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Genomics > Linkage Analysis > Flashcards

Linkage Analysis Flashcards

1
Q

What is genetic variation?

A

Genetic variation refers to differences in the DNA sequence between individuals in a population

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2
Q

What causes genetic variation?

A

Variation can be inherited or due to environmental factors (e.g. drugs, exposure to radiation)

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3
Q

What are the different effects of genetic variation?

A

Alteration of the amino acid sequence (protein) that is encoded by a gene
Changes in gene regulation (where and when a gene is expressed)
Physical appearance of an individual (e.g. eye colour, genetic disease risk)
Silent or no apparent effect

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4
Q

What is the significance of variation?

A
  1. Genetic variation underlies phenotypic differences
    among different individuals
  2. Genetic variations determine our predisposition to
    complex diseases and responses to drugs and
    environmental factors
  3. Genetic variation reveals clues of ancestral human
    migration history
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5
Q

What is a mutation / polymorphism?

A

errors in DNA replication

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6
Q

What is the effect of a polymorphism?

A

This may affect single nucleotides or larger portions of DNA

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7
Q

What are germline mutations?

A

Germline mutations: passed on to descendants

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8
Q

What are the effects of somatic mutations?

A

Somatic mutations: not transmitted to descendants

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9
Q

What are the effects of de novo mutations?

A

de novo mutations: new mutation not inherited from either parent

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10
Q

What is gene flow?

A

the movement of genes from one population to another (e.g. migration) is an important source of genetic variation

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11
Q

What is genetic recombination?

A

shuffling of chromosomal segments between partner (homologous) chromosomes of a pair

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12
Q

How does a mutation differ from a polymorphism?

A

A rare change in DNA sequence that is different to the normal (reference) sequence.
The ‘normal’ allele is prevalent in the population and mutation changes this to a rare ‘abnormal’ variant

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13
Q

How does a polymorphism differ from a mutation?

A

A DNA sequence variant that is common in population. In this case no single allele is regarded as the ‘normal’ allele. Instead there are two or more equally acceptable alternatives

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14
Q

What is the arbitrary cut off between polymorphisms and mutations?

A

The arbitrary cut-off point between a mutation and a polymorphism is a minor allele frequency (MAF) of 1%
(i.e. to be classed as a polymorphism, the least common allele must be present in ≥1% of the population)

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15
Q

What is meiosis?

A

Meiosis - The creation of haploid gametes (i.e. sperm and eggs)

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16
Q

How does chromosomal recombination occur?

A

Maternal and paternal chromosomes line up at the equator during metaphase => results in crossing over between chromosomes = genetic variation

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17
Q

Why is recombination significant in linkage analysis?

A

Mechanism is used in linkage analysis to track regions of the genome that are being transmitted throughout a family

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18
Q

What is crossing over?

A

The reciprocal breaking and rejoining of homologous chromosomes during meiosis

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19
Q

What is the result of crossing over?

A

Results in exchange of chromosome segments and new allele combinations

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20
Q

What is a genotype?

A

The genetic makeup of an individual

Details the two alleles an individual carries for a specific gene or marker

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21
Q

What is the phenotype?

A

The physical expression of the genetic makeup

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22
Q

What are alleles?

A

Genes are found in alternative versions called alleles

For each characteristic, an organism inherits two alleles, one from each parent; the alleles can be the same or different

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23
Q

Describe a homozygous genotype

A

A homozygous genotype has identical alleles

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24
Q

What is a heterozygous genotype?

