Interactions between the gut microbiome and host gene regulation in cystic fibrosis, bioRxiv, 2019-04-03

AbstractCystic Fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have lead to markedly increased longevity of patients with CF, but new complications have emerged, such as early onset of colorectal cancer (CRC). Although the pathogenesis of CRC in CF remains unclear, altered host-microbe interactions might play a critical role. Here, we characterize the changes in the gut microbiome and host gene expression in colonic mucosa of CF patients relative to healthy controls. We find that CF patients show decreased microbial diversity, decreased abundance of taxa such as Butyricimonas, Sutterella, and Ruminococcaceae, and increased abundance of other taxa, such as Actinobacteria and Firmicutes. We find that 1543 genes, including CFTR, show differential expression in the colon of CF patients compared to healthy controls. Interestingly, we find that these genes are enriched with functions related to gastrointestinal and colorectal cancer, such as metastasis of CRC, tumor suppression, cellular dysfunction, p53 and mTOR signaling pathways. Lastly, we modeled associations between relative abundances of specific bacterial taxa in the gut mucosa and host gene expression, and identified CRC-related genes, including LCN2 and DUOX2, for which gene expression is correlated with the abundance of CRC-associated bacteria, such as Ruminococcaceae and Veillonella. Our results provide new insight into the role of host-microbe interactions in the etiology of CRC in CF.

biorxiv genomics 0-100-users 2019

Common DNA sequence variation influences 3-dimensional conformation of the human genome, bioRxiv, 2019-03-30

ABSTRACTThe 3-dimensional (3D) conformation of chromatin inside the nucleus is integral to a variety of nuclear processes including transcriptional regulation, DNA replication, and DNA damage repair. Aberrations in 3D chromatin conformation have been implicated in developmental abnormalities and cancer. Despite the importance of 3D chromatin conformation to cellular function and human health, little is known about how 3D chromatin conformation varies in the human population, or whether DNA sequence variation between individuals influences 3D chromatin conformation. To address these questions, we performed Hi-C on Lymphoblastoid Cell Lines (LCLs) from 20 individuals. We identified thousands of regions across the genome where 3D chromatin conformation varies between individuals and found that this conformational variation is often accompanied by variation in gene expression, histone modifications, and transcription factor (TF) binding. Moreover, we found that DNA sequence variation influences several features of 3D chromatin conformation including loop strength, contact insulation, contact directionality and density of localciscontacts. We mapped hundreds of Quantitative Trait Loci (QTLs) associated with 3D chromatin features and found evidence that some of these same variants are associated at modest levels with other molecular phenotypes as well as complex disease risk. Our results demonstrate that common DNA sequence variants can influence 3D chromatin conformation, pointing to a more pervasive role for 3D chromatin conformation in human phenotypic variation than previously recognized.

biorxiv genomics 0-100-users 2019

Polygenic architecture of human neuroanatomical diversity, bioRxiv, 2019-03-29

AbstractWe analysed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and SNP data from &gt; 20,000 individuals. Our results replicate previous findings of a strong polygenic architecture of neuroanatomical diversity. SNPs captured from 40% to 54% of the variance in the volume of different brain regions. We observed a large correlation between chromosome length and the amount of phenotypic variance captured, r∼0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a more local scale, SNPs within genes (∼51%) captured ∼1.5-times more genetic variance than the rest; and SNPs with low minor allele frequency (MAF) captured significantly less variance than those with higher MAF the 40% of SNPs with MAF&lt;5% captured less than one fourth of the genetic variance. We also observed extensive pleiotropy across regions, with an average genetic correlation of rG∼0.45. Across regions, genetic correlations were in general similar to phenotypic correlations. By contrast, genetic correlations were larger than phenotypic correlations for the leftright volumes of the same region, and indistinguishable from 1. Additionally, the differences in leftright volumes were not heritable, underlining the role of environmental causes in the variability of brain asymmetry. Our analysis code is available at <jatsext-link xmlnsxlink=httpwww.w3.org1999xlink ext-link-type=uri xlinkhref=httpsgithub.comneuroanatomygenomic-architecture>httpsgithub.comneuroanatomygenomic-architecture<jatsext-link>.

biorxiv neuroscience 0-100-users 2019

 

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