L7&8- Molecular basis of inherited disease Flashcards
Which direction is DNA synthesised?
DNA sequences are written in a 5´-3´ direction
This is the direction in which DNA and RNA are synthesized
Single-copy sequences
(non-repetitive)
Genes
Repetitive sequences
-Interspersed repeats
e.g. Alu repeats
-“Satellite” DNA
Large blocks of repetitive sequence
Heterochromatin
What are genes
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
Look up gene structure
E.g promoter region
untranslated region
Introns
exons
Where does transcription, polyadenylation and splicing occur?
In the nucleus
Where does translation and post-translational modifications occur?
In the cytoplasm
What is alternative splicing
When splicing occurs it can skip an exon
What are processed genes?
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
Repetitive DNA
-Satellite DNA
Large blocks of repetitive DNA sequence
-Interspersed repeats
Scattered around the genome
Satellite DNA
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
Alphoid DNA
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
Interspersed repeats
-Scattered around the genome
-Individual copies are present at many locations
Maybe between or within genes
Example: Alu repeat
Types of mutation
-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
Haemaphilia A
Inverted segment in q arm
What kind of mutation can a point mutation (substitution) be?
-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.
Frameshift mutation
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.
Dominant inheritance sometimes (not always) results from mutations that result in gain or alteration rather than loss of function
Example – achondroplasia
Trinucleotide repeat expansions
-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))