A

A heterozygous genotype has two different alleles

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25
What is a haplotype?
A haplotype is a group of alleles that are inherited together from a single parent
26
What is a chromosome pair?
Homologous chromosomes with genes at the same loci | The allele at that locus may be the same (homozygous) or different (heterozygous)
27
What are the different classifications of genetic disease?
- Mendelian / Monogenic - Non-mendelian / polygenic - Multifactorial
28
What is mendelian / monogenic disease?
Disease that is caused by a single gene, with little or no impact from the environment (e.g. PKD)
29
What is non-mendelian / polygenic disease?
Diseases or traits caused by the impact of many different genes, each having only a small individual impact on the final condition (e.g. psoriasis)
30
What is a multifactorial disease?
diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)
31
How does a mendelian disease differ from a complex disease?
Mendelian (one gene = one disease) vs. Complex (many genes = one disease)
32
Which genetic diseases are mapped by linkage analysis?
Linkage analysis focuses on the mendelian single gene disorders which are rare
33
What genetic diseases are more common?
Common variants are at the other end of the spectrum and are very common
34
What is the allele frequency of common variant genetic diseases?
generally with allele frequencies >1%, and have a very low effect ∴ need multiple hits in those genes to cause disease
35
How are common variant genetic diseases investigated?
these are investigated using GWAS
36
What is linkage analysis?
This is a method used to map the location of a disease gene in the genome
37
What does the term 'linkage' mean in terms of linkage analysis?
The term ‘linkage’ refers to the assumption of two things being physically linked to each other
38
What assumptions are made using linkage?
We can use genetic markers to identify the location of a disease gene based on their physical proximity
39
What do genetic maps show us?
Genetic maps look at information in blocks or regions (similar to zones on a tube map)
40
How do physical maps differ from genetic maps?
Physical maps provide information on the physical distances between landmarks (e.g. stations on a tube map) based on their exact location
41
What is genetic linkage?
Genetic linkage is the tendency for alleles at neighbouring loci to segregate together at meiosis
42
How do loci get linked?
To be linked, two loci must lie very close together
43
What is the significance of haplotypes in identifying disease genes?
Haplotypes mark chromosomal segments which can be tracked through pedigrees and populations
44
When is chromosomal cross over most likely to occur?
Cross-overs are more likely to occur between loci separated by some distance than those close together
45
How is genetic variation introduced when a disease gene is a long distance away from a genetic marker?
independent assortment | -> high likelihood of recombination
46
How is variation introduced when the disease gene is close to a marker on the same chromosome?
non-independent assortment | - > larger proportion of non-recombinants expected i. e. greater likelihood of co-segregation of marker with the gene
47
How can we use principles of gene linkage to identify disease genes?
Can use this idea to try identify disease gene by looking at markers across the whole length of the chromosome and can identify those markers that are co-segregating with the disease gene
48
How is linkage mapping carried out?
Uses an observed locus (genetic marker) to draw inferences about an unobserved locus (disease gene)
49
Describe the likelihood of inheritance if a marker is linked to a disease gene
If a marker is linked to a disease locus (i.e. M3 and M4), the same marker alleles will be inherited by two affected relatives more often than expected by chance
50
What is the chance of inheritance if the disease gene and marker are unlinked?
If the marker and the disease locus are unlinked (i.e. M5 – M8), the affected relatives in a family are less likely to inherit the same marker alleles
51
On pedigree diagrams how do we identify diseased individuals?
Disease individuals filled in colour
52
What is the critical linkage interval?
where everyone in the family that is affected has the same chromosome
53
How often are microsatellite markers used?
- less common now - highly polymorphic STRs (2-6bp) - may differ in length between chormosomes (heterozygous) - relatively widely spaced apart
54
Explain why SNPs are the chosen genetic markers now
- genetic marker of choice now - less heterozygous than microsatellites - spaced much closer together - more informative
55
