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GENE 5: Mapping the genome Flashcards

1
Q

What is a genome map?

A

A diagram of the chromosomes which highlight the positions of key features such as genes and control regions

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2
Q

What are genome maps used for?

A

identifying disease genes and regions which are medically important

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3
Q

What type of resolution do cytogenic (karyotype) maps have?

A

Low

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4
Q

Name three types of genomic maps

A
  • cytogenic
  • genetic
  • physical
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5
Q

What do genetic maps show?

A

How close the genes for co-inherited traits are to one another, by measuring their frequencies, using linkage studies

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6
Q

What is genetic distance measured in?

A

Centimorgans (cM)

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7
Q

What are centimorgans defined as?

A

The probability of a recombination happening between 2 points (1cM = 1% chance of recombination)

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8
Q

What statistical tests do genetic maps use?

A

‘Logarithm of Odds’ scores and measurements of linkage to polymorphic DNA markers

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9
Q

What does physical mapping do? What is used to do this?

A

Directly examines DNA using restriction enzyme mapping and DNA sequencing in order to measure distances in base-pairs.

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10
Q

Identification of genes responsible for a specific trait require a _______ of genetic and physical mapping

A

combination

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11
Q

What methods are being used to identify key sequences not yet found?

A

Computational and experimental reverse genetic methods

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12
Q

What genetic approaches are used in linkage analyses?

A

forward genetic approaches: which are used in family studies of monogenic phenotypes, and methods that study allele frequencies in whole populations

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13
Q

How do you identify the genes involved in creating polygenic phenotypes?

A

genome-wide association studies (GWAS) and linkage disequilibrium analyses.

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14
Q

What does linkage analysis rely on?

A

meiotic recombination between homologous chromosomes

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15
Q

This crossing-over has the potential to ____ linked alleles and prevents _________ in every generation

A

Split

co-inheritance

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16
Q

During linkage analysis, if there are fewer recombinant phenotypes, what does this say about the distance between the genes on a chromosome?

A

the fewer the recombinant offspring, the closer the genes are on the chromosome

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17
Q

Recombinant frequency cannot exceed 50%, why?

A

Multiple cross-overs are possible

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18
Q

How do you calculate recombination frequency?

A

Recombination Frequency = (Recombinant offspring/Total offspring) x 100

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19
Q

In humans, how many kb is 1cM roughly equal to?

A

1200kb

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20
Q

Why is cM not an absolute distance?

A

Varies as recombination does not occur with equal likelihood at all chromosomal positions

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21
Q

Give three reasons why linkage analysis is difficult in humans

A
  • Difficulties assigning genes to autosomes
  • Limited pedigree sizes
  • Insufficient number of informative loci
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22
Q

What was established to have a close relationship with colour blindness?

A

Haemophilia A

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23
Q

How do you determine if a gene is on a sex chromosome?

A

pedigree analysis

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24
Q

Initially how was assigning a gene to a specific autosome carried out?

A

Viewing chromosome abnormalities under a microscope (e.g. uncoiling of chromosome 1)

