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Genomics > Linkage analysis > Flashcards

Linkage analysis Flashcards

1
Q

What is genetic variation?

A

Differences in the DNA sequence between individuals in a population

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2
Q

Variation can be

A

Inherited or due to environmental factors (e.g. drugs, exposure to radiation)

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3
Q

4 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

Linkage analysis

A

Utilize common (most likely silent) variation to inform us about protein-altering variation

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5
Q

Why is genetic variation important?

A
  1. Genetic variation underlies phenotypic differences among different individuals
  2. Genetic variation 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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6
Q

Mutation/polymorphism

A

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

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7
Q

Germline mutations

A

Passed on to descendants

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8
Q

Somatic mutations

A

Not transmitted to descendants

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9
Q

De novo mutations

A

New mutation not inherited from either parent

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10
Q

Homologous recombination

A

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

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11
Q

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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12
Q

Polymorphism

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

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13
Q

Mutation

A

Rare change in the DNA sequence that is different from 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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14
Q

Difference between mutation and polymorphism

A

A polymorphism, the least common (minor) allele must be present in ≥1% of the population)

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15
Q

MAF

A

Minor Allele Frequency - how common the least common allele is in the general population.

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16
Q

Variant and polymorphism

A

Variant MAF of 1% or greater is classed a polymorphism

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17
Q

Variants and mutations

A

Minor allele is seen in less than 1% of the population (e.g. 0.001, equivalent to 1 in 1000), the variant may be classed as a mutation

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18
Q

Homologous recombination

A

 Crossing over: reciprocal breaking and re-joining of the homologous chromosomes during meiosis
 Results in exchange of chromosome segments and new allele combinations

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19
Q

New allele combination

A

A,B, c and a, b, C

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20
Q

Genotype

A

Genetic Makeup of an individual

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21
Q

Phenotype

A

Physical expression of the genetic makeup

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22
Q

Genes

A

Found in alternative versions called alleles

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23
Q

Homozygous

A

Identical alleles

24
Q

Heterozygous

A

Two different alleles

25
Q

Haplotype

A

Group of alleles that are inherited together from a single parent

26
Q

Homozygosity

A

Represented here by the identical colours at locus 1 – both the paternal and maternal copies of the gene are the same (i.e. blue)

27
Q

Heterozygosity

A

represented by the different colours at loci 2 and 3 – the paternal and maternal copies of each gene are different (locus 2: red and green; locus 3: blue and purple)

28
Q

Mendelian/monogenic

A

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

29
Q

Non-Mendelian/Polygenic

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)

30
Q

Multifactorial

A

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

31
Q

Mendelian

A

One gene = one disease

32
Q

Complex

A

Many genes = one disease

33
Q

Linkage analysis

A

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

34
Q

Linkage

A

Refers to the assumption of two things being physically linked to each other

35
Q

Genetic mapping

A

Look at the information in blocks or regions

36
Q

Physical maps

A

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

37
Q

Principles of genetic linkage

A

The tendency for alleles at neighbouring loci to segregate together at meiosis

38
Q

Cross - overs

A

More likely to occur between loci separated by some distance than between loci close together on the chromosome

39
Q

Recombinant

A

The recombinant chromosomes break up the haplotypes, creating new allele combinations of the ‘1’ and ‘2’ alleles (i.e. allele A1 with B2, and allele A2 with B1)

40
Q

Non - recombinant

A

Chromosomes are the same as the original (i.e. alleles A1 and B1 segregate together, A2 and B2 segregate together)

41
Q

Genetic markers

A

Microsatellite, Single Nucleotide polymorphisms

42
Q

Single Nucleotide polymorphism

A

Single Base substitutions
Typically biallelic (i.e. 2 alleles)
SNPs are not the disease causing variant.
They are polymorphisms that are used in linkage analysis to identify the likely location of the disease gene

43
Q

How many SNPs are required for Genome wide linkage analysis?

A

Approx 6,000 SNP

44
Q

Usage pf Microsatellite genotyping

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
45
Q

Microsatellite genotype

A

PCR- based method that is used to amplify highly repetitive regions of the genome

46
Q

Fluorescent genotyping

A
  • fluorescently-tagged PCR primers
  • Allows for multiplexing of PCR products with different colours and fragment lengths
  • Fragment sizes separated down to 1bp resolution
  • Look at the 3 microsatellite genotypes on the left
47
Q

SNP genotyping 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
  • Alleles are identified by relative fluorescence
  • homozygous for allele 1 = green signal
  • homozygous for allele 2 = red signal
  • heterozygous (1/2) = yellow signal
48
Q

LOD

A

Logarithm of the ODds score

49
Q

Statistical analysis of linkage

A
  • The probability of linkage can be assessed using a LOD 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)
50
Q

LOD scores

A

Higher LOD score means - higher likelihood of linkage

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

  • 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
51
Q

Different linkage soft

A
  • Vitesse
  • PLINK
  • MERLIN
  • Alohomora
  • Fastlink etc…
52
Q

Parametric analysis

A

• Specifies analysis parameters (e.g. inheritance pattern, disease allele frequency, penetrance)

53
Q

Non-parametric analysis

A
  • No parameters specified

* Looks for allele sharing between affected individuals

54
Q

Adams - oliver syndrome

A

Adams-Oliver syndrome (AOS) is a rare development disorder characterised by birth defects of the limbs and scalp. The photographs highlight the wide range of severity (clinical heterogeneity). A proportion of patients also have associated features, including neurological, cardiac or vascular defects.
It is believed to be caused by a problem during vascular development in the womb.

55
Q

Linkage analysis and AOS

A

Linkage analysis in two autosomal dominant families detected a statistically significant locus on chr 3
Analysis of two large autosomal dominant AOS families was conducted using ~6,000 SNP markers.
Merlin software was used for linkage analysis, under a model of autosomal dominant inheritance with reduced penetrance (85%).

56
Q

Process of identifying the gene for AOS

A
  • Refinement of minimal linkage interval using microsatellite and SNP markers across the region
  • Maximum LOD score of 4.93 at marker rs1464311
  • Maximum linkage interval defined by markers D3S3670 and rs1127030

We used a program called GeneDistiller to identify which genes were located within our linkage peak

We decided to focus on our critical (smallest) linkage interval, between 115 Mb and 121 Mb.
- Within this region, there were 26 genes

Genomics (19 decks)

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