Germline determinants of the somatic mutation landscape in 2,642 cancer genomes, bioRxiv, 2017-11-02

AbstractCancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertionsdeletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.

biorxiv genomics 0-100-users 2017

Evolutionary dynamics of bacteria in the gut microbiome within and across hosts, bioRxiv, 2017-10-31

AbstractGut microbiota are shaped by a combination of ecological and evolutionary forces. While the ecological dynamics have been extensively studied, much less is known about how species of gut bacteria evolve over time. Here we introduce a model-based framework for quantifying evolutionary dynamics within and across hosts using a panel of metagenomic samples. We use this approach to study evolution in ∼30 prevalent species in the human gut. Although the patterns of between-host diversity are consistent with quasi-sexual evolution and purifying selection on long timescales, we identify new genealogical signatures that challenge standard population genetic models of these processes. Within hosts, we find that genetic differences that accumulate over ∼6 month timescales are only rarely attributable to replacement by distantly related strains. Instead, the resident strains more commonly acquire a smaller number of putative evolutionary changes, in which nucleotide variants or gene gains or losses rapidly sweep to high frequency. By comparing these mutations with the typical between-host differences, we find evidence that some sweeps are seeded by recombination, in addition to new mutations. However, comparisons of adult twins suggest that replacement eventually overwhelms evolution over multi-decade timescales, hinting at fundamental limits to the extent of local adaptation. Together, our results suggest that gut bacteria can evolve on human-relevant timescales, and they highlight the connections between these short-term evolutionary dynamics and longer-term evolution across hosts.

biorxiv evolutionary-biology 100-200-users 2017

Gut microbiota has a widespread and modifiable effect on host gene regulation, bioRxiv, 2017-10-28

AbstractVariation in gut microbiome is associated with wellness and disease in humans, yet the molecular mechanisms by which this variation affects the host are not well understood. A likely mechanism is through changing gene regulation in interfacing host epithelial cells. Here, we treated colonic epithelial cells with live microbiota from five healthy individuals and quantified induced changes in transcriptional regulation and chromatin accessibility in host cells. We identified over 5,000 host genes that change expression, including 588 distinct associations between specific taxa and host genes. The taxa with the strongest influence on gene expression alter the response of genes associated with complex traits. Using ATAC-seq, we show that a subset of these changes in gene expression are likely the result of changes in host chromatin accessibility and transcription factor binding induced by exposure to gut microbiota. We then created a manipulated microbial community with titrated doses of Collinsella, demonstrating that both natural and controlled microbiome composition leads to distinct, and predictable, gene expression profiles in host cells. Together, our results suggest that specific microbes play an important role in regulating expression of individual host genes involved in human complex traits. The ability to fine tune the expression of host genes by manipulating the microbiome suggests future therapeutic routes.

biorxiv genomics 200-500-users 2017

 

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