Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?
Across independent cancer genomes it has been observed that some sites have been recurrently hit by single nucleotide variants (SNVs). Such recurrently hit sites might be either (i) drivers of cancer that are postively selected during oncogenesis, (ii) due to mutation rate variation, or (iii) due to sequencing and assembly errors. We have investigated the cause of recurrently hit sites in a dataset of >3 million SNVs from 507 complete cancer genome sequences. We find evidence that many sites have been hit significantly more often than one would expect by chance, even taking into account the effect of the adjacent nucleotides on the rate of mutation. We find that the density of these recurrently hit sites is higher in non-coding than coding DNA and hence conclude that most of them are unlikely to be drivers. We also find that most of them are found in parts of the genome that are not uniquely mappable and hence are likely to be due to mapping errors. In support of the error hypothesis, we find that recurently hit sites are not randomly distributed across sequences from different laboratories. We fit a model to the data in which the rate of mutation is constant across sites but the rate of error varies. This model suggests that ∼4% of all SNVs are errors in this dataset, but that the rate of error varies by thousands-of-fold between sites.
School of Life Sciences, University of Sussex , Brighton , East Sussex , United Kingdom.
Thomas C A
TC
Smith
Genome Damage and Stability Centre, University of Sussex , Brighton , East Sussex , United Kingdom.
Antony M
AM
Carr
School of Life Sciences, University of Sussex , Brighton , East Sussex , United Kingdom.
Adam C
AC
Eyre-Walker
Cancer; Mutation; Mutation rate variation; Sequencing error; Somatic; Variation
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3439-44
25733855
Trends Genet. 2010 Aug;26(8):345-52
20594608
Nucleic Acids Res. 1980 Apr 11;8(7):1499-504
6253938
Nat Genet. 2015 Jul;47(7):822-6
25985141
Nature. 2015 Feb 19;518(7539):360-4
25693567
Mol Biol Evol. 2005 Mar;22(3):650-8
15537806
PLoS One. 2012;7(1):e30377
22276185
Nature. 2012 Aug 23;488(7412):504-7
22820252
Nat Methods. 2008 Dec;5(12):1005-10
19034268
Genetics. 2000 Sep;156(1):297-304
10978293
Nat Rev Genet. 2011 Oct 04;12(11):756-66
21969038
Nature. 2012 Aug 23;488(7412):471-5
22914163
Nat Rev Genet. 2011 Nov 29;13(1):36-46
22124482
Nucleic Acids Res. 1999 Jan 15;27(2):573-80
9862982
Genome Res. 2014 Sep;24(9):1445-54
25079859
Nucleic Acids Res. 2012 Jan;40(Database issue):D84-90
22086963
Nucleic Acids Res. 2014 Jun;42(11):6826-38
24753423
Science. 2015 Sep 25;349(6255):1483-9
26404825
Hum Mutat. 2016 May;37(5):488-94
26857394
Nature. 2013 Jul 11;499(7457):214-8
23770567
PLoS Biol. 2009 Feb 3;7(2):e1000027
19192947
Mol Biol Evol. 1986 Jul;3(4):322-9
3444408
Hum Genet. 1990 Jun;85(1):55-74
2192981
J Mol Evol. 1982;18(5):360-9
7120431
Genome Biol. 2011 Nov 08;12(11):R112
22067484
Cell. 2012 Dec 21;151(7):1431-42
23260136
Nat Commun. 2012;3:1004
22893128
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
14681465
Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):13994-4001
15292512
Nature. 2013 Aug 22;500(7463):415-21
23945592
Nat Rev Genet. 2015 Apr;16(4):213-23
25732611
Hum Mutat. 2012 Jan;33(1):136-43
21953857
Biotechniques. 2009 Mar;46(3):229-31
19317667
Science. 2013 Feb 22;339(6122):957-9
23348506
Nat Commun. 2013;4:1502
23422670
G3 (Bethesda). 2014 Jul 03;4(9):1667-70
24996580
Curr Biol. 2011 Jun 21;21(12):1051-4
21636278
Nucleic Acids Res. 2010 Oct;38(18):6102-11
20488869
Genome Biol Evol. 2011;3:842-50
21572094
Nature. 2010 Dec 16;468(7326):973-7
21107323