Abstract
There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5′-UTR and 3′-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome.
Highlights
Lateral gene transfer (LGT) is the transmission of genetic material by means other than direct vertical transmission from progenitors to their offspring, and has been best studied for its ability to transfer novel genotypes between species
Considering that (a) some human cells are in a constant and intimate relationship with the microbiome, (b) eukaryotes have widespread LGT from bacteria [3], (c) bacteria in vitro can transform the mammalian genome [4], and (d) viruses integrate into the human genome and cause disease [5,6], we sought to investigate if LGT from bacteria to human somatic cells may be a novel mutagen and play a role in diseases associated with DNA damage like cancer
Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome, tumor genomes
Summary
Lateral gene transfer (LGT) is the transmission of genetic material by means other than direct vertical transmission from progenitors to their offspring, and has been best studied for its ability to transfer novel genotypes between species. During the original sequencing and analysis of the human genome, 113 proteins putatively arising from bacterial LGT were initially identified [7]. This was later refuted by an analysis that demonstrated that the number of putative LGTs is dependent on the number of reference genomes used in the analysis suggesting that the proteins found exclusively in both bacteria and humans at that time were due to the small sample size of genomes sequenced, instead of LGT [8]. A subsequent phylogenetic analysis of LGT in the human genome overlooked comparisons with all prokaryotes [9]. Both analyses only focused on full length genes, missing any smaller LGTs or LGT of non-coding DNA. While LGT to the germ line can affect future generations and potentially the evolution of our species, LGT to somatic cells has the potential to affect an individual as a unique feature of their personal genome
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