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ISOM > exam 1 > Flashcards

exam 1 Flashcards

1
Q

Genes can modify

A 
MEAD
metabolism
excretion
absorption
distribution
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2
Q

warfarin dosing

A

CYP (cytochrome P450) enzymes catalyze activation/inactivation of drugs

warfarin dose is genotype dependent based on type of CYP isoform

faster metabolism= high dose need

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3
Q

Avery, Macleod, McCarty experiment

A

mice

heat killed virulent strain + rough non virulent strain = death

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4
Q

nucleotide and uses (4)

A

nucleoside + phosphate group (1 or more)

constituents of DNA/RNA, cofactors, energy currency, cell signalling

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5
Q

spontaneous deamination of bases

cytosine
adenine
guanine
5-methylcytosine

A

cytosine -> to uracil
adenine -> hypoxanthine
guanine -> xanthine
5-methylcytosine -> thymine

thymine cannot be deaminated

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6
Q

analogs of base/nucleoside/nucleotide are used as

A

therapeutic agents

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7
Q

base analog

A

5-fluorouracil (cancer therapeutic)

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8
Q

nucleoside analogs (2)

A

gancyclovir (CMV retinitis therapy)

AZT/Zidovudine (HIV/AIDs)

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9
Q

nucleotide analog

A

Adefovir (hepatitis)

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10
Q

phosphodiester

A

5’ phosphage and 3’ OH bond of phosphate backbone

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11
Q

forms of DNA

A

A- right handed, 11 bases/turn
B- predominant in humans, right handed, 10b/t
Z- left handed, 12 b/t

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12
Q

DNA denaturation kinetics

A

zero order, NOT dependent on concentration

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13
Q

DNA renaturation

A

2nd order kinetics, dependent on concentration

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14
Q

purpose of non watson crick base pairing and examples

A

gene regulation and telomere stability

G-Quadruplex- G rick regions, increase telomere stability

i-Motif- C rich regions, pronated and neutral C on a single strand of dsDNA, cause stacking of DNA, vary with cell cycle phases (max in G1/S phase)

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15
Q

alkylating agents

A

distort DNA structure

cyclophosamide, nitroureas, cisplatin

cistplatin bind to g -> intrastrand crosslinking -> distortion in DNA structure -> cell death
causes side effects because of indiscriminate binding

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16
Q

start codon

A

AUG

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17
Q

stop codons

A

UAA, UGA, UAG

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18
Q

chromatin

A

organized structure of chromosomal DNA complexed with proteins

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19
Q

nucleosome (core particle)

A

147 bp DNA

flat octomeric disc- made of histones (H2A, H2B, H3, H4)

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20
Q

DNA charge

A

negative due to phosphate groups

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21
Q

histone charge

A

arginine gives histones positve charge

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22
Q

heterochromatin

A

transcriptionally inactive
higher methylation, low acetylation

present in mitosis, telemere, centromeric regions

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23
Q

euchromatin

A

transcriptionally active
lower methylation, higher acetylation

present in interphase

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24
Q

histones

A

102-135 AAs
conserved histone fold
N-terminal for modification (A)
3 a-helices connected by loops (B)

H3/4 most conserved across species

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25
Q

types of histone modification

A
  • acetylation
  • methylation
  • phosphorylation
  • methylation of CpG islands
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26
Q

acetylation

A

removes positive charge on histone (particularly on lysines) -> loosens interaction with DNA -> increases transcription

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27
Q

methylation

A

methylated lysine attract heterochromatin specific protein -> strengthen interaction -> gene silencing

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28
Q

phosphorylation

A

adds negative charge -> repel negative charge of backbone -> increases activity/ trancription

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29
Q

methylation of CpG

A

methylation of CpG island (promotor region) -> recruits methyl-binding proteines -> chromatin factors heterochromatin -> gene silenced

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30
Q

epigenetic regulation

A

control of gene expression by histone modification and modification of DNA bases but NOT the sequences (epigenetic- “on top of DNA modifications”)

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31
Q

PWS vs AS

prader-willi syndrome and Angelman syndrome

A

deletions on chromosome 15q11-q13 causes 2 different disorders

maternal imprinted and paternal deleted -> PWS

paternal imprinted and maternal deleted -> AS

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32
Q

henderson-hasselbalch

A

pH= pKa + log [A-]/[HA]

pKa [A-} = [HA] for weak acids

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33
Q

pH> pKa

pH

A

deprotonated

protonated

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34
Q

amino group pKa

A

9.0

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35
Q

carboyxlate pKa

A

2.0

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36
Q

common buffers

A

used because most drugs are weak bases/acids, easier to pass membrane if uncharged

  1. bicarb and carbonic anhydrase
  2. Phosphate buffer
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37
Q

peptide formed through what rxn?

