Molecular Basis of Inherited Disease (7 & 8)

Question 1

DNA structure

Answer 1

Deoxyribose nuclei acid, base - O - Cl, hydroxyl group - nucelphillic attack on diester bond, splits the chain - RNA much more unstable

Question 2

In which direction is DNA and RNA synthesised?

Answer 2

5’ to 3’

Question 3

Chromosome

Answer 3

Single linear strand of double stranded DNA

Question 4

Genome

Answer 4

3000Mbp/haploid genome

Question 5

What percentage of the genome is non-coding?

Answer 5

Over 90%

Question 6

How many protein-coding genes are there?

Answer 6

20,000

Question 7

Gene

Answer 7

Functional units of DNA

Question 8

Transcription

Answer 8

Copying into RNA

Question 9

Translation

Answer 9

Turning RNA into protein

Question 10

Alternative splicing

Answer 10

Exons spliced together, may/may not be included in gene

Question 11

Pseudogene

Answer 11

Used to be genes, now non-functional, very close in sequence with functional genes

Question 12

What is the potential problem with pseudogenes?

Answer 12

Can interfere with medical diagnosis

Question 13

Processed genes

Answer 13

Intronless copies of other genes, remote from parent gene

Question 14

How are processed genes formed?

Answer 14

Reverse transcription and reintegration (retrovirus)

Question 15

Are processed genes functional?

Answer 15

Occasionally remain functional (PGK2 testis specific), but most non-functional (mutation)

Question 16

Repetitive DNA

Answer 16

Satellite or Interspersed

Question 17

Satellite DNA

Answer 17

large blocks of repetitive DNA sequences at centromeres and heterochromatic chromosomal regions, simple tandemly repeated sequences, size of blocks may be polymorphic (1, 9, 16, Y)

Question 18

Alphoid DNA

Answer 18

Type of satellite DNA found at centromeres, 171 bp repeat unit, shows chromosome-specific sequence variation (use for identifying individual human chromosomes), required for assembly of centromere

Question 19

Interspersed repeats

Answer 19

Scattered around genome, present at many locations (between/within genes)

Question 20

Example of interspersed repeat

Answer 20

Alu, dispersed by retrotransposition, role in generation of molecular pathology, 500,000 copies, 300bp, 5% genome

Question 21

Errors in the genome

Answer 21

Alignment process can go wrong, depends on presence of interspersed repeats, unequal cross-over products aren’t balanced in terms of exons > frameshift

Question 22

Types of mutations

Answer 22

• Large deletions/insertions
• Gross rearrangements
• Point mutations
• Trinucleotide repeat expansions

Question 23

Clinical example of large deletions

Answer 23

Duchenne Muscular Dystrophy

Question 24

Clinical example of large insertions

Answer 24

Charcot-Marie-Tooth disease

Question 25

Problems with PCR and large deletions/insertions..

Answer 25

If heterzygous, as sequence on nucleotides doesn’t change except at break point

Question 26

Clinical example of gross rearrangements

Answer 26

Haemophilia A

Question 27

Point mutation

Answer 27

Missense/silent/nonsense

Question 28

Acidic amino acids

Answer 28

Glu and Asp

Question 29

Basic amino acids

Answer 29

Lys and Arg

Question 30

Polar amino acids

Answer 30

Ser Thr Asn Gln Ser (His)

Question 31

Non-polar amino acids

Answer 31

Ala Val Leu Ile Met

Question 32

Aromatic amino acids

Answer 32

Phe Tyr Trp (His)

Question 33

Other amino acids

Answer 33

Gly Pro

Question 34

Truncate

Answer 34

Shorten by cutting off top edge, can be used to detect mutation (point mutation nonsense)

Question 35

Frameshift mutation

Answer 35

Alters protein sequence beyond mutation, may truncate protein

Question 36

Mutation nomenclature

Answer 36

Genomic DNA (g)
cDNA (c)
Protein (p)

Question 37

Hyper mutability of CpG dinucleotides

Answer 37

More mutable than other targets in DNA, gets methylated on C of CG, methyl cysteine chemically similar to thymine C > T deamination, mismatch repair cannot tell if T or G is right base, 1/3rd mutations CG > TG

Question 38

Mutation spectrum - recessive

Answer 38

Mutational heterogeneity is frequent - mutation testing’s challenging

Question 39

Examples of recessive mutations causing diseases

Answer 39

Cystic fibrosis and B-thalassaemia

Question 40

Mutation spectrum - dominant

Answer 40

Sometimes results from mutation > gain/alteration rather than loss of function, smaller mutation spectrum, new mutations are comparatively common

Question 41

Examples of dominant mutations causing diseases

Answer 41

Achondroplasia - FGFR3 G380R (glycine > aginine)

Question 42

Trinucleotide repeat expansions

Answer 42

• Polyglutamine repeats (CAG)
• Large non-coding repeat expansions
• Mutational instability

Question 43

Examples of diseases caused by polyglutamine repeats

Answer 43

Huntington’s disease and spinocerebellar ataxias

Question 44

Examples of diseases caused by large non-coding repeat expansions

Answer 44

Fragile X and myotonic dystrophy

Question 45

Examples of diseases caused by mutational instability

Answer 45

Huntington’s (occasional) and Fragile X (frequent)

Question 46

Fragile X syndrome

Answer 46

CGG repeat expansion, within non-coding DNA, structure alters, grows to thousands, transcription of gene shuts down, can lead to mental handicap