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Unit 2 > MCP > Flashcards

MCP Flashcards

1
Q

DNA gel electrophoresis

A

presence size and quantity of purified DNA

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2
Q

Southern blot/assay

A

presence and size of specific DNA sequence in a complex mixture/sample

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3
Q

PCR

A

amplify a specific DNA sequence from a complex mixture

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4
Q

rtPCR

A

amplify a specific RNA sequence from a complex mixture

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5
Q

multi-plex PCR

A

amplify multiple specific sequences from a complex mixture in a single PCR reaction

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6
Q

northern blot/assay

A

presence and size of a specific RNA sequence in a complex mixture/sample

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7
Q

denaturing gel electrophoresis of proteins

A

separate proteins by size/molecular weight

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8
Q

non-denaturing/native protein gel electrophoresis

A

separate proteins based on size/shape and charge at a particular pH

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9
Q

iso-electric focusing

A

separate proteins based on pI (pH at which protein is uncharged)

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10
Q

pI

A

pH at which protein is uncharged

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11
Q

western blot/assay

A

presence, size and abundance of a specific protein in a complex mixture/sample

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12
Q

immune-fluorescence microscopy

A

the presence and localization of a protein in a fixed tissue/cell sample

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13
Q

GTP fluorescence

A

determine the localization and dynamics of a protein of interested fused to GFP

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14
Q

micro-array based expression analysis

A

determine the presence and relative abundance of all mRNA species in different samples/cells/tissues

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15
Q

RNAi/morpholinos

A

down regulate the expression of a specific gene in a cell/tissue

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16
Q

Fragile X syndrome (physical and mental features)

A

physical: elongated face, large/protruding ears and large testicles (obvious when older)
mental: retardation, anxiety and aggression
* *most common cause of mental retardation

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17
Q

Fragile X syndrome (molecular cause)

A

expansion of CGG triplet repeat affecting FMR1 gene on X chromosome resulting in the failure to express FMRP (fragile X mental retardation protein)

**methylation of FMR1 gene- deficiency of protein

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18
Q

Fragile X syndrome (MOI)

A

X linked dominant with reduced penetrance (80% in males and 30% in females) and dependent on X inactivation pattern

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19
Q

Fragile X syndrome (expansion)

A

occurs during transmission from a female permutation carrier and is dependent on length of repeat and whether the CGG repeats are interrupted with an AGG

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20
Q

Fragile X related Tremor/Ataxia syndrome (FXTAS)

A

FXTAS- increased risk in premutation males of Fragile X syndrome
*lack of voluntary coordination of muscle movements

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21
Q

POF

A

ovarian failure is at a higher risk to premutation carrying females of Fragile X syndrome

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22
Q

CGG>200

A

abnormal methylation and unstable mitosis

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23
Q

Repeats>200

A

abnormally methylated and also mitotically unstable resulting in a smear of bands

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24
Q

Hemoglobinopathies

A

mutations in the alpha or beta globin chain genes which complex together with heme to carry oxygen in the blood

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25
Q

Thalassemias

A

imbalance in the quantity of the two chains

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26
Q

Beta Thalassemia

A

mutations involving beta globin genes leading to a deficiency of beta globin thus an excess of alpha globin forming alpha4 homotetramers (Heinz bodies) destroying RBCs

  • beta globin gene mutations = point mutations
  • *single bp sub with allelic heterogenity
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27
Q

embryology

A

study of development between fertilization and birth that has helped with new diagnostics, treatments and preventative strategies

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28
Q

embryogenesis

A

first 8 weeks in which organs form followed by fetal period (differentiation and growth) from weeks 9-38

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29
Q

Carnegie stages

A

based on physical attributes

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30
Q

Postovulatory age

A

based on time that has passed

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31
Q

Ovulation to implantation (long answer)

A

sperm fertilizes egg in fallopian tube with help of uterine contractions–> zygote –> cleavage (increase of number of cells which are tightly packed by tight junctions but size of zygote remains constant) –> morula (16 cells) with zona pellucida (ECM) –> blastocyst (ICM, blastocoel and trophoblast cells)–>implantation in uterus wall after protease on trophoblast cell membrane makes hole in zona pellucida so blastocyst can hatch and attach to endometrium with help of L-selectins (carbohydrate binding proteins)

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32
Q

ICM

A

inner cell mass; pluripotent cells that give rise to the embryo (ES- embryonic stem cells) and differentiates into hypoblast and epiblast layers on day 9 forming a flat bilaminar disc

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33
Q

Trophoblast cells

A

contribute to extra-embryonic tissues and differentiates on day 8 into cyotrophoblast (inner layer) and syncyiotrophoblast (outer layer)

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34
Q

ectopic pregnancy

A

abnormal blastocyst implantation which is usually fatal for fetus and harmful for mother

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35
Q

Placenta components

A

mother’s uterine endometrium and baby’s chorion

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36
Q

Chorions in twins

A

separate if split happens before formation of trophoblast during day 5 and shared if split happens between its formation on day 5 and aminon formation on day 9

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37
Q

Implantation

A

after week 1 and the trophoblast cells attach to the uterine wall epithelium

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38
Q

3 germ layers

A

ectoderm (skin and CNS), mesoderm (bone and muscle), endoderm (respiratory and digestive) formed from the bilaminar disc which is made up od ICM’s layers (hypoblast and epiblast)

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39
Q

Gastrulation

A

**when the endoderm and mesoderm move from outer surface to inside giving rise to internal organs during the 3rd week of development

formation of a primitive streak which turns into the primitive node (narrow groove that organizes gastrulation events) surrounding a primitive pit. this is followed by invagination of epiblast cells

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40
Q

body axes

A

formed before and during gastrulation

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41
Q

neurulation

A

process by which the neural plate forms the neural tube and divides the ectoderm into 3 domains (surface, neural crest and neural tube)

day 25- closure of cranial end
day 28- closure of posterior end

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42
Q

Spina bifida

A

failure of neural tube closure at posterior end

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43
Q

Ancephalopathy

A

failure of neural tube closure at anterior end

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44
Q

Craniorachischisis

A

complete failure of neural tube closure

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45
Q

Folate

A

can help prevent neural tube defects (essential coenzyme)

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46
Q

neural crest cells

A

follow specific migration pathways from neural tube to contribute to several tissues (cranial, cardiac, trunk and enteric) and undergo an epithelial-to-mesenchymal transition

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47
Q

PCR and Southern blots in relation to Fragile X

A

PCR cannot detect the full mutation or larger pre-mutations due to allelic drop-out

Southern can detect it

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48
Q

what carries oxygen in the blood?

