L7&8- Molecular basis of inherited disease

Question 1

Which direction is DNA synthesised?

Answer 1

DNA sequences are written in a 5´-3´ direction

This is the direction in which DNA and RNA are synthesized

Question 2

Single-copy sequences

Answer 2

(non-repetitive)

Genes

Question 3

Repetitive sequences

Answer 3

-Interspersed repeats
e.g. Alu repeats
-“Satellite” DNA
Large blocks of repetitive sequence
Heterochromatin

Question 4

What are genes

Answer 4

Functional units of DNA
-Genes are expressed
Some place, some of the time

Transcription – copying into RNA
Translation – turning RNA into protein
-Not all
-Short and long non-coding RNAs inc. miRNAs

Components
Exons
Introns
Regulatory sequences
Promoters, enhancers, locus control regions

Question 5

Look up gene structure

Answer 5

E.g promoter region
untranslated region
Introns
exons

Question 6

Where does transcription, polyadenylation and splicing occur?

Answer 6

In the nucleus

Question 7

Where does translation and post-translational modifications occur?

Answer 7

In the cytoplasm

Question 8

What is alternative splicing

Answer 8

When splicing occurs it can skip an exon

Question 9

What are processed genes?

Answer 9

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 10

Repetitive DNA

Answer 10

-Satellite DNA
Large blocks of repetitive DNA sequence

-Interspersed repeats
Scattered around the genome

Question 11

Satellite DNA

Answer 11

Large blocks at centromeres and heterochromatic chromosomal regions

-Simple tandemly repeated sequences
Many types e.g. alphoid DNA
Centromere repeat
Chromosome-specific

-Size of blocks may be polymorphic
1, 9, 16, Y

Question 12

Alphoid DNA

Answer 12

A type of satellite DNA found at centromeres

Repeat unit sequence shows chromosome-specific sequence variation (different for each chromosome so you can identify each chromosome)

Alphoid DNA is required for assembly of the centromere

Question 13

Interspersed repeats

Answer 13

-Scattered around the genome

-Individual copies are present at many locations
Maybe between or within genes
Example: Alu repeat

Question 14

Types of mutation

Answer 14

-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 15

Haemaphilia A

Answer 15

Inverted segment in q arm

Question 16

What kind of mutation can a point mutation (substitution) be?

Answer 16

-silent
least harmful as there is no noticeable effect on the protein
If common= Polymorphism

-missense
the change in nucleotide leads for a different amino acid
This may have little effect, or it may greatly change the resulting protein.
Conservative/non-conservative changes of amino acids
The cytosine amino acid most commonly is mutated (CG–>TG)

-Nonsense
the amino acid that should have been coded for is changed to a stop code and the protein terminates at this point (TRUNCATED protein). This will likely lead to a useless protein.

Question 17

Frameshift mutation

Answer 17

Alters protein sequence beyond mutation
May truncate protein

When a nucleotide base is either inserted or deleted it disrupts the amino acids coded for from the site of the mutation on to the end of the gene.

Question 18

Dominant inheritance sometimes (not always) results from mutations that result in gain or alteration rather than loss of function

Answer 18

Example – achondroplasia

Question 19

Trinucleotide repeat expansions

Answer 19

-Polyglutamine repeats (CAG)
Neurodegenerative disorders
Huntington’s disease
Spinocerebellar ataxias

-Large non-coding repeat expansions
Fragile X syndrome (CGG repeats) – transcriptional silencing
Myotonic dystrophy

-Mutational instability
Occasional (eg Huntington’s)
Frequent (eg fragile X-(CGG repeats))