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25
How is assigning a gene to a specific autosome carried out now?
Somatic cell hybridisation - fusing a human and rodent cell to create hybrid cell lines to test for correlation between a particular chromosome and a cellular phenotype such as the production of a particular human protein or human cDNA. These were tested for using Western and Southern blotting or PCR and enzyme assays.
26
Why is it harder to do pedigree in humans?
inability of the scientist to choose human breeding partners which makes it difficult to establish parental genotypes
27
Why is the resolution of genetic maps often low for genetic diseases?
Pedigrees involving individuals afflicted with genetic disease are often small thereby limiting the number of meioses that can be analysed, which decreases the resolution of the map
28
How do you combat low resolution of maps of genetic diseases?
mathematical models are used to determine the uncertainty in inferring linkage from an observed set of births
29
Describe the mathematical models that determine uncertainty in genetic disease pedigrees. What software can be used? Calculation used?
A parametric logarithm of odds (LOD) score is calculated which defines the ratio between the likelihood of the alternative hypothesis versus the null hypothesis. These models can be defined using computer software such as GeneHunter which is an established program for conducting linkage analyses. The LOD score is calculated as follows: LOD score = log10(probability of linkage/probability of no linkage)
30
What are informative genes?
present in two distinguishable alleles within a family pedigree
31
What does DNA cloning now utilise for linkage mapping?
Polymorphic sequences
32
What do polymorphic sequences include?
* Single nucleotide polymorphism (SNP) * Simple sequence repeat (SSR) or Simple sequence length polymorphism (SSLP) or Short tandem repeat (STR) * Restriction fragment length polymorphisms (RFLP)
33
How often do SNPs occur in the genome?
Once every 300bp
34
How are Single nucleotide polymorphism (SNPs) identified?
Hybridisation of oligonucleotide probes using PCR or microarrays, or by targeted DNA sequencing
35
How are Simple sequence length polymorphism (SSLPs) detected?
Gel electrophoresis following PCR amplification and can be used to investigate dominant disease alleles
36
How are Restriction fragment length polymorphisms (RFLPs) detected?
Gel electrophoresis or PCR
37
Why can RFLPs be used in forensic investigations or determining an individual’s risk of developing a genetic disorder?
unique in different individuals
38
What would linkage analysis results mean if a marker was close to the disease gene?
It is possible that the polymorphism is within the disease gene, or corresponds to the disease-causing mutation in the gene. Although, it is more likely that the polymorphism is several hundred kb away and physical mapping is required for better resolution.
39
What size can metaphase FISH not resolve beyond?
4Mb
40
FISH is an example of what type of mapping?
Physical
41
What does higher resolution physical mapping involve?
restriction enzyme mapping and DNA sequencing
42
How is higher resolution physical mapping carried out?
Genomes can be broken down into 200-2000bp fragments which overlap, and these are sequenced and computationally pieced together
43
What is the major issue faced by shotgun sequencing? why?
Repeat sequences - no way of knowing how long the sequences are and where the overlap can be found
44
Restriction enzyme mapping and DNA sequencing has been used to do what?
successfully sequence most bacterial genomes and almost completely sequence the human genome, although this process is difficult in more complex eukaryotes.
45
What size of DNA fragments are cloned into a BAC or other large capacity vector in order to identify the specific sites of overlap?
~150kb
46
Explain method of cloning overlapping DNA fragments into BAC or other large capacity vector
* Non-repetitive probe from an insert is hybridised to the BAC * The ends of the BAC inserts are sequenced and compared * Similarities between the patterns of the DNA fragments following RE digestion of the BAC are identified * BACs which share sequence tagged sites are identified
47
What are Sequence Tagged Sites (STS)?
Genetically mapped regions 100-500bp long which are adjacent to DNA markers such as RFLPs and SSLPs
48
What does Sequence Tagged Sites (STS) allow for?
Physical and genetic mapping to be aligned in order to check for contiguous (overlapping DNA fragment) misalignment.
49
Following assembly of STSs what can occur?
The contiguous BAC inserts can be shotgun sequenced to complete genome sequencing.
50
The combination of genetic and physical mapping also allows for _______ cloning
positional
51
What does positional cloning allow?
disease genes can be identified and cloned
52
What has positional cloning been carried out for, before the altered protein/mRNA was identified?
monogenic disease genes such as cystic fibrosis and muscular dystrophy
53
The genetic map position was first used to identify a region ____ which was then screened for ________ genes in the physical mapping position.
~20Mb | candidate
54
Why was positional cloning not needed in the case of sickle cell disease?
It was known that the B-globin protein was affected
55
What is functional cloning and give an example
Isolating the mRNA of a protein known to be affected by a disease and screening for the protein's gene in a genome wide library
56
What is the problem with predicting the sequences that encode proteins within the genome? explain
cannot know whether sequence variation of that sequence would directly link to phenotype. Most disease-causing genetic variations would be selected out meaning most genetic variations observed would not be directly associated with diseased phenotypes.
57
Why can most phenotypic traits in humans not be mapped by linkage analysis?
Most phenotypic traits are polygenic, which cannot be mapped traditionally by linkage analysis as individual markers may only be slightly associated with a given phenotype in the absence of the other contributing genes
58
What does GWAS aim to do?
identify linked genetic markers across large populations.
59
What does GWAS no consider?
generational inheritance
60
What is case-control study design?
A simple model are used to count the frequencies of genetic markers in affected and unaffected individuals and compare them
61
What does case-control study design involve?
Calculating the probability of the difference in ratio of alleles occurring by chance using the chi-squared test on a 2 x n contingency table: •n = number of alleles •n – 1 = degrees of freedom
62
What are the requirements for a chi-squared test used in a case-control study?
* Non-parametric statistical test with no underlying probability model applied to the data * Count data is required so adjusted/normalised/transformed values cannot be used * Allele genotypes must be mutually exclusive and random sampling must be used, as selective sampling (clinical studies) inflates significance * Large samples of all alleles must be used, so for rarely observed categories the Fisher’s exact test would be more appropriate
63
For rarely observable categories, what test should be used instead of chi-squared test?
Fisher’s exact test
64
Why must adjustments be made to the statistical testing methods, proceeding GWAS?
GWAS uses multiple hypothesis testing
65
What adjustment is used following GWAS?
Bonferroni | The p-value is divided by the number of tests performed e.g. p<0.05/2,000,000=2.5x10^-8
66
When using GWAS the null hypothesis is for?
un-associated loci
67
How do you increases the statistical power of a test? How does this help in GWAS?
Obtain a larger sample size. In GWAS, larger numbers decrease the likelihood of un-associated SNPs exhibiting segregation between case and control groups.
68
What do results from GWAS show?
Alleles which are strongly associated with diseases are unlikely to be prevalent in large numbers in the population, therefore GWAS studies alleles showing weaker association to disease making large sample sizes even more important
69
What have International HapMap project and 1000 Genomes Consortium project have attempted to do?
Maps the degree of co-occurrence of SNPs within different populations based on linkage disequilibrium (LD) analysis
70
How does Linkage disequilibrium arise?
through meiotic recombination linking loci to phenotype-associated genetic variants.
71
What factors does linkage disequilibrium include?
* Selective pressure for a specific combination of alleles across different genes on different chromosomes as seen in polygenic traits. * Not all positions on the genome are equally likely to undergo recombination
72
What is the extend of linkage disequilibrium computationally calculated between?
All pairs of loci within genotyped family pedigrees
73
What is the problem with LD data collection?
A large number of individuals are required and there is difficulty in obtaining DNA from large numbers of related individuals which is why LD is examined in GWAS cohorts
74
Why is LD examined in GWAS cohorts, useful for imputation?
It is a good estimate of non-measured genotypes can be made based on the alleles of measured loci in LD. By imputing most variants of the human genome, associations of the causal variant are more likely to be detected and the reason it causes a diseased trait can be found.
75
Why could improper population stratification lead to false positives within GWAS?
• Population stratification in which the case and control groups have an uneven distribution of subpopulations could cause false positives. E.g. HLA-AI allele could be falsely associated with the ability to use chopsticks as it is more common in Asian populations than Caucasian ones.
76
Why could cryptic relatedness lead to false positives in GWAS?
• Cryptic relatedness is a phenomenon in which individuals in a case-control group are closely related, but this is unknown to the investigator
77
What can technical variations such as measurement errors in a batch of samples in a study where sample collection was not randomised between case and control samples, lead to? Why?
False positives within GWAS: where genetic features arising due to the measurement error can be wrongly associated with the phenotype of interest

Genetics (10 decks)

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