A

condensation

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38
Q

protein structure

A

1- AA sequence
2- linear arrangement alpha helix (intrachain H bonds) B-pleated sheets (H bonds between segments, parallel and anti-parallel, 4 AAs proline kinks and glycine H-bond formation minimal steric hindrance)
3- 3D conformation
4- subunit arrangements

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39
Q

disulfide bond

A

2 cysteines can stabilize protein fold

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40
Q

suprasecondary structures

A

beta-hairpin
coilied-coils
BaB
Greek key

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41
Q

huntington’s disease

A

polyQ expansions (many CAG or Gln codon) lease to disruption in clathrin-mediated endocytosis -> cell death

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42
Q

prion disease

A

infected prion disrupts a helix and b pleated sheet to trigger abnormal protein folding in the brain

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43
Q

collagen structure and formation

A

rigid structure for support and structural integrity

3 left handed alpha helices form right handed triple helix, high pro and gly

formation:

  1. hydroxylation
  2. glycosylation
  3. a helix formation
  4. disulfide bond formation
  5. triple helix formation
  6. pretoeolytic cleavage
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44
Q

EDS

A

stretchy skin, inability to remove N/C termini or cross link alpha chains

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45
Q

osteogenesis imperfecta

A

brittle bones due to mutions that replace gly preventing triple helix formation
can be due to haploinsuffciency or dominant negative effect (loss of function becomes dominant)

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46
Q

elastin

A

found in lungs, walls of large arteries, elastic ligaments

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47
Q

marfan syndrome

A

mutations in fibrillin 1 (FBN1), leads to impaired structual integrity, autosomal dominant

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48
Q

elastase

A

degrades elastin in alveolar walls and other structural proteins
important for remodeling

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49
Q

alpha 1-antitrypsin

A

inflammation protection

serine protease inhibitor protects tissue from protease released by inflammatory tissues

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50
Q

smoking leading to emyphysema

A

smoking oxidizes methylation of a1-antitrypsin (inhibits elastase and other proteases), degrades elastin in lungs, damages lungs

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51
Q

bacteria vs humans DNA replication

A

Bacteria:
o Single origin of replication, initiated by dnaA
o Longer Okazaki fragments
o DNA Polymerase subunits:

▪ I: 5’-3’ polymerization, 5’-3’ exonuclease & 3’-5’ exonuclease
▪ II: 5’-3’ polymerization & 3-5’ exonuclease
▪ III (Replicase):5’-3’ polymerization & 3’-5’ exonuclease
▪ All DNA Pol have 3’-5’ exonuclease abilities, Pol I is unique in its addition of 5’-3’ exonuclease activity
▪ Pol IIIActually does most of the replication
o Use Topoisomerase II and IV

Humans:
o Multiple origins of replication, initiated by recognition complex
o DNA Polymerase subunits: α (primase), β (repair),γ (mitochondrial replication),δ (nuclear replication), and ε (nuclear replication)
o Use Topoisomerase I and II

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52
Q

helicase

A

(hexameric ATP dependent protein) unwinds the DNA

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53
Q

single stranded binding proteins

A

stabilize the unwound strands

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54
Q

initiation and opening

A

in bacteria:
1 replication of origin
bacterial initiator protein (dnaA)

in euks:
thousands origins of replications in humans
origin recognition complex binds to origin and denatures A-T base pairs

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55
Q

primer synthesis

A

in bacteria- primase
DNA polyerase III/replicase can add new nucleotides to the 3’ strand

in humans- polymerase alpha makes RNA primers
DNA polyerase can add new nucleotides to 3’ strand

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56
Q

removal of primers

A

bacteria- DNA pol 1

humans- RaseH

both have 5’-3’ exonucleases

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57
Q

mutations in RNase H2=

A

neuroinflammatory disorder and SLE

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58
Q

DNA ligase (ATP independent)

A

joins fragments

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59
Q

type II topoisomerase (gyrase)

A

relieves supercoiling/ overwinding
cuts both strands allowing DNA to rotate

used in bacteria and humans

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60
Q

antibiotics and topoiomerase

A

quinolones/fluuroquinolones (antibiotics) target toposimoserase, prevent reversible ligation leading to cell death

point mutations in gyrase N terminal of GyrA and C term of Gyr B can lead to antibiotic resistance

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61
Q

Topotecan (chemotherapy) mechanism

A

used in ovarian and small cell lunger cancer

stabilizes the topo-I DNA complex and prevents the re-ligation, thus inhibits replication

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62
Q

end replication problem

A

for Euks
RNA primare cannot be placed for Okazaki fragment when the end of the DNA is reached (no room to clamp on)
section of the DNA will not be replicaticated (no polymerase available with 3’-5’)

solution: telomeres- hexameric repeats of TTAGGGG (Tell them all genes get gone)

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63
Q

telomerase composition and activity

A

Composed of:

▪ Protein + RNA (Ribonucleoprotein→ RNP)

▪ Hexameric repeats (up to 15 Kb of repeating TTAGGG)

▪ Reverse transcriptase (RNA dependent DNA polymerase: hTERT)