A

complex of heme, alpha globin chain, and beta globin chain

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49
Q

sickle cell anemia vs. thalassemia

A

sickle cell anemia- change in structure of globin chain

thalassemia- change in quantity of globin chain

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50
Q

sickle cell anemia

A

mutation that alters Mnl I and Dde I restriction site

selective advantage in heterozygotes (sickle cell trait)
disadvantage/disease in homozygotes (sickle cell disease)– Hb S/ Hb S

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51
Q

beta gene

A

in a cluster with 5 other beta globin-like genes on chromosome 11

  • 5/6 are active in different times during development
  • 6th= pseudogene which is inactive
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52
Q

Heinz bodies

A

alpha4 homotetramers which precipitate and cause destruction of the RBC

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53
Q

Alpha Thalassemia

A

mutations (usually deletions) involving the alpha globin genes leading to a deficiency of alpha globin

  • thalassemia 1= 2 alpha genes deleted from same chromosome
  • thalassemia 2= 1 alpha gene is deleted from each chromosome
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54
Q

alpha gene

A

alpha 1 and alpha 2 are in a cluster on chromosome 16 with 3 alpha globin-like genes
*2 of the 3 alpha globin-like genes are pseudogenes

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55
Q

HbH

A

disease when 3/4 alpha genes are deleted forming beta4 homotetramers which form inclusion bodies that destroy the RBCs

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56
Q

Hydrops Fetalis

A

having no alpha genes–> lethal

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57
Q

locus control regions

A

coordinate the appropriate developmental expression of the genes within the alpha globin and beta globin gene clusters they also coordinate

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58
Q

Hereditary Persistence of Fetal Hemoglobin (HPFH)

A

results when the delta and beta globin genes are deleted and the gamma globin gene continues to be expressed later in development than usual

*this can compensate for the lack of beta globin chains in patients who also have beta thalassemia

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59
Q

cystic fibrosis

A

progressive chronic lung disease with pancreatic insufficiency caused by one of 1900 CF disease causing mutations such as delta F508

*no locus heterogeneity

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60
Q

probability of further CGG expansion in Fragile X

A

related to size of expansion in female carrier

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61
Q

Sherman paradox

A

effects of Fragile X occur more frequently with each passing generation

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62
Q

when does critical movement occur?

A

when hemoglobin shifts from oxygenated to deoxygenated state

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63
Q

what occurs at birth in terms of globin genes

A

gamma gene activity is replaced by beta gene activity

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64
Q

Hb Constant spring

A

mutation of UAA to CAA in normal termination codon 142 so that a longer and unstable alpha chain mRNA is produced (+31 AAs)

*results in tetramers of beta globin chains (Hb H) which do not release O2 in the peripheral tissues

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65
Q

cluster analysis

A

method to display DNA-microarray data

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66
Q

nucleic acid hybridization

A

annealing one strand to its complement

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67
Q

restriction enzymes

A

cut at specific DNA sequences

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68
Q

cloning

A

isolation and amplification

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69
Q

T4 DNA ligase

A

connects what was cut by restriction endonucleases

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70
Q

vectors

A

move, manipulate and amplify DNA

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71
Q

bacterial plasmids

A

transfer antibiotic resistance genes

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72
Q

bacteriophage lambda

A

reproduces genome by rolling circle replication

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73
Q

cosmids

A

gutted out bacteriophage lambdas that only contain a sequence to replicate DNA and package it into viral particles

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74
Q

BACs

A

way to fool bacteria to carry large pieces of DNA

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75
Q

YACs

A

way to carry human genomic fragments in yeast

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76
Q

library

A

recombinant DNA clones

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77
Q

genomic library

A

bacteria with plasmids containing human DNA fragments that were fragmented by restriction nuclease and put into plasmids by ligase

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78
Q

cDNA library

A

based on expression

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79
Q

Kalydeco

A

increases the time the CFTR channel remains open in G155Dmutated CF patients

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80
Q

dynamic mutation

A

disease becomes more severe with each generation and the greater the copy number, the more likely expansion will occur

  • meiotic instability
  • repeat expansion=genomic instability
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81
Q

two classes of pathologic mechanism

A
  1. non-coding (loss of function)
    - alter the stability or splicing of the mRNA
    - disrupt regulatory elements or change gene dosage
  2. coding (gain of function)
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82
Q

where is the oocyte fertilized

A

the ampullary region of the uterine tube

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83
Q

week 1 of embryogenesis

A

start- oocyte is fertilized
end- blastocyst implants into uterine wall

**cleavage of zygote to morula to blastocyst

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84
Q

what does the fertilization of oocyte create

A

diploid zygote

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85
Q

series of cleavage mitotic divisions

A

reduces the size of the cells and increases the number of cells

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86
Q

timing of cell clevages

A

(30 hrs)- 2 cells
(40 hrs)- 4 cells
(3 days)- 16 cells
(4 days)- late morula

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87
Q

compaction

A

after cleavage to 8 cells, there is maximum cell-cell adhesion which is stabilized by tight junctions

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88
Q

cavitation

A

trophoblast cells secrete fluid into the morula to create a blastocoel

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89
Q

totipotent

A

(morula); can differentiate into any cell type including extra-embryonic tissues

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90
Q

pluripotent

A

(ES cells); can differentiate into any cell type in the body

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91
Q

zona pellucida

A

extracellular matrix of the egg essential for sperm binding during fertilization and acts as a protective layer

*embryo hatches from here to adhere to uterine wall (implantation)

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92
Q

how does blastocyst attach to uterus

A

L selectins on trophoblast cells attach to carbohydrate receptors on uterine epithelium

  • rolling and tethering
  • proteases from trophoblasts degrade extracellular matrix of uterine tissues enabling blastocyst to bury itself within uterine wall

***abnormal= ectopic pregnancy (outside the uterus)

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93
Q

cytotrophoblast

A

inner that adheres to endometrium

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94
Q

syncytiotrophoblast

A

outer that furthers the progression of the embryo into the uterine wall by digesting uterine tissue

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95
Q

two components of placenta

A

uterine endometrium (maternal portion) and chorion (baby portion)

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96
Q

days of formation for chorion and amnion

A

chorion- day 5

amnion- day 9

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97
Q

invagination

A

when epiblast cells migrate towards the primitive streak and slip beneath it during gastrulation giving rise to endoderm and mesoderm

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98
Q

ectoderm gives rise to:

A

CNS, neural crest and outer surface

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99
Q

mesenchyme

A

loosely organized connective tissue of any origin

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100
Q

FISH

A

fluorescence in situ hybridization that combines cytogenetics and molecular diagnostics

*used to determine if a gene, a specific mutation or a particular chromosomal rearrangement is present or absent using a well characterized and specific probe (that just covers the critical region and not the entire deletion)

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101
Q

control probe in FISH

A

used to make sure that a missing signal is due to a disease related issue and not a technical error (failure of probe to bind to target)

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102
Q

person with a deletion- what will be detected with FISH if there is a control

A

two signals on one chromosome and a single signal on the deleted chromosome (which would be the control probe)

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103
Q

the three types of FISH

A
  1. repeat sequences
  2. single copy DNA
  3. chromosome painting
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104
Q

repeat sequences probes

A

isolated from telomere or centromere regions

*recognizes base repeats present such as in a telomere

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105
Q

unique/single copy sequence probes

A

isolated from cloned DNA of a disease-causing gene or fragment of DNA known location associated with a particular gene
*identifies presence or absence of gene, gene region or chromosomal rearrangement of interest

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106
Q

sub-telomere probes

A

DNA sequences from the distal ends of the chromosomes in region sproximal to the actual telomere regions

*identifies very small deletions and rearrangements that cannot be seen by standard karyotype analysis

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107
Q

chromosome painting

A

cocktail of many unique DNA fragments from along the entire length of a chromosome such that following hybridization, the entire chromosome fluoresces

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108
Q

critical region of deletion

A

probe covers this region as opposed to the entire deletion

*could cause miss of other abnormalities that occur within the same gene that is outside of the region associated with the probe

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109
Q

contiguous gene syndromes

A

associated with a particular region in the genome where a group of adjacent genes are all related to a particular outcome even though individually, the normal functions of those genes are unrelated

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110
Q

Williams Syndrome

A

7q contiguous gene syndrome associated with the deletion of the elastin gene (ELN) and those adjacent to it leading to issues that occur without elastin and also low IQ, blue sclera, terribly math skills and stellate iris (which have to do with the unrelated genes that were also affected)

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111
Q

Velocardiofacial syndrome

A

VCFS- interstitial microdeletion on chromosome 22 including 40 genes and 8 pseudogenes in which there is an error during crossing over due to similarities in the sequences of the repeats

*cleft palate and conotruncal heart defects; learning disabilities

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112
Q

why parents may not be affected in those with VCFS

A

different set of alleles than the combination that the child has.

normal chromosome in parent may have alleles that could compensate for what is missing on the deleted chromosome

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113
Q

gene chip technology

A

*test DNA is compared to a reference DNA that has a known genetic component

gene arrays–> looking at specific DNA sequences

expression arrays–> looking at gene products to understand which genes are being expressed in a particular cell type at a particular time

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114
Q

gene arrays

A

identify: genetic polymorphisms, specific mutations or copy number variation (CNV)
* won’t detect balanced rearrangements since chromosome number does not change in this case

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115
Q

expression arrays

A

detects high levels of expression (red) and low levels of expression (green) by labeling a cDNA, made from RNA extracted from a tissue of interest, with fluorochrome

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116
Q

chromosome microarray

A 
peaks= duplications
valleys= loss
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117
Q

when should microarray analysis by the first study done?

