Lecture 2: Genetic Basis of Human Disease

Question 1

Archibald Garrod was the

Answer 1

Founder of Biochemical Genetics Originator of the concept of : Inborn Errors of Metabolism “ 1909

Question 2

Archibald Garrod looked at the disease

Answer 2

Alkaptonuria

Question 3

Alkapatonuria is a

Answer 3

defect in the enzyme Homogentisate 1,2 Dioxygenase

Question 4

Alkaptonuria causes

Answer 4

Homogentisic acid accumulates 
in joints, causing cartilage damage 
& back pain; precipitates 
as kidney / prostate stones; 
high levels are excreted, blackening urine 
- allows diagnosis.

Question 5

what allows diagnosis of alkaptonuria

Answer 5

BLACKENING URINE

Question 6

Garrods discovery that Alkaptonuria was inherited as a ____ led to

Answer 6

AUTOSOMAL RECESSIVE

..led to the identification of other inherited metabolic diseases

Question 7

other inherited metabolic diseases after Garrod did

Answer 7

Cystinuria 
Phenylketonuria
Albinism (tyrosinase defect)
Glycogen Storage Disorders
Galactosaemia

Question 8

William Bateson began to

Answer 8

catalogue human diseases that exhibited Mendelian Inheritance (1909)

• skin disorders
• eye disorders
• neurological disorders
• inborn errors of metabolism
• anatomical abnormalities

Question 9

skin disorders:

Answer 9

• Epidermolysis bullosa

- multiple telangiectasia

Question 10

eye disorders:

Answer 10

Aniridia, red-green colour blindness

Question 11

Neurological disorders

Answer 11

Huntingtons, chorea

Question 12

Inborn Errors of metabolism

Answer 12

Alkaptonuria (after Garrod), haemophilia

Question 13

Anatomical abnormalities

Answer 13

Brachydactyly (short digits)

Question 14

Autosomal recessive

Answer 14

Alkaptonuria, Cystic Fibrosis

Question 15

Autosomal dominant

Answer 15

Brachydactyly

Huntington’s Disease

Question 16

Autosomal co-dominant

Answer 16

sickle cell anaemia

Question 17

x-linked: limited to males (mostly)

Answer 17

Duchenne Muscular Dystrophy
X-linked mental retardation
Haemophilia

Question 18

Sickle cell anaemia is

Answer 18

painful, sometimes life-threatening disorder of erythrocytes

Question 19

haemoglobin is a

Answer 19

tetramer of 2 α-globin and 2 β-globin

protein subunits

Question 20

sickle cell anaemia is cause by

Answer 20

a single point mutation in the codon for amino acid 6
in the β-globin subunit

Glu codon Val codon

Haemoglobin tetramers
Containing HbS tend to form large insoluble polymers which distort erythrocyte shape

Question 21

SCA and malaria:

Answer 21

Heterozygous carriers of HbS have Sickle Cell Trait but exhibit increased resistance to malaria – Heterozygotes are fitter than HbA and HbS homozygotes

Question 22

Hb^A and Hb^s alleles exhibit

Answer 22

co-dominance, i.e. heterozygote sickle cell phenotype is intermediate between wild-type and Sickle Cell Anaemia – “Sickle Cell Trait”

Question 23

co-dominance

Answer 23

genetic scenario where neither allele is dominant or recessive and both get expressed

Question 24

karyotyping allows

Answer 24

each chromosome to be distinguished.

Question 25

Until karyotyping became possible in the ___, the human genome was almost
entirely uncharted territory.

Answer 25

Until karyotyping became possible in the 1970s, the human genome was almost
entirely uncharted territory.
A few genes had been assigned to the X-chromosome because of their Sex-linked
inheritance patterns.

Question 26

in Karyotyping abnormalities in banding

Answer 26

due to mutagenic
rearrangements can
be recognised and
associated with specific phenotypes.

Question 27

karyotyping allows

Answer 27

genes to be mapped to specific chromosomal locations.