▪ RNA, which functions as a template

▪ Short, single stranded regions that loop back to end and form G-Quadruplex (quartets) that stabilize the end of chromosomes

o Activity: Telomerase binds, extends 3’ end via RNA-templated DNA synthesis, f/b completion of lagging strand via DNA polymerase

▪ Telomeres also seal the ends of chromosomes to prevent undesirable fusion and prevent aberrant recombination and attach chromosomes to nuclear envelope

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64
Q

Telomeres in somatic cells, germ cells, stem cells, tumor cells, aging

A 
somatic- no detectable telomerase activity
germ cells + activity
stem cells + activity
cancer cells + activity
aging + activity serves as mitotic clock
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65
Q

HIV and AZT

A

replication of HIV requires:
1 reverse transcriptase activity RNA to DNA
2 integrase activity incorporate into hose

AZT- analog of deoxythymidine, prevents chain elongation be reverse transcriptase (absence of 3 OH’, prevents chain)

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66
Q

5-fluorouracil as a chemo agent

A

thymidylate synthase catalyzes synthesis of dTMP

dTMP -> dTTP (componant of DNA replication)

5-fluorouracil inhibits TS via substrate unavailability = no replication

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67
Q

DNA damage misincorporation

A

wrong base is placed/replication slips -> change overall code

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68
Q

DNA damage- deamination

A

base change

ex cytosine to uracil

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69
Q

DNA damage- depurination

A

removes purine from nucleotide, results in deletion of nucleotide pair

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70
Q

DNA damage- UV radiation

A

pyrimidine dimers, DNA cannot be copied

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71
Q

replication errors and repair

A

mismatch of bases or replication slippage (misalignment or repeat DNA sequences)

Repair:
DNA polymerase can repair through proof reading (3’ to 5’ exonuclease actvity)- mismatch repair

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72
Q

post replication errors

A

transitions- (purine to purine, pyrimidine to pyrimidine)
transversions- (pyrimidine to purine or vice versa)
frameshift- addition or deletion in bases, not a multiple of 3
structural changes- due to metabolic activity, heat, pH, radiation, or toxicity
spontancous changes- deaminations or dpurnations
UV damage

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73
Q

post replication repair

A

BER- base excision repair

NER- nucleotide excision repair

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74
Q

how to fix replication error (mismatch repair) in bacteria

A

marks with methylation

MutS- sees mismatch, forms clamp
MutL- bind to MutS sliding clamp
MutS- activates MutH endonucleases
MutH nicks unmethylated strand

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75
Q

how to fix replication error (mismatch repair) in humans

A

single strand breaks or nicks provide signal repair

MutS- see mismatch
MutL- scans for nick
DNA and Exo 1 nuclease degrades strand
correct strand is repaired

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76
Q

lynch syndrome: hereditary non-polyposis colon cancer

A

mutations in MSH2 (homologue of metS) and MLH1 (humolog of mutL)

problems with detected areas to repair

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77
Q

BER

A
  1. Wrong/damaged base is recognized and cleaved (Specific DNA glycosylase)
  2. Sugar- P is removed (AP endonuclease and Phosphodiesterase)
  3. Gap filled (DNA polymerase)
  4. Nick sealed (DNA ligase)
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78
Q

NER

A
  1. Either side of section is cut (Excision nuclease)
  2. Section (oligonucleotide) removed (Helicase)
  3. Repaired (DNA polymerase) and sealed (DNA ligase)
  4. This pathway is either transcription coupled or follows a global repair pathway (both pathways involve a common set of proteins)
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79
Q

double strand break repair pathways (2)

A

homologous recombination- complete sequence restored, problems with this in BRCA

non-homologous end joining- sequence loss, altered segment with missing nucleotides

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80
Q

xeroderma pigmentosum

A

XP mutation

skin malignancies

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81
Q

Cockayne sydnrome

A

ERCC6/ERCC8 mutation

premature aging, photo sensitivity, hearing loss

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82
Q

colon cancer

A

hereditary due to mutations in repair genes

MSH2 and MSH1

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83
Q

breast cancer

A

mutation in BRCA 1 and 2- defect in double strand break repair by homologous recombination

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84
Q

Werner syndrome

A

defect in BER

cataract, short stature, premature graying

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85
Q

bloom syndrome

A

defect in double strand break repair

stunted growth, sunlight sensitivity, chromosome breakage, cancer risk

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86
Q

protein functions

A 
signal structure
transport
energy product
immunity
enzyme
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87
Q

enzymes

A

specific type of protein

all most all are proteins (ribozymes are made of RNA)

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88
Q

transferases

A

mediate group transfer (ex C,N,P)

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89
Q

hydrolase

A

cleavage of bonds via addition of water

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90
Q

lyase

A

cleavage of C-C, C-S, and C-N
tend to release CO2
form beta keto acids

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91
Q

isomerase

A

rearrangement
intramolecular group transfer
no net change in bonding, change formation

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92
Q

ligase

A

links 2 molecules, formation of bonds (C-O, C-S, C-N)
input of energy (ex ATP)
includes synthetases

