Volume 48 Issue 10, October 2016

A new study based on single-nucleus sequencing reports that triple-negative breast cancers acquire copy number aberrations in short punctuated bursts in the earliest stages of tumor evolution, rather than continuously and gradually, challenging prevailing models of tumor evolution.

A common ancestor of the modern codfish acquired a set of mutations that eliminated a major arm of the adaptive immune system—the MHC II pathway of antigen presentation to CD4⁺ T cells. Subsequent to this event, there was a radiation of these fish in which the number and diversity of MHC I genes increased in species-specific ways.

A new study demonstrates that genomic sequencing coverage of plasma DNA fragments around transcription start sites reflects the expression levels of genes in corresponding tumors. This approach may enable noninvasive monitoring of treatment-induced changes in gene expression for patients with cancer.

Douglas Ruderfer, Shaun Purcell and colleagues characterized the rates and properties of rare genic copy number variants in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium. These data are available through an integrated database that spans the spectrum of human genetic variation, aiding in the interpretation of personal genomes and population-based disease studies.

Ben Lehner and colleagues analyze data from matched exomes and transcriptomes from tumors across 27 cancer types to elucidate rules linking premature termination codon location to nonsense-mediated mRNA decay (NMD). They propose a model that explains variability in NMD efficiency and find evidence of positive and negative selection on NMD-initiating mutations in tumors.

Nicholas Navin and colleagues use highly multiplexed single-nucleus sequencing to investigate DNA copy number evolution in patients with triple-negative breast cancer. Their data suggest that most copy number alterations are acquired at the earliest stages of tumor evolution in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.

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.

Housheng Hansen He and colleagues perform an integrated analysis and identify 45 candidate long noncoding RNAs (lncRNAs) associated with prostate cancer risk. They further show that a prostate cancer risk allele in the 8q24 region results in upregulation of the lncRNA PCAT1, which promotes prostate cancer cell proliferation and tumor growth.

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.

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.

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.

Howard Chang, Ravindra Majeti and colleagues define the chromatin accessibility and transcriptional landscapes in 13 human primary blood cell types and in acute myeloid leukemia cells. They identify potential regulators governing hematopoietic differentiation and genetic elements linked to regulatory evolution in cancer cells.

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.

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.

Xiaowu Wang, Jian Wu, Guusje Bonnema and colleagues report resequencing and subgenome selection analysis of 199 Brassica rapa and 119 Brassica oleracea accessions representing diverse morphotypes. They identify 4 subgenome loci with evidence of parallel selection among subgenomes and 15 subgenome loci with evidence of parallel selection between species.

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.

Feng Qin and colleagues perform a genome-wide association study for drought tolerance in maize seedlings and find 42 candidate genes. They characterize a promoter insertion in the ZmVPP1 gene containing MYB-binding sites, which enables the drought-inducible expression of ZmVPP1, leading to drought tolerance, a phenotype confirmed through transgenic experiments.

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.

Murat Günel and colleagues identify recurrent mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II, in a subset of meningiomas. They find that POLR2A-mutant tumors can be distinguished on the basis of their super-enhancer and gene expression profiles, which show dysregulation of key meningeal identity genes.

Mathieu Lupien and colleagues report an enrichment of somatic mutations at the ESR1 cis-regulatory region in 7% of ESR1-positive breast cancers. They find that the activity of the recurrently mutated ESR1 enhancer is also influenced by breast cancer risk–associated SNPs.

Shankar Balasubramanian and colleagues examine endogenous DNA G-quadruplex (G4) structures in the context of chromatin by using G4 antibody-based ChIP–seq. They find that G4 structures are enriched in nucleosome-depleted regions and the promoters and 5′ UTRs of highly transcribed genes, suggesting a relationship between chromatin state, transcriptional output and G4 status.

Michael Speicher and colleagues analyze plasma DNA whole-genome sequencing data from healthy donors and patients with cancer to infer nucleosome positioning on the basis of read depth coverage patterns. They use this approach to accurately predict expression of cancer driver genes from circulating tumor DNA in regions with somatic copy number gains.

Jonathan Marchini, Gonçalo Abecasis, Richard Durbin and colleagues describe the construction of a reference panel of human haplotypes from whole-genome sequencing data. They are able to use this to accurately impute genotypes at low minor allele frequency and present remote server resources for use by the community.

Christian Fuchsberger, Gonçalo Abecasis and colleagues describe a new web-based imputation service that enables rapid imputation of large numbers of samples and allows convenient access to large reference panels of sequenced individuals. Their state space reduction provides a computationally efficient solution for genotype imputation with no loss in imputation accuracy.

Runjun Kumar, S. Joshua Swamidass and Ron Bose present an unsupervised parsimony-guided method, ParsSNP, for prioritizing candidate cancer driver mutations. They apply ParsSNP to a gastric cancer data set and predict potential driver mutations not detected by other methods, including truncations in known tumor-suppressor genes and previously confirmed drivers.