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Molecular Basis Of Disease > Genetics part 1 > Flashcards

Genetics part 1 Flashcards

1
Q

What is genetic variation?

A

Describes the variation in the DNA sequence in each of our gene

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2
Q

What does genetic variation make us?

A

unique

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3
Q

What are the most common type of genetic variation amongst people?

A

single nucleotide polymorphism

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4
Q

What does each single nucleotide polymorphism represent?

A

Difference in a single DNA base
ACGT
in a person’s DNA

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5
Q

How much does SNP occur on average?

A

Once in every 300 bases

Also found in the DNA between genes

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6
Q

What does genetic variation result in?

A

Different forms, or alleles of genes

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7
Q

What does genetic variation explain?

A

Some differences in disease susceptibility

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8
Q

What can genetic basis to a disease be?

A
  1. Inherited
  2. Acquired

Different forms of inheritance

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9
Q

What is an example of acquired genetic changes?

A

Ovarian cancer

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10
Q

What is the advantage of finding genetic basis?

A

Define the disease

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11
Q

Define risk factors

A

characteristic or exposure of an individual that increases the likelihood of developing a disease or injury

Genetic molecular changes

Doesnt give us the disease but predisposes us to that disease

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12
Q

What is genetic testing?

A

Changes in chromosome, genes or protein

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13
Q

What does genetic testing do?

A
  1. confirms a suspected genetic condition
  2. Determine a person’s chance of developing or passing on a genetic disorder
  3. Determine whether a person is a carrier of a certain genetic mutation
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14
Q

What are examples of genetic testing?

A
  1. Diagnostic - looking at families
  2. Pre-syomptomatic
  3. Prenatal diagnosis
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15
Q

What is not always diagnostic?

A

phenotypic observation and test

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16
Q

What is mostly hidden?

A

Genetic risk factors

Identifying underling pathology

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17
Q

What is an example of inherited disease?

A

Sickle cell disease

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18
Q

Where can the prevalence of carrier frequency be very high?

A

West Africa

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19
Q

Who carries sickle cell disease gene?

A

1 in 20 people

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20
Q

What is progeria?

A

a rare syndrome in children characterized by physical symptoms suggestive of premature old age

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21
Q

What are rare diseases?

A

collectively common

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22
Q

What is factor V Leiden?

A

specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels

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23
Q

Define allele frequency

A

How common is the genetic variant within the population

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24
Q

What is some plausible explanations for the missing heritability

A
  1. Rare variants not captured in genotyping microarrays
  2. Many variants of small effect
  3. Structural variants not captured in short read sequencing
  4. Epistatic effects: non-linear gene-gene interactions
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25
Q

What is missing heritability a combination of?

A
  1. genes that supposedly underlie behavior genetic estimates of heritability simply do not exist
  2. Genetic effects are actually epigenetics
  3. Genetic effects are generally non-additive and due to complex interactions. a model has been introduced that takes into account epigenetic inheritance on the risk and recurrence risk of a complex disease
  4. Genetic effects are not due to the common SNPs examined in the candidate-gene studies & GWASes, but due to very rare mutations, copy-number variations, and other exotic kinds of genetic variants
  5. Traits are all misdiagnoses
  6. GWASes are unable to detect genes with moderate effects on phenotypes when those genes segregate at high frequencies
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26
Q

What does rare alleles cause?

A

Mendelian disease

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27
Q

What does low frequency give rise to?

A

Variants with intermediate effect

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28
Q

What are common variants implicated in?

A

Common disease by GWA

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29
Q

What is hard to identify by genetic means?

A

Rare variants of small effect

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30
Q

What does 5X increase risk of thrombosis give?

A

1 in 20 carrier frequency

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31
Q

What does 1.1x increase risk of coeliac give?

A

1 in 2.5 carrier frequency

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32
Q

When does an enzyme become dysfunctional?

A

one amino acid substitution to another

Cripple the catalytic site of enzyme

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33
Q

What can be tolerated?

A

Majority of the amino acid substitution

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34
Q

What are genetic markers?

