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Cellular And Molecular Pathology > Genetics > Flashcards

Genetics Flashcards

0
Q

What cells are used in cytogenetic analysis?

A

Any nucleated cells, blood most common

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1
Q

How do you do cytogenetic analysis?

A 
Centrifuge blood
Hypotonic solution to lose rbc
Stimulate wbc division with mitogen PHA-phylohaemiagglutinin
Metaphase block called colchicine
Drop from height to see banding patterns
Stain
Microscope
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2
Q

Types of germ line defects?

A

Chromosomal defects
Mitochondrial disorders
Monogenic disorders
Polygenic disorders

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3
Q

Types of somatic defects?

A

Cancer
Mosaics
Chimeras

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4
Q

How do you get banding on chromosomes?

A

Treat with protease like trypsin which attacks chromatin so when stained bands show

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5
Q

What does banding on chromosomes show?

A

The density of genes- light bands means more genes

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6
Q

What does a missing band mean?

A

Chromosomal defect

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7
Q

What are acrocentric chromosomes?

A

Don’t have a short arm

Repeat units only

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8
Q

What does FISH stand for?

A

Fluorescence in situ hybridisation

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9
Q

Why can we use FISH?

A

We know the sequence of the human genome

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10
Q

What is FISH used for?

A

Detecting more subtle defects..chromosomal abnormalities

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11
Q

How is FISH carried out?

A

Localises a region of DNA in a chromosome
DNA probe labelled with fluorescent dye
Denature probe and hybridise with patients sample
Fluorescent microscope

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12
Q

What are centromeres probes?

A

Repetitive sequences found around the centromere of a specific chromosome
Diagnosis of trisomies using sample of chorionic villi

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13
Q

What are chromosome specific unique sequence probes?

A

Specific for a single locus

Submicroscopic deletions and duplications

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14
Q

What are telomeric probes?

A

Simultaneous analysis of the subtelomeric region of every chromosome
Identifies tiny cryptic subtelomeric abnormalities

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15
Q

What are whole chromosome ‘paint’ probes?

A

Cocktail of probes obtained from different parts of a chromosome
Relevant chromosome fluoresces
Subtle translocations and identifying the origin of additional material

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16
Q

Name the three types of autosomal abnormalities

A

Numerical
Structural
Sex chromosome

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17
Q

What is polyploidy?

A

Extra whole complement of chromosome…triploid

Lethal

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18
Q

What is monosomy?

A

Missing one chromosome

Not compatible with normal growth

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19
Q

What is trisomy?

A

Extra copy of one chromosome

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20
Q

Which chromosome has an extra copy in Down’s Syndrome?

A

Chromosome 21

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21
Q

Why can people with Down’s survive?

A

Smaller chromosome so less genes to mess up genome

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22
Q

How is Down’s caused?

A

Non-dysjunction in female meiosis

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23
Q

What is a Robertsonian translocation?

A

Two acrocentric chromosomes lose their short arms and fuse together

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24
Q

What is a Reciprical Translocation?

A

Material exchange between homologous chromosomes

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25
Q

What happens if someone inherits balanced translocations?

A

Often no effect
Can produce offspring with unbalanced chromosomal complement
Can give partial trisomy or monosomy

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26
Q

What will a visible deletion most likely cause?

A

Mental retardation

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27
Q

Klinefelter’s syndrome

A

XXY males

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28
Q

Turner’s Syndrome

A 
XO females
Sterile
Short stature
Webbed neck
Only monosomy compatible with development
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29
Q

How many copies of DNA in each mitochondria?

A

2-10 copies circular DNA

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30
Q

Mitochondrial DNA maternally or paternally inherited?

A

Maternally

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31
Q

What does heteroplasmic mean?

A

Mutation in some mitochondrial DNA
Affects how strong phenotype is
Can pass to some offspring but not others
Severity of disease can change over time

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32
Q

What is LHON?

A 
Leber's hereditary optic neuropathy
Mitochondrial mutation
Mutation in NADH dehydrogenase
Optic nerve damage
Blindness
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33
Q

What is Leigh’s syndrome?

A

Mitochondrial mutation
Mutation in ATP Synthase
Degeneration of basal ganglia
Problem with nervous system

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34
Q

What is Pearson’s syndrome?

A

Mitochondrial mutation
Deletion of mitochondrial DNA
Bone marrow failure
Problem with immune system and blood

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35
Q

What is a monogenic disorder?

A

Defects in a single gene

Simple, Mendelian patterns of inheritance

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36
Q

What is penetrance?

A

Chance of inheriting disease if carrying the mutation
Genetic background determines if you have mutation
Some diseases can be decreased with changing diet and environment

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37
Q

What is expressivity?

A

Variation in phenotype in affected individuals due to genetic background

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38
Q

What is genomic imprinting

A

Expression of alleles depends on which parent they are inherited from
Only affects minority of genes

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39
Q

Name some imprinting disorders

A

Prader-Willi syndrome
Angelman syndrome
Beckwith-Wiedemann syndrome

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40
Q

What is the hardy-Weinberg principle?

A

Allele and genotype frequencies remain the same unless specific disturbing influences are introduced

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41
Q

What are the disturbing influences regarding the hardy-Weinberg principle?

A 
Non-random mating
Mutations
Selection
Random genetic drift
Gene flow
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42
Q

What is the hardy-Weinberg equation?

A

P+q=1
p2+q2+2pq=1

Homozygous AA=p2 aa=q2
Heterozygous Aa=2pq

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43
Q

What is positional cloning?

A 
Disease
Map position of gene
Gene
Gene product
Functional studies
From genotype to phenotype
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44
Q

What is linkage analysis?

A

Based on genetic distance
Find genetic marker coinherited with disease
Markers 10^6 apart have 1% recombination frequency meaning they are likely to be coinherited
Polymorphic markers vary person-person and chromosome-chromosome
Measure linkage by LOD score…>3 indicates linkage

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45
Q

What are RFLPs?

A

Restriction fragment length polymorphisms
Polymorphic marker
Single base changes - gain/loss or restriction site

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46
Q

What are VNTRs?

A

Variable number tandem repeats
Polymorphic markers
20-30bp repeats

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47
Q

What are microsatellites?

A

Used in fingerprinting

Di, tri, tetra nucleotide repeats

48
Q

What are SNPs?

A

Single base changes occur every 300bp

Linkage analysis

49
Q

Pre-genome project how was gene mapping done?

A

Regional genetic map
Markers to select genetic clones
Produce a contig

50
Q

What is a contig?

A

Overlapping fragments of cloned DNA representing the entire region

51
Q

What is a contig used for?

A 
Screen cDNA libraries
Search for CPG Islands
Zoo blotting
Exon trapping 
CDNA selection
52
Q

How is gene mapping done now?

A 
Genetic maps available
Thousands mapped genes and Expressed Sequenced Tags
Genes predicted from genomic sequence
Rapid identification of candidate genes
Computers used
53
Q

Symptoms of cystic fibrosis

A 
Chronic lung disease
Bowel obstruction
Pancreatic failure
Increased sweat electrolytes
Premature death
54
Q

How was the CF gene isolated?

A

RFLP linkage on 7q31
MET is a target kinase receptor, it is close to CF gene but need even closer marker
Chromosome jumping and walking

55
Q

Properties of CF gene

A

250kb
27 exons
6.5kb mRNA
1480 amino acids

56
Q

In CF, what protein is affected?

A

Cystic fibrosis transmembrane conductance regulator
Transmembrane protein
ATP binding site
Chloride channel when fails increases salt conc making thicker mucus

57
Q

How is the CF protein mutated?

A

Mainly phenylalanine deletion

58
Q

Functional analysis of CF

A

Cell culture studies to create transport defects

Knockout mice to develop correct pathology to disease when exposed

59
Q

What is Duchenne Muscular Dystrophy?

A

X-linked recessive
1:4000 boys
Death before 30
chromosome translocations through Xp21 in girls, deletion in boys

60
Q

Molecular studies of DMD

A

Xp21 probes - one loosely linked marker
Cloned Xp21 translocation - tightly linked marker
Subtractive cloning using Xp21 deletions to mark out what was missing - close marker

61
Q

DMD gene

A 
2000kb
>65 exons 
16kb mRNA 
368 amino acids
Mutations common
62
Q

Protein involved in DMD

A

Dystrophin
427kb
Features in common with muscle structural proteins
0.002% muscle protein
Links actin to protein complex in plasma membrane
Links muscle cells to basal lamina

63
Q

Mutations in DMD

A 
Large deletions (highly truncated protein) causes severe disease
Small deletions so only partly truncated causes mild disease
64
Q

Functional analysis of DMD

A

Mice have dystrophin deletion didn’t show symptoms
Eventually diaphragm disintegrated as that muscle worked the most
Failure of repair so degradation

65
Q

Features of Huntington’s disease

A

Autosomal dominant
Progressive neurodegeneration
Late onset
First disease to be mapped by linkage 1983

66
Q

Mutation in Huntington’s

A

Normal 16-36 repeats
HD 42-86 repeats
First example of trinucleotide repeat expansion

67
Q

What are trinucleotide repeat disorders?

A

All involve (XYZ)n sequence
N is increased
All have same markers
Severity increases through succeeding generations
Can be mitosis/meiotically unstable - increase expansions

68
Q

How does repeat expansion cause disease in fragile sites?

A

(CGG) >200

Increase methylation so decrease transcription

69
Q

How does repeat expansion cause disease in neurodegenerative disorders?

A

(CAG) <150

Multiple effects on protein-protein interactions and toxic protein aggregates

70
Q

How does repeat expansion cause disease in myotonic dystrophy?

A

(CTG) 200-400
In 3’ untranslated region - direct RNA mediated effects
Neuromuscular system affected

71
Q

How does repeat expansion cause disease in Friedrich’s ataxia?

A

(GAA) 200-900
In intron - decreased transcription of Frataxin
Affects mitochondrial protein

72
Q

Structure of Sickle Cell Anaemia

A 
Autosomal recessive
Single base change
Heterozygous advantage of malaria resistance
GAG to GTG beta globin defect
Haemoglobin precipitates
73
Q

What are some other abnormalities in the structure of haemoglobinopathies?

A 
Point mutations
Deletions - uneven crossover in meiosis
Insertions making stronger globin chains
Frame shifts
Chain termination to make longer chains
Fusion chain where two Hb stick together
74
Q

What are thalassaemias?

A

Single gene disorders
Autosomal recessive
Decreased synthesis of one or more Hb chains

75
Q

If all 4 alpha Hb genes deleted in alpha thalassaemias?

A

Alpha0 homozygote - gamma 4 - death

76
Q

If 3 alpha Hb genes deleted in alpha thalassaemias?

A

Alpha0/alpha+ compound heterozygote - variable anaemia

77
Q

If 2 or 1 alpha Hb genes deleted in alpha thalassaemias?

A

Alpha0 heterozygote
Alpha0+ homozygote - mild anaemia
Alpha0+ heterozygote

78
Q

How are beta thalassaemias formed?

A

Beta0 complete lack of B chains
Beta+ decreased B synthesis
Not due to deletions
Nonsense mutations- premature termination
Promoter mutations- decrease transcription
Defective splicing- decrease translation

79
Q

What are gamma/beta thalassaemias?

A

Decreased synthesis of gamma and beta chains
Rare
Variable anaemia
Mild form is hereditary persistence of foetal Hb

80
Q

What are polygenic disorders?

A

Many genes
Unclear inheritance
Many factors

81
Q

What does epistasis mean?

A

Interaction between genes acting in a common pathway

82
Q

What is genetic heterogeneity?

A

Alternate genes in different pathways

83
Q

What is the liability model?

A

All contributing factors in disease termed liability
Population shows normal distribution
Above threshold disease develops
Genetic factors shift curve right increasing chance of disease

84
Q

What is heritability?

A

Proportion of risk attributable to genetic factors
Schizophrenia 81%
Type2 diabetes 26%

85
Q

Problems with genetic analysis

A

Not all susceptible individuals affected due to environmental factors
Genetic heterogeneity- don’t know what genes actually affected as many susceptible
Phenocopy - disease purely from environment

86
Q

Parametric vs non-parametric linkage analysis

A

Parametric - difficult to apply as assume pattern of inheritance and don’t know if dominant or recessive
Non-parametric - more successful, do sufferers share common part of DNA that may carry disease gene

87
Q

What are association studies?

A

Genome wide association studies

  • SNPs
  • HapMap to see if inheriting in blocks
  • thousand genome project
88
Q

Schizophrenia using linkage analysis

A

Problems of phenocopy and low penetrance in families
Two linkages now refuted
Suggest linkage to 6p

89
Q

Schizophrenia using GWAS

A

Copy number variations at 1q, 15q, 22q
6p-HLA region so perhaps some autoimmune disease
1000s common variants have small effects, difficult to use data

90
Q

How are genes identified in type 1 diabetes using non-parametric allele sharing?

A

See if individuals inherit same chromosomal region

Whole genome scan to pick out common regions associated with disease

91
Q

How are genes identified in type 1 diabetes using animal models?

A

Inherited diabetes in mice

Look for homologous genes in man as genomes very similar

92
Q

How are genes identified in type 1 diabetes using GWAS?

A

> 40 loci identified
6p21 HLA region most important
Genetic changes more likely to cause disease
Different genes affected in individuals to give a type of diabetes

93
Q

How is the gene identified in type 2 diabetes?

A

Linkage analysis unsuccessful as genetically complex
Rare inherited forms
Many GWAS done as big problem
HLA not important - not auto immune disease
No main predisposing loci
Alleles discovered to increase risk by small a,punt especially if all together but mainly diet

94
Q

What is familial hypercholesterolaemia?

A 
Autosomal dominant
Monogene disorder
Mutation in LDL receptor gene
Heart attacks in children
30 loci associated with circulating lipid levels....lipid metabolism important in cardio disease
95
Q

Genes associated with hypertension?

A

Angiotensin gene causes blood vessel constriction
Polymorphism in angiotensin converting enzyme linked to risk of heart attack
GWAS 14 loci identified

96
Q

What is Gestmann-straussler disease?

A

Autosomal dominant
PrPc mutation
Could get somatic mutations in gene like cancer

97
Q

What is Alzheimer’s disease?

A

Senile dementia
Genetic predisposition
Neurofibrillary tangles and amyloid protein plaques which are pathogenic
Age related

98
Q

Genes involved in Alzheimer’s disease?

A

Plaques from amyloid precursor protein - APP on chr 21 - mutations in early onset families
Presenilin 1 on chr14 and presenilin 2 on chr1 - mutations in early onset families
Apolipoprotein E on chr19 - lipid transport, late and early onset, 3 major alleles with E4 giving increased risk

Epistasis and genetic heterogeneity evident
Most late onset no genetic origin

99
Q

What is the mechanism for Alzheimer’s disease?

A

APP into fragments by B secretase
Fragments form AB peptide by presenilin
Peptide forms plaques with apoliopoproteins
Neuronal death

100
Q

What is prenatal testing used for?

A

Monogenic defects and Down’s syndrome

101
Q

What is amniocentesis?

A

Remove amniotic fluid and grow foetal cells
16-18 weeks gestation
Takes weeks to grow cells
Increased miscarriage

102
Q

What is chorionic villus sample?

A

Remove part of chorionic villus
11-12 weeks gestation
Immediate analysis
Sample divides rapidly

103
Q

What is neonatal testing used for?

A

Diagnosis and blood screening
Heel prick
Tests for phenylketonuria as can’t break down phenylalanine

104
Q

What is adult testing used for?

A

Carrier detection
Pre-symptomatic diagnosis of late onset disease
Eg. Huntington’s

105
Q

What is molecular analysis?

A

PCR based investigations of specific genes
Indirect determination
DNA sequencing to look for deletions or truncated PCR products
Point mutations if there is a known mutation
Unknown mutations using screening methods like SSCP and sequencing

106
Q

How are point mutations found using molecular analysis?

A

Amplification refractory mutation system - PCR primers specific for mutations
Loss/gain of restriction enzyme site - can pick up polymorphisms
Allele specific oligonucleotides can be hybridised to PCR products
Sequencing

107
Q

When is the indirect determination method used in molecular analysis?

A

Gene not cloned
Relies on genetic linkage
Allele linkage due to founder effect, polymorphism always associated with mutation
Locus linkage- work out linkage of mutant allele to a polymorphic marker in a family, can be unreliable

108
Q

Conventional treatment for genetic disease?

A

Physiotherapy and antibiotics for cystic fibrosis

Expands lifespan but doesn’t cure

109
Q

Environmental modification to treat genetic disease?

A

Avoidance of sunlight for xeroderma pigmentosa

110
Q

Surgery to treat genetic disease?

A

Correction of virilisation in girls with congenital adrenal hyperplasia
Plastic surgery for Down’s- controversial

111
Q

Metabolic manipulation to treat genetic disease?

A

Restricting phenylalanine intake in patients with phenylketonuria
Prevents retardation from build up of metabolites

112
Q

Gene product replacement to treat genetic disease?

A

Insulin for diabetes

Factor VIII administration for haemophiliacs

113
Q

Tissue and organ transplant to treat genetic disease?

A

Natural - heart and lung in CF
- bone marrow for thalassaemias to help symptoms
Artificial - neoorgans experimental

114
Q

Stem cell therapy to treat genetic disease?

A

Pluripotent stem cells - embryonic (ethical)
- induced stem cells by putting differentiated cell in mixture of 4 genes

Multi potent stem cells- many cell types but not all
- mesenchymal stem cells

115
Q

What is gene therapy?

A

Correct gene defect with with transgene

Replace gene with homologous recombination- theoretical

116
Q

What are viral vectors in gene therapy?

A

Retroviruses, lentiviruses
Role to take over cell machinery so efficient
Safety problems - must be replication deficient and have insertional mutagenesis

117
Q

What are the physical methods of gene therapy?

A

Liposomes
Direct DNA injection
Receptor mediated endocytosis
Can’t cross infect so safe

118
Q

What are the problems of gene therapy?

A

Producing and sustaining high level transgene expression

Foreign gene may be inactivated

Cellular And Molecular Pathology (3 decks)

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