Mapping mandelian disease

Question 1

Independent assortment

Answer 1

• Chromosomes segregate independently of one another during meiosis
• Alleles that are located on separate chromosomes get sorted into gametes independently of one another

Question 2

Linkage

Answer 2

Two alleles are located on the same chromosomes

Question 3

Linkage equilibrium

Answer 3

the frequency of alleles inherited from one parent in a given population have the same value that they would have if the alleles at each locus were combined random

Question 4

Two regions on the same chromosome. Freqiency of allele A is found to be 0.5 and the frequency of allele B is 0.5. Assuming normal linkage equilibrium, what is the expected frequency of AB?

Answer 4

0.5 x 0.5 = 0.25

so all genetic variations will be 0.25

Question 5

Frequency of allele A is found to be 0.5 and the frequency of allele B is 0.5. However, the frequency of AB is found to be 0.49 in the same population. What genetic principle most likely explains this finding?

Answer 5

AB 49%
ab 49%
Ab 1%
aB 1%

Linkage disequilibrium

Question 6

Mendelian/ monogeic:

Answer 6

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

Question 7

Non-Mendelian/ polygenic

Answer 7

: 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)

Question 8

Multifactorial

Answer 8

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

Question 9

Gene identification by gene mapping

Answer 9

Homozygosity mapping
Linkage analysis
GWAS

Question 10

How do we find disease-causing mutations?

Answer 10

Sequencing

Question 11

How do we prove they cause disease?

Answer 11

Using in silico, in vitro and in vivo tools

Question 12

Genetic linkage

Answer 12

The tendency for alleles (A1, A2, B1 and B2) at neighbouring loci to segregate together at meiosis
Therefore to be linked, two loci must lie very close together

Question 13

Halotype

Answer 13

• A haplotype defines multiple alleles at linked loci. Haplotypes mark chromosomal segments, which can be tracked through pedigrees and populations

Question 14

Recombination events

Answer 14

During meiosis are more likely to occur between loci separated by some distance than those close together

Question 15

Linkage analysis

Answer 15

• Gene mapping tool
• Using observed loci (alleles) to draw inferences about an unobserved locus (disease gene)
• Family-based design (from a few large families to many small nuclear or sib-pairs)

Question 16

Steps for linkage analysis

Answer 16

1. First take a pedrigree and get as many DNA samples as possible
2. Use some kind of tool to observe alleles, i.e. generate genotyping data for your pedigree
3. Generate a file with your pedigree information plus the genotyping data from the SNP array
4. Run your file in a linkage programme

Question 17

LOD score >3.0

Answer 17

Significant evidence for linkage

Question 18

LOD score below 2

Answer 18

Significant non-linkage

Question 19

LOD score between -2 and 3

Answer 19

inconclusive

Question 20

Lymphoedema treatment

Answer 20

Treatment 
•	Compression socks,
•	Lymphatic drainage 
•	Exercise – aids natural drainage of fluid 
•	Skincare

Question 21

Symptoms of lymphoedema

Answer 21

• Debilitating
• Embarrassing
• Stressful
• Recurrent infections

Question 22

Primary lymphoedema

Answer 22

• Chronic oedema caused by a developmental abnormality of the lymphatic system
• Often progressive

Question 23

Generalised lymphatic dysplasia (Hennekam syndrome (HS)

Answer 23

• Antenatal hydrops with ascites and pleural effusions
• Oedematous at birth
• Intestinal lymphangiectasia
• Peripheral lymphoedema; arms, legs, face
• Mild developmental delay

Question 24

4- limb lymphoedema

Answer 24

• Autosomal dominant
• Pubertal/adult onset
• Associated with venous incompetence
• No other abnormalities

Question 25

How do we find disease-causing mutations?

Answer 25

•	Traditional Sanger sequencing
	 Candidate gene screen (as seen in the previous example)
•	Next generation sequencing (NGS)
	 Whole genome sequencing (WGS)
	 Whole exome sequencing (WES)