A

Used to identify different features in DNA sequence that can be used to differentiate between individuals in a population

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35
Q

What does the genetic marker do?

A

Tag a piece of DNA and can be used to track genes in families or populations

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36
Q

What does genetic marker have?

A

Short DNA sequence such as a sequence surrounding a single base-pair change or a long one i.e. minisatellites

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37
Q

What is a short tandem repeat?

A

Short sequences of DNA (2-5 bp), repeated numerous of times in head-tail manner

Regions of non-coding DNA that contains repeat of same nucleotide sequence

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38
Q

What is genetic markers used for?

A
  1. Anonymous region of genome
  2. Fingerprints
  3. Fingerprinting in forensics
  4. Paternity testing
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39
Q

What is SNP?

A
  1. Polymorphic

2. When the frequency of the minor allele in the population is >1%

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40
Q

What is single nucleotide polymorphism?

A
  1. Single base pair difference in sequence of particular region of DNA from one individual compared to another of the same species or population
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41
Q

What does the little identifier serve as?

A

single nucleotide changes

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42
Q

What does the TERT gene provide?

A

Instructions for making one component of an enzyme called telomerase

Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of the chromosome

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43
Q

SNP

A

In a population you can have either C or T in a population

The gene is in the TERT gene

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44
Q

What is the functional consequence synonymous?

A

Coding sequence of gene but does not change the amino acid

Effect: Low

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45
Q

What is Minor allele frequency?

A

The frequency at which the second most common allele occurs in a given population

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46
Q

What is MAF used in population genetics provide?

A

Information to differentiate between common and rare variants in the population

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47
Q

Rare variants (MAF < 0.05)

A

Appeared more frequently in coding regions than common variants (MAF >0.05) in this population

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48
Q

What does Global MAF illustrate?

A

11% of allele in the population are T

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49
Q

What is the least common genotype?

A

TT - Minor allele

C- Green
T- Red

Homozygous for C
Heterozygous for C/T
Homozygous for T - chromosome 2

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50
Q

What is disease gene identification?

A

Process by which scientists identify the mutant genotypes responsible for inherited genetic disorder

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51
Q

What does positional cloning start with?

A

Identification of candidate gene according to chromosomal location

Followed by mutation analysis in affected individuals

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52
Q

Positional candidate

A
  1. Identified through genome wide genetic linkage analysis and/or homozygosity mapping
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53
Q

Positional candidates

A
  • Define candidate region – small region
  • Obtain clones of all DNA in region
  • Identify all genes in region
  • Priotize them for mutation screening
  • Test candidate gene for mutations in affected people
  • Take patients with this disease and do genome wide genetic link analysis
  • Genetic linkage analysis: establish linkage between genes
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54
Q

X-linked families

A

Males i.e.

  1. Haemophilia
  2. Mental retardation
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55
Q

What does dominant family pass

A

successive generations

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56
Q

Recessive disease

A
  1. Parents are asymptomatic (no symptoms) i.e.
  2. Sickle cell disease
  3. Cystic fibrosis
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57
Q

What is an example of dominant disease?

A

Huntington disease

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58
Q

What happens through consanguineous marriage?

A

The mutation becomes homozygous and causes autosomal recessive disease

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59
Q

What is SNP genotyping?

A

Measurement of genetic variations of SNP between members of a species

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60
Q

What does regions of extended homozygosity appear to contribute to?

A

Development of complex disease or traits involving recessive variants such as heart disease, hypertension and elevated total/low-density lipoprotein cholesterol levels

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61
Q

What is homozygosity mapping?

A

A common method for mapping recessive traits in consanguineous family

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62
Q

Why is homozygosity mapping powerful?

A

It does not require DNA of other family members than the affected offspring

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63
Q

What does the normal workflow of homozygosity mapping consist of?

A

Genome-wide linkage analysis with microsallelite or increasingly SNP

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64
Q

What does the homozygosity mapping minimize?

A

The need for sequencing multiple genes

65
Q

What can you distinguish from homozygosity mapping?

A

Identification of a disease gene lines between 2 markers

  1. rs16954293
  2. rs9939133
66
Q

What did sequencing all ~60 genes in the chromosome 16 region identify?

