Lecture 3: Genetic basis of disease (2)

Question 1

a catalogue of inehrited clinical disorders established by

Answer 1

Victor McKusick in 1966.

current online version describes 3958 human disorders with Mendelian inheritance.

Question 2

out of 3958 how many have been assigned to a specific gene. multiple genes

Answer 2

3645

Question 3

Many chronic non-communicable human disease are caused by

Answer 3

multiple genes interacting both with each other and environmental factors
impossible to identify “the gene” in such situations, since many genes
are involved

Question 4

e.g. of Many chronic non-communicable human diseases cause by multiple genes

Answer 4

Heart disease

Diabetes

Obesity

Cancer

Hypertension

Schizophrenia, autism & other neuropsychiatric disorders

Multiple Sclerosis

Question 5

SNPs

Answer 5

Single nucleotide polymorphisms

• total of ~ 3x107 SNPs within the human genome
• SNPs are distributed randomly across the genome

Question 6

~500,000 SNps distributed throughout the human genome provide

Answer 6

a detailed map of DNA sequence variation across the genome

Question 7

How can SNPs be used to identify DNA sequences associated with
common diseases?

Answer 7

1. Genome-wide analysis allows all of the SNP sequence variation to be
   catalogued and compared from one person to the next
2. The SNPs present in each individual genome within a group of patients are
   compared to the SNPs present in the genomes of healthy individuals
   - a case versus control comparison

3. SNPs are identified that are more frequently found in patients (cases) than in 
healthy individuals (controls).

4. Such high-scoring SNPs are thus associated with the disease and may play
   potentially causative roles in the disease process.
5. These studies are called Genome Wide Association Studies (GWAS).

Question 8

if out of two alleles within an SNP associated with a disease an allele is more frequent than the other then

Answer 8

the locus is associated with the disease.

Or if the 2 alleles are found in equal proportions in patients with this disease? If so then this
locus is not associated with the disease

Question 9

GWAS

Answer 9

Genome Wide Association Studies

Question 10

Genome Wide Association Studies can identify

Answer 10

Single Nucleotide

Polymorphisms (SNPs) that are associated with disease phenotypes

Question 11

Genomic imprints are

Answer 11

structural modifications to specific regions of particular chromosomes that prevent the transcription of genes within such regions.

• inc. methylation of DNA sequences

Question 12

imprinting of genes in mammals: Different imprints are introduced into the chromosomes of

Answer 12

sperm and eggs

The patterns of DNA methylation on the chromosomes of spermatozoa and eggs persist in the somatic tissues of the progeny that are formed at fertilisation

….but they are removed during germ line development within the embryo and re-applied in a pattern dependent on the sex of the embryo

Question 13

Methylation of DNA on cytosine bases in CpG dinucleotides is a hallmark
of imprinted chromatin:

Answer 13

helps to switch genes off

Question 14

in methylation of DNA on cytosine bases in CpG dinucleotides: cytosine becomes

Answer 14

cytosine –methylation–> 5-methylcytosine

Question 15

Localised methylation of DNA occurs on a specific subset of genes during

Answer 15

oogenesis (Chromosome
From mother
maternal copy
-not expressed carries maternal imprint) & spermatogenesis (Chromosome
from father
paternal copy - not expressed carries paternal imprint)

Question 16

oogenesis

Answer 16

is the production of an ovum

Question 17

spermatogenesis

Answer 17

the process in which spermatozoa are produced from spermatogonial stem cells by way of mitosis and meiosis

Question 18

Reciprocal genomic imprinting of UBE3A and SNORD116 complex

of genes on Human Chromosome 15 – in NORMAL somatic tissues

Answer 18

Human Chromosome 15 from mother
maternal copy:
-SNORD116 not expressed - IMPRINTED
-UBE3A Expressed

Human Chromosome 15 from father
paternal copy
-SNORD116 Expressed
-UBE3A not expressed (imprinted)

UBE3A carries a paternal imprint
SNORD116 carries a maternal imprint

Question 19

MATERNAL / PATERNAL IMPRINTS ARE CREATED DURING

Answer 19

Gametogenesis.
Egg; SNORD116 not expressed, UBE3A expressed

Sperm: SNORD116 expressed, UBE3A not expressed.

Are then maintained in the somatic cells of an embryo

Question 20

Imprint are erased in

Answer 20

EMBRYONIC PRECURSORS OF GERM CELLS

DURING EMBRYONIC DEVELOPMENT

Question 21

MATERNAL / PATERNAL IMPRINTS ARE STABLE BUT

Answer 21

NOT PERMANENT
EPIGENETIC CHANGES:

RE-ESTABLISHED DURING SPERMATOGENESIS / OOGENESIS
DEPENDING ON SEX OF OFFSPRING

Question 22

Since only one of the two alleles of an imprinted gene is transcribed in
somatic cells, heterozygosity for a mutation that inactivates the product
encoded by the transcribed copy may cause

Answer 22

disease

Question 23

Prader-Willi Syndrome:

Answer 23

Low muscle tone, short stature, cognitive disability,

Chronic hunger, morbid obesity - caused by mutation of SNORD116 complex

Question 24

Angelman Syndrome:

Answer 24

Cognitive disability, sleep disturbance, seizures, jerky

movements, frequent smiling - - caused by mutation of UBE3A

Question 25

The genomic imprints and the impacts of syndromic mutations are

Answer 25

parent-of-origin specific

Question 26

The human genome project revealed that

Answer 26

there is an enormous amount of

DNA sequence variation between individuals.

Question 27

Some variation is associated with

Answer 27

human diseases and identifies

individual genes that contribute to polygenic disorders.

Question 28

. Genetic defects in Imprinted Genomic Regions can cause parent-of-origin

Answer 28

specific syndromes in heterozygous individuals: when a loss-of-function mutation in the non-imprinted allele is combined with a wild-type imprinted allele, then neither allele produces wild-type gene product and the clinical phenotype results.