A

in unexplained cases involving: developmental delay, intellectual disability, autism spectrum disorders and multiple congenital anomalies

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118
Q

next generation sequencing

A

provides a high resolution genome wide scan that will detect mutations associated with an individual’s medical concerns

**usually targeted so there isn’t an overwhelming amount of information

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119
Q

homologous gene

A

genes in different species that have similar structure, evolutionary origin and function

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120
Q

genome equivalence

A

genetic material is identical in every cell but different genes express different sets of genes

proven by cloning since somatic cell nuclei contain all of the genes necessary to generate an adult organism

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121
Q

differential gene expression and what it controls

A

genetic material is identical in every cell but different cell types express different sets of genes

controls fundamental cellular processes:

  1. proliferation
  2. movement
  3. specialization
  4. interaction
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122
Q

RNA in situ hybridization

A

technique use to detect mRNA expression in cells or tissues

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123
Q

induction

A

when one group of cells changes the behavior of an adjacent set of cells

  • requires- inducer and responder with its ability to respond to the signal (competence)
  • signals are often transmitted via paracrine or juxtacrine signaling
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124
Q

optic vesicle in frog Xenopus laevis

A

optic vesicle induces formation of lens in the anterior/head portion of ectoderm with help of Pax6 (TF) to provide competence

*no optic vesicle–> abnormal or absent lens

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125
Q

Pax6

A

transcription factor that provides competence to help lens respond to inducer (optic vesicle)

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126
Q

morphogens

A

paracrine signaling molecules that cause concentration-dependent effects that direct target cells into different developmental pathways

ex. zebra fish embryo

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127
Q

signaling cascases

A

extracellular signaling molecule binds to receptor thus changing its conformation and giving it enzymatic activity in the cytoplasm–> cascade of phosphorylation processing activating a TF in the nucleus that binds DNA and alters gene expression in the cell

ex. Transforming growth factor - beta (TGFBeta)

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128
Q

Sonic hedgehog homolog

A

turns on transcription of target genes

*example of signal transduction cascade

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129
Q

3 types of hedgehog homologs

A
  1. desert
  2. indian
  3. sonic
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130
Q

situs solitus

A

normal symmetry

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131
Q

situs inversus totalis

A

complete mirror-reversal of organ LR asymmetry

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132
Q

heterotaxy

A

situs ambigus–> which can cause congenital disease

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133
Q

asplenia

A

right isomerism

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134
Q

polysplenia

A

left isomerism

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135
Q

cardiac looping

A

aligns chambers and vascular connections of the heart

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136
Q

Kartagener’s syndrome

A

bronchiectasis
infertility
situs inversus (50%)

*suggests that ciliary beating somehow controls which way the left-right axis is oriented (asymmetric fluid flow–> signaling cascade which drives morphogenesis)

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137
Q

mitochondrial diseases

A

mutations of ox/phos
*mutation rates are high

most serious in CNS and muscle

commonly includes: neuropathies, encephalopathies and myopathies

usually progressive with late onset

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138
Q

mitochondria

A

has its own set of genes but depends on the nuclear genes since it is not a self sufficient organelle

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139
Q

homoplasmy for mitochondrial genes

A

same genetic composition

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140
Q

heteroplasmy for mitochondrial genes

A

2+ different populations of mitochondria present in a cell

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141
Q

differences in mitochondrial mutations

A

different levels of mutant mitochondrial lead to a range of phenotypes

*different tissues may receive different numbers of mitochondria resulting in differential expression of phenotype

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142
Q

diagnosis of mitochondrial mutations is complicated by:

A
  1. heteroplasmy and variable expression
  2. maternal inheritance
  3. progressive nature of disease
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143
Q

DNA analysis

A

examine the regions of the DNA that have the highest degree of polymorphisms

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144
Q

sources of error in forensic DNA analysis

A
  1. quality of specimen

2. statistical analysis and interpretation

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145
Q

mitochondrial analysis

A

siblings carry the same mitochondrial DNA due to same maternal inheritance

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146
Q

nuclear DNA analysis

A

able to identify individuals whereas mitochondrial analysis is only able to identify maternal lineage

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147
Q

congenital malformations

A

structural
metabolic
functional
behavioral

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148
Q

most common birth defect

A

congenital heart disease

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149
Q

Axenfeld-Rieger Syndrome

A

the result of a mutation in a two genes (FOXC1 and PITX2) and can alter the development of multiple systems
*primarily an eye disorder but can affect face, teeth, and belly button

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150
Q

PITX2 and FOXC1

A

mutated in Axenfeld-Rieger syndrome

**produce transcription factor proteins that help the development of the eyes

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151
Q

complex traits

A

*multifactorial

complex traits have many contributing genes and non-genetic influences

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152
Q

Holoprosencephaly

A

due to the failure of the forebrain/prosencephalon from dividing

  • environmental factor= maternal diabetes
  • genetic factors= chromosomal abnormality (deletion/duplication) or mutation in a single gene; multiple genes that use the hedgehog signaling pathway could be the cause

*autosomal dominant

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153
Q

SHH

A

human sonic hedgehog gene that could be mutated leading to a loss of function

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154
Q

Congenital rubella syndrome

A

if a mother is exposed to rubella viral infection, her embryo could have abnormalities including microcephaly, PDA and cataracts
*this could lead to congenital rubella syndrome in which the baby has heart defects and can be deaf

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155
Q

Hyperthermia

A

can interfere with neurulation and cause neural tube defects

*example of how infectious agents could cause birth defects

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156
Q

which environmental factors could cause birth defects?

A 
infectious agents
pharmaceutical agents
ionizing radiation
hyperthermia
metabolic conditions in the mother
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157
Q

Thalidomide

A

a pharmaceutical agent for morning sickness that caused a birth defect (limb defect) due to the induction of oxidative stress or disruption of angiogenesis

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158
Q

Teratology

A

the study of birth defects from environmental causes (such as drugs, infectious agents, hyperthermia, ionizing radiation and metabolic conditions of the mother)

159
Q

teratogen

A

agents that cause birth defects

160
Q

FASD- Fetal Alcohol Spectrum Disorders

A

all alcohol-related defects

  • alcohol is the major cause of congenital mental retardation
  • severity based on amount, timing and genetics
161
Q

FAS- Fetal Alcohol Syndrome

A

most severe of the FASD; microcephaly, narrow upper lip, indistinct philtrum, flat midface, low nose bridge

*brain size and development are affected

162
Q

how does alcohol affect an embryo?