A

A homozygous loss of function mutations in the C16orf57

67
Q

What is functional candidates?

A

Identified by a functional association with previously identified disease genes

68
Q

What is Fanconi aneamia a result of?

A

Genetic defect in a cluster of proteins responsible for DNA repair via homologous recombination

69
Q

Functional candidates

A

o Already found the disease gene
o Look at another patient that has the same disease but doesn’t have the mutation in the gene you found
o Fanconi anaemia – caused by bad genetic variants
o Fanconi pathway feed into the DNA repair proteins
o Fanconi anaemia – recessive
o BRCA1 famous risk factor – heterozygous
o Find one disease gene, investigate pathway, find other disease genes

70
Q

What is exome sequencing?

A

Sequencing all of the protein-coding genes in a genome

  1. Select the subset of DNA that encodes proteins
  2. Sequence the exonic DNA using any high-throughput DNA sequencing technology
71
Q

How many exons does humans have?

A

180,000 exons
constitutes about 1% of human genome
Approximately 30 million base pairs

72
Q

What is the goal of exome sequencing?

A

Identify genetic variants that alter protein sequences at a much lower cost

Much easier to do
Cheaper
Computational space

73
Q

Define a variant

A

Something in the sequence which is different from reference genome

74
Q

How many exomes and genetic variants are there?

A
  1. Exomes - 23,000

2. Genetic Variants - 3 and 1/2 million genetic variants

75
Q

What does allelic series describe?

A

Different mutant alleles of a gene that cause a range of phenotypewhereby each one carries a single point mutation within different regions of the same gene.

76
Q

What are some examples of diagnosis?

A
  1. Confirmation, clarification
  2. Pre-symptomatic, monitoring, search for donor
  3. Pattern of inheritance, carrier testing
  4. Prenatal, preimplantation ,genetic counselling
77
Q

What are examples of treatment?

A
  1. Tailor treatment: appropriate drugs
  2. Storing cells
  3. Rational drug design
  4. Gene therapy
78
Q

What is wider pathology?

A

Mutation in patients with idiopathic disease

79
Q

What is allelic series?

A

Identification of the gene that causes Freeman-Sheldon syndrome

80
Q

What is RTEL 1 gene associated with?

A

Autosomal recessive dyskeratosis

81
Q

What os MSH6 gene associated with?

A

Hereditary non-polyposis colon cancer type 5

82
Q

What is DNA sequencing techniques?

A
  1. Sanger sequencing - DNA is copied many times - fragments of different lengths
83
Q

What does DNA sequencing techniques determine?

A

many relatively small fragments of human DNA

84
Q

What are the fragments aligned based on?

A

Overlapping portions to assemble the sequences of larger regions of DNA and entire chromosomes

85
Q

What does the fluorescent ‘‘chain terminator’’ nucleotides mark?

A

The ends of fragments and allow the sequence to be determined

86
Q

What are next generation sequencing?

A

techniques are new, large-scale approaches that increase the speed and reduce the cost of DNA sequencing

87
Q

What are targeted gene panels?

A

Useful tools for analysing specific mutations in a given sample

88
Q

What does the focused panels contain?

A

A select set of genes or gene region that have known or suspected association with the disease or phenotype

89
Q

What does targeted gene panels produce?

A

Smaller, more manageable data set

make analysis easier

90
Q

What is Sanger sequencing?

A

Still the gold standard to confirm results and for many genetic conditions with common variants e.g. thalassaemia

91
Q

What are Targeted gene panels?

A

Based on a set of selected genes designed around a phenotype

92
Q

What is whole exome/genome sequencing?

A

Open sequencing

Where the clinician and bioinformatic analysis defines the genes of interest

93
Q

What are all the signal that has come out of the genome wide association?

A

Intergenic

94
Q

What is missense (non-synonymous)?

A

Change one amino acid to another

95
Q

What are indels?

A

Insertion or deletion of bases in the genome of an organism

Used as genetic markers in natural population

96
Q

What are indels that are not multiple of 3?

