Biochem and medical genetics
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| Types of mutation | Range from single base pair changes to alterations in whole chromosomes or chromosome sets
Spontaneous - due to chemical properties of the nucleic acids or problems during replication
Induced - due to radiation or chemicals
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| Deamination | In the presence of water cytosine will lose an amine group to form uracil. 5-methyl cytosine will form thymine
This leads to a substitution, which is not repaired leads to the wrong base pairing on replication, so will be propagated
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| De-purination | In the presence of water purine bases can be lost to leave a sugar phosphate with no base
The base pair is lost in replication as there is nothing to base pair a new strand with
Leads to a deletion of that base pair
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| Mistakes during replication | Replication errors can occur where the wrong base is added, changing the base paring on one of the grand-daughter strands
This can be recognised by repair machinery and fixed, but this is difficult in repeat regions
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| Extension of repeat regions | In tandem repeat sections the replication machinery can slip, inserting additional repeats.
This is often inherited, with everyone having different repeats
This can lead to disease if it occurs in the exons
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| Thymine Dimers | Exposure to UV can cause dimerization of thymine.
two thymine are covalently linked, affecting structure of the DNA, such as introducing kinks, which affects replication
E.g. Melanoma. Mutation is repair enzymes affect susceptibility to melanoma
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| Repair mechanisms | Nucleotide damage - nucleotide excision by XP proteins
Single strand breaks - PARP, XRCC1
Recombination repair of double strand breaks - BRCA1/2 (homologous), DNAPKcs, XRCC$ (non-homologous)
Mismatch repair - MSH2, MLH1
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| If mutations affect repair genes | If repair is compromised by mutations in genes encoding repair complexes this can elevate susceptibility to cancer
Nucleotide exision repair - XP genes leads to Xeroderma Pigmentosa and Cockayne Syndrome
Double strand breaks - breast cancer
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| Mis-sense mutation | A mutation that alters a codon so that it is recognised by a different t-RNA and consequently a different amino-acid is introduced into the polypeptide chain
This changes the protein properties, function and interactions
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| Non-sense mutation | Characterises a change that introduces a premature stop codon in the mRNA
This results in a shortened protein that might be non-functional or displays and altered function/regulation
E.g. if kinases loose their regulatory area they become uncontrollable
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| Classes of mutation | Substitution - synonymous (silent), non-synonymous (missense, nonsense or splicing)
Deletion - multiple of 3, frame shift or large deletion
Insertion - multiple of 3 , frame shift or large insertion
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| Consequences of mutation on protein production | Gain of function - novel or excess protein
Loss of function - reduces or eliminates protein
Dominant negative mutation - produces abnormal protein that interferes with normal protein
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| Single nucleotide polymorphisms | One in 300 nucleotides in the human genome is polymorphic. Usually no significant phenotype so not selected for or against
Needs to be present in >1% of the population
Tend to be associated with disease as they are inherited with other mutations
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| Phenotype | Observable characteristics
Due to genotype and environment
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| Genotype | Description of the genetic composition
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| Chromosomal abnormalities - Aneuploidy | Changes in the number of chromosomes
Due to non-disjunction
Monosomy - loss of a chromosome
Trisomy - gain of a chromosome
Most common is chromosome 21 - Down syndrome
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| Chromosome abnormalities - Breakage | Double strand break - can be fused incorrectly
Parts of chromosomes can be exchanged
e.g. change in regulation of genes by moving them on the chromosome (Philadelphia myeloid leukaemia) or loss of sections of chromosome if exchanged areas are different
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| Recombination | Homologous chromosomes line up in pairs in meiosis
Reciprocal exchanges between chromatids - frequency depends on distance between loci
A normal pathway in meiosis and not a cause of disease
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| Two genomes in eukaryotes | Nuclear genome - linear chromosomes inherited from both maternal and paternal side
Mitochondrial genome - circular chromosomes inherited from only the maternal side
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| Different sequence classed in nuclear and mitochondrial genome | Nuclear genome has a very small proportion of coding genes
Mitochondrial genome had mostly coding genes and is much smaller
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| The mitochondrial genome | Circular and encodes 37 genes, 24 of which encode non-coding RNAs and only 13 encode polypeptides
The genes are tightly clustered and do not contain introns
Vast majority of mitochondrial proteome is in nucleus
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| Different forms of satellite DNA | Describes larger repeats of sequences originating form polymerase slipping in DNA replication
Satellite DNA - 170 nucleotide repeats in centromeres, telomeres
Mini-satellites - repeat units 10-50 nucleotides
Micro-satellite - repeat units up to 4 bases
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| Microsatellites and disease | Hyper-expansion of repeats in genes can lead to disease
Microsatellite expansions play a role in neurological diseases including Huntington's and Friedrich Ataxia
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| DNA transposons | Cutting sequence and pasting somewhere else
DNA moves by a cut and paste mechanism
The DNA encodes proteins which move them around
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| DNA retrotransposons | RNA intermediates reverse transcribed into DNA
Lines - Long interspersed elements encoding exo-nuclease and reverse transcriptase
Sines - short nuclear elements made of Alu repeats. Depend on line gene product to move
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| Alu elements | Alu element location is biased towards gene-rich regions and are located in intergenic, intronic or exonic regions
Can act as cis-elements and affect gene regulation at the transcriptional, pre-mRNA processing and post-transcriptional level
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| Protein encoding genes | Only around 1% of the genome
Chromosome 18 has 270 protein encoding genes
Orientation of genes is on either strand
Some chromosomes have low gene density (e.g. 13) with a large distance between genes whilst others have a high gene density (e.g. 19)
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| Robertsonian Mutations | Parts of chromosomes are exchanged with non-homologous chromosomes
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