A

interferes with cell migration, proliferation, adhesion, survival and signaling

*several genes are misregulated following exposure to alcohol

163
Q

antidepressants and birth defects

A

SSRIs could cause: heart defects, persistent pulmonary hypertension, neural tube defects, cleft lip and palate and autism

*teratogen

164
Q

embryonic period

A

weeks 3-8 in which the embryo is most susceptible to birth defects from teratogens

165
Q

congenital heart defects (ASD and VSD)

A

10% of all fetuses and is associated with laterality defects

Atrial septal defect (hole in septum that separates atria)–> LA to RA (then back to lungs) instead of going to the LV which would have pumped the oxygen-rich blood to the body

Ventricular septal defect (hole in septum that separates ventricles)–> oxygen-rich blood from LV to RV instead of the aorta

  • usually from multifactorial causes
  • same malformation can result from disrupting different targets
166
Q

Dextrocardia

A

heart is positioned on the right side of the thorax instead of the left

167
Q

heterotaxy in congenital heart malformations

A

could lead to:

  1. septal defects
  2. double outlet RV (DORV)
  3. transposition of great arteries (TGA)
168
Q

signs and symptoms of congenital heart defects

A

cyanosis, rapid breathing, fatigue, poor circulation

*cyanosis= oxygen-poor blood from the right side of the heart enter the left side of the heart directly instead of traveling to the lungs for more oxygen

169
Q

22q11.2 deletion syndrome

A

3 million bp deletion on chromosome 22
autosomal dominant
*malformations of the cardiac outflow tract that are likely caused by defects in cardiac neural crest development

  • truncus arteriosus
  • tetraology of fallot
170
Q

Truncus arteriosus

A

one common blood vessel combining the aorta and pulmonary artery
*single common valve (truncal valve) which has a mix of oxygenated and de-oxygenated blood

171
Q

tetralogy of fallot

A

4 defects of the heart and its blood vessels:

  1. VSD (ventricular septal defect)
  2. pulmonary stenosis- pulmonary valve and artery are narrowed
  3. overriding aorta- increases flow
  4. ventricular hypertrophy
172
Q

outflow tract

A

remodels to form the aorta and pulmonary artery in heart development
*cardiac neural crest cells contribute by migrating from dorsal neural tube to arterial pole

173
Q

familial abnormality

A

parent is a known carrier of a structural chromosome rearrangement of there is a previous child which a chromosome abnormality

174
Q

consanguinity

A

increased risk of inheriting deleterious alleles

175
Q

MSAFP

A

maternal serum alphafetoprotein which is associated with fetal abnormalities

  • measured in blood and refers to the AFP produced by the fetal liver that crosses the placenta
  • correlates to age of gestation
  • test is sensitive to various variables
  • risk assessment, not diagnosis
176
Q

age and risk of abnormalities

A

the greater your age, the higher the chance of chromosomal abnormalities

177
Q

invasive sampling

A

a needle or other device is inserted to collect fetal cells, tissues or fluids

178
Q

ultrasound

A

18 weeks
nuchal translucency ~ possible abnormality
-detects defects that are associated with known syndromes (neural tube defects, clefting) and anomalies due to isolated organ defects

179
Q

anencephaly and encephalocele

A

anencephaly- absence of brain (lethal)

encephalocele- brain is extruded from skull

180
Q

AFP

A

albumin-like protein produced by the fetal liver that crosses the placenta and can be detected in mother’s blood (MSAFP)

*correlated to age of gestation

181
Q

maternal serum quad test

A

four different pregnancy related proteins increases the level of significance
*15-21 weeks

182
Q

integrated pre-natal testing

A

low PAPP-A= increased risk for DS

*10-13 weeks

183
Q

NIPS/NIPT

A

non-invasive prenatal screening

184
Q

cfpDNA

A

10-22 weeks
10-15%= fetal in origin
*DNA sequencing can be done to identify each individual fragment of cfpDNA and determine the chromosome of origin

185
Q

aneuploidy

A

any increase or decrease in the total value for a particular chromosome
*screening test that needs to be confirmed by a diagnostic test

186
Q

2 non invasive tests and 2 invasive tests

A

noninvasive- US, MSAFP

invasive- aminocentesis and chorionic villus sampling

187
Q

aminocentesis

A

needle is inserted through abdomen into amniotic cavity to withdraw amniotic fluid for testing
*16-18 weeks

*removing too much fluid or performing this before 13 weeks can result in developmental defects

188
Q

AFAFP (and the meaning of high AFP and low AFP)

A

fetal analog to MSAFP and is a test done on the amniotic fluid retrieved from the aminocentesis procedure

*screening test that confirms MSAFP findings

  • low AFP = trisomies, mosaic turner syndrome, triploidy, unbalanced translocations (confirmed by karyotype analysis)
  • high AFP= ONTD, teratoma, renal agenesis/obstruction, uropathy, upper GI obstruction, bladder/cloacal exstrophy (confirmed by AChE testing)
189
Q

AChE

A

confirms high AFP levels

*ACH is obtained from the neural tube

190
Q

chorionic villus sampling

A

invasive test
10-12 weeks
transabdominally or transvaginally
*good test to give an early option for termination

  • <10 weeks= risk of limb reduction
  • samples the PLACENTA (since placenta and fetus are derived from the original zygote and thus are usually biologically the same)
  • therefore, it requires the placenta and the fetal cells to be the same
191
Q

64 cell embryo components

A

3- fetal
10-12- amnion/yolk sac
50- chorion/placenta

192
Q

confined placental mosacism

A

only the placenta has the mutation so the CVS will incorrectly assume the fetus is affected

193
Q

confined fetal mosacism

A

only the fetus has the mutation and this will not be detected with CVS since this test only takes a look at the placenta

194
Q

genetic counseling

A

NON-DIRECTIVE- provide the patient with all the relevant information so that they can make their own decision
*risk assessments (from inheritance patterns and recurrence risk) are developed/presented

195
Q

ART- Assisted Reproductive Technologies

A
  1. IVF (in vitro fertilization)
  2. ICSI (intracytoplasmic sperm insertion)
  3. ZIFT (zygote intrafallopian transfer)
  4. donor egg
196
Q

ICSI

A

intracytoplasmic sperm insertion

  • single sperm is injected into an egg
  • following fertilization, embryo is implanted into female
  • for males with low sperm count
197
Q

ZIFT

A

zygote intrafallopian transfer

  • donor egg or sperm
  • in vitro fertilized eggs are transferred to fallopian tube
198
Q

IVF

A

in vitro fertilization

  • eggs and sperm from partners are mixed in vitro
  • after fertilization, embryo is implanted
199
Q

polar body analysis

A

allows for embryo selection when it is known that parents are carriers

  • if polar body has mutation, then the egg doesn’t
  • if the polar body does not have a mutation, then the egg does
200
Q

pre-implantation genetic diagnosis

A

screening technique for embryos at the 8 cell stage in which a single cell is separated out and a general assay looks for chromosomal aneuploidies (FISH or molecular assay)

*karyotype analysis is not used because you will not have a metaphase cell to evaluate

201
Q

donor egg

A

used for those with Turner Syndrome or mitochondrial mutations

*donor egg is mixed with father’s sperm and implanted in woman’s uterus (she can experience being pregnant and the baby will be at least biologically from the father)

202
Q

the importance of proteins

A
  • the machinery of life
  • when defective, they cause genetic disease
  • catalyze and control chemical reactions
  • transmit information
  • their structure affects their function
  • the target of drugs
203
Q

proteome

A

all of the proteins within a cell

204
Q

Tipranivir

A

anti-HIV drug that is similar in structure to the natural peptide substrate but is non-hydrolyzable