A

Particularly uncommon in coding region but relatively common in non-coding regions

97
Q

What is frame shift?

A

A genetic mutation caused by indels of a number of nucleotides in a DNA sequence that is not divisible by 3

98
Q

How do you name a sequence variant?

A

C.1 = A of the ATG initiation codon
Specify coding sequence using unique identifiers of coding sequence NM
1601G>A cause factor V Leiden
NM = nucleotide sequence
Name the protein sequence
P.1 =The N-terminal Met residue
Use base number on human genome reference sequence

99
Q

What is library preparation?>

A
  • Take DNA of interest in patient of disease
  • Shear DNA by sonication into fragments, 250bp
  • Tie up the ends – phosphorylate/adenylate
  • The adenylation/phosphorylation are crucial for the addition of linker/adaptor
  • Library – all the fragments from one particular person
  • Molecule is a simple oligonucleotide – fork and paired
  • DNA insert and a lot of sequences put at the end – asymmetrical, tucked is a unique identifier
  • Ligating adaptors onto a sheared DNA fragments
100
Q

What is exon capture?

A

o Extract and sequence the exome in a genome and compare this variation across a sample of individual organisms

101
Q

How to do exome?

A
  • Make RNAse complementary all through the exons of every single gene
    o RNA – bait – have biotin at the end
    o Streptavidin bind biotin strongly
    o Streptavidin – coating a magnetic bead
102
Q

What is ILLumina dye sequencing

A
  • Technique used to determine the series of base pairs in DNA (DNA sequencing)
  • Primers attach to the forward strands and polymerase adds fluorescently tagged nucleotides to the DNA strand
  • Only one base is added per round
  • A reversible terminator is on every nucleotide to prevent multiple additions in one round
  • Use four-colour chemistry, each of the four bases has a unique emission, and after each round, the machine records which base was added
  • Once the DNA strand has been read, the strand that was just added is washed away
103
Q

What is variant calling pipeline?

A

to allow researchers to rapidly identify and annotate variants

104
Q

What does variant calling pipleline employ?

A

Genome Analysis Toolkit (GATK) – perform variant calling – a list of variants using genome viewer

105
Q

What is the content of genome?

A

50 million base

106
Q

How can you visualise genetic variant?

A

using genome viewer

107
Q

What is Annovar?

A

annotate the genetic variants – predicting the likelihood of being pathogenic

108
Q

What is ExAC?

A

Very big data base of nucleotides

109
Q

What is variant calling pipeline?

A

Predict the severity of a variant on the function of a protein

110
Q

What are the different criteria for variant calling pipeline?

A

computational data, functional and allele date to see it going from benign to pathogenic

111
Q

What is the TERT protein?

A

1500 amino acids long
Predicted loss of function
Predicted to be null

112
Q

What are the different ways of annotating single nucleotide variants?

A
  1. Differentiating
  2. Annotation
  3. Prediction
113
Q

Differentiation

A
  1. Coding/Non-coding
  2. Known/unknown (dbSNP, ExAC, gnomAD)
  3. Homozygous/heterogous
114
Q

Annotation

A
  1. Affected gene/transcript name
  2. silent, missense, nonsense, splicing, indel
  3. Amino acid change
  4. Loss of function versus hypomorphic versus neutral
115
Q

Prediction

A
  1. Conservation, protein structure

2. SIFT, Polyphen, Mutation Taster, CADD score

116
Q

What are approaches to variant classification?

A
  1. Searching medical literature
    (can be decisive, clear known precedent)
  2. Searching databases
  3. Using in-silico tools
117
Q

What classes are useful for reporting variants?

A

Class 1 - Benign

Class 2 - Pathogenic

118
Q

What mutation are in the oncogene?

A
  1. K-ras

2. DCC

119
Q

What is De-novo mutation?

A

Genetic alteration that is present for the first time in one family member as a result of a variant

can be hereditary or somatic

120
Q

Where does mutation occur?

A

In a person’s egg or sperm cell but is not present in any of the person’s other cells

121
Q

What is acquired mutation?

