Volume 52 Issue 3, 2 March 2020

Efforts to systematically characterize silencers in animal genomes have been limited. Two studies in this issue of Nature Genetics bring silencers into the spotlight, identifying these elements genome wide in human and mouse cells, and providing insights into their function.

Deep mRNA sequencing at eight time points during memory CD4⁺ T cell activation identifies widespread dynamic allele-specific expression events that are enriched in HLA and other autoimmune disease loci.

A genome-wide screen identifies silencer regions in human cells. Deletion of silencers linked to the transporter genes ABCC2 and ABCG2 causes their up-regulation and chemo-resistance.

Chromatin interaction analysis identifies PRC2-bound silencers in mESCs, which, when deleted in mice, can lead to developmental phenotypes. Silencers in pluripotent cells can transition into active tissue-specific enhancers during development.

Replacement of lysine 4 or 36 with alanine in histone H3.3 impairs ESC differentiation and induces widespread gene expression changes. Expression of H3.3K4A, but not H3.3K36A, leads to H3.3 depletion, reduces remodeler binding and increases RNA polymerase II activity.

Analysis of whole-genome doubling (WGD) by using cancer sequencing data combined with simulations of tumor evolution suggests that there is negative selection against homozygous loss of essential genes before WGD but not after.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Analysis of mitochondrial genomes (mtDNA) by using whole-genome sequencing data from 2,658 cancer samples across 38 cancer types identifies hypermutated mtDNA cases, frequent somatic nuclear transfer of mtDNA and high variability of mtDNA copy number in many cancers.