Articles in 2016

Nir Hacohen, Bruce Walker, David Sabatini, Eric Lander and colleagues perform a CRISPR–Cas9-based screen for host factors that are required for HIV infection. They identify two known and three novel factors that are necessary for viral infection but that are not required for cell viability, making them potential targets for antiviral therapy.

Manju Kurian and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance. Their findings highlight a clinically recognizable form of dystonia and demonstrate a crucial role for KMT2B in the physiological control of voluntary movement.

Jaroslaw Maciejewski, Seishi Ogawa and colleagues examine the clonal dynamics of myelodysplastic syndromes (MDS) by analyzing whole-exome and targeted sequencing data from a large patient collection. They find that progression steps previously defined by pathologic criteria are accompanied by distinct molecular changes, and they show that driver genes can be classified into molecular subtypes differentially associated with low-risk MDS, high-risk MDS or secondary acute myeloid leukemia.

Gerald Crabtree, Cigall Kadoch and colleagues report that BAF complexes oppose PRC by rapid, ATP-dependent eviction in the absence of Pol II occupancy, transcription or replication, leading to the formation of accessible chromatin. They also find that tumor-suppressor and oncogenic mutations in BAF subunits result in differential effects on PRC eviction.

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.

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.

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.

Yuehui He and colleagues show that VAL1 and VAL2 bind to a cis-regulatory element at the FLC locus and are required for its epigenetic silencing during vernalization in Arabidopsis. They further report that VAL proteins recognize the repressive histone mark H3K27me3 and are necessary for genomic binding of the Polycomb silencing partner LHP1.

Sebastien Gagneux and colleagues analyze a global collection of Mycobacterium tuberculosis clinical isolates to classify sublineages by phylogeography. They find globally distributed ‘generalist’ and geographically restricted ‘specialist’ sublineages of lineage 4, indicating that different evolutionary strategies were adopted to succeed in various ecological niches.

Melinda Mills, Nicola Barban, Harold Snieder, Marcel den Hoed and colleagues perform a meta-analysis of data from over 300,000 individuals for age at first birth and number of children ever born. They identify 12 significant loci that associate with these traits, providing insights into the genetic basis of human reproductive behavior.

Xu Tan, Yong Yang and colleagues identify patients with epidermolysis bullosa harboring mutations in KLHL24, which encodes a cullin 3–RBX1 ubiquitin ligase substrate receptor. They find that truncating mutations stabilize the protein by abolishing autoubiquitination, leading to enhanced ubiquitination and degradation of KRT14, the target substrate of KLHL24.

Marika Charalambous and colleagues show that, in mice, the fetus is the source of maternal circulating DLK1, which regulates the mother's metabolism during pregnancy. They also find that maternal circulating DLK1 levels predict embryonic weight in mice and associate with fetal growth restriction in a human cohort.

Daehyun Baek and colleagues present a systematic analysis of more than 2 billion potential miRNA–gene target interactions using publicly available human microarray data. The authors find evidence for four canonical and seven non-canonical site types that show detectable downregulation of target genes, and they present functional validation for the new site types.