A

– acquired early on in development or will be acquired in the germ cell
Some acquired diseases can be inherited to some extent

122
Q

Who is closer to getting a colon cancer?

A

Individuals with inherited mutation in APC gene

123
Q

What are monogenic diseases?

A

Single defective gene on the autosomes

Inherited according to Mendel’s Law

600 known
• 1 in every 200 birth

124
Q

What can monogenic diseases be?

A

The mutation can be spontaneous and where there is no previous family history

125
Q

What is an example of monogenic diseases?

A
  1. Cystic Fibrosis

2. Alzheimer’s disease

126
Q

What is polygenic disease?

A
  • A genetic disorder that is caused by the combined action of more than one gene
  • Environmental factors and lifestyle factors come into play
  • E.g. Alzheimer’s disease
127
Q

What is Locus heterogeneity?

A

• Single disorder, trait, pattern of traits caused by mutations in genes at different chromosomal loci

128
Q

What are examples of locus heterogeneity?

A

Dyskeratosis congenita

  • Lots of phenotype in a lot of different body systems e.g. bone marrow
  • It affects the health of stem cells
  • Also found in skin and oral cavity
129
Q

What can different genes lead to?

A

Same disease

130
Q

What is penetrance?

A

Percentage of individuals who express gene as a particular phenotype

131
Q

What does complete penetrance carry?

A

genes for a trait expressed in all the population and have clinical symptoms of the disease

132
Q

What does incomplete penetrance demonstrate

A

individuals who acquire the disease do not express the trait, even though they carry the trait and accounts for only part of the population

133
Q

What is variability in phenotypes caused by?

A

number of factors: modifier genes that can alter expression of alternative gene, environmental and genetic interactions

134
Q

What is expressivity>?

A

When a phenotype is expressed to a different degree among individuals with the same genotype
• Either get variable penetrance or variable expressivity
• Example – Neurofibromatosis – NF1
• Some patients show
- Café-au-lait spots (moles)
- Neurofibroma tumours (tumours at the end of neurons)

135
Q

Types of mutation

A

• Mutations in the coding sequence – change the amino acid sequence
• Epigenetics
- Study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself
• Genome quite heavily methylated
• Nucleosomes accessible to transcription factor and tightly packed
• Enhancers are a long way from gene

136
Q

What doesn’t transcriptional control (quantity of proteins) necessarily change?

A

The coding sequence of genes but changes the amount of transcript produced

137
Q

What are the causes of transcriptional control?

A
  • Mutation in regulatory element i.e. enhancer element
  • Repeat expansion
  • Epigenetics
  • Deletion/insertion/inversion/translocation
138
Q

Translocation – Philadelphia chromosome

A

chromosome 9 and 22
Brings 2 genes together bcr and abl
Abl – tyrosine kinase – drives cell cycle

139
Q

What are symptoms of single gene disorder?

A
  • Sickle cell crisis
  • Anaemia
  • Infection
  • Jaundice and gallstones
  • Avascular necrosis
  • Leg ulcer
  • Delayed growth
140
Q

What is the consequence if a particular polymorphic markers are close to disease mutation?

A

Inherited together

141
Q

When is 50% of the diseases are going to be inherited together ?

A

If you have disease mutation on one chromosome, a polymorphic marker on the other chromosome

142
Q

When is it always inherited with polymorphic marker?

A

If the disease mutation is right next to 3 repeats

143
Q

What is X-linked recessive?

A
  • Mother carries affected gene on X chromosome
  • Females are carriers
  • Only males are affected by the disorder
  • Some example
  • Duchenne Muscular Dystrophy
  • Haemophilia
  • Hunter disease
  • Because men pass their Y chromosome on to their sons and their X chromosomes to their daughters, men who are affected will not pass the condition on to their sons but all their daughters will be carriers
144
Q

What is X-linked dominant?

A
  • Females usually have two X chromosomes, while most males have one X and one Y chromosome
  • If a child has inherited the mutation from the X chromosome from one of their parents they will have the condition
  • Woman with an X-linked dominant disorder has a 50% chance of having an affected daughter or son with each pregnancy
  • The sons of a man with an X-linked dominant disorder will not be affected (since they inherit their only X chromosome from their mother), but his daughters will all inherit the condition
145
Q

What is Autosomal recessive?

