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Genomics > Linkage Analysis > Flashcards

Linkage Analysis Flashcards

1
Q

What is genetic variation?

A

The differences in the DNA sequence between individuals in a population

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2
Q

How does variation occur?

A

It 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

Why is genetic variation important?

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

Mechanisms of genetic variation

A
  • Mutation/polymorphism
  • Gene flow
  • Genetic recombination
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6
Q

What is a mutation/polymorphism? What does this affect?

A

Errors in DNA replication. This may affect single nucleotides or larger portions of DNA.

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7
Q

What are germline mutations?

A

Passed on to descendants in the germline

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8
Q

What are somatic mutations?

A

Not transmitted to descendents in the tissues

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9
Q

What are de novo mutations?

A

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

Define a mutation

A

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

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13
Q

Define polymorphism

A

A DNA sequence variant that is common in the population. In this case, no single allele is regarded as the ‘normal’ allele. Instead there are two or more equally acceptable alternatives. Do not have a “reference normal” and one this is “different” like in a mutation.

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14
Q

What is a minor allele frequency?

A

The arbitrary cut-off point between a mutation and a polymorphism is a MAF of 1%.

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15
Q

What does the MAF need to be to be classed as a polymorphism?

A

The least common allele must be present in equal or more than 1% of the population.

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16
Q

How does the creation of haploid gametes occur?

A

Meiosis and Recombination

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17
Q

Summarise the creation of haploid gametes

A
  • Start off with a diploid germ cell.
  • Replication stage - DNA replicates.
  • Next stage - lining up of homologous chromosomes that can lead to the crossing over and can cause the switching of DNA from maternal and paternal DNA.
  • At the end, there are haploid cells that have a combination of maternal and paternal DNA.
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18
Q

What is homologous recombination?

A

Crossing over: reciprocal breaking and re-joining of the homologous chromosomes during meiosis.

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19
Q

What does the homologous recombination result in?

A

In exchange of chromosome segments and new allele combinations

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20
Q

Define genotype

A

The genetic makeup of an individual

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21
Q

Define phenotype

A

The physical expression of the genetic makeup

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22
Q

Alleles

A

Genes are found in alternative versions

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23
Q

How do organisms inherit alleles?

A

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

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24
Q

What is the relation between genotype and alleles?

A

A genotype details the two alleles an individual carries for a specific gene or marker.

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25
Q

What are the alleles of homozygous genotype?

A

Identical alleles

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26
Q

What are the alleles of heterozygous genotype?

A

Two different alleles

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27
Q

What is a haplotype?

A

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

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28
Q

What is a chromosome pair?

A

Homologous chromosomes with genes at the same loci

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29
Q

Describe the positioning of an allele at a locus in the homozygous or heterozygous

A

In a homozygous chromosomes, there is the same allele of gene 1 on both loci.
In a heterozygous chromosomes, there is different alleles of gene 2 and gene 3 on each homologue on the loci.

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30
Q

What are the classification of genetic disease?

A
  • Mendelian/Monogenic
  • Non-mendelian/Polygenic
  • Multifactorial
31
Q

What is a mendelian disease?

A

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

32
Q

What is a non-mendelian 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). Cumulative effect of changes in different genes that cause the disease.

33
Q

What is multifactorial disease?

A

Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease). For example, having a genetic predisposition and drank frequently - more likely to have heart disease.

34
Q

Describe the linkage analysis and different genomic variation disease.

A
  • Mendelian disorders are very rare, but very high penetrance.
  • Low-frequency variants with intermediate penetrance
  • Polygenic/Common complex diseases are common and low penetrance.
  • Hard to identify genetically are very rare and low penetrance
  • Highly unusual for common diseases are high penetrance but common.
35
Q

What is linkage analysis?

A

A method used to map the location of a disease gene in the genome. The term “linkage” refers to the assumption of two things between physically linked to each other.

36
Q

What are linkage assumptions that are used?

A

Use genetic markers to identify the location of a disease gene based on their physical proximity.

37
Q

Why is genetic mapping important?

A

To look at information in blocks or regions

38
Q

What is genetic linkage?

A

The tendency for alleles at neighbouring loci to segregate together at meiosis. Therefore to be linked, two loci must lie very close together.

39
Q

What is the importance of a haplotype?

A

Defines multiple alleles at linked loci. Haplotypes mark chromosomal segments which can be tracked through pedigrees and populations.

40
Q

When are crossovers more likely to occur?

A

It is more likely to occur between loci separated by some distance than those close together.

41
Q

What are the two principles of genetic linkage?

