Genetic Linkage and Direct Testing

Question 1

What is Linkage ?

Answer 1

The tendency of genes and segments of DNA closely positioned along a strand of DNA to segregate together in meiosis and therefore be inherited together

Question 2

Is linkage analysis direct or indirect analysis ?

Answer 2

Indirect DNA analysis

Question 3

What is linkage analysis ?

Answer 3

The use of several DNA markers that are near or within a gene of interest to track within a family of inheritance of a disease causing mutation of that gene

Question 4

What is a marker ?

Answer 4

An identifiable segment of DNA (SNP, satellite, VNTR, ) with enough variation between individuals that the inheritance and co-inheritance of alleles of a given gene can be traced

Question 5

What is a phase ?

Answer 5

That for two or more closely linked markers the alleles are contained on the same chromosome

Question 6

What is linkage disequilibium ?

Answer 6

In a population, co-occurance of specific alleles at a higher frequency than would be predicted by random chance; over-representation of specific haplotypes

Question 7

What is haplotype analysis ?

Answer 7

Molecular genetic testing to identify a set of closely linked segments of DNA; used in linkage analysis or when a given traits is in linkage disequilibrium with a marker or set of markers

Question 8

What is one way a cell can generate new haplotypes in the offspring ?

Answer 8

Through recombination

Question 9

What kind of markers do you want for linkage analysis ?

Answer 9

Markers that are very tightly linked

Question 10

How is linkage an indirect analysis ?

Answer 10

You are indirectly measuring a marker very close to the gene of interest. The closer the gene of interest is to the marker the more accurate the whole process is. This is useful when you are not sure exactly what the specific allele for the phenotype is

Question 11

What is the accuracy of clinical linkage analysis based on ?

Answer 11

The accuracy of clinical diagnosis, The distance between the disease casing mutation and the markers, the informativeness of the genetic markers

Question 12

What kind of haplotypes are best for linkage analysis ?

Answer 12

Haplotypes that are very tightly linked because this will lower the chances of recombination

Question 13

What are the three factors that determine the limitations of linkage analysis ?

Answer 13

1. The accuracy of the clinical diagnosis
2. The distance between the disease causing mutation and the genetic markers
3. Informativeness of genetic markers

Question 14

What is the utility of indirect genetic analysis ?

Answer 14

1. When direct DNA analysis is not possible

2. When the disease causing mutation within the gene of interest is unknown in a specific family

Question 15

What is the significance of the haplotype ? or Phase

Answer 15

It must be established in each family

Question 16

What genetic tool can you use to determine if recombination has taken place?

Answer 16

Flanking markers which reside on each part of the chromosome of interest

Question 17

Using Flanking sequences you can determine if a cross over has occured between your markers ? What implication will this have on your pedigree analysis ?

Answer 17

You will be unable to determine if the cross over was above or below the diseased gene and you wont be able to determine which gamete got the diseased gene.

Question 18

What are the three categories of genetic testing ?

Answer 18

Infectious Disease Testing
Cancer Genetics
Molecular Genetics

Question 19

What are common uses in linkage analysis ?

Answer 19

Muscular Dystrophy
Cystic Fibrosis
Inherited Cancer Syndrome
Any disease where the mode of inheritance is known.

Question 20

What are two steps that are a must to do linkage analysis ?

Answer 20

You have to know the diagnosis and mode of inheritance

*You have to have multiple family members involved in the analysis

Question 21

What is phase the same as ?

Answer 21

Haplotype

Question 22

What are the molecular mechanisms of trinucleotide repeats ?

Answer 22

Inaccurate DNA replication and slippage when crossing over

Question 23

What is direct testing good for ?

Answer 23

Determination of genotype for one or more specific mutations. Specific mutation in Favtor 5 Leiden Mutation, CF is less effective due to the fact that there are hundreds of mutations

Question 24

What is the mechanism of inheritance for Fragile X ?

Answer 24

X linked, Expansion of the 5’ UTR that will result in a loss of function, accompanied with DNA methylation

Question 25

What is the mode of inheritance for Huntingtons disease ?

Answer 25

A autosomal dominant TNR in a coding region that will result in a gain of function that leads to the diseased phenotype

Question 26

What is the progression between Copy Number and diseased phenotype ?

Answer 26

There is a threshold where a small number of repeats can be tolerated and the gene can maintain stability. The premutated allele has a moderate degree of stability but if expansion continues there is a threshold where the diseased phenotype will predominate

Question 27

In Huntington’s disease what is the correlation between number of TNR’s and the age of disease onset ?

Answer 27

The higher the copy number the earlier the disease will show up. This is a phenomena called anticipation

Question 28

Will males amplify the copy number in Fragile X ?

Answer 28

No they will pass the disease to their daughters with the same number of TNR’s as they inherited

Question 29

Is X linked expression a common theme in TNR’s ?

Answer 29

It is present in Fragile X but is not a common theme

Question 30

In direct Testing what will PCR distinguish between ?

Answer 30

The size of the copy repeats. Be careful with deletion mutations because they will give a false negative on the test.

Question 31

What will PCR Fluorescence Detection show you ?

Answer 31

It will indicate if the patient has a single base mutation and is allele specific

Question 32

First cousins share what percentage of their genome ?

Answer 32

1/8

Question 33

Are TNR’s due to unequal crossing over ?

Answer 33

No,