205
Q

AD

A

characterized by a misfolded protein (amyloid fibers) that occurred from the improper cleaving of the precursor protein (APP) which is 42 residues and should have been cleaved to 40

*extra two AA’s –> conversion to a toxic/sticky peptide that builds up in the brain

206
Q

protein folding

A

a polypeptide will spontaneously loop back and forth on itself to form a roughly globular, highly compact, 3D structure

207
Q

formation of a peptide bond

A 
condensation reaction (loss of H2O)
charges of terminal amino and carboxyl groups is lost

*planar (which reduces bond rotations to 2) and trans

208
Q

Ramachandran map

A

tells the small fraction of phi and psi values that are allowed due to the limited amount of space (more are allowed for Gly due to fewer repulsions because of -H side chain)

209
Q

pKa’s of Asp, Glu, His, Cys, Lys, Arg, and carboxy and amino terminus

A

4, 4, 6.5, 8, 10, 12 (DGHCKR)

4, 8

210
Q

Aromatic hydrophobic

A

MWFY

211
Q

Aliphatic hydrophobic

A

PILVA

212
Q

hydrophobic

A

poorly soluble in water and these residues would rather associate with themselves than with water

213
Q

pKa

A

the pH at which half the ionizing groups are protonated and half are deprotonated

*can be changed by environment

high= tight bind to H+ (will protonate)
low= weak bind to H+ (will deprotonate)
214
Q

polar side chains

A

presence of electronegative atoms- S,O,N (strong electron withdrawing effect)

*do not accept of give up another H+ except at extremely low or high pH

215
Q

disulfide bond formation

A

oxidation of two -SH groups

*introduction of cross links

216
Q

what allows proteins to adopt their shape?

A

non-covalent forces that are individually weak

*folded proteins are instable allowing them to unfold and refold (dynamic structure)

217
Q

electrostatics

A

a non-covalent force that helps fold proteins due to the interaction between charges (based on Coulomb’s law)

218
Q

Fo ring of ATP synthase

A

buried charge (rare)

219
Q

dipole

A

partial positive and partial negative charges without a formal net charge

  • energetically favorable when aligned antiparallel (like in beta sheets)
  • aligned in a parallel fashion in alpha helices
220
Q

hydrogen bonding

A

electrostatic attraction in which Hs bound to electronegative atoms (S,O,N) end up with a more positive charge since these atoms pull the electron density of the H towards them

221
Q

the 4 non-covalent forces

A
  1. electrostatics
  2. H bonding
  3. van der waals
  4. hydrophobic effect
222
Q

H bonding

A

directional component (strongest when atoms lie in a straight light)

  • S,O, N are electronegative and pull the electron density from H atom causing partial positive and partial negative to occur
  • acceptor and donor
223
Q

van der waals

A

non-covalent force

  • electric dipole that is induced when two atoms are brought close together
  • transient dipole= when electron density is temporarily asymmetric

*maximized when proteins fold

224
Q

core packing in ubiquitin

A

nonpolar on inside and polar on outside
*repacking will causes changes such as gaps or crowding

this causes destabilization–> will not fold

225
Q

hydrophobic effect

A

tendency of hydrophobic/nonpolar molecules to interact with themselves instead of water when place in aqueous solutions which is due to the properties of water

**driving force for folding

*hydrophobic molecules lack charge, polar groups and H-bonding groups

226
Q

secondary protein structures

A

when non-covalent interactions are turned on forming:

  1. alpha helix
  2. beta sheet
  3. beta turn

they are short, simple repeating structures

227
Q

tertiary structures

A

when secondary structures interact with one another and form 3D conformation that is held by short and long range interactions

228
Q

alpha helix

A

proteins are 31% alpha helix
NH of i residue to CO of i + 4 residue

  1. 6 residues a turn (favorable backbone dihedral angles)
  2. 4 Angstroms a turn
229
Q

stabilizing interactions of alpha helices

A

backbone-backbone (H-bonding)
side chain-backbone (permanent dipole)
side chain-side chain (periodicity=4)

230
Q

helix formers and breakers

A

former- Ala
breaker- beta branched or bulky–> Pro, Gly
indifferent- long and straight (rotate fairly well)

231
Q

beta sheet

A

28% of protein
straight, extended and H bonded at each peptide group
periodicity=2

  • pleated
  • strands could be parallel (H-bonds are bent) or anti-parallel (which is seen more often)
232
Q

what portion of residues are involved in tight turns?

A

1/3 (Pro- kinks; Gly- relieve steric clashes)

233
Q

loop

A

lack regular H-bond conformations and aren’t secondary structures
*not periodic

234
Q

domains

A

assembled secondary structures forming distinct patterns (folds)

*stable and semi-independent units of structure

235
Q

motif

A

short stretches of secondary structures and are usually not stable by themselves

236
Q

HTH

A

helix-turn-helix
motif in which proteins recognize specific sequences of DNA

*recognition alpha-helix and a support alpha-helix connected by a turn

237
Q

recognition alpha helix

A

sits in the major groove and binds to specific sequences of nucleotides (part of HTH- helix-turn-helix motif)

238
Q

zinc finger motif

A

DNA binding motif

  • Zn2+ holds it together without the need for a hydrophobic core
  • hydrophobic side chains stabilizes the helix which binds to the major groove of the DNA
239
Q

coiled-coil

A

heptad repeat

  • found in fibrous proteins and TF’s
  • protein-protein recognition, mechanical force transduction, viral penetration

ex: GCN4 TF

a,d- glue
e,g- electrostatics

240
Q

influenza haemagglutinin

A

harpooning mechanism to gain entry into cell

triple-stranded coiled-coil

  • virus is endocytosed into a vesicle that becomes acidic due to vacuolar ATPase proton pumps…conformational change and then extended loop folds into alpha helix and the coiled-coil lengthens which then thrusts outward and penetrate the vacuolar membrane
  • fusion of two membranes–> release of viral RNA into the cell causing infection
241
Q

Hsp70

A

chaperone protein that prevents aggregation by covering up sticky hydrophobic patches

242
Q

Hsp60

A

chaperone protein that is shaped like a hollow donut and allows the misfolded protein to come in. GroES cap seals it and ATP hydrolysis will unfold the misfolded protein so that it could be properly folded

243
Q

GroEL/GroES mechanisms

A

isolation (Anfinsen box), confinement, forced unfolding (iterative annealing)

244
Q

3 enzymes of ubiquitination

A

E1- activating enzyme
E2- conjugating enzyme
E3- ligating enzyme

245
Q

protein degradation/turnover

A

goes one of two ways–> lysosomes/proteases or ubiquitin/proteasome pathway

246
Q

ubiquitination

A

ligation involves ATP is it is the binding of ubiquitin to epsilon-amino group of Lys of the protein
*polyubiquitination chain (Lys are attached)

then degradation by the proteasome*

247
Q

degradation by the proteasome and its structure

A

26S that has a 20S core and 19S caps
protein threaded through 20S which is where ubiquitin is taken off so it could be reused
20S degrades it (ATP helps unfold the protein) and 19S influences the cleavage
either sent to ER or recycled which requires further degradation

248
Q

diseases of ubiquitin-proteasome pathway

A

cancer (degradation of tumor suppressors)
neurodegenerative diseases (accumulation of ubiquitin proteins in plaques)
CF
autoimmune

249
Q

molecular basis of protein disease and how balance of structure matters

A

loss of protein function
gain of function
alternate conformations/aggregates

direct knockout- mutation in a residue–> altered critical side chain
destabilization- unfolded
toxic conformation- incorrectly folded