A
  • Two of the defective genes are inherited
  • Parents are carriers of the mutated gene
  • The risk of an affected child being born is 25% for each pregnancy
  • Examples: phenylketonuria, cystic fibrosis
146
Q

What is autosomal dominant?

A
  • Single copy of defective gene
  • Conditions carried on the autosomes, males and females are equally affected
  • Chance of it being passed on is 50% for each pregnancy
  • If faulty gene is inherited, it will result in an affected individual
  • Examples include: Huntington disease, polycystic kidney disease
147
Q

What is imprinting genes?

A

epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner

involves DNA methylation and histone methylation without altering the genetic sequence

These epigenetic marks are established (“imprinted”) in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism

148
Q

What is Angelman syndrome?

A

Neuro-genetic disorder - several different phenotypes and it caused by Ube3a gene

It is a ubiquitin ligase

149
Q

Where is Angelman sundrome gene expresses from?

A

Maternally inherited chromosome

150
Q

What did John Langdon state?

A

phenotypic features of down syndrome are the same regardless of ethnicity

151
Q

What are the 4 phases of Mitosis?

A

Prophase
- Duplicated chromosomes are compacted
- Easily visualised as sister chromatids
- Chromosomes pair up
Metaphase
- Mitotic spindle latches onto the sister chromatids at the centromere
- Chromosomes are aligned in the middle of the cell
Anaphase
- The mitotic spindle contracts and pulls the sister chromatids apart
- Begin to move to opposite ends of the cell
Telophase
- The chromosomes reach either end of the cell
- The nuclear membrane forms again and the cell body splits into two (cytokinesis)

152
Q

Where is Down syndrome caused by?

A

Non-disjunction

153
Q

What is Non-disjunction?

A
  • The failure of one or more pairs of homologous chromosomes or sister chromatids to separate normally during nuclear division
  • Results in an abnormal distribution of chromosomes in the daughter nuclei
  • It can happen in either meiosis I or II, sometimes in mitosis early on in development
154
Q

Where does non-disjunction happen?

A
  • Mainly maternal – 90% of the case – meiosis I error
  • Paternal error – 8%
  • Meiosis I – 3%
  • Meiosis II – 5%
  • After fertilization – 5%
155
Q

What are Down syndrome phenotype features?

A
  • 100% of down cohort – mental retardation
  • Neuropathology seen in Alzheimer’s disease – plaques and tangles
  • Muscle hypotonia – 100% of the cases
  • Malformation to the bowel
  • Increase in leukaemia – both acute lymphocytic and acute milocytic leukaemia
  • Short stature
  • Short broad hands
  • Iris Brushfield spots
  • Flattened facial profile and nose
156
Q

What is mutated in people with down syndrome?

A

GATA1acute megakaryoblastic leukaemia

157
Q

Where is GATA 1 located?

A

From X chromosomes

158
Q

Patient with down syndrome?

A
  • Mutation in GATA1 – frame shift mutation on exon 2
  • Frame shift – shorter version of protein – translation from methionine 84 instead of methionine 1 – western blot
  • Used specific antibodies to GATA1
159
Q

Autosomal Recessive

A

• Cystic fibrosis
• Quite prevalent: 1 in 3000 new born, 1 in 25 people a carrier
• Affects different organ systems in body e.g. lungs and sweat glands
• Salty skin – diagnose cystic fibrosis
• Diagnosed even earlier through a neonatal blood spots
• Cause
- Mutation in cystic fibrosis transmembrane conductance regulator
• Large protein – 180,000 base pairs on chromosome 7 – long arm
• Encode 1500 amino acid proteins
• Takes chloride ions across membrane and down regulate sodium channel
• Salty skin – chloride channel affected – no reabsorption
• Lungs – changes in ions
• Sticky mucus – inflammation and bacterial infection

Molecular Basis Of Disease (7 decks)

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