Mendelian Inheritance and mitcohcondrial genetics

Question 1

What contributions lead to human disease?

Answer 1

Genetic and environmental

Question 2

What are the classification of genetic disorders?

Answer 2

Single gene 
Multifactorial
Chromosome
Mitochondrial
Somatic

Question 3

How can gain or loss of gene function come about?

Answer 3

But mutations in DNA

Question 4

What is a genotype?

Answer 4

A pair of alleles at a locus

Question 5

What are some single gene disorders?

Answer 5

Autosomal Dominant
Autosomal Recessive
X-linked

Question 6

What is autosomal dominance?

Answer 6

A dominant allele (mutation) will determine a
phenotype when only one copy is present
in the genome.

Question 7

What are some autosomal dominant disoders?

Answer 7

FAP - Familial Adenomatous polyposis

Achondroplasia - Dwarfism

Marfan Syndrome

Question 8

What are the features of autosomal dominant inheritance?

Answer 8

Affected individuals in every generation

Male and female equally likely to be affected

Inherited from one OR other affected parent

Question 9

What phenotypes are generally encountered in autosomal dominant families?

Answer 9

Wild type and heterozygous mutant

Homozygous are usually very severe and often not seen

Question 10

What type of disorder is cystic fibrosis?

Answer 10

Autosomal recessive

Question 11

What are the features of cystic fibrosis?

Answer 11

Problems with:
Lungs
Pancreas
Sweat glands
Sometimes other organs

Encodes a transmembrane protein that transports chloride ions, Mutations disrupt this chloride conductance

Affects 1/2500 people

Question 12

What are some other autosomal recessive disorders?

Answer 12

Primary Haemochromatosis
Cystic fibrosis
Sickle cell disease
Phenylketonuria
Ataxia Telangiectasia

Question 13

What causes Ataxia Telangiectasia?

Answer 13

Biallelic mutation of ATM gene

Mutation can occur at any point in the gene and produces the same effect

Question 14

What are autosomal recessive disorders?

Answer 14

A recessive allele has no effect on the organism’s
phenotype if only one copy of the allele is present
in the genome.

You could be carrying a mutation in a gene and be
totally unaware of this- case for carriers of recessive
Diseases

Question 15

What are the features of autosomal recessive disorders?

Answer 15

Only seen in one generation

Both parents are normally carriers

Question 16

What is the origin of recessive mutations?

Answer 16

Most random mutations will either be neutral
or inactivating.

Default state of mutations is therefore recessive.

In the homozygous state there will be no function
and consequences will be seen in clinical state.

In the heterozygous state there will be no effect
of the allele on the organism.

Question 17

How does dominance of a mutation occur?

Answer 17

Dominant disorders outnumber recessive.
Occur via molecular basis:
Reduced gene dosage (haploinsufficiency)
 Increased gene dosage 
 Altered expression of mRNA
 Increased protein activity
 Dominant negative effects 
 Altered structural proteins
 Gain of new function

Question 18

What are the features of X-linked inheritance?

Answer 18

1. Incidence of the trait is much higher in males than females
2. The gene responsible for the condition is transmitted from an affected man through all his daughters.
3. The gene is never transmitted from father to son.
4. Sons always inherit their X chromosome from their mother.

Question 19

Give an example of a disease that is X-linked inherited?

Answer 19

Haemophilia

Duchenne Muscular Dystrophy

Question 20

What is multifactorial inheritance?

Answer 20

Multifactorial inheritance disorders are caused by a combination of small inherited variations in genes, often acting together with environmental factors.

Heart disease, diabetes, and most cancers are examples of such disorders.

Behaviors are also multifactorial, involving multiple genes that are affected by a variety of other factors.

Genetic contribution to behavioral disorders such as alcoholism, obesity, mental illness and Alzheimer’s disease.

Question 21

How are chromosome disorders caused?

Answer 21

Chromosome disorders are caused by an excess or deficiency
of the genes that are located on chromosomes, or by structural changes within
chromosomes. Down syndrome, for example, is caused by an
extra copy of chromosome 21 (trisomy 21), although no
Individual gene on the chromosome is abnormal.

Question 22

Why is the frequency of mitochondrial disorders high?

Answer 22

MtDNA has a much higher proportion of
coding DNA (93%) compared with about 3% in nuclear
DNA. Remember, however there is still about 100Mb
nuclear DNA.

Higher mutation rate in mtDNA. Rate at which
mutations are fixed in mtDNA is about 10x higher than/.
in nuclear DNA.

Question 23

How are mitochondrial mutations fixed?

Answer 23

the mitochondrial molecule has to replace all other molecules to return to homoplasmy.

Question 24

What are mitochondria deficient in?

Answer 24

Recombination

Question 25

What is Lebers optic atrophy?

Answer 25

The relationship between the genotype (mutation) and phenotype (clinical picture) can be complex

i. Homoplasmy may be tissue specific. Tissue examined may not be the critical tissue in the pathogenesis.
ii. MtDNA is more variable than nuclear DNA. May need the mutation together with some polymorphism
iii. Some mitochondrial diseases seem to have a quantitative nature. Need a threshold deficit to develop symptoms.
iv. Many mitochondrial functions are encoded by nuclear genes. So these may modify the mitochondrial phenotype.

Question 26

How is mitochondrial DNA inherited?

Answer 26

MtDNA is inherited from the maternal oocyte

Question 27

What diseases predominantly arise from mitochondrial mutations?

Answer 27

Neuromuscular diseases

Question 28

What is heteroplasmy?

Answer 28

Presence of two DNA populations such as nuclear and mitochondrial