Biology subjects

Aguet, F.

Publications and source records attributed to Aguet, F..

4 recordsLinked to original sources

bioRxiv2018

A comprehensive analysis of RNA sequences reveals macroscopic somatic clonal expansion across normal tissues

Cancer genome studies have significantly advanced our knowledge of somatic mutations. However, how these mutations accumulate in normal cells and whether they promote pre-cancerous lesions remains poorly understood. Here we perform a comprehensive analysis of normal tissues by utilizing RNA sequencing data from [~]6,700 samples across 29 normal tissues collected as part of the Genotype-Tissue Expression (GTEx) project. We identify somatic mutations using a newly developed pipeline, RNA-MuTect, for calling somatic mutations directly from RNA-seq samples and their matched-normal DNA. When applied to the GTEx dataset, we detect multiple variants across different tissues and find that mutation burden is associated with both the age of the individual and tissue proliferation rate. We also detect hotspot cancer mutations that share tissue specificity with their matched cancer type. This study is the first to analyze a large number of samples across multiple normal tissues, identifying clones with genomic aberrations observed in cancer.

genomics↗

bioRxiv2018

A systematic survey of human tissue-specific gene expression and splicing reveals new opportunities for therapeutic target identification and evaluation

Differences in the expression of genes and their splice isoforms across human tissues are fundamental factors to consider for therapeutic target evaluation. To this end, we conducted a transcriptome-wide survey of tissue-specific gene expression and splicing events in the unprecedented collection of 8527 high-quality RNA-seq samples from the GTEx project, covering 36 human peripheral tissues and 13 brain subregions. We derived a weighted tissue-specificity scoring scheme accounting for the similarity of related tissues and inherent variability across individual samples. We showed that ~50.6% of all annotated human genes show tissue-specific expression, including many low abundance transcripts vastly underestimated by previous array-based expression atlases. As utilities for drug discovery, we demonstrated that tissue-specificity is a highly desirable attribute of validated drug targets and tissue-specificity can be used to prioritize disease-associated genes from genome-wide association studies (GWAS). Using brain striatum-specific gene expression as an example, we provided a template to leverage tissue-specific gene expression to identify novel therapeutic targets. Mining of tissue-specific splicing further reveals new opportunities for tissue-specific targeting. Thus, the high quality transcriptome atlas provided by the GTEx is an invaluable resource for drug discovery and systematic analysis anchored on the human tissue specific gene expression provides a promising avenue to identify novel therapeutic target hypotheses.

genomics↗

bioRxiv2017

Modified penetrance of coding variants by cis-regulatory variation shapes human traits

Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.

genetics↗

bioRxiv2017

DroNc-Seq: Deciphering cell types in human archived brain tissues by massively-parallel single nucleus RNA-seq

Single nucleus RNA-Seq (sNuc-Seq) profiles RNA from tissues that are preserved or cannot be dissociated, but does not provide the throughput required to analyse many cells from complex tissues. Here, we develop DroNc-Seq, massively parallel sNuc-Seq with droplet technology. We profile 29,543 nuclei from mouse and human archived brain samples to demonstrate sensitive, efficient and unbiased classification of cell types, paving the way for charting systematic cell atlases.

genomics↗