250
Q

p53 function and structure

A

function: tumor suppressor protein that functions to cause cell death in the presence of DNA damage
* prevents the accumulation of chromosomal mutations
structure: (modular) DNA binding domain, C-term, disordered N-term

251
Q

DNA, contact and stability mutants

A

DNA- alters side chains
contact- reduces DNA binding
stability- decreases thermodynamic stability

252
Q

how is p53 normally degraded

A

p53 activates transcription of its own E3 ubiquitin ligase MDM2

253
Q

PhiKan083

A

small molecule that stabilizes the folded state of a mutated form of p53 (Y220C tumorigenic mutations)

254
Q

treatment options for delta F508 CFTR mutation

A

CF patients
-small organic molecules (helps stabilize folded protein)
-chaperones (prevents misfolding)
inhibiting degradation by ubiquitin/proteasome pathway

255
Q

alpha 1- AT deficiency

A 
Z type (Glu 342--> Lys) and S type (Glu264--> Val)
*causes liver disease or emphysema

*usually is an inhibitor of polypeptide cleavage (serine protease inhibitor)

256
Q

serpins

A

3 beta sheets and 9 alpha helices

target protease cleaves an internal site in reactive center

binding to target protease prevents it from binding substrate

257
Q

alpha 1 AT

A

uses stored energy to trap its target

target protease binds and cleave reactive center loop (RCL)

RCL goes into beta sheet and drags the protease with it
*the central beta sheet must be flexible enough to accept the RCL as part of the normal inhibitory process

258
Q

polymerization of alpha 1 AT

A

central beta sheet opens and allows part of the reactive loop of a second protein to inset into the lower portion of the sheet and stable (beads-on-a-string) aggregates form

*can be blocked and reversed by peptides

259
Q

what is used to stain CJD

A

thioflavin T and congo red to detect amyloid plaques

*vCJD forms vacuoles

260
Q

TSE

A

transmissible spongiform encephalopathies

261
Q

what reduces infectivity of prions

A

protein denaturants (NaOH, SDS)

262
Q

PrP^sc

A

insoluble and protease resistant

  • come together and form stable beta sheet
  • forms seed since it is the building block for amyloid fibril
263
Q

structural models of PrP^sc

A

a) trimer stacks
b) beta sheet backbone- PrP attach and spiral
c) extended sheet- stack of parallel beta strands

264
Q

definition of amyloidosis and prevention mechanism

A

the formation of amyloid fibers from misfolded PrP^c

prevention-

  1. reduce the amount of PrP^c by silencing siRNA
  2. stabilize PrP^c by binding compounds to prevent it from changing to PrP^sc
  3. immunotherapy to clear the toxic substance from the species
265
Q

AD

A

incorrectly cleavage of APP leading to the formation of ABeta42 (beta amyloid) that has two extra residues

*small, soluble aggregates of the misfolded peptide that form before the mature amyloid fibril cause neuronal cell death

266
Q

ABeta42

A

parallel in-register beta sheet stabilized by side chain interactions

267
Q

problems with AD treatment ideas

A

inhibiting secretase could affect other cellular pathways besides ABeta

blocking fibril formation may cause pre-fibrillar aggregates to accumulate (pre-fibrillar species disrupt cell membranes)

268
Q

insulin and IAPP

A

higher insulin causes higher IAPP which binds to lipid bilayers which accelerates the rate of formation of amyloid fibrils

269
Q

peptide inhibitors of ABeta and IAPP fibril formation

A

stabilized by side chain side chain interactions and peptide peptide H bonds so blocking peptide nitrogens on the growing face of the beta strand prevents the formation of H bonds to neighboring peptides

*beta sheets and thus capped and prevented from growing

270
Q

mature fibril

A

helps protect the cell membrane from being disrupted

*process of amyloid fiber formation is what is harmful

271
Q

tumor

A

benign or malignant

overgrowth of abnormal cells

272
Q

malignancy

A

significant changes in karyotype of the cells

273
Q

metastasis

A

cells become invasive or migrate to another site but retain the original cell morphology

274
Q

sarcoma

A

type of cancer of the mesenchymal tissue

275
Q

carcinoma

A

type of cancer of the epitheloid tissue

276
Q

how are cancers classified

A

location
tissue type
degree of malignancy

277
Q

exposure to environmental mutagens

A

could lead to changes in normal cell regulation and/or development

278
Q

CIN

A

chromosome instability: gain, loss or rearrangement of chromosomes

279
Q

oncogene

A

associated with unregulated cell proliferation that can change host cells
normal: proto-oncogenes which can be mutated (increase in activity) to become oncogenes= gain of function

*only one mutation required

280
Q

CML

A

chronic myelogenous leukemia
-translocation of chromosomes 9 and 22 resulting in chimeric protein (combination of proto-oncogene and 2nd gene) which causes the loss of control and increase in tyrosine kinase

281
Q

Gleevec

A

drug targeted at inhibiting the overproduction of tyrosine kinase from the translocation of chromosomes 9 and 22 in CML (chronic myelogenous leukemia)

282
Q

APL

A

acute promyelocytic leukemia

  • translocation of chromosomes 15 and 17 which breaks the PML gene on chromosome 15 and the RARA gene on chromosome 17
  • chimeric protein product–dual fusion probe
283
Q

tumor suppressor

A

gatekeepers (prevent tumors by regulating cell cycles) and caretakers (repair DNA damage); tissue specific

mutation-recessive since it requires 2 mutations (loss of function)

loss or inactivation will lead to a change in phenotype and ultimately neoplasmic growth

284
Q

examples of tumor suppressors

A

P53 Rb1

285
Q

Rb1

A

tumor suppressor gene located on chromosome 13 that controls the progression from G1 to S

286
Q

Retinoblastoma

A

mutation of Rb1 and affects the eye

  • sporatic-unilateral
  • inherited-bilateral; all of the cells of the body will have the mutation and symptoms occur earlier

secondary cancer= osteosarcoma (cancer of the mesenchymal cells of the bones)

287
Q

Li Fraumeni

A

familial cancer syndrome associated with multiple neoplasia and an inherited mutation of p53

288
Q

Breast cancer

A

familial or sporatic

  • mutations from errors in homologous recombination and DNA repair defects
  • two genes associated- BRCA1 (near 17-p53) and BRCA2 (near 13-Rb1)
  • *survivor guilt, affected males
  • increased risk in Ashkenazi Jews
289
Q

caretaker mutations

A

defect in DNA repair ability

*breakage syndromes- leads to deletion and genomic defects

290
Q

triradicals

A

Y shaped chromosomes from being instable

291
Q

HNPCC

A

hereditary nonpolyposis colon cancer

  • error in mismatch repair genes
  • **malfunction in a normal cellular process
  • 90% risk in males who inherit one mutation
292
Q

what does microsatellite analysis detect?