A

Scenario 1: disease gene is a long distance away from a genetic marker on the chromosome

Scenario 2: disease gene is close to a marker on the same chromosome

42
Q

When the disease gene is a long distance away what is the chance of recombination?

A

Independent assortment will occur if the disease gene is a long distance away as it leads to the high likelihood of recombination.

43
Q

When the disease gene is close to a marker on the same chromosome what type of assortment occurs?

A

Non-independent assortment will occur leading to a larger proportion of non-recombinants expected (i.e. greater likelihood of co-segregation of marker with the gene)

44
Q

Explain the linkage mapping using genetic markers

A
  • Uses an observed locus (genetic marker) to draw inferences about an unobserved locus (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.
  • 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.
45
Q

What unit is the genetic distance measured in?

A

centiMorgans (cM)

46
Q

What are some types of genetic markers?

A
  • Microsatellite Markers

- Single nucleotide polymorphisms

47
Q

Microsatellite Markers

A
  • Less common now.
  • Highly polymorphic short tandem repeats of 2 to 6 bp.
  • May differ in length between chromosomes (heterozygous)
  • Are relatively widely spaced apart
48
Q

Single nucleotide polymorphisms

A
  • The genetic marker of choice
  • Biallelic - a SNP will be one of two possible bases
  • Less heterozygous than microsatellites, but spaced much closer together
  • More informative
49
Q

What is microsatellite genotyping used for?

A
  • DNA fingerprinting from very 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
50
Q

What is a SNP?

A
  • Single base change
  • Most common type of variation
  • Thought to occur approximately 1 per 1,000 bases
  • Human genome is 3 billion base pairs (i.e. 2 x 3,000 Mb)
51
Q

Why is SNP genotyping microarrays used?

A
  • Provides genome-wide coverage of SNP markers
  • SNPs are proxy markers; NOT the casual disease variants
  • Can amplify thousands of markers in a single experiment
  • Alleles are identified by relative fluorescence
52
Q

What is the relative fluorescence for alleles?

A
  • Homozygous for allele 1 = green signal
  • Homozygous for allele 2 = red signal
  • Heterozygous (1/2) = yellow signal
53
Q

What is SNP genotyping microarrays used for?

A
  • Linkage analysis in families (affected vs unaffected relatives)
  • GWAS in populations (unrelated cases vs matched controls)
54
Q

What is types of linkage analysis in families?

A

Homozygosity mapping (autosomal recessive) and mapping of Mendelian traits

55
Q

What is GWAS in populations?

A

Non-Mendelian disorders and multifactorial traits

56
Q

What types of coverage of the human genome occurs?

A
  • Microsatellite coverage

- SNP coverage

57
Q

When there are black areas in the Microsatellite and SNP coverage on the array what do these represent?

A

Represent gaps in the human genome sequence, primarily centromeres and telomeres.

58
Q

What is used to assess the probability of linkage?

A

LOD score

59
Q

What is a LOD score?

A

Logarithm of the odds score

60
Q

When is the LOD score used?

A

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.

61
Q

What is the recombination fraction?

A

The proportion of recombinant births

62
Q

What does a high LOD score state?

A

The higher the LOD score, the higher the likelihood of linkage

63
Q

When calculating LOD scores what can they be used for?

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 and Parametric analysis specifies the pedigree structure and inheritance pattern

64
Q

What increases the LOD score in families?

A

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

65
Q

What LOD score is considered for evidence for linkage?

A

If the LOD score is greater than or equal to 3 then this is considered evidence for linkage.

66
Q

What LOD score is considered for evidence against linkage?

A

If the LOD score is less than or equal to 2 then this is considered evidence against linkage.

67
Q

What is the Adams-Oliver syndrome?

A

An example of mapping an autosomal dominant disease gene using linkage analysis.

68
Q

What are the symptoms of Adams-Oliver syndrome?

A
  • Terminal transverse limb defects (TTLD)
  • Scalp aplasia cutis congenita (ACC)
  • Neurological anomalies
  • Cardiac malformations
  • Vascular defects (e.g. cutis marmorata telangiectatica congenita, dilated veins)
69
Q

What is the maximum LOD score?

A

4.93

70
Q

What does refinement of minimal linkage interval use?

A

Uses microsatellite markers across the region

71
Q

How many genes are in the minimal linkage interval?

A

21 genes (115-121 Mb)

72
Q

How is ARHGAP31 identifed?

A

It is identifed using a candidate gene analysis approach

73
Q

What is ARHGAP31?

A

A GTPase regulatory protein

Genomics (19 decks)

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