Volume 47 Issue 3, March 2015

Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target.

Tumors from pediatric patients generally contain relatively few somatic mutations. A new study reports a striking exception in individuals in whom biallelic germline deficiency for mismatch repair is compounded by somatic loss of function in DNA proofreading polymerases, resulting in 'ultra-hypermutated' malignant brain tumors.

Heterogeneity is the single most important factor driving cancer progression and treatment failure, yet little is understood about how and when this heterogeneity arises. A new study shows that colorectal cancers acquire their dominant mutations early in development and that subsequent mutations, even if they confer greater fitness, are unlikely to sweep through the tumor.

Arul Chinnaiyan and colleagues report the curation of 7,256 RNA sequencing libraries from tumors, normal tissues and cell lines. They find 58,648 lncRNAs, of which 79% are previously unnannotated.

Christina Curtis, Darryl Shibata and colleagues report genomic profiling of 349 individual glands sampled from 15 human colorectal tumors. They observe high within-tumor heterogeneity and mixing of subclones in distant tumor regions, supporting a model whereby tumor growth occurs predominantly as a single expansion, with most detectable subclonal mutations arising during the earliest phases of tumor growth.

Lusheng Huang, Jun Ren and colleagues report the genome sequences of 69 pigs, representing 11 geographically distinct breeds and 3 wild boar populations, from within China. They identify loci related to high- and low-latitude adaptation and infer a likely ancient introgression event in northern Chinese pigs.

Dominic Kwiatkowski and colleagues report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin. They identify markers of a genetic background on which kelch13 mutations conferring artemisinin resistance are likely to emerge.

Daniel Jeffares, Jürg Bähler and colleagues report the genome sequences of 161 natural isolates of Schizosaccharomyces pombe, finding moderate genetic diversity and weak global population structure. They also report genome-wide association studies for 223 quantitative traits.

Thierry Wirth, Philip Supply, Stefan Niemann and colleagues analyze 4,987 Mycobacterium tuberculosis strains of the Beijing lineage isolated from 99 countries. They report whole-genome sequencing of 110 representative strains, characterize global population structure and reconstruct the evolutionary history of this lineage.

Trever Bivona and colleagues show that the Hippo pathway effector YAP promotes resistance to RAF and MEK inhibitor therapy in multiple types of BRAF-mutant tumors. The findings suggest that combined suppression of YAP and RAF-MEK signaling might enhance treatment response and prevent drug resistance.

Adam Shlien, Peter Campbell, Uri Tabori and colleagues report genome and exome sequencing of biallelic mismatch repair deficiency cancer samples from 12 children, including 10 high-grade gliomas. The hypermutational signature of the malignant glioma samples was consistent with a driver role for observed mutations in DNA polymerases ɛ or δ.

Jun Yang, Clinton Stewart and colleagues report the results of a genome-wide association study of cisplatin-induced ototoxicity among children undergoing treatment for brain tumors. They identify common variants in ACYP2 strongly associated with cisplatin-induced hearing loss and ototoxicity severity.

Furen Zhang and colleagues report the results of a three-stage genome-wide association study of leprosy in the Chinese population. They discover six new susceptibility loci and observe substantial overlap with loci previously implicated in autoimmune and inflammatory diseases.

Andrew Foote and colleagues report the whole-genome sequences and de novo assemblies of three marine mammal species—the walrus, killer whale and manatee—and an improved bottlenose dolphin genome. Their comparative genomic analysis finds evidence of parallel evolution across the marine mammal genomes.

Adam Siepel and colleagues develop a statistical method, fitCons, which combines comparative and functional genomic data to estimate the probability that a point mutation will influence fitness. They generate fitCons scores for three human cell types from ENCODE data sets and demonstrate improved prediction power for cis regulatory elements in comparison to conventional conservation-based scores.

Alkes Price, Po-Ru Loh and colleagues report the BOLT-LMM method for mixed-model association. They apply their method to 9 quantitative traits in 23,294 samples and demonstrate that it provides improvements in computational efficiency as well as gains in power that increase with the size of the cohort, making it useful for the analysis of large cohorts.

Benjamin Neale and colleagues report the LD Score regression method, used to distinguish the relative contributions of confounding bias and polygenicity to inflated test statistics in GWAS. They apply their method to summary statistics from GWAS for over 30 phenotypes, confirm that polygenicity accounts for the majority of inflation in test statistics and demonstrate use of this method as a correction factor.

Steven McCarroll and colleagues report an analysis of multiallelic copy number variants (mCNVs). They characterize mCNVs in 849 whole-genome sequences from the 1000 Genomes Project and find that mCNVs give rise to most gene dosage variation in humans.