Articles in 2016

Charles Mullighan, Jinghui Zhang and colleagues characterize a subtype of B-progenitor acute lymphoblastic leukemia with deregulated DUX4 and ERG. They find that aberrant DUX4 activation results in loss of ERG function, either through deletion or by the induction a novel transforming ERG isoform, ERGalt, that inhibits wild-type ERG activity.

Mark Rubin, Francesca Demichelis and colleagues study the evolution of urothelial carcinomas by performing whole-exome sequencing of tumors collected from patients before and after chemotherapy. They find marked within-patient tumor heterogeneity and increased mutations involved in integrin signaling pathways and APOBEC-induced mutation signatures after treatment.

Ming-Rong Wang, Benjamin Berman and colleagues perform whole-exome sequencing and global methylation profiling on different tumor regions of esophageal squamous cell carcinoma. They find evidence for intratumoral heterogeneity and identify late driver mutations targeting oncogenes and early driver mutations occurring in tumor-suppressor genes.

Gelareh Zadeh, Kenneth Aldape and colleagues present an integrative genomic analysis of schwannomas. In addition to finding recurrent mutations in ARID1A, ARID1B and DDR1, they identify a recurrent SH3PXD2A-HTRA1 fusion that confers increased proliferation, invasion and in vivo transformation, and is associated with sensitivity to MEK inhibition.

Andre Franke and colleagues perform a genome-wide association study for the gut microbiome, examining the influence of host genetics on overall microbial variation and individual taxa. They find significant associations at the VDR (vitamin D receptor) locus and observe correlations between microbiota and metabolites of VDR, including bile acids.

Jamel Chelly and colleagues identify mutations in the E3 ubiquitin ligase gene NEDD4L that cause a syndrome of periventricular nodular heterotopia associated with neurodevelopmental disorders, cleft palate and toe syndactyly. The authors show that the mutations affect the mTORC1 and AKT pathways and cause defects in mouse brain development.

Susan Gasser and colleagues find that methylation at histone H3 lysine 9 (H3K9me) is required for repression of simple repeats and transposons in Caenorhabditis elegans. Loss of H3K9me in worms leads to extensive accumulation of insertions and deletions at repeat elements, which correlate with R-loop formation and increased sensitivity to replication stress.

Howard Chang and colleagues identify a long noncoding RNA, DINO, that is transcribed upstream of CDKN1A and induced by p53 in response to DNA damage. They show that DINO binds to p53 protein and promotes its stabilization, producing a feedback loop that amplifies DNA damage signaling.

Laurent Fasano and colleagues identify TSHZ3 deletions in patients with autism spectrum disorder. Tshz3-mutant mice show functional changes at synapses established by cortical projection neurons and exhibit autism-like behavioral patterns.

Ludmila Prokunina-Olsson and colleagues report a fine-mapping and association analysis of germline variants in the APOBEC3 region associated with cancer risk. They identify two variants with differential effects in bladder and breast cancer, and their in vitro results suggest that environmental exposures may induce tissue-specific APOBEC mutagenesis and contribute to oncogenesis in carriers of APOBEC3 risk variants.

Bjarni Halldorsson, Kari Stefansson and colleagues use SNP array and whole-genome sequencing data to estimate the meiotic gene conversion rate (G) in humans. They find that G for SNPs is 7.0 conversions/Mb per generation, is 2.17 greater in mothers than in fathers, and increases with maternal age.

Patricia Munroe, Christopher Newton-Cheh, Andrew Morris and colleagues perform association studies in over 340,000 individuals of European ancestry and identify 66 loci, of which 17 are novel, involved in blood pressure regulation. The risk SNPs are enriched for cis-regulatory elements, particularly in vascular endothelial cells.

Patricia Munroe, Joanna Howson and colleagues genotype ∼350,000 individuals and identify 30 new blood pressure– or hypertension-associated risk loci. Their analyses provide insights into the pathophysiology of hypertension and highlight new potential targets for clinical intervention.

Daniel Chasman, Daniel Levy, Christopher Newton-Cheh, Georg Ehret and colleagues perform an association meta-analysis for blood pressure in ∼330,000 individuals and identify 31 new risk loci, implicating biological pathways related to vascular function and cardiometabolic traits. Their findings highlight potential therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.

Mingfang Zhang, Sally Mackenzie and colleagues report the genome sequence of allopolyploid Brassica juncea and through comparative analysis suggest that A-subgenome evolution contributes to differences in agricultural subvarieties. They find that differential homoeolog gene expression from the subgenomes helps to shape the selection that distinguishes vegetable- and oil-use Brassica.

Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment.

Yanick Crow and colleagues report that biallelic mutations in SNORD118, which encodes the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts. The mutations affect U8 expression, processing and protein binding and suggest a role for this snoRNA in cerebral vascular homeostasis.

Kjetill S. Jakobsen, Sissel Jentoft and colleagues assemble partial draft genomes and analyze sequences from 66 teleost fish species to determine major histocompatibility complex (MHC) class I and class II gene status. They find that MHC II is absent from the Gadiformes lineage, while MHC I gene expansions have occurred multiple times.

Ken-ichi Noma and colleagues use ChIA-PET to identify genome-wide associations mediated by condensin and cohesin in fission yeast. They find that cohesin and condensin generate small and larger chromatin domains, respectively, and that condensin, but not cohesin, connects cell cycle–regulated genes bound by mitotic transcription factors.

Nicholas Feasey and colleagues report whole-genome sequence analysis of 675 isolates of Salmonella enterica serovar Enteritidis from 45 countries. They find evidence for a global epidemic clade associated with enterocolitis and two novel clades restricted to distinct regions of Africa and associated with invasive disease.