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93
Q

reason for zymogens

A

inactive enzyme to prevent action in unwanted locations

protease enzymes are mase as zymogens then activated through hydrolysis

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94
Q

thiamine pyrophosphate (TPP), coenzyme

A

oxidative decarboylation, transfer of aldehyde

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95
Q

FAD/FADH2, coenzyme

A

redox rxn

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96
Q

NAD(P)+/NAD(P)H, coenzyme

A

redox e carrier

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97
Q

CoA-SH, coenzyme

A

acyl group transfer

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98
Q

Pyridoxal phosphate (PLP), coenzyme

A

transamination, deamination, decarboxylation

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99
Q

Biotin, coenzyme

A

carboxylation carries O2

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100
Q

tetrahydrofolate

A

transfers one carbon fragments

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101
Q

apoenzyme

A

inactive enzyme

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102
Q

holoenzyme

A

active enzyme

=apoenzyme + coenzyme

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103
Q

isoenzymes definition and example

A

proteins with same functional properties, but differences in sequence, produce diagnostic signatures

tissue damage-> large increases in cellular proteins

ex CK
brain B (pI= 5.34, negatively charged at pH 6)
heart M/B
skeletal M (pI=6.77, positively charged at pH 6)
can be seperated with native gel at particular pH

104
Q

post translational modifications

A
  1. phosphorylation
  2. glycoslyation of extracellular proteins
  3. ubiquitinoylation
  4. Sumoylation
  5. oxidation/reduction
  6. acetylation
  7. lipidation
  8. methylation
105
Q

post translational modifications, phosphorylation

A

control enzyme function, form salt bridges by recruiting target proteins, global regulation of cell function

ex- kinases add Ps

106
Q

glycosylation of extracellular proteins

A

self recognition, accurate presentation to outside cell

107
Q

ubiquitinoylation

A

makes proteins for degradation, targets lysine

108
Q

SUMOylation

A

regulates protein regulates protein localization, protein-DNA binding, protein-protein interaction, transcriptional regulation, DNA repair

added to lysine to control other functions

109
Q

ox/redox

A

facilitation disulfide bonds (made in oxidizing environments)

110
Q

acetylation

A

affect selective gene transcription and chromatin function

modifies interaction with other proteins, DNA (acetylated lys residues activate transcription)

111
Q

lipidation

A

anchor modified proteins to different membrane locations, alters protein function

112
Q

methylation

A

modify translation, alter protein structure, block protein modification particularly on lys or arg

113
Q

michaelis menten assumes

A
  1. steady state- [ES] is constant
  2. free ligands- [S]&raquo_space;> [E]
  3. rapid equilibrium- kcat<
114
Q

Vmax

A

maximum rate of rxn

115
Q

Km

A

[substrate] at 1/2 Vmax

116
Q

low Km=

A

high affinity

117
Q

substrate regulation/ michaelis-menton enzymes curve

A

hyperbolic curve

118
Q

allosteric regulation

A

binding of a molecule at regulatory site
sigmoidal curve
change rate smaller with change in substrate concentration
typically catalyze rxns with large decreases in free energy (large delta G)
binding of 1 molecule increases bindning of subsequent molecules (increases affinity) due to conformational change

119
Q

ways to modify enzyme activity

A

substrate concentration

allosteric effectors/regulators (shift left or right)

post-translational modifications

abundance of enzyme

120
Q

competitive inhibitors

A

binds to same place as substrate
vmax-same
Km- increases
EI only (no ESI)

121
Q

competitive inhibitors examples

A
  • statins on HMG-CoA reductase
  • methotrexate blocks nucleotide biosynthesis inhibits dihydrofolate reducatse
  • Salicylate cycloooxygenase (COX) block inflammation
122
Q

noncompetitive inhibitors

A

binds to allosteric site
forms EI and ESI (non productive)
vmax-decreases
km- same

123
Q

noncompetive inhibitors examples

A

cyandie bind cytochromes
D-JNKI-1 binds JNK block apoptosis of beta cells in pancreas
nifedipine- inhibits P450 CYP2C9, block morphine metabolism

124
Q

mixed (uncompetitive) inhibitors

A

inhibitor binds to ES complex, making nonproductive ESI
rarer
vmax- decrease
km- decrease

125
Q

mixed (uncompetitive) inhibitor examples

A

pepstatin- inhibits pepsin
trypsin inhibitor- inhibits trypsin
ethanol- inhibits acid phosphatase

126
Q

irreversible inhibitor example

A

aspirin- covalently modifies COX 1 and 2 by acylation of ser near active site

advantage-
selectivity
lower doses
lower side effects
prolonged duration of inhibition
lower risk of drug resistance due to active site residue changes
127
Q

common themes in physiology

A
  1. structure determine function
  2. homeostatic functions to maintain constant interval
  3. cells can communicate/coordinate
  4. substances/info moves across membranes
  5. cell and body are compartmentalized
  6. systems tend toward equilibrium, but many are kept at a steady state with energy input and output
128
Q

homeostasis

A

body’s ability to maintain a relatively stable (within narrow limits) internal enviornment

