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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
Q

What is a haplotype?

A

A haplotype is a group of alleles that are inherited together from a single parent

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26
Q

What is a chromosome pair?

A

Homologous chromosomes with genes at the same loci

The allele at that locus may be the same (homozygous) or different (heterozygous)

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27
Q

What are the different classifications of genetic disease?

A
  • Mendelian / Monogenic
  • Non-mendelian / polygenic
  • Multifactorial
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28
Q

What is mendelian / monogenic disease?

A

Disease that is caused by a single gene, with little or no impact from the environment (e.g. PKD)

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29
Q

What is non-mendelian / polygenic disease?

A

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)

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30
Q

What is a multifactorial disease?

A

diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)

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31
Q

How does a mendelian disease differ from a complex disease?

A

Mendelian (one gene = one disease) vs. Complex (many genes = one disease)

32
Q

Which genetic diseases are mapped by linkage analysis?

A

Linkage analysis focuses on the mendelian single gene disorders which are rare

33
Q

What genetic diseases are more common?

A

Common variants are at the other end of the spectrum and are very common

34
Q

What is the allele frequency of common variant genetic diseases?

A

generally with allele frequencies >1%, and have a very low effect ∴ need multiple hits in those genes to cause disease

35
Q

How are common variant genetic diseases investigated?

A

these are investigated using GWAS

36
Q

What is linkage analysis?

A

This is a method used to map the location of a disease gene in the genome

37
Q

What does the term ‘linkage’ mean in terms of linkage analysis?

A

The term ‘linkage’ refers to the assumption of two things being physically linked to each other

38
Q

What assumptions are made using linkage?

A

We can use genetic markers to identify the location of a disease gene based on their physical proximity

39
Q

What do genetic maps show us?

A

Genetic maps look at information in blocks or regions (similar to zones on a tube map)

40
Q

How do physical maps differ from genetic maps?

A

Physical maps provide information on the physical distances between landmarks (e.g. stations on a tube map) based on their exact location

41
Q

What is genetic linkage?

A

Genetic linkage is the tendency for alleles at neighbouring loci to segregate together at meiosis

42
Q

How do loci get linked?

A

To be linked, two loci must lie very close together

43
Q

What is the significance of haplotypes in identifying disease genes?

A

Haplotypes mark chromosomal segments which can be tracked through pedigrees and populations

44
Q

When is chromosomal cross over most likely to occur?

A

Cross-overs are more likely to occur between loci separated by some distance than those close together

45
Q

How is genetic variation introduced when a disease gene is a long distance away from a genetic marker?

A

independent assortment

-> high likelihood of recombination

46
Q

How is variation introduced when the disease gene is close to a marker on the same chromosome?

A

non-independent assortment

- > larger proportion of non-recombinants expected
i. e. greater likelihood of co-segregation of marker with the gene

47
Q

How can we use principles of gene linkage to identify disease genes?

A

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
Q

How is linkage mapping carried out?

A

Uses an observed locus (genetic marker) to draw inferences about an unobserved locus (disease gene)

49
Q

Describe the likelihood of inheritance if a marker is linked to a disease gene

A

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
Q

What is the chance of inheritance if the disease gene and marker are unlinked?

A

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
Q

On pedigree diagrams how do we identify diseased individuals?

A

Disease individuals filled in colour

52
Q

What is the critical linkage interval?

A

where everyone in the family that is affected has the same chromosome

53
Q

How often are microsatellite markers used?

A
  • less common now
  • highly polymorphic STRs (2-6bp)
  • may differ in length between chormosomes
    (heterozygous)
  • relatively widely spaced apart
54
Q

Explain why SNPs are the chosen genetic markers now

A
  • genetic marker of choice now
  • less heterozygous than microsatellites
  • spaced much closer together
  • more informative
55
Q

Describe the features of microsatellite markers

A
  • 400 (200) microsatellite markers
  • average 9cm (20cm) spacing
  • PCR based system
  • Fluorescently labelled primers
  • labour intensive
  • whole genome scan 2-3 months
56
Q

Describe the features of SNP markers

A
  • ~6000 SNPs
  • spaced throughout genome
  • Microarray based system
  • genotypes assigned automatically
  • highly automated
  • data returned within 1-2 months
57
Q

What is microsatellite genotyping typically used for?

A

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
Q

What are SNPs?

A

Single base change

e.g. CCT 🡪 CTT
Proline) (Leucine

59
Q

How often do SNPs occur within the genome?

A

Most common type of variation

Thought to occur approximately 1 per 1,000 bases

60
Q

How big is the human genome?

A

Human genome is 3 billion base pairs (i.e. 2 x 3,000 Mb)

61
Q

How is SNP genotyping carried out using microarrays?

A
  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
Q

What is the significance of SNP genotyping via microarrays ?

A

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
Q

How alleles identified during microarrays of SNP genotyping?

A

Alleles are identified by relative fluorescence
homozygous for allele 1 = green signal
homozygous for allele 2 = red signal
heterozygous (1/2) = yellow signal

64
Q

When is SNP genotyping via microarrays used?

A

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
Q

Why are SNP markers preferred over the use of microsatellites?

A

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
Q

How is the probability of linkage analysed?

A

The probability of linkage can be assessed using a LOD score

67
Q

What is a LOD?

A

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
Q

What does the LOD score tell us?

A

The higher LOD score, the higher the likelihood of linkage

69
Q

How are LOD scores calculated?

A

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
Q

How do individual genotypes within a family contribute to the LOD score of a disease gene?

A

LOD scores are additive – different families linked to the same disease locus will increase the overall score

71
Q

How do we know when a LOD score is significant?

A

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
Q

Describe quantitatively the significant LOD scores

A

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
Q

What are the associated features of Adams-Oliver syndrome?

A

Neurological anomalies
Cardiac malformations
Vascular defects (e.g. cutis marmorata telangiectatica congenita, dilated veins)

74
Q

Describe how we can use GWAS using SNP markers to identify disease genes

A

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
Q

Outline how locus refinement aids gene identification

A

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
Q

Describe the conclusion found from GWAS and locus refinement in identifying the disease gene for Adams-Oliver Syndrome

A

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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