzymes involved in synthesizing the building blocks of DNA and RNA methyl donor for regulating gene expression regulates AA metabolism
67
what is the most common facial defect?
cleft lip/palate
68
what causes craniofacial anomalies?
deficiency in vit. A and excess in its metabolite (retinoic acid)
69
what are the functions of retinoic acid?
epithelia - promotes differentiation and strong adhesion mesenchyme - helps proliferation and differentiation
70
what is the significance of RBP4?
mobilizes retinol from liver, delivering it to peripheral tissues (determines bio-availability) aniamls missing RBP4 cannot access stored vit. A
71
what are the types of genetic alterations in cancer?
subtle alterations - base modifications chromosome number changes chromosomal translocation amplifications exogenous sequences
72
what are the 4 classes of genes mutated in caner?
proto-oncogene = promote cell proliferation (oncogene = uncontrolled proliferation) tumor suppressor gene = inhibit proliferation mutator gene = ensure accurate replication and maintenance of genome MicroRNA = produce small RNAs that silence expression other genes
73
driver vs passenger mutation
driver = initiation and progression of cancer passenger = aid in progression and spread of cancer
74
explain MEN1
TUMOR SUPPRESSOR aka Wermers syndrome MEN1 gene makes menin protein histone modification, epigenetic regulation, inhibits cell division appears dominant in pedigree but acts RECESSIVE due to loss of heterozygosity
75
explain MEN2
ONCOGENE MEN2A is most common form of MEN2 Ret gene (receptor tyrosine kinase) appears dominant in pedigree and acts DOMINANT, always active, 60% of developing THYROID CARCINOMA
76
explain the process of RB and DNA replication
RB binds to E2F when it is unphosphorylated, preventing it from entering S phase when cells are ready for cell proliferation, it will send signals to phosphoproteins to phosphorylate RB, activate CDKs and cyclins, and release E2F E2F is now able to transition from G1 to S phase for DNA replication
77
what is the function of P53?
tumor suppressor guardian of genome, sensing cell stress, to induce either cell cycle arrest or apoptosis
78
explain the process of P53 and cell cycle progression
P53 levels are low in normal cells MDM2 will bind to P53 and target it for degradation if MDM2 and P53 are both phosphorylated, MDM2 cannot bind to P53 to degrade it, leading to accumulation P53 will then activate cell cycle inhibitors like P21 which inhibits CDK4 and cyclin D1 Because P21 inhibits CDK and cyclin, it also blocks the phosphorylation of RB from E2F --> inhibit cell cycle progression any mutations in this path will lead to uncontrolled proliferation
79
what happens if there's a mutation in RB?
this means that RB can't bind to E2F, more E2F is free, leads to cell cycle re-entry proliferation
80
what happens if there's a mutation in P53?
unable to activate P21, can't inhibit CDKs and cyclins, leads to cell cycle re-entry proliferation
81
how is LFS suspected in individuals?
before age 46 and at least one 1st or 2nd degree relative with LFS before age 56 OR multiple tumors, two of which belong to LFS tumor spectrum and 1st occured before age 46 OR adrenocortical carcinoma, choroid plexus tumor, rhabdomyosarcoma of embryonal anaplstic subtype, irrespective of family history OR female proband with breast cancer before age 31 etc (slide 32, lecture 12)
82
what is the function of APC?
it is a tumor suppressor that functions to inhibit cell proliferation via the Wnt pathway
83
explain the process of APC and WNT pathway
APC binds to beta-catenin and signals its destruction if there is no APC, then beta-catenin is free to enter nucleus, activates TCF4 which will transcribe cell proliferation genes but if APC is present, then no cell proliferation
84
what is the diagnosis of px with FAP?
classic: 95% have polyps by 35 y/o, colorectal caner if untreated by 39 y/o attenuated: fewer polyps in proximal colon, CRC later in life
85
explain base excision repair
deamination of DNA nucleotides are repaired by base excision DNA glycosidases break the glycosidic bonds XRCC1 protein will recognize DNA alterations Damaged base is removes, repaired by DNA polymerase and ligase deficits in these genes are associated with cervical, breast, and lung cancer
86
explain NT excision repair
XPA/XPC binds to damaged DNA, RPA binds to SS DNA XPD/B is a DNA helicase XPF makes 5' incision, XPG makes 3' incision DNA pol delta and gamma is gap-filling DNA synthesis DNA ligase feels in nicks in DNA
87
what is diagnostic of xeroderma pigmentosum?
biallelic mutation
88
what does high microinstability in tumor tissue indicate?
Lynch syndrome
89
explain the process of SSB repair
PARP will recognize SSB and binds to DNA PARP will add ADP-ribose to chains surrounding the damage, which will act as a signal to repair the damage XRCC1 is recruited and acts as a scaffold for other proteins to repair DNA
90
explain DS DNA break repair
BRCA1 is phosphorylated in response to ds DNA breaks BRCA1 will bind to BRCA2 and interact with other proteins to form a complex that repairs the ds DNA breaks
91
what population is BrCa common in?
Ashkenazi Jewish ancestry
92
Ret gain-of-function leads to..., but Ret loss-of-function leads to...
MEN Hirschsprung Disease
93
when do you do first trimester screenings and what are they?
11-13 wks ultrasound to look at subcutaneous edema of infant neck --> measures nuchal transparency and dates the pregnancy maternal blood serum diagnoses trisomy 13,18, and 21 triple test --> beta-HCG, nuchal transparency, and PAPP-A
94
what is significant about nuchal transparency?
average is 1.2 mm at 11 wks and 1.5 at 14 wks > 3 mm = 305 x increased risk for aneuploidy, increased in trisomy's 45 X
95
what values are significant in maternal serum measurements?
PAPP-A is low in trisomy 13, 18, and 21 HCG is high in trisomy 21
96
when is NIPS (noninvasive) performed and what is it?
10 wks after 6 gestational wks, fragmented pieces of fetal DNA detected in maternal blood detects trisomy 13, 18, and 21, sex chromosome aneuploidy, and copy number variants
97
when is a CVS performed?
10-12 wks syncytiotrophoblast biopsy transcervical and transabdominal
98
what is important to note about CVS?
does not provide information on NTD, like spina bifida
99
when do 2nd trimester screenings occur?
15-22 wks screening for AFP, hCG, estriol, and inhibin triple screen is without inhibin, quad is with it
100
when do you screen for NTDs?
16-18 wks screen maternal or fetal AFP AFP made in the fetal liver, fetal circulation, excreted through kidneys and fetal urine into amniotic fluid crosses the placenta, maternal circulation sampling AFP from maternal or amniotic fluid
101
what is elevated in NTDs?
AFAFP amniotic fluid 80-85% open NTDs by MSAFP
102
what values are significant in Edward's syndrome?
low uE3 and hCG
103
what values are significant in DS?
elevated hCG and inhibin A (DIA) hCG is elevated in both 1st and 2nd trimester
104
when can an amniocentesis be performed?
at 15 weeks from last menstrual period traditional time is 16-20 wks measures AFP and karyotype
105
explain preimplantation genetic screening
blastocyst biospy screening of embryos for specific genetic diseases transfer of healthy embryo into uterus PCR for a KNOWN disease
106
SRY is on the...
P arm,
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