Volume 50 Issue 4, April 2018

Noncoding expanded repeats have been implicated in a wide range of diseases. A new report uncovers expanded TTTCA and TTTTA repeats in an intronic region of SAMD12, and at least two other genes, in individuals with benign adult familial myoclonic epilepsy.

The switch from fetal to adult hemoglobin relies on repression or silencing of the upstream γ-globin gene, but identification of the transcriptional repressors that bind to the sites at which a cluster of naturally occurring variants associated with HPFH (hereditary persistence of fetal hemoglobin) are found has been elusive. A new study provides mechanistic evidence for the direct binding of BCL11A and ZBTB7A, two previously identified γ-globin gene repressors.

In vivo verification of tumor suppressors and their interactions with each other has required complex experiments. A report in this issue uses a novel CRISPR–Cas9 technology with barcodes to test, in parallel, the tumorigenic potential of functional loss of multiple tumor-suppressor genes in the context of a genetically engineered mouse model of lung adenocarcinoma with mutant Kras.

In vivo analysis of pairwise combinations of tumor suppressor losses using a barcode-based assay in mice identifies unpredicted genetic interactions and shows that the effects of tumor suppressor alterations can be context-dependent.

Analysis of whole-genome sequencing data from 1,291 parent–offspring trios identifies patterns of clustered de novo mutations. Clusters increase in number with maternal age and are associated with DNA double-strand-break processes.

Single-cell RNA sequencing (scRNA-seq) of ~25,000 peripheral blood mononuclear cells from 45 donors identifies new celltype-specific cis-eQTLs and genetic variants that significantly alter co-expression relationships (‘co-expression QTLs’).

The fetal globin gene repressors BCL11A and ZBTB7A directly bind γ-globin gene promoter regions. Repressor binding is disrupted by naturally occurring point mutations located upstream of the transcriptional start site that are associated with hereditary persistence of fetal hemoglobin.

The authors study the cis-regulatory evolution of the Shh locus in vertebrates. Using genomic editing and chromatin profiling, they conclude that paired fins emerged through the co-option of developmental programs for the median fins of gnathostomes.

The authors present a CRISPR-library-based approach for highly efficient and precise genome-wide variant engineering. They examine the functional consequences of premature termination codons within all annotated essential genes in yeast.

This study investigates the effects of MYCN on the chromatin and transcriptional landscape of neuroblastoma. The authors find that, at oncogenic levels, MYCN binds to canonical E-boxes at promoters and invades enhancers, leading to transcriptional amplification.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

A transcriptome-wide association study integrating genome-wide association data with expression data from brain, blood and adipose tissues identifies new candidate susceptibility genes for schizophrenia, providing a step toward understanding the underlying biology.

Genome-wide association study for osteoarthritis using data from UK Biobank identifies loci for knee- and hip-specific disease. Functional analyses of chondrocytes provide further insight into candidate causal genes.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Analysis of the imprinted KLF14 locus shows that the type 2 diabetes risk alleles in this region act in adipocytes to reduce KLF14 expression and modulate the expression of almost 400 genes in trans, leading to a shift in body-fat distribution and insulin resistance specifically in females.

This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

Whole-genome DNA methylation profiling and analysis of normal tissues from both human and mouse reveal that hypomethylation within partially methylated, late-replicating domains depends on sequence context, starts early in development, accumulates with cell divisions and progresses with organismal aging.

A genome-wide CRISPR screen for suppressors and enhancers of C9ORF72 dipeptide-repeat protein toxicity identifies candidate genes involved in nucleocytoplasmic transport and other pathways including RNA processing and chromatin modification.

Analysis of whole-genome sequences and transcription data from tumors identifies noncoding loci in which mutations affect target gene expression. These somatic eQTLs can classify tumors into pathway-based subtypes and are disrupted in 88% of tumors.

A new method tests whether disease heritability is enriched near genes with high tissue-specific expression. The authors use gene expression data together with GWAS summary statistics for 48 diseases and traits to identify disease-relevant tissues.