129
Q

intracellular fluid

A

includes blood cells

130
Q

extracellular fluid

A

vascular and interstitial fluid

includes plasma

131
Q

can set points/intervals changes

A

yes

132
Q

feedback system parts

A 
stimulus
sensory receptor
afferent pathway
control center
efferent pathway
effector
133
Q

negative feedback

A

return to set point to maintain homeostasis, most common

134
Q

positive feedback

A

move further from set point, outside factor is required to shut off

ex child birth, blood clotting

135
Q

autocrine

A

signal cell to target cell

136
Q

paracrine

A

signal to adjacent cell

137
Q

neurocrine

A

signal cell is a neuron, signal molecule is neurotransmitter

138
Q

endocrine

A

signal to target cell over longer distance via hormone

139
Q

canon’s postulates

A
  1. nervous system works to preserve conditions for organ function
  2. tonic level of activity in many systems (blood vessels)
  3. no tonic activity then antagonistic control (parasympathetic vs sympathetic)
  4. same chemicals can have different effects (epi vasoconstricts intestines and dilates skeletal muscles)
140
Q

growth

A

increase in cell number, size, extracellular matrix

141
Q

differential growth

A

one part grows more than other

142
Q

induction

A

chemical signal cause change in cells

143
Q

cell differentiation

A

undifferentiated to differentiated cells

determination- activated
restriction- inactivated

metaplasia- de/re differentiation

144
Q

selective cell death

A

cells programed to die
important for development

ex fingers and fetal brain

145
Q

migration

A

movement of cells from one location to another

amoeboid vs chemotaxis

146
Q

epithelial folding

A

after inducation, edges of some types of undifferentiated, flat epithelia fold over themselves to form a tube or ball

147
Q

cavitation/canalization

A

opening of paces in orginally solid tissues move to peripheral location

creates blastocyst cavity, celom and lumen of gut cavity

148
Q

morphagens (4 examples)

A

diffusible molecules create gradients for developmental responses

TGF-beta
Bone morphogenic proteins (BMPs)
Hedgehog series
wingless related integration site (WNT)

149
Q

TGF-beta

A

cell growth/differentiation, SMAD pathway

150
Q

bone morphogenic proteins

A

cell differentiation

pivotal developmental signaling molecules

151
Q

hedgehog series

A

critical development gene
requires cholesterol to become active SHH

development of vertebrae
SHH-initiates paraxial mesoderm
muscle maturation

152
Q

wingless-related integration sire

A

critical pattern development and axis pattern
muscle development/ maturation
differentiation of somites

153
Q

notch signaling pathway

A

direct cell to cell contact
determine cell fate
delta like/jagged, transmembrane surface bound ligands interact with notch proteins

154
Q

transcription factors

A

binds to DNA, regulate gene expression

includes:
histones
hox/homeobox
paried box (Pax)
basic helix loop helix (HLH)
155
Q

receptor tyrosine kinases

A

cell surface receptors
involved in expression of growth factors

3 domains
extracellular ligand binding
transmembrane
intracellular kinase

156
Q

meiosis

A

gamete formation
4n to 2n (23 replicated chromosomes) to n (23 nonreplicated chromosomes, 4 daughter cells)
1 DNA replication, 2 divisions

157
Q

mitosis

A

4n -> 2n (2 daughter cells, 46 individual non-replicated chromosomes)
PMAT

158
Q

gametogonium

A

first cell in line of gamete cell development, 46 replicated chromosomes, divides by standard mitosis, daughter cells can differentiated into primary gametocytes

159
Q

primary gametocyte

A

46 chromosomes line up in homologous pairs (4n)
divides in division I (reduction division) to form 2 secondary gametocytes w/ 23 chromosomes (2n)
divides into divsion II to form 2 gamates (total 4) with 23 nonreplicated chromosomes (n)

160
Q

spermatogenesis

A 
spermatogonium (4n)
mitosis
primary spermatocyte
meiosis I
secondary spermatocyte (1n) x 2 cells
meiosis II
spermatid (1n) x 4 cells
differentiation
4 sperm
161
Q

oogenesis

A 
primary oocyte (46;xx)
meiosisI
first polar body (to get rid of extra DNA) and secondary oocyte (1n or 23;x)
meiosis II
3 more polar bodies, ovum (1n or 23;x)
162
Q

heritability

A

proportion of the trait variation in a population explained by genetic favors

=0 genes do not contribute to disease
=1 genes fully contribute to trait/disease

163
Q

locus

A

unique chromosomal location

164
Q

allele

A

alternative forms of the same locus

165
Q

codominant

A

codominant- both alleles are dominant ->additive effect on phenotype

166
Q

haplotype

A

combination of alleles on the same chromosome

167
Q

genotype

A

combination of alleles at a locus

can by homozygous or heterozygous

168
Q

variants

A

difference in DNA between individuals

most peoples genomes sequence is about ~99.5% indentical

169
Q

polymorphism

A

MAF >1% frequency

does not imply effect on phenotype

170
Q

mutation

A

MAF <1%

does not imply effect on phenotype

171
Q

minor allele frequency (MAF)