A

mismatch repair defects alter total number of repeats so presence of extra bands is indicative of a disease diagnosis (ex. HNPCC)

293
Q

proto-oncogenes vs tumor suppressors mutations

A

proto- GOF, chromosome translocation, amplification

tumor- LOF, deletions, chromosome loss

294
Q

clonality

A

a normal cell may have a single mutation which proliferates and generates an abnormal clone

acquired change in a limited number of cells in which further chromosomal changes may modify the karyotype and produce additional clones

295
Q

loss of heterozygosity

A

loss of the entire gene and surrounding chromosomal region

296
Q

remission and relapse

A

suppression of a disease by a treatment but if the symptoms recur and tests indicate that the genetic abnormality has returned, the patient is considered to be in relapse

297
Q

Somatic stem cells

A

can only differentiate into the cell types present in the tissue of origin

298
Q

autologous vs allogeneic

A

from self vs from matched donor

299
Q

mRNA processing

A

making RNA usable for protein synthesis

300
Q

central dogma

A

genetic information flows from DNA to RNA to protein
(some viruses use RNA as a source of genetic information and template for replication- Polio; whereas HIV converts RNA into DNA to integrate it into the host genome)

301
Q

mRNA

A

carry information coding for proteins

302
Q

special feature of RNA

A

is single stranded and can fold up or base pair with other nucleic acids (DNA or RNA)

303
Q

RNA-RNA hybrids

A

ribozymes (catalytic)

miRNA (regulatory)

304
Q

terminators and promoters

A

promoter- start sequences located at 5’ (not transcribed)
*orientation dictates which strand will be transcribed

terminator- stop sequence located at 3’ (transcribed even though is non-coding)

305
Q

steps of transcription

A
  1. initiation
    * **cells regulate which proteins are produced and at what rate
  2. elongation
  3. termination
306
Q

5’ and 3’ UTR

A

sequences prior to the first AUG initiation codon and after the termination codon present in RNA transcripts that are not translated (untranslated sequences)

307
Q

differences between RNA and DNA polymerases

A

RNA-
rNTPs instead of dNTPs
Uracil instead of thymine
de novo without primers instead of using primers
no exonuclease activity instead of exonuclease activity

308
Q

RNA polymerase II

A

transcribes protein-coding genes

  • eukaryotes have two more types (I, III)
  • bacteria- only have one type commonly targeted by antibiotics
309
Q

Amanita phalloides

A

poisonous mushrooms that contain a toxin, alpha-amanitin that inhibits eukaryotic RNA polymerase II

310
Q

RNA Pol II transcription steps

A

TBP (TATA binding protein) binds to TATA box
TFs are recruited
RNA polymerase is recruited
**formation of pre-initiation complex
phosphorylation of RNA pol II
recruitment of enzymes
pol II leaves promoter and transcribed mRNA

***co-transcriptional covalent modification
(bacteria- modification does not occur and mRNA is translated immediately)

311
Q

prokaryotic vs eukaryotic translation

A

prokaryotes- mRNA is translated co-transcriptionally without modification

eukaryotes- mRNA is processed then transported out of the nucleus into the cytoplasm where mRNA can be translated into protein

312
Q

modification of eukaryotic mRNA

A

covalent modification that occurs co-transcriptionally
*5’ capping (5’-5’ linkage of 7-methyl G to RNA) and 3’ polyadenylation (non-templated)

  • stabilizes the mRNA by protecting it from degradation
  • modifications are necessary for nuclear export and translation initiation
313
Q

creation of mature mRNA

A

introns are removed (and then degraded) by mRNA splicing from the pre-mRNA (primary transcript) to become the mature mRNA

314
Q

snRNPs

A

recognize specific sequences at introns and cleave them while covalently linking exons together (RNA splicing)

lariat intermediate

315
Q

lariat formation

A

intermediate in RNA splicing which contains an unbranched intron sequence that has a unique 2’ to 5’ phosphodiester linkage and is released and degraded

cut at 5’ end of intron and attaches to adenine forming a loop

  • free 3’ end of EXON reacts with beginning of second exon sequence that is attached to the intron thus cutting the intron at its 3’ end
  • lariat (loop of intron)
316
Q

alternate splicing

A

genes can be spliced in various ways to produce different mRNAs (protein isoforms from same gene)

*normally programmed event as opposed to splicing mutations which lead to Progeria

317
Q

Progeria

A

splicing mutation

  • normal= splicing of LMNA= lamin A
  • 1824C–>T mutation leads to abnormal splicing deleting 150 bases from the mRNA removing 50 AAs
  • abnormal progerin remains bound to membrane
318
Q

OMIM

A

online mendelian inheritance in man

*genetic information online database

319
Q

similarity percentage between two individuals

A

99.5% similar

320
Q

evidence of personalized medicine

A

drug therapy
idiopathic disease (spontaneous origin)
cancer diagnosis, prognosis, treatment (oncology)
prenatal testing and newborn screening

321
Q

pharmacogenetics

A

relation of heritable variation with inter-individual variation in drug response

322
Q

pharmacogenomics

A

field of new drug development based on out increasing knowledge of all genes in the human genome

323
Q

pharmacokinetics

A

mechanisms of absorption and distribution of an administered drug

324
Q

different outcomes of drug ingestion

A

drug- toxic or not toxic

outcome- beneficial or non-beneficial

325
Q

CYP2C19

A

mutation in a gene that leads to the inability to interact with the drug

326
Q

cytochrome p450

A

gene family in which a variety of different enzymes are involved in drug metabolism (mutations will change enzyme’s ability to perform function)

327
Q

CYP2D6 and its classes of function

A

affects the ability of an individual to metabolize certain drugs
*classes of function

  1. poor- no functional allele (cannot convert drug to useable form–accumulation of chemicals= toxic)
  2. intermediate- one functional, one mutant (utilize drug at slower rate so require lower dose to prevent toxic build-up)
  3. extensive- two functional alleles (work in expected fashion)
  4. ultra- duplicate copies of functional alleles (degrades drugs rapidly so more of drug is needed to prevent degradation before therapeutic levels are reached)
328
Q

Warfarin

A

synthetic anti-coagulant that inhibits the enzyme epoxide reductase which inhibits Vitamin K metabolism

(Vitamin K- clotting factors)
(Coumadin= natural anti-coagulant)

  • garlic and ginger help it
  • green veggies (vit K) decrease its effectiveness
329
Q

thrombosis

A

blood clotting

330
Q

genes that affect Warfarin metabolism

A

VKORC1 allele of the VKOR gene

CYP2C9 of cytochrome p450 (involved in drug metabolism)

331
Q

microarray technology in terms of personalized medicine

A

can be used to do a genome wide scan of an individual’s genetic complement and utilized to manage the patient’s health throughout life

*increased personal approach to individual disease

332
Q

ROH

A

regions of homozygosity- kinship is same

*identity by descent

333
Q

GINA

A

genetic information nondiscrimination act

*prohibits discrimination in health coverage and employment based on genetic information

334
Q

3 types of screening

A
  1. prenatal (MSAFP, AFAFP, maternal quad)
  2. newborn (disorders- endocrine, hemoglobinopathies, infectious disease, inborn errors of metabolism)*required
  3. carrier
335
Q

similarities and differences between PWS and AS

A

both Prader-Willi Syndrome and Angelman syndrome have microdeletions of proximal long arm of chromosome 15 and FISH will detect their presence but clinical diagnosis will distinguish between the two

  • PWS- gain weight quickly, temper, small hands and feet, hypogonadism, developmentally delayed
  • AS- severely mentally retarded and laugh at inappropriate times, hyperactivity, short stature, microcephaly, seizures and ataxia
336
Q

maternal vs. paternal origin difference

A

PWS- deletion on chromosome from father or maternal uniparental disomy (two copies of mother’s chromosome)

AS- deletion on chromosome from mother or paternal uniparental disomy (two copies of father’s chromosome)

337
Q

how to detect UPD

A

molecular probe technology and microarray since in karyotype, homologs will look alike

338
Q

heterodisomy

A

from different sources
*from nondisjunction error leading to trisomy and then a loss of one- 1/3 of time will lead to uniparental heterodisomy where as 2/3 times it will lead to biparental heterodisomy

339
Q

isodisomy

A 
duplicate copies (thus from same source)
*nondisjunction error followed by duplication
340
Q

expected inheritance

A

biparental heterodisomy (can result from nondisjunction error causing trisomy in which one is lost (2/3 times it results in biparental heterodisomy whereas 1/3 of the time it results in uniparental heterodisomy)