Describe the features of microsatellite markers
- 400 (200) microsatellite markers - average 9cm (20cm) spacing - PCR based system - Fluorescently labelled primers - labour intensive - whole genome scan 2-3 months
56
Describe the features of SNP markers
- ~6000 SNPs - spaced throughout genome - Microarray based system - genotypes assigned automatically - highly automated - data returned within 1-2 months
57
What is microsatellite genotyping typically used for?
DNA fingerprinting from v. small amounts of material Standard test uses 13 core loci making the likelihood of a chance match 1 in three trillion Paternity testing Linkage analysis for disease gene identification
58
What are SNPs?
Single base change | e.g. CCT 🡪 CTT Proline) (Leucine
59
How often do SNPs occur within the genome?
Most common type of variation | Thought to occur approximately 1 per 1,000 bases
60
How big is the human genome?
Human genome is 3 billion base pairs (i.e. 2 x 3,000 Mb)
61
How is SNP genotyping carried out using microarrays?
1. DNA of each individual placed in wells on microscope slide 2. Probes located on slide for each of the SNPs around the genome 3. DNA hybridises to these probes and is measured by fluorescence
62
What is the significance of SNP genotyping via microarrays ?
Provides genome-wide coverage of SNP markers SNPs are proxy markers; NOT the causal disease variants Can amplify thousands of markers in a single experiment
63
How alleles identified during microarrays of SNP genotyping?
Alleles are identified by relative fluorescence homozygous for allele 1 = green signal homozygous for allele 2 = red signal heterozygous (1/2) = yellow signal
64
When is SNP genotyping via microarrays used?
Linkage analysis in families (affected vs unaffected relatives) > homozygosity mapping (autosomal recessive) and mapping of Mendelian traits GWAS in populations (unrelated cases vs matched controls) > non-Mendelian disorders and multifactorial traits
65
Why are SNP markers preferred over the use of microsatellites?
Microsatellites much more spaced throughout the genome although they’re more polymorphic - give us lots of info but very distant SNPs cover more of the genome
66
How is the probability of linkage analysed?
The probability of linkage can be assessed using a LOD score
67
What is a LOD?
LOD = logarithm of the odds score Assesses the probability of obtaining the test data if the two loci are linked, to the likelihood of observing the same data purely by chance i.e. calculates a likelihood ratio of observed vs. expected (no linkage, θ=0.5)
68
What does the LOD score tell us?
The higher LOD score, the higher the likelihood of linkage
69
How are LOD scores calculated?
LOD scores can be calculated across the whole genome using genotype data for many genetic markers in multiple members of a family e. g. - Merlin software - Parametric analysis: specifies pedigree structure and inheritance pattern (model)
70
How do individual genotypes within a family contribute to the LOD score of a disease gene?
LOD scores are additive – different families linked to the same disease locus will increase the overall score
71
How do we know when a LOD score is significant?
A LOD score ≥ 3 is considered evidence for linkage Equivalent to odds of 1000:1 that the observed linkage occurred by chance Translates to a p-value of approximately 0.05 A LOD score ≤ -2 is considered evidence against linkage
72
Describe quantitatively the significant LOD scores
Once you plot your LOD scores look for a score ≥3 which is significant evidence for linkage Lower scores ~1 are positive and still suggestive Anything below -2 can be excluded
73
What are the associated features of Adams-Oliver syndrome?
Neurological anomalies Cardiac malformations Vascular defects (e.g. cutis marmorata telangiectatica congenita, dilated veins)
74
Describe how we can use GWAS using SNP markers to identify disease genes
Linkage analysis in two autosomal dominant families detected a statistically significant locus on chr 3 Chromosome 3 had a really large peak with a significant LOD score ≥3
75
Outline how locus refinement aids gene identification
Refinement of minimal linkage interval using microsatellite markers across the region Maximum LOD score of 4.93 21 genes in the minimal linkage interval (115 – 121 Mb) ARHGAP31 identified using a candidate gene analysis approach ARHGAP31 is a GTPase regulatory protein
76
Describe the conclusion found from GWAS and locus refinement in identifying the disease gene for Adams-Oliver Syndrome
Heterozygous mutations of the terminal exon 12 detected in four unrelated families All mutations predicted to result in premature protein truncation

Genomics (20 decks)

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