Mapping Mendelian Disease

Question 1

What is the definition of Mendelian disease?

Answer 1

A disease caused by a single gene with little or no impact from the environment

Question 2

What is an example of mendelian disease?

Answer 2

PKD

Question 3

What is the definition of non mendelian disease?

Answer 3

Diseases or traits caused by the impact of many different genes each having only a small individual impact on the final condition

Question 4

What is an example of a non mendelian disease?

Answer 4

Psoriasis

Question 5

What is the definition of a multifactorial disease?

Answer 5

Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors

Question 6

What is an example of a multifactorial disease?

Answer 6

Heart disease

Question 7

What are the 3 ways of identifying a gene by mapping?

Answer 7

→ Homozygosity mapping
→ Linkage analysis
→ GWAS

Question 8

How do you find disease causing mutations?

Answer 8

Sequencing

Question 9

How do you prove genes cause disease?

Answer 9

In silico, in vitro and in vivo tools

Question 10

What is genetic linkage?

Answer 10

The tendency for alleles at neighbouring loci to be segregated together at meiosis

Question 11

When are crossovers more likely to occur?

Answer 11

Between loci separated by some distance than those close together

Question 12

If a marker and a disease locus are unlinked what does this mean?

Answer 12

The affected individuals in the family are less likely to inherit the same marker alleles

Question 13

If a marker and a disease locus are linked what does this mean?

Answer 13

Affected individuals are more likely to inherit this haplotype block

Question 14

What are the steps for the linkage analysis method?

Answer 14

1) A pedigree is taken
2) Genotyping data is generated like a GWAS SNP array

3) Physical and genetic distribution of markers on genotypic array
4) A file is generated with pedigree information and genotyping data from microarray
5) Linkage programme is run

Question 15

What is non parametric linkage testing?

Answer 15

→ Not having assumptions about linkage data
→No rules imposed in NPL –inheritance pattern is not taken into consideration

Question 16

What does non parametric linkage testing look for?

Answer 16

→ All affected regions are equal but different to unaffected regardless of inheritance pattern
→ Any LOD score above 3

Question 17

What does parametric analysis look for?

Answer 17

→ All affected are equal but different to unaffected
→ AND genotypes follow the imposed inheritance pattern

Question 18

What does a LOD score of -2 mean?

Answer 18

Significant non linkage

Question 19

What does a LOD score of -2 to 3 mean?

Answer 19

Inconclusive

Question 20

Where is a gene likely to be located if the LOD score is ?> 3?

Answer 20

Between the two markers defining the linkage peak

Question 21

What are the symptoms of generalised lymphatic dysplasia?

Answer 21

→ Antenatal hydrops
→ Intestinal lymphangiectasia
→ Mild developmental delay
→ Oedematous at birth
→ Peripheral lymphoedema

AIMOP

Question 22

What kind of a disease is 4 limb lymphoedema?

Answer 22

Autosomal dominant

Question 23

What are the two methods of finding disease causing mutations?

Answer 23

→ Traditional Sanger sequencing
→ Next generation sequencing

• whole genome
• whole exome

Question 24

What are the black areas on SNP arrays?

Answer 24

Represent gaps in the human genome sequence, primarily centromeres and teleomeres

Question 25

How is parametric analysis different from NPL?

Answer 25

Imposes rules about inheritance and disease frequency

Question 26

What rules would you apply to autosomal dominant for parametric analysis?

Answer 26

Apply a rule for affected family members to be heterozygous

Question 27

What rules would you apply to autosomal recessive for parametric analysis?

Answer 27

Apply a rule for affected family members to be homozygous for the mutant allele

Question 28

What are the features of 4-limb lymphedema?

Answer 28

→ Pubertal/adult onset
→ Associated with venous incompetence
→ No other abnormalities

Question 29

If two alleles are on the same chromosome, are they always linked and inherited together?

Answer 29

→ Alleles are not always inherited together. This depends on how far apart the genes
→ There is an equal likelihood of them being inherited together or separated during crossing over – there is linkage equilibrium.