Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?
نویسندگان
چکیده
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.
منابع مشابه
O-36: Genome Haplotyping and Detection of Meiotic Homologous Recombination Sites in Single Cells, A Generic Method for Preimplantation Genetic Diagnosis
Background: Haplotyping is invaluable not only to identify genetic variants underlying a disease or trait, but also to study evolution and population history as well as meiotic and mitotic recombination processes. Current genome-wide haplotyping methods rely on genomic DNA that is extracted from a large number of cells. Thus far random allele drop out and preferential amplification artifacts of...
متن کاملAn integrated map of genetic variation from 1,092 human genomes
By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information ac...
متن کاملThe mutational landscape of phosphorylation signaling in cancer
Somatic mutations in cancer genomes include drivers that provide selective advantages to tumor cells and passengers present due to genome instability. Discovery of pan-cancer drivers will help characterize biological systems important in multiple cancers and lead to development of better therapies. Driver genes are most often identified by their recurrent mutations across tumor samples. However...
متن کاملIn silico analysis for determining the deleterious nonsynonymous single nucleotide polymorphisms of BRCA genes
Recent advances in DNA sequencing techniques have led to an increase in the identification of single nucleotide polymorphisms (SNPs) in BRCA1 and BRCA2 genes, but no further information regarding the deleterious probability of many of them is available (Variants of Unknown Significance/VUS). As a result, in the current study, different sequence- and structure-based computation...
متن کاملStudy of Cytochrome P450 1A1 (T3801C) Single Nucleotide Polymorphism in Patients with Breast Cancer in Mazandaran Province-Northern Iran
Background: Breast cancer is the first leading cause of cancer-related death in women. Pesticides which are excessively used in northern Iran are one of the most important risk factors for breast cancer incidence. The cytochrome P450 1A1 (cyp1A1) is a key enzyme in xenobiotics metabolism and SNPs of its coding gene has been verified to be important in cancer susceptibility. The aim of thi...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 4 شماره
صفحات -
تاریخ انتشار 2016