Molecular basis of inherited disease

Question 1

What percentage of the human genome is non-coding?

Answer 1

90%

Question 2

Approximately how many protein coding genes are found within the human genome?

Answer 2

20,000

Question 3

What is satellite DNA?

Answer 3

Heterochromatin

Question 4

How are genes structured?

Answer 4

Exons

• coding DNA

Introns

• non-coding, spliced out of mature RNA

Regulatory sequences

• enhancers, promotors, locus control regions

Question 5

Where does RNA splicing take place?

Answer 5

Nucleus.

Question 6

Aside from splicing, what other modifications are made to RNA?

Answer 6

Capping

Polyadenylation.

Question 7

What is alternative splicing?

Answer 7

Exons may be skipped (spliced out with introns) to produce a variety of mRNA products.

Question 8

What is mutually exclusive exon choice?

Answer 8

A form of alternative splicing where if a particular exon is chosen for inclusion a different exon will be excluded, and vice versa.

Question 9

What are gene families?

Answer 9

Evolution of genes progresses by duplication and divergence

Most genes belong to a family of structurally related genes

Members of a gene family may be clustered or widely dispersed

Question 10

What are pseudogenes?

Answer 10

DNA sequences that resemble protein-coding genes but are not transcribed a messenger RNA (mRNA) in a way that could then be translated into functional protein.

Question 11

What are interspersed repeats?

Answer 11

Short stretches of repetitive, non-coding DNA scattered around the genome.

Question 12

What are processed genes?

Answer 12

Intronless copies of other genes - Usually remote from parent gene

Reverse transcription and reintegration - cf. retroviruses

Occasionally remain functional - e.g. PGK2 (testis-specific)

Most are non-functional

Question 13

Where would you find large blocks of heterochromatic DNA?

Answer 13

Centromeres

Question 14

What is alphoid DNA?

Answer 14

A type of satellite DNA found at centromeres

171-bp repeat unit

Repeat unit sequence shows chromosome-specific sequence variation - Probes for individual chromosome identification

Alphoid DNA is required for assembly of the centromere

Question 15

What is the use of alphoid DNA?

Answer 15

Used for identifying specific chromosomes.

Question 16

Why might there be many copies of the Alu repeat scattered across the genome?

Answer 16

Retrotransposition.

Question 17

How might unequal crossing over cause molecular pathology?

Answer 17

Unequal crossing over may result in one long arm with DNA duplications and one truncated arm with loss of DNA.

Question 18

What are the different types of mutation possible?

Answer 18

Large deletions or insertions
–Effects may be variable
–May be missed by PCR-based screening methods if heterozygous
–Duchenne muscular dystrophy (deletions)
–Charcot-Marie-Tooth disease (duplication)

Gross rearrangements
–Haemophilia A

Point mutations

Trinucleotide repeat expansions

Question 19

What is the mechanism behind the haemophilia A mutation?

Answer 19

End of chromosome loops up and a recombination event occurs, resulting in an inverted segment.

Question 20

What is the result of a missense point mutation?

Answer 20

Insertion of the incorrect amino acid.

Question 21

Why is cystine particularly prone to mutation?

Answer 21

Because it is very easily methylated. This results in a CG -> TA mutation. Happens in roughly a 3rd of mutations.

Question 22

What is the result of a nonsense point mutation?

Answer 22

The mutation results in the premature insertion of s stop codon and a truncated protein.

Question 23

What is the most common feature of dominatly inherited mutations?

Answer 23

Usually result in a gain/altered function rather than a loss.

Question 24

Give two diseases that are caused by polyglutamine (CAG) repeats.

Answer 24

Huntington’s disease

Spinocerebellar ataxia

Question 25

Give examples of diseases that are caused by large non-coding repeat expansions.

Answer 25

Fragile X (CCG)

Myotonic dystrophy