Clinical cytogenetics: linkage

Question 1

Linkage:

Answer 1

tendency for genes or segments of DNA closely positioned along a chromosome to segregate together at meiosis and therefore be inherited together

Question 2

linkage analysis

Answer 2

use of several DNA markers (normal variants) that are near or w/in gene of interest to track w/in a family the inheritance of a disease-causing mutation in that gene

Question 3

linkage marker:

Answer 3

identifiable segment of DNA w/ enough variation between individuals that its inheritance and co-inheritance w/ alleles of a given gene can be traced

Question 4

Linkage phase:

Answer 4

for 2 or more closely linked markers, the alleles contained on the same chromosome; haplotype

Question 5

linkage disequilibrium:

Answer 5

in a population, co-occurrence of specific species alleles at a higher frequency than would be predicted by random chance;

over-representation of specific haplotypes

Question 6

Haplotype analysis:

Answer 6

molecular genetic testing to identify a set of closely linked segments of DNA

used in linkage analysis or when a given trait is in linkage disequilibrium with a marker or set of markers

Question 7

If you get recombination between alleles, what is the result?

Answer 7

causes new haplotypes in offspring

Question 8

What determines the extent of linkage?

Answer 8

recombination frequency

Question 9

Describe direct and indirect testing wrt linkage

Answer 9

direct testing is done with a known disease allele

Indirect testing is down with unknown disease allel using multiple, closely linked and flanking markers

Question 10

What can be used for linkage analysis?

Answer 10

any known variant that is in linkage with an unknown causative mutation potentially can be used for linkage analysis

Question 11

When should you use linkage analysis?

Answer 11

when direct DNA analysis is not possible

when disease-causing mutation w/in gene of interest is unknown in specific family

Question 12

In linkage analysis, describe the significance of haplotype (phase)

Answer 12

must be established in each family

only in rare instances of linkage disequilibrium is a specific haplotype highly likely to be associated w/ specific disease causing mutation

Question 13

What are the limitations to linkage analysis and what is the accuracy dependent on?

Answer 13

1. accuracy of clinical diagnosis
2. distance bw the disease-causing mutation and the markers
3. informativeness of genetic markers in the family

Question 14

In most situations, what type of genetic marker in a family is not informative or may be informative?

Answer 14

homozygous marker => not informative

heterozygous marker => may be informative

Question 15

In doing linkage analysis, what may yield false tests?

Answer 15

false positive and false negative results if recombination bw markers occurs during gamete formation

Question 16

During linkage analysis, when is the risk of recombination the lowest?

Answer 16

if intragenic markers are used

Question 17

recombination limits the accuracy of linkage analysis, but what may reveal occurrence of a crossover?

Answer 17

flanking markers

Question 18

What are the 3 categories of DNA diagnostics?

Answer 18

infectious disease

cancer genetics

molecular genetics

Question 19

What is involved in infectious disease testing?

Answer 19

presence/absence of disease organism

qualitative and quantitative

Question 20

What is tested in cancer genetics?

Answer 20

acquired mutations

functional genomics

Question 21

What is tested in molecular genetics?

Answer 21

inherited mutations

functional genomics

Question 22

What are the levels of genetic information when doing a genetic test?

Answer 22

• cytogenetic => genomic abnormalities
• DNA => mutations or genetic variants / inherited or acquired
• RNA => gene function / quantitative
• protein => metabolic: analyste or enzyme assay / gene product

Question 23

What are the uses of molecular genetic testing?

Answer 23

Medical care

• diagnosis
• management (personalized med)
• predictive with a treatement

Personal decision-making

• predictive w/o a treatment
• carrier testin/screening
• prenatal diagnosis
  *

Question 24

Describe the 3 approaches to genetic testing

Answer 24

• linkage analysis=> indirect testing of multiple family members to track segregation of disease gene
• direct testing=> test for presence/absence of one or more specific mutations
• gene scanning => screen all or a portion of a gene lookin for any mutation

Question 25

What are the common uses of linkage analysis?

Answer 25

any disease gene where mode of inheritance and gene identity are known, but specific mutation cannot be identified by other approaches

Cystic fibrosis=> (AR) => mutations not identified by direct testing

Duchenne muscular dystrophy => XL => nondeletion case or carrier screening in females

Inherited cancer syndrome => AD => direct testing or scanning methods unsuccessful; gene identity certain

Question 26

What are the steps in linkage analysis?

Answer 26

1. establish Dx: specific gene and known mode of inheritance
2. Pedigree inspection => multiple fam members required
3. identify informative markers
4. determine phase (haplotype)
5. use marker information to predict disease status in consultand

Question 27

What is linkage analysis always limited by?

Answer 27

the chance of recombination because it is indirect