Articles in 2016

Peter 't Hoen, Lude Franke, Bastiaan Heijmans and colleagues present a combined analysis of methylome and transcriptome data from a large collection of whole-blood samples to infer the downstream effects of disease-associated variants. They identify a large number of trait-associated SNPs influencing methylation of CpG sites in trans, providing insights into the downstream functional effects of many disease-associated variants.

Zachary Lippman, José Jiménez-Gómez and colleagues show that cultivated tomatoes have lost day-length-sensitive flowering, compared to their wild relatives, as a result of cis-regulatory variation affecting expression of SP5G, a paralog of the florigen gene SFT. They engineered SP5G loss-of-function mutant plants, resulting in rapid flowering and early yield.

Investment in national infrastructure should include a scalable open informatics solution for agricultural genomics, germplasm and crop traits. This is a priority measure for economic stimulus and food security. As building this knowledge harvester should be simpler than the infrastructure required for precision medicine, it will also pave the way to that goal.

A new study demonstrates that the most widespread lineage of the causative agent of tuberculosis consists of both globally distributed and geographically restricted sublineages. The geographically restricted sublineages are likely able to infect only specific human populations, whereas the globally distributed ones likely have a broader human host range.

Unspecific and unexplained medical complaints can be frustrating to both patients and clinicians. A cause for these complex symptoms and signs may now have been identified.

Polycomb-mediated silencing of the floral repressor gene FLC in response to long-term cold is a central event during vernalization in Arabidopsis thaliana, but how it is initiated is unclear. Two new studies identify a DNA element that mediates FLC silencing by attracting a pair of transcriptional repressors, VAL1 and VAL2, which in turn trigger epigenetic silencing by the Polycomb complex PHD–PRC2.

Sanjay Sinha and colleagues use a vascular model derived from human induced pluripotent stem cells from patients with Marfan syndrome with fibrillin-1 alterations to study aortic aneurysms. They find defects that mimic Marfan pathology as well as novel targets for treatment and can rescue the phenotype by correcting the mutation through genome editing.

Yoshitaka Fukada, Hikari Yoshitane and colleagues report that rhythmic expression of ADARB1, an RNA-editing enzyme that catalyzes adenosine-to-inosine conversion, controls mRNA oscillations in the mouse liver. Mice with Adarb1 mutations exhibit short-period rhythms in locomotor activity and gene expression.

Hanno Glimm, Jan Korbel and colleagues present a computational framework called cis expression structural alteration mapping (CESAM), which they use to identify somatic copy-number alterations affecting cis-regulatory elements in cancer. They find that enhancer hijacking leads to overexpression of IRS4 and IGF2 in cancer.

Andrew Lane and colleagues analyze somatic alterations across 21 tumor types for evidence of sex bias. They find that an excess of genes on the non-pseudoautosomal region of the X chromosome harbor loss-of-function mutations more frequently in males, suggesting that biallelic expression of these genes in females contributes to reduced cancer incidence in females across a variety of tumor types.

Trever Bivona and colleagues use an in vivo lung cancer metastasis model to show that the transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. CIC inactivation leads to upregulation of ETV4 and MMP24, which is necessary and sufficient for metastasis.

Stuart Cook and colleagues study the role of TTN (titin)-truncating variants using a combination of heart physiology experiments in rats and genomic analysis in humans. Their data show that TTN variants are associated with a range of cardiac phenotypes in healthy individuals and in patients with dilated cardiomyopathy.

The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia.

Luca Lotta, Robert Scott, Stephen O’Rahilly, Claudia Langenberg, David Savage, Nicholas Wareham, Inês Barroso and colleagues identify 53 genomic regions associated with insulin resistance phenotypes. Their findings suggest that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology.

Déborah Bourc’his and colleagues report that mouse embryos deficient for Liz (long isoform of Zdbf2) develop normally but fail to activate Zdbf2 in the postnatal brain and show growth reduction. These data suggest that transcription during an early embryonic stage may program a stable epigenetic state with later physiological consequences.

Jian Hu and colleagues use mouse models to show that Qki deficiency promotes gliomagenesis by allowing neural stem cells to maintain their stemness outside the subventricular zone. Mechanistically, they show that Qki deficiency decreases endolysosome-mediated degradation of receptors that are essential for maintaining self-renewal, allowing cells to cope with low ligand levels outside of their niche.

Thomas Hoffmann, Neil Risch and colleagues use longitudinal electronic health records from almost 100,000 individuals to conduct genome-wide association studies for blood pressure measurements. They find new significant loci that replicate in independent cohorts and can double the variance explained by using multiple blood pressure data points.