Question 28

Aniridia

Answer 28

an autosomal dominant phenotype caused by

deletion or loss-of-function point mutations in one copy of the gene

Question 29

Duchenne muscular dystrophy (DMD) is an

Answer 29

X LINKED DISEASE
Progressive muscle damage and wasting disease

Lethal in childhood or early adulthood

DMD gene located at chromosome position Xp21

Question 30

DMD gene was identified by a DNA sequence that was

Answer 30

deleted

Question 31

whats the largest known human gene

Answer 31

dystrophin (>2 x10^6 bp gene encoding a >3500 a.a. protein )

Question 32

Dystrophin protein is part of a

Answer 32

bridging complex 
connecting each muscle fibre
to the extra cellular matrix, 
thus maintaining tissue 
integrity

Question 33

Huntington’s disease is a —- and discovered by

Answer 33

progressive, late-onset, inherited
neurodegenerative disorder.

A dementia and movement disorder, first described by George Huntington (1872)

Question 34

HD gene is approx

Answer 34

1.7 x 10^5 base pairs in size

Question 35

molecular pathology of HD

Answer 35

HD mutations expand a CAG repeat sequence in the first exon of the HD gene, increasing the size of a polyglutamine tract in the HD protein.

wild 10-35 glutamine residues
HD patients 36-121 glutamine residues

Question 36

the expanded polyQ tract makes the

Answer 36

mutant Huntingtin protein toxic to neurons.

Question 37

some animal virus genomes contain

Answer 37

genes that cause cancer

Question 38

Peyton Rous

Answer 38

1879-1970
was the first to discover a tumour-causing virus:
Rous Sarcoma Virus (1911

Question 39

Tumorigenicity of Rous Sarcoma Virus is due to

Answer 39

presence of DNA sequences captured from the
chicken genome - the v-src oncogene

v-src encodes an abnormally hyperactive version of a tyrosine kinase encoded by
a cellular gene - the c-src proto-oncogene

Question 40

examples of viruses that have been discovered to contain oncogenic mutant versions of host cellular porto-oncogenes (v-onc)

Answer 40

Rous Sarcoma Virus (v-src)

Harvey Murine Leukaemia Virus (v-H-ras)

Avian Erythroblastosis Virus (v-erbB)

Mouse Mammary Tumour Virus (wnt-1)

Abelson Murine Leukaemia Virus (v-abl)

Question 41

viral oncogenes are

Answer 41

Dominant, gain-of-function mutant alleles of cellular genes

Question 42

Chromosomal rearrangements that disrupt, truncate, or reassemble
cellular proto-oncogenes can cause

Answer 42

cancer

Question 43

Chronic Myelogenous Leukaemia is caused by

Answer 43

a chromosomal translocation in haemopoietic progenitor cells that creates the “Philadelphia Chromosome”

Question 44

Loss of function mutation cause

Answer 44

cancer

.……by inactivation of tumour suppressor genes, e.g. Retinoblastoma

Question 45

retinoblastoma is a

Answer 45

rare retinal tumour that can be either

hereditary or non-hereditary

Question 46

tumours can be

Answer 46

unilateral or bilateral

Question 47

Non-hereditary retinoblastomas are typically _____

BUT

Hereditary retinoblastomas are typically ____

Answer 47

unilateral

BUT

bilateral

Question 48

Alfred Knudsons hypothesis

Answer 48

that retinoblastoma is caused by mutations in a Tumour Suppressor gene that normally prevents cells from becoming cancerous

Question 49

Alfred Knudsons Two-hit hypothesis states that

Answer 49

retinoblastoma

is caused by inactivation of both alleles of a Tumour Suppressor gene

Question 50

Alfred Knudson’s insight:

Answer 50

Individuals who are born heterozygous for a recessive mutation in the
Retinoblastoma gene will develop tumours in both eyes if independent secondary
mutations inactivate the remaining wild-type copy in cells of each eye

Question 51

steps for retinoblastoma Alfred Knudons theory

Answer 51

Non-hereditary retonibloastoma: 
-first somatic
RB mutation
acquired in 
retinal cell
-second somatic
RB mutation
acquired in 
retinal cell (rare to be in
 same cell)

Hereditary retinoblastoma: 
-Inherited
germline mutation
present in all cells
-first somatic
RB mutation
acquired in 
retinal cell

Question 52

Many human diseases are caused by

Answer 52

single gene defects

Question 53

Advances in molecular biology enables disease genes to

be identified solely on

Answer 53

the basis of their chromosomal position

without prior knowledge of the functions of their proteins

Question 54

Cancer:

caused by dominant, gain-of-function mutations in

Answer 54

Proto-oncogenes

Question 55

Cancer: caused by recessive, loss-of-function mutations in

Answer 55

Tumour supressor genes