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Cancer genomes are now rapidly yielding to analysis, showing the heterogeneity of the mutational events and processes contributing to disease. This diversity is enormous and occurs at many levels. Consequently, the first clues from exome sequencing will increasingly need to be complemented by integrated analyses and extended to implicate mutations relevant to treatment outcomes.
A new study in mice shows that, during meiosis, the decision to mature a double-strand break into a crossover is controlled by a dosage-sensitive regulator, RNF212. This finding provides insight into the crossover maturation process and may help explain how sequence polymorphisms in RNF212 alter the frequency of crossing over in humans.
A recent study shows that the life history of chronic lymphocytic leukemia is characterized by a complex and dynamic architecture involving the development of subclones with changing dominance over time. This innovative study provides a framework to design anticipation-based chemotherapy approaches for cancer treatment.
Two new loci for premature fusion of the cranial sutures in humans suggest a common endpoint in osteoblast regulation, linking upregulation of phosphorylated ERK1/2 and TWIST1 haploinsufficiency.
Jake Gratten and colleagues discuss challenges in interpreting the role of de novo mutations in neuropsychiatric and other complex diseases. They argue that the burden of proof for causality for a single de novo mutation must be set high and that curation of de novo mutations and their associated phenotypes in databases will be critical for the robust interpretation of exome sequencing studies.
Tim Chan and colleagues report the identification of recurrent somatic mutations in FAT1 in glioblastoma, colon cancer and head and neck cancer and show that inactivation of FAT1 promotes Wnt signaling and tumorigenesis.
Heymut Omran, Mary Porter and colleagues identify the nexin link–dynein regulatory complex subunit DRC1 from Chlamydomonas and show that mutations in the human DRC1 homolog CCDC164 cause primary ciliary dyskinesia. Their analyses show that