A

the frequency of the least abundant allele in a population

172
Q

allele frequency of A1

A

= # of A, alleles in population/ total # of alleles in population

173
Q

main types of genetic variations

A
  • single nucleotide variant (SNV)
  • structural variation
  • copy number variant (CNV)
  • microsatellite
174
Q

single nucleotide variant (SNV)

A

most abundant type of genetic variation
single nucleotide polymorphisms
most are bialleic but some have 3-4

source- DNA replication and repair

175
Q

structural variation

A

can occur during DNA recombination

involves more than 1 base bair

176
Q

copy number variants (CNV)

A

DNA sequence whose number of copies varies between individuals

177
Q

microsatelite

A

tandemly repeated sequences of 2-4 nucleotides

a type of copy number variation, but smaller than true CNV

178
Q

germline mutation

A

mutation in every cell, heritable

179
Q

somatic mutation

A

only some tissues/single cells have mutation, non heritable

ex sporatic cancer and aging

180
Q

mosaicism

A

the presence of cells with different genotypes

result of somatic mutations

181
Q

types of genetic variants

A
  • neutral variants (most common)
  • pathogenic variants
  • functional variants
182
Q

allelic effect size

A

alleles impact on disease

183
Q

odds ratio

A

odds of disease in presence of allele/odds of disease w/o allele

> 1 risk allele
=1 not associated with the disease
<1 protective allele

184
Q

non-coding variants

A
  • splicing (structural)

- transcriptional regulatory region (ex enhancers/promoters)

185
Q

intronic variants (2)

A

exon skipping

intron retention

186
Q

coding variants

A

silent
missense- 1 AA sub
nonsense- early term
frameshift- insertion/deletion, non multiple of 3

187
Q

know naming

A

this replaced with this ter, count from change

188
Q

loss of function variants

A

reduced or no function
most common
types: missense, nonsense, frameshift, splicing
recessive

189
Q

gain of function variants

A

increased or new function
rare
types: missense, in-frame insertion, structure (gene fusion)
dominant

190
Q

haploinsufficency

A

1 normal allele is insufficent for normal phenotype
LOF allele dominant

mild osteogenesis imperfecta (COLA1)

191
Q

dominant negative (DN) effect

A

altered gene producted that antagonistcally affects the wt-gene
LOF alleles
missense mutations in COL1A1 leads to disruption in procollagen triple helix
severe osteogenesis imperfecta

192
Q

monogenic disease

A

single strong variant drives phenotype
rare

examples:
muscular dystrophy
hutchinson-gilford
amyotrophic lateral sclerosis
CF
193
Q

polygenic disease

A

multiple “weak” variants
common

examples:
obesity
DM
IBS
CVD
HTN
schizophrenia
194
Q

susceptibility

A

sum of all genetic and enviornmental factors affecting disease

individuals above threshold have disease

195
Q

association

A

tendency of 2 characters (ex alleles or disease) to occur to together at nonrandom frequencies. The strength of association can be measured by odds ratio

196
Q

genes of monogenic disease can be indentified by:

A

linkage analysis
whole genome sequencing
whole exon sequencing

197
Q

GWAS (genome-wide association study)

A

analysis of association between SNVs and disease
identifies alleles associated with the disease
analyzes 10,000 to 100,000 genes

can indentify new disease etiology and functions of different genes

198
Q

polygenic risk score

A

composite of measure of genetic risk conferred by all disease-associated loci in an individual
determine how likely it is that an individual will get a disease

to find:

  1. identify disease associated variants
  2. in each individual add up effects of risk/protective alles to obtain individual PRS
  3. correlate PRS disease risk in population
  4. estimate individual relative disease risk
199
Q

composition of chromosome

A

telomeres-GT rich sequences at the end of the chromosomes

centromeres

  • metacentric: central
  • submetacentric: intermediate
  • acrocentric: terminal position

arms (p short, q long)-> regions-> bands
regions get longer, further down

200
Q 
abbreviation for
deletion
insertion
duplication
inversion
translocation
terminal
ring chromosome
isochromosome
A 
del
ins
dup
inv
t
ter
r
i
201
Q

karyotype and types (3)

A

the staining and display of chromosomes from metaphase spread

types:
G banding
FISH
Array CGH

202
Q

g-banding karyotype

A

blood draw-> culture cells

lowest resolution

chromosomal imbalances, can detect aneuplodies, polyplodies, translocation, large deletions, inversions, duplication, isochromosome, ring chromosome

