[ensembl-dev] How can a SNP cause a frameshift mutation

Robert Bradbury robert.bradbury at gmail.com
Sat Nov 6 02:34:53 GMT 2010


It is also worth noting that if an exon is not a "complete"
translatable sequence, e.g. a 3xN base sequence which codes for a
complete in-frame amino acid sequence that SNPs in splice sites could
easily cause frame shift mutations by losing (or more rarely adding)
exons to be translated and thus messing up the entire sequence after
the faulty splice site.

Also due to the the exonuclease activities of WRN and DCLRE1C
(Artemis) during DNA Double Strand Break repair -- there is a high
probability for the introduction of indels which result in frameshifts
whenever DSB repair takes place in exon or splice sites.  As all
sequencing work on the "average" genome of large numbers of cells one
never knows which cells harbor specific frameshift mutations randomly
distributed throughout each cell's genome.  Though not widely accepted
yet this is probably one of the primary causes of aging (accumulation
of indels and frameshifts corrupting the cellular genome and
eventually shutting down the cell through the activation of the
ER/mitochondria unfolded protein responses).

Robert


On 11/3/10, Will McLaren <wm2 at ebi.ac.uk> wrote:
> Hi Andrea,
>
> I suspect you are either defining the coordinates of your SNPs
> incorrectly, or defining the allele_string incorrectly.
>
> A SNP in Ensembl should have its end coordinate equal to its start
> coordinate, since by definition it affects only a single base.
>
> It's allele_string should look something like "A/G" where A is the
> reference allele and G is the variant allele.
>
> It's hard for me to say which is causing the problem without seeing
> your data, but try following these tips and it should be OK.
>
> Cheers
>
> Will McLaren
> Ensembl Variation
>
> On 3 November 2010 16:15, Andrea Edwards <edwardsa at cs.man.ac.uk> wrote:
>> Hi
>>
>> I think I am doing something seriously wrong with the ensembl variation
>> database. I have a thousand SNPs which I am looking at, all of which are
>> in
>> exons and not a single SNP according to my code is a synonymous or non
>> synonymous coding SNP. The vast majority of my SNPs seem to be frameshift
>> coding. I don't see how a SNP can cause a frameshift mutation - only
>> insertions and deletions can cause that.
>>
>> I'd be grateful if anyone can see what I am doing wrong
>>
>> #get adaptors
>> my $vfa = $reg->get_adaptor($species, 'variation', 'variationfeature');
>>        my $sa = $reg->get_adaptor($species, 'core', 'slice');
>>        my $transcript_adaptor =$reg->get_adaptor($species,
>> 'core','Transcript');
>>
>> #iterate through my SNPs
>>
>> while (my $ref = $sth->fetchrow_hashref()) {
>>
>>        my $slice = $sa->fetch_by_region('chromosome',$ref->{'Chr'});
>>                my $new_vf =
>> Bio::EnsEMBL::Variation::VariationFeature->new(
>>                        -start => $ref->{'LiftPos'},  #position of SNP
>>                        -end => $iLiftPos,
>>                        -slice => $slice,           # the variation must be
>> attached to a slice
>>                        -allele_string => $iallele,    # the first allele
>> should be the reference allele
>>                        -strand => 1,
>>                        -map_weight => 1,
>>                        -adaptor => $vfa,           # we must attach a
>> variation feature adaptor
>>                        -variation_name => 'newSNP',
>>                    );
>>
>>            foreach $transcript_variant
>> (@{$new_vf->get_all_TranscriptVariations}) {
>>
>>                    foreach $consequence
>> (@{$transcript_variant->consequence_type}) {
>>                        print "$consequence\n";
>>                    }
>>                }
>>
>> }
>>
>> I've stripped the code right down to its minmum as shown above. Not a
>> single
>> consequence is synonymous or non synonymous out of 1000 SNPs in exons.
>> Plenty of them are intronic but that's to be expected as  SNP might be in
>> the exon of one gene but the intron of another.
>>
>> I'm going to find all the known SNPs in my DNA of interest (cow chromosome
>> 7) and see what my code says when ran on known synonymous and
>> non-synonymous
>> SNPs.
>>
>> Any advice or help appreciated
>>
>> thanks
>>
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>
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