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MC2 > Diagnostic (Washington and Kruzka) > Flashcards

Diagnostic (Washington and Kruzka) Flashcards

1
Q

What is a Rare orphan disease?

A

It is defined as a disease that affects fewer than 200,000 Americans at any given time

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2
Q

What are cloning vectors used for?

A

DNA mapping and genotyping.

Method for fractioning complex starting DNA populations.

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3
Q

Functional cloning

A

Gene function precedes identifying gene; requires knowledge about the function and structure of protein product

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4
Q

What are examples of functional cloning?

A

Bioinformatics

Microarrays

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5
Q

Positional cloning

A

gene mapping precedes gene identity (characterize the gene, its locus, and its allele) ; requires knowing the map position of a gene (physical and genomic)

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6
Q

What are examples of positional cloning?

A

Genome/exome sequencing

Halotype maps

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7
Q

What us Genomic mapping?

A

Describes the order of genes, markers, and the spacing between them

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8
Q

Genetic map?

A

linkage association based on genetics recombination (statistical probability) in pedigree (linked to a marker)
- has immediate clinical application to provide information about a genes location

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9
Q

Physical map

A

base pair sequence (sequencing/HGP)

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10
Q

What are the two basic types of polymorphism that can be used for genotyping?

A

Restriction site polymorphism (RSP) - used to study disease

Variable number tandem repeats (VNTR) or restriction fragments polymorphism (RFLP)

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11
Q

Single Nucleotide Polymorphism (SNPs)

A

exist as a base pair change in DNA

- subset of SNPs have been detected by loss of gain of a restriction site at the place of the change base = RSP

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12
Q

VNTR

A

Repeat units ~9-65 bp long
arise from instability on an array of tandem repeats causing variable exchange in the repeat until
- looks at microsatalite and minisatallite region

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13
Q

Linkage vs association

A

Linkage it the relationship between loci (Genetic). Provides powerful method for scanning the gene in 20-50Mb segments to locate a disease gene

Association is the statistical statement about co-occurrence of alleys and phenotypes

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14
Q

Linkage Association

A

narrow down candidate gene region

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15
Q

Non-syntenic vs systenic

A

Two genes are systemic if they are located on the same chromosome (both on chromosome 1)

Non-Syntenic - located on different chromosomes (one on chromosome 1 and the other on chromosome 2)

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16
Q

Phase

A

a heterozygous genotype for each of two linked genes can have allele in either of two configurations - cis or trans

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17
Q

trans configuration phase

A

also known as repulsion

mutant and marker alleles on opposite homologous chromosomes

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18
Q

cis configuration phase

A

also know as coupling

both mutant and marker allele on the same homologous chromosome

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19
Q

Chaismata in prophase results in what?

A

Recombinant allels - non parental chromosomes

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20
Q

What does recombination fraction define?

A

Genetic distance (not physical distance

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21
Q

Recombination equals to 0.5 tells you what?

A

That the allele/genes reside on the different chromosome or systemic alleles are very far apart

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22
Q

Recombination equals to 0 tel you what?

A

That the allies reside close together, crossover rarely occurs and they are considered to be linked

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23
Q

Linkage equilibrium (LE)

A

Two loci inheritance is an independent event = random assortment

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24
Q

Linkage disequilibrium (LD)

A

two particular alleles at different loci are not segregating independently in a population (if you are not at 50% segregation)

This plays a fundamental role in gene mapping, fine mapping of complex disease genes and GWAS

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25
Q

When a new mutation occurs what does it create?

A

Linkage disequilibrium

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26
Q

quantify disequilibrium

A

difference between observed frequencies of two-locus calotype minus the frequencies it would be expected to show if the alleles are segregating at random.

D = P (AB) - P(A) x P(B)

Max - 0.5 (in linkage or in repulsion)

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27
Q

How does time and recombinational distance affect linkage distance?

