Mapping mendilian disease

Question 1

Mendelian Disease

Answer 1

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

Question 2

Non-mendelian/ polygenic Disease

Answer 2

diseases or traits caused by the impact of many different genes (polygenic), each having only a small individual impact on the final condition (e.g. psoriasis)

Question 3

Multifactorial Disease

Answer 3

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

Question 4

Gene identification

Answer 4

Finding the gene underlying disease of a patient by gene mapping:

• homozygosity mapping
• linkage analysis
• GWAS

Question 5

How do we find the exact gene-causing mutations?

Answer 5

When we find out where the gene defect is, sequencing is carried out to find the disease-causing mutations.

Question 6

How do we prove that these genes cause the disease?

Answer 6

In Vitro experiments (biopsy, cell culture techniques)
using silico
in vivo

Question 7

Genetic Linkage

Answer 7

tendency for alleles of genes at neighbouring loci on the same chromosome to co-segregate at meiosis and be inherited together

Question 8

Haplotype

Answer 8

A group of alleles of different genes on a single chromosome at linked loci

Question 9

Crossing over

Answer 9

Non-sister chromatids exchanging DNA segments during meiosis

more likely to occur between loci separated by some distance than closer together (if closer together they co-segregate and are linked)

Question 10

Aim of linkage analysis

Answer 10

To find the genomic region(s) linked to the disease

Question 11

How is linkage analysis used to identify disease causing genes?

Answer 11

DNA markers (observed locus) are used to draw inferences about a disease gene (unobserved locus) on a chromosome somewhere in the genome. If a marker is linked to a disease locus, the same marker alleles will be inherited by two affected relatives more often than expected by chance.

If markers from a specific region of the genome are always inherited together, it is very likely that the disease gene is in that region.

If the marker and the disease locus are unlinked, the affected individuals in a family are less likely to inherit the same marker alleles.

If the marker and the disease locus are linked, all the affected individuals in a family are more likely to inherit this haplotype block.

Question 12

Steps of Linkage Analysis

Answer 12

1) Take a Pedigree
2) Blood samples taken from many family members
3) Genotype data used to generate a file with pedigree information plus the genotyping data from the microarray. File is put in a computer program
4) Run a linkage program on the computer

Question 13

Non-Parametric Linkage Analysis

Answer 13

NPL studies the probability of an allele being identical by descent with itself
- no rules imposed in NPL (no particular genetic model assumptions)

no peaks = no linkage
high peaks = linkage

NPL highlights regions (with high LOD scores) where the variant calls for:
- all affected are equal/identical, but different to unaffected

Question 14

Parametric linkage analysis

Answer 14

studies probability that a disease-causing gene is linked to a genetic marker through the LOD score
- imposes rules about inheritance and disease frequency (genetic model assumptions)

highlights regions (with high LOD scores), where:

• all affected are equal/identical, but different to unaffected
• and the genotypes follow the imposed inheritance pattern

Question 15

LOD Scores

Answer 15

LOD scores > 3.0 are taken as significant evidence for linkage.

LOD scores < -2.0 show significant non-linkage.

LOD scores between -2 and 3 are inconclusive.

Question 16

Lymphatic system

Answer 16

The lymphatic system is a network of tissues and organs that help rid the body of toxins, waste and other unwanted materials. function : to transport lymph, a fluid containing infection-fighting white blood cells, throughout the body.
lymph vessels are thin

Question 17

Functions of the lymphatic system

Answer 17

fluid homeostasis
immune function
fatty acid transport

Question 18

Primary lymphoedema

Answer 18

chronic oedema caused by a genetic defect, resulting in developmental abnormality of the lymphatic system. fluid retention

Question 19

Treatment of primary lymphoedema

Answer 19

no cure
symptom treatment:
>Manual Lymph Drain (MLD) Massage
>Bandaging

Question 20

Linkage Analysis of Hennekam Syndrome

Answer 20

Autosomal recessive model applied

Question 21

4-Limb lymphoedema

Answer 21

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

Question 22

Linkage Analysis of 4-limb lymphoedema

Answer 22

Autosomal dominant model applied

Question 23

Methods Used to find disease-causing mutations

Answer 23

Traditional Sanger Sequencing
- candidate gene screen

Next Generation Sequencing (NGS)

• whole genome sequencing (WGS)
• whole exome sequencing (WES)

Question 24

What is linkage disequilibrium?

Answer 24

Alleles are in linkage disequilibrium when there is a decreased chance that recombination will separate them.

Question 25

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

Answer 25

Alleles are not always inherited together. This depends on how far apart the genes they represent are from one another on the chromosome

Question 26

If two genes are on the same chromosome, are they always inherited together?

Answer 26

enes on the same chromosome will always be inherited together. Genes do not move around between chromosomes.

Question 27

Hennekam Syndrome (Generalised lymphatic dysplasia)

Answer 27

Swelling all over the body

- feet, legs, arms, abdomen and face