203
Q

FISH

A

takes advantage of nucleic acid sequences and metaphase, looks at intact chromosome
looks for specific areas (centromeric, telmeric, chromosome-specific)
multiple FISH or SKY can look for more than one area at a time

benefits- medium resolution

can detect aneuplodies, polyplodies, translocation, small deletions, inversions, duplication, isochromosome, ring chromosome
limits- you have to know what you are looking for, specific location

204
Q

Array CGH

A

patient compared to control DNA
green- increased pt DNA, red- more control DNA, yellow- equal

benefits-highest resolution, quicker
can detect aneuplodies, small deletions, duplication, isochromosome (not optimal), ring chromosome
used to detect intellectual disabilities in toddlers/newborns

limits-cannot detect changes not involving amount of DNA (inversion and balanced translocations), CANNOT detect triploidy or mitochrondrial DNA

205
Q

translocations

A

Transfer of genetic material from one chromosome to another (non-homologous)

Can be balanced or unbalanced, reciprocal or Robertsonian

▪ Unbalanced: translocations with loss or gain of chromosome material

▪ Balanced: no loss or gain of chromosome material

206
Q

deletion

A

Loss of part of chromosome [del(chr#)(area deleted)]

o Can either be interstitial (w/in chromosome) or terminal (at end of chromosome)

o If deletions are large enough then it is not viable

o Large (visible with chromosome banding) or submicroscopic (microdeletions, detectable by FISH and aCGH)

207
Q

Inversions:

A

Reversing positions of chromosomal segments due to errors in replication/repair

o Can either be pericentric (involve centromere) or paracentric (don’t include centromere)

o Inversion carriers are asymptomatic (unless breakpoint is at important gene) but offspring can have clinical consequences b/c pairing/crossover is affected

o Only detects with chromosome banding or FISH (NOT aCGH)

208
Q

duplications

A

Extra copies of a segment of chromosome due to errors in replication/repair

209
Q

Isochromosomes

A

Loss of one arm with duplication of another

o Thought to occur due to centromere dividing transversely rather than longitudinally (with end up with having 2 p arms and no q arms and also 2 q arms with no p arms)

o Autosomal isochromosomes are lethal

210
Q

Ring Chromosomes:

A

Break occurs at each arm that fuse together

o Unstable in mitosis so its common to find ring chromosome in only a proportion of the pt cells. Other cells in individual are monosomic for that chromosome bc of absence/loss of ring chromosome

211
Q

euploid

A

normal chromosome number
2n somatic
n gametes

212
Q

ploidy

A

change in chromosome number
aneuploidy
polyploidy

213
Q

changes in ploidy occur due to non-disjuntion in meiosis during gamete formation

A

meosis 1- all daughter cells affected

meosis 2- 1/2 daughter cells affected

214
Q

reciprical translocation

A

Breaking and exchange between chromosomes and formation of 2 new derivative chromosomes (can be balanced or unbalanced

215
Q

robertsonian translocation

A

Acrocentric chromosomes → New derivative chromosome

o Non- disjunction during meiosis can cause trisomies (e.g Trisomy 21)

can be determined by g banding or FISH

216
Q

autosomal dominant

A

: Expressed in homozygotes (AA) & heterozygotes (Aa)

o Parent to child transmission

o Every generation affected

o Unaffected parents do not transmit to children

o Males & females equally affected

o Male to male transmission (differentiates ADT from XLD

217
Q

Autosomal recessive:

A

Only expressed in homozygotes

o Unaffected parents can have affected children

o 25% of children affected

o Affected parents can have unaffected children

o Males & females equally affected

look for generation skipping

218
Q

x linked dominant

A

No male/female carriers → Those that have allele are affected

o Both males and females affected

o Mother transmits to daughters & sons

o Father transmits only to daughters

o Every generation affected

219
Q

x linked recessive

A

Males are always affected if they have disease allele

o Unaffected males do not transmit

o Carrier woman transmit to sons

o All daughters of affected males are carriers (Obligate carriers)

220
Q

consanguinity

A

mating occurs among relatives
homozygotes are more common if wide spread

suspect this in rare AR disease

221
Q

penetrance

A

Fraction of individuals w/ same genotype that show expected phenotype

222
Q

incomplete penetrance

A

Phenotype expressed in a fraction of individuals that all have the disease genotype

shown as percentage

ex: huntington’s disease and retinoblastoma

223
Q

Expressivity:

A

Range of phenotypes produced by a specific genotype

o Example: Marfan, Cystic Fibrosis, Polycystic Kidney Disease

224
Q

Delayed Age of Onset:

A

Individual has genotype but does not develop condition until later in life

Example: Huntington’s Disease, most hereditary cancer syndromes

225
Q

Pleiotropy:

A

Effects of a single gene on multiple organ systems/tissues

Example: Marfan, Cystic fibrosis

226
Q

Locus heterogeneity:

A

Mutations in different loci produce same disorder

o Example: Retinitis pigmentosa, BRCA1/BRCA2

227
Q

Mutational heterogeneity:

A

Different mutations in same locus

o Example: Cystic Fibrosis, Beta thalassemia

▪ Individuals with two different mutations at the same locus → compound heterozygotes. Most individuals with AR disorders are compound heterozygotes unless their parents are related

228
Q

new mutations

A

example achondroplasia

no family history

229
Q

Uniparental disomy:

A

individual inherits both homologous chromosomes in a pair from a single parent. Can be isodisomy or heterodisomy

o Mechanism: Due to non-disjunction in Meiosis I or II in one parent

230
Q

Unstable repeat expansion

A

Increase number of nucleotide repeats in successive generation

o If repeats exceed threshold #, disease occurs

o Mechanism: Slippage of DNA polymerase during replication in gametes or unequal crossover, repeats are usually CG rich

231
Q

Herdy-Weinberg Law

A

p+q=1
AA=p^2
Aa=2pq
aa=q^2

1/#

232
Q

Hardy-Weinberg Assumptions

5

A

● Random mating

● No selection for any genotype

● No population migration

● Large population size

● No new mutations

233
Q

Expansion of trinucleotide repeats:

A

increase in number of repeats in successive generations

Can be transmitted as autosomal dominant, autosomal recessive, or X-linked

234
Q

anticipation

A

Progressively earlier age of onset & severity of symptoms due to increased number of repeats

235
Q

Law of independent assortment

A

members of different gene pairs assort to gametes independently of one another

o Not true for genes on the same chromosome they will be inherited together (in genetic linkage)

236
Q

Recombination:

A

occurs between homologous chromosomes during meiosis I… when 2 loci are on chromosome, they can be separated by recombination

o when 2 loci are 1 cM apart crossover occurs 1/100 meioses

o recombination is more frequent in female than in male games

237
Q

haplotype:

A

combination of alleles at linked loci on chromosome (new haplotypes different than parental) are found in gametes

238
Q

genetic linkage analysis

A

pattern of makers in affected individuals

pros:
determines genomic interval where disease lies

cons:
slow
requires large families with disease
requires additional method to find actual gene and causative mutations

239
Q

whole genome sequencing

A

next generation sequencing of whole genome

pros- few affect family members or relatively fuew unrelated affected individuals
good for monogenic disease and new genes

cons- expensive
privacy impacts

240
Q

whole exon sequencing

A

same as WGS but misses

intronic, regulatory, and non-coding variants

241
Q

methods used for identification of monogenetic disorders

A

linkage analysis

whole genome and exon sequencing

242
Q

methods used for testing/screening

A 
PCR
		PCR-RFLP
		ARMS-PCR
		Allele-specific oligonucleotide hybridization
		Southern blotting
		Sanger Sequencing
243
Q

gene expression methods (RNA)

A

nothern blots

gene expression microarrays

244
Q

PCR

A

amplification of area of interest

can detect:

  • insertions
  • point mutations
  • viral and bacterial infections

very sensitive, requires little DNA

245
Q

PCR-RFLP

restriction fragment length polymorphism

A

detects point mutations

smaller fragments if mutation is present

246
Q

amplification-refractory mutation system PCF

ARMS PCR

A

allele specific primers

o Wt-specific primer only extends when annealed to Wt DNA

o When annealed to Mut DNA Mismatch @ 3’ end and no product

o 2 separate PCR reactions per pt sample

Amplification product with specific primer pair will only be obtained if there is no mismatch

247
Q

Allele-Specific Olgionucleotide (ASO) Hybridization

A

Similar to ARMS-PCR, uses allele specific oligonucleotides to hybridize only Wild type (Wt) or Mutant (Mt) allele

Utility
▪ Detection of point mutations, small deletions (bps), & small insertions

▪ Doesn’t require electrophoresis

▪ Can test for several mutations at a time (multiplex

248
Q

southern blotting

A

detects insertions, deletion, point mutation that disrupt restriction site

good for trinucleotide expansions

no amplification required
radiolabed probe, size electrophoresis

249
Q

sanger DNA sequencing

A

“gold standard”

pros: picks up all mutations within region
do not have to know what you are looking for (good for unknown mutations)
high fidelity
optimal for many mutations on same gene
indentifies deletions, insertions, duplications, point mutations

cons: expensive
time consuming

250
Q

detect changes in gene expression

A

northern blotting

gene expression microarrays (red, yellow, green)

251
Q

tissues to test

A

must test effected tissue where gene is expressed

252
Q

gene therapy in vivo

A

WT gene delivered to the patient (ex CF)

253
Q

gene therapy ex vivo

A

target cell removed and vector introduced

much lower risk of immune rejection

254
Q

viral vectors

A

remove disease causing aspects of virus (infect but to lyse), just for delivery (vector and packaging)

pro:
more effective

con:
can elicit immune response or inactivate essential gene

255
Q

non-viral vectors

A

less efficient, lower risks, assemble lysosome for delivery

256
Q

CRISPR

A

Edits DNA (cut and paste), for cell response memory, not clinical yet

ISOM (9 decks)

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