A

It cause Linkage disequilibrium to decrease

Look at slide 17

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28
Q

Calculating Theta Recombination

A

The number of recombination/total

Convert fraction -> decimal -> cM -> bases apart

ex. Theta = 0.2 = 20% = 20cM = 2 x 10^7 bases apart

every 10% = 10cM = 1 x 10^6

Above 50% means that the genes are not close together

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29
Q

Lod Score

A

The ratio of the 2 likelihoods gives the odds of linkage

Most efficient statistic for evaluating pedigrees for linkage

Calculated for a range of theta values

Most likely recombinant is the value which the score is at its maximum

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30
Q

What does it mean when LOD (Z): >/= 3.0 (1000:1)

A

It means that it (linkage) is in favor

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31
Q

What does it mean when LOD (Z): = 2.0 (1:100)

A

It mens that it is against linkage

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32
Q

LOD (Z) equation

A

1/2 non recombination probability x 1/2 probability recombination / probability of no linkage

Non recombination fraction = 1-theta so the frequency with 2 parental types = 1-theta / 2

recombination fraction = theta so frequency with two parental yes is theta/2

frequency of no linkage with two parental types is 0.5/2

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33
Q

What is the phase for DMD marker alleles?

A

This is Duchane’s muscular dystrophy and the D2 and L128 marker alleles are in coupling

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34
Q

Haploid Genotype

A

Also known as a halotype
A combination of alleles that are transmitted together on the same chromosome
- considered a unit
- no recombination

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35
Q

What is a HapMap?

A

tool that allows researcher to find genes and genetic variations that affect health and disease

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36
Q

What is GWS?

A

Genome Wide Association Studies?
Technology: Genomic DNA probes
Analysis: single nucleotide polymorphism ; estimate decrease in risk but you don’t know which gene it is

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37
Q

HapMap and GWAS are generated by using?

A

By using single nucleotide polymorphism (SNPs) on a single chromatid that are statistically associated

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38
Q

What does mapping the relationships among SNPs tell you

A

How close these genes are (how related we are to others). By looking at SNPs you can determine what changes cause the disease to be more severe and what changes are helpful.

ex. CHF genetic SNP association decrease risk of AMD
In african americans for atherosclerosis and alzheimers having the ApoE2 mutation is better than having the ApoE4 mutation

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39
Q

fluorescence in situ hybridization (FISH)

A

Technology fluorescently labeled probes
Analysis: locate the position of specific DNA sequence on chromosome (del/dup. translocations)
This specifically looks at chromosome changes

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40
Q

Comparative Genomic Hybridization (CGH)

A

Technology: Genomic DNA Probes
Analysis: copy number variations, similarities and differences between the function, gene expression, and gene regulation

41
Q

DNA microarray (DNA chip)

A

Technology: Small glass slide and DNA hybrid
Analysis: genetic variation at millions known genetic variants

42
Q

How can you detect very small deletions (0.5-1X 10^7 basses), t to 10Mb?

A

by using FISH or Spectral Karyotyping (SKY)

Probes are derived from genomic libraries

43
Q

Identification of Wolf Hirshorn syndrome (-4p) and Cri-du-chat syndrome (-5p) is done by?

A

FISH

Chromosome staining occurs -> macro-changes to chromosome -> identification

44
Q

Identification and diagnosis of DiGeorge and VCFS syndrome, Ph+CML (Clinical Cancer Vignette, trisomy 8), translocation of partial trisomy 21 46 XX +21 is done by what?

A

FISH

45
Q

What is clinical cancer vignette?

A

Chromosome 9 - abl segment
Chromosome 22 - bar segment
Two segments break off and join -> hybrid chromosome -> Philly chromosome
Creates a different fluorescent color

46
Q

What is Spectral Karyotyping (SKY) and multiplex-FISH (M-FISH)?

A

chromosome specific - labeled DNA fragments covering the length of each individual chromosome

detect inerchromosomal rearrangements and aneuploidy

used for hybridization experiments with metaphase chromosome spreads. Maternal and paternal copy of each chromosome labeled with same color

47
Q

Deletion of the DMD gene can be detected by?

A

FISH

48
Q

BRCA1 BrCa can be treated with?

A

olaparib 400mg twice daily

49
Q

What only identifies variation in DNA that is common in the population?

A

Genome Wide Searches

50
Q

Sequencing?

A

Determines every letter in DNA sequence, reveals rare mutations

51
Q

Exam/transcriptome sequencing?

A

used to analyze rare mutations in expressed and coding regions

52
Q

How are DNA microarrays used in GWAS?

A

Shows

  1. Expression Analysis
  2. Mutation analysis
  3. Comparative analysis
53
Q

What is a chip array?

A

cDNA copies correspond to a large number of different mRNAs = probes

54
Q

What is expression analysis?

A

cDNA probe target cDNA transcriptome. Compares gene expression profile b/tw normal and diseased tissues.

55
Q

What is mutation analysis?

A

gDNA probe targets gDNA variation - SNPs

56
Q

What is comparative Genomic hybridization?

A

Identification of an increase or decrease chromosomal fragments harboring genes involved in a disease

57
Q

comparative genomic hybridization (CGH)

also used in GWAS

A

also known as chromosomal microarray analysis (CMA) - analysis of copy number changes (gains/loses in the DNA content) and can only detect unbalanced chromosomal changes (not balance or inversions)

used in diagnosis of tumor cells

Abnormalities (< 5 Mb( detected with banding - microscopic

58
Q

How do you analyze Array CGH?

A

Fluorescent signals are typically presented as rations - tells yo intensity of hybridization

Ratio = 1 = single equivalent to a control sample

Ratio = 1.5 = Trisomy for an autosome (case to control ratio of 3:2)

Ratio 0.5 = Monosomy for an autosome (case to control ratio of 1:2)

Samples are usually hybridized with control of sex

59
Q

Who is the father of Genomics?

A

Frederick Sanger
deduced the complete sequence of insulin
developed
- methods for determine small sequence of RNA
- using the dideoxycytidine technique
- adaptation of efficient cloning methods for whole-genome shotgun

60
Q

What does everyone respond differently to medicines?

A

Variations in our SNPs and cytochrome P45

61
Q

Pharmacogenetics?

A

study of monogenic traits involving individual variations in drug metabolism

62
Q

Pharmacogenomics?

A

study of pathways encoding proteins that influence pharmacokinetics and pharmacodynamics

63
Q

What is a major cause in inter-indivual variation of drug affect?

A

allele polymorphism

64
Q

What are the four basic stages in drug metabolism?

A 
Absorption 
Distribution 
Metabolism 
Interaction 
Excretion

ADME

65
Q

What are the pharmocokinetic factors ?

A

absorption, distribution, excretion = METABOLISM/CATABOLISM

66
Q

What are the Pharmacodynamic factors?

A

target interaction, signaling cascade of downstream target = THE EFFECT

67
Q

What are two classical enzymatic examples of RxGenetics?

A

gutyrlcholinesterase (BCHE) - hydrolysis of succinylcholine, short acting muscle relaxant (neurotransmitter antagonist)

N-acetyle transferase (NAT) - acetylation of isoniazid), anti-tuberculosis drug

68
Q

What is the monogenic variation of BCHE?

A

Some treated with short-acting succinycholine -> prolonged muscle paralysis -> lethal adverse response

To determine if they metabolize choline well you give the dibucaine -> tells you if you are a fast or slow metabolizer

Atypical form - missence - SNPG290A -> affects active site -> reduces catalytic hydrolysis of succinylcholine -> reduce resistance to inhibition by dibucaine

69
Q

What is NAT?

A

It is a isoniazid (prodrug) that reached therapeutic concentrations in serum but must be processed first

metabolism via acetylation where isonicotinic acyl is coupled with NADH by bacteria enzyme leads to inhibition of synthesis of mycobacterial call wall

70
Q

What is the monogenetic variation of NAT2?

A

Slow acytlaters: 10-20% reduction of NAT2 in liver cytosol - affect messenger RNA -> phenotypes by caffeine catabolism

71
Q

Where are the NAT genes located?

A

NAT1, NAT2, AND NATp are located on chromosome 8

72
Q

What are the genes for NAT2?

A

G191A, C282T, T341C

73
Q

What are the side effects for NAT2?

A 
severe and sometimes fatal hepatitis 
headache 
poor concentration 
weight gain 
poor memory 
depression

increased risk of autoimmune disorders post drug exposure

74
Q

NAT2 polymorphism: T431C/C481T is more prevalent in?

A

White and African - 28% (unlike asians 7%)

75
Q

NAT2 polymorphism: G191A is more prevalent in?

A

Asians - 10-18% (unlike where and africans <5%)

76
Q

What is CYP2D6?

A

A type of Cytochrome P450 that has deletions, critical SNPs, duplications (highly polymorphic).

They are important in drug metabolism

77
Q

CYP2D6 Homozygous deletion, frameshift, and stop codon

A

Slow metabolizers

78
Q

CYP2D6 heterozygous deletion, frameshift, and stop codon

A

Intermediate metabolizers

79
Q

CYP2D6 duplicated, multiplied

A

fast metabolizers

Don’t give them as much as the drug

80
Q

Cytochrome P450 2C9

A

absent in 1% caucasians and africans -Americans

Primary metabolism of
- NSAIDS (cOX-2)
S-Warfarin (active form)
- Phenytoin

Inhibited by Fluconazole

81
Q

No CYP2D enzyme and CYP2D6 duplications is more common in?

A

Europe

82
Q

For SNP what does the minor allele frequency have to be?

A

> 1%

83
Q

What date did the human genome project complete?

A

14 April 2003

84
Q 
Case 1
12 y.o girl 
Short stature 
Normal development 
Pulmonary stenosis
A

Noonan syndrome

85
Q

What are the symptoms of Noonan syndrome?

A

Eyes wides, ears low
Congenital heart disease
Characteristic craniofacial findings
Developmental delay (variable)

86
Q

What is Noonan syndrome caused by?

A

Caused by mutations in the RAS-MAPK pathway (gain function), with PTPN11 being the most common mutated gene. (single base pair change)

87
Q

What test would you use to detect Noonan Syndrome?

A

Sanger Sequencing Based on selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication
(most widely used for 25 years but is now being replaced by Next Generation Sequencing)

88
Q 
Case 2
10 year old boy from Lagos Nigeria
Being seen today for tetralogy of Fallot (heart tubes mixed up)
Nasal voice
Developmental delay
A

22q11.2 deletion syndrome - diGeorge Syndrome (Velocardioficial syndrome; Shprintzen)

89
Q

What are the symptoms of 22q11.2 deletion syndrome?

A

Heart malformations conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus)
Palatal abnormatlities (velopharyngeal incompetence)
Distinctive facial characteristics
Immune system anomalies
Developmental delay
Increased risk for mental illness

90
Q

How do you test for 22q11.2 deletion?

A

This condition contains copy number variant which Array CGH would be used to detect (Probe hybridization)

Microarray is based on hydrogen bonding

91
Q

What is copy number variant (CNV)?

A

alternative structure in genomic DNA that typically includes deletions (reduced copy number) and duplications (more copies) in adjacent segments of DNA.
CNVs may be disease causing OR may vary innocently among individuals, thus we can also consider them to be a type of polymorphism

92
Q

What are the steps for Array CGH?

A

1-3: Patient and control DNA are labeled with fluorescent dyes and applied to the microarray

4: Patient and control DNA compete to attach, or hybridize to the microarray
5: microarray scanner measure the fluorescent signal
6: computer software analyzes the data and generates a plot

You that where the allele is missing there will be some amplification. Everything else will look normal and have the same ratio.

93
Q

Case 3

How can genomic technology be used in a case control study to evaluate a common disease such as autism?

A

You would use a SNP chip with GWAS

SNPs of disease population will be compared to SNPs of normal population - looking for common SNP

It allows you to find association of genes.
You will not know exact specifics but will know that certain SNPs are more prevalent in diseased population

94
Q

What are some Mendelian diseases caused by rare alleles?

A

Achondroplasia
Duchenne Muscular Dystrophy
Huntington Disease

95
Q

What are some common disease caused by common variants? Detected by GSA

A

Type II Diabetes
Coronary artery disease
PTSD
Autism (common genetic variants on 5p14.1)

96
Q

Case 4
Multifactoral
Difficult case
Patient has multiple symptoms that don’t line up with on particular spectrum
What do you do when you end up in this situation?

A

Next Generation sequencing = Massive parallel sequencing

Chop up chromosome and align it with a reference sequence (from Human genome project) -> this will allow you to detect heterozygosity and nucleotides that have been changed -> PCR is used to amplify sequence

97
Q

What is the scope and limitations of next generation sequencing?

A

5 – 10% of the genome cannot be confidently mapped/aligned to reference genome
SNV ~ 90% of total burden of genetic variation with a sensitivity of > 95%
Insertions and deletions (~ 10%) with sensitivities of 50-80%

98
Q

Whole Exome Sequencing (protein coating)

A

Condenses genome to 1.5 billion -> obtain fragments -> hybridize -> Bate with beads -> capture DNA -> sequence

99
Q

What can cause rare disorders that occurred in case 4? Where there was no specific disease that was able to be diagnosed.

A

It could have been a possibility of gremlin mosaicism

As in the the Zebrafish

MC2 (3 decks)

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