341
Q

imprinting

A

differential modification leads to differential expression of parental alleles during development and in the adult

not sufficient to have a pair- they need to be the correct configuration

  • chromosomes look alike at the molecular level but there are important differences between male and female chromosomes
  • associated with methylation of DNA (epigenetic modification)
342
Q

methylation

A

epigenetic effect in which a methyl group is attached to a cytosine residue in DNA

  • pattern lasts one generation (applied at meiosis)
  • reimprinting (stripping down and replacement)
343
Q

causes of PWS

A
  1. deletion of paternal chromosome 15 resulting in only maternal alleles
  2. UPD with only maternally imprinted alleles
  3. imprinting error where complement is comprised of one chromosome from father and one from mother but paternal chromosome has a maternal imprint resulting in functionally only maternal alleles

**dads info is missing!

344
Q

causes of AS

A
  1. deletion of maternal chromosome 15 resulting in only paternal alleles
  2. UPD with only paternal imprinted alleles
  3. imprinting error where the complement is comprised of one chromosome from father and one from mother but the maternal chromosome has a parental imprint resulting in functionally only paternal alleles

**mom’s info is missing

345
Q

Paternal imprint genes

A

SNRPN

necdin

346
Q

Maternal imprint genes

A

UBE3A

347
Q

epigenetics

A

the study of heritable changes in gene function that are NOT caused by change in the DNA sequence
*modification of transcription that alters gene expression

  1. methylation (important in X inactivation and imprinting)
  2. histone modification
  3. chromatin remodeling
348
Q

methylation in cancer

A

hypomethylation- development of oncogenes

hypermethylation- inactivation of tumor suppressors

349
Q

TF as epigenetic modifiers

A

bind to DNA to alter expression

350
Q

miRNA as epigenetic modifiers

A

bind to mRNA and can alter expression

351
Q

Rett syndrome

A

mutation in the MECP2 TF leading to lack of proper neural development causing a variety of negative phenotypic expressions

*disease severity is also linked to X inactivation since MECP2 is on distal long arm and is subject to X inactivation

**regions of methylated CpG that are normally repressed by recruitment of HDACs (deacetylation) are now activated

352
Q

main site of gene control

A

initiation of transcription this affecting gene expression

353
Q

examples of transcription diseases

A

cancer
R-T and Rett syndromes
thalassemia

354
Q

eukaryotic DNA binding domains

A

contain a recognition alpha helix that inserts in the major groove of DNA and makes multiple contacts

355
Q

operon

A

cluster of genes in bacteria that is transcribed from a single promoter

356
Q

polycistronic mRNA

A

bacterial characteristic signifying that a single mRNA can create multiple proteins

357
Q

operator

A

binding sites in bacteria for repressor proteins

358
Q

activator

A

helps recruit and/or stimulate RNA polymerase to begin transcription

359
Q

modularity

A

fusion of different factors could result in a novel activity (could be bad)

360
Q

overexpression of HOX11

A

overexpression of protein in hemapoietic cells causing uncontrolled growth

361
Q

what do transcription regulators recruit

A 
RNA polymerase II
chromatin modifiers (loosened so pol II can bind)

*they increase the rate of transcription initiation

362
Q

types of chromatin modifiers

A

covalent histone modifications

ATP-dependent nucleosome remodeling (use ATP)

363
Q

histone modifications

A

occurs on the Lys N terminal tails of H3 and H4

HATs- acetyltransferase–> activation
HDACs- deacetylases–> deactivation

  • methylation (activation or deactivation)
  • phosphorylation (coupled to acetylation)
364
Q

chromatin remodeling enzymes

A

displace nucleosomes from promoters or reposition them thus clearing the way for the assembly of the transcription initiation complex

365
Q

mechanisms that regulate TF synthesis and activity

A

covalent modification
intracellular trafficking
selective degradation

366
Q

what causes drug side effects?

A

the fact that each regulator targets multiple genes

367
Q

hematopoiesis is a good example of:

A

cell differentiation pathways being controlled by transcription regulators

368
Q

how can you measure relative mRNA levels?

A 
DNA microarray (large chunks) 
RNA seq (whole genome)
369
Q

Beta globin gene regulatory proteins

A

has two enhancers (upstream and downstream) that recruit chromatin remodeling complexes, histone modifying enzymes, the general TF and RNA polymerase

370
Q

LCR mutation

A

locus of control region- when not expressed the (beta) gene is tightly packed into a heterochromatin-like structure

*if LCR is mutated, the gene is silenced and prevents (beta) globin production–> beta thalassemia

371
Q

autoregulation transcriptional mechanism

A

transcription factor activates other genes but also its own gene

372
Q

what does the HWE (Hardy-Weinberg Equation) allow us to do?

A

estimate how many people in a population are asymptomatic AR carriers and compare this to the likelihood of a new mutation

373
Q

assortative mating

A

choosing mating like yourself

  • reduces proportion of heterozygotes
  • increases inbreeding and frequency of AR diseases
374
Q

assumptions of HWE

A
  1. random mating (in regard to disease gene)
  2. large population (decreases chance for inbreeding and stabilizes allele frequencies)
  3. no natural selection/constant selection
375
Q

consanguinity

A

inbreeding (recent ancestor in common)–> increases homozygosity and AR diseases

376
Q

drift

A

random change in allele frequency

377
Q

outcome of no mutation

A

no variation or ability to adapt to environmental change thus no capacity to evolve

378
Q

two types of breast cancer

A

lobular, ductus (lobes and ducts)

379
Q

how does a breast tumor cell proliferate

A

it has estrogen receptors and when estrogen binds it proliferates

380
Q

how to stop breast tumor cell proliferation

A

drugs- Tamoxifen and Raloxifene
(estrogen receptor antagonists)

or endocrine therapy

381
Q

Gail Model

A

way to assess risk of developing breast cancer

382
Q

endocrine therapy

A

prevents estrogen production or blocks estrogen receptors

383
Q

ERBB2

A

protein encoded by oncogene

384
Q

trastuzumab

A

binds ERBB2 and upregulates p27 which prevents cell proliferation

385
Q

what is used for bone pain in stage 4 breast cancer

A

bisphosphonates

386
Q

4 main molecular classes of breast cancer

A

A–> ERBB2 -
B–> ERBB2 +
ERBB2–> ER - PR -
Basal–> EGFR +

387
Q

oncotype DX

A

for A and B (since ER +)

tests for presence of 16 cancer-related genes and 5 reference genes
RT-PCR

388
Q

mammaprint

A

risk of metastasis
molecular assay using 70 gene signature for breast cancer

> 0.4 = good prognosis

389
Q

percentages of familial vs sporatic breast cancer causes

A

familial- 10-15% (60% from having BRCA 1 and BRCA2)

sporatic- 80%

390
Q

BRCA1 and BRCA2 chances of getting breast cancer

A

BRCA1- 40-85%
BRCA2- 15-20%

*these are tumor suppressors

391
Q

BRCA1 and BRCA 2 normal functions

A

1- generation of ssDNA at ds breaks, stabilization of genome, checkpoint control (G2-M), mitotic spindle formation and regulation of topoisomerase IIa

2-recruits RAD51

392
Q

HER2

A

proto-oncogene, member of tyrosine kinase family

expression is increased in breast cancer

can’t bind ligand but can form heterodimers

393
Q

tests to detect presence of HER2

A

FISH
CISH (light microscope)
SISH (deposits metals onto probe target and requires fewer reagents)
IHC (antibodies)

394
Q

Lapatinib

A

inhibitor of HER2 kinase activity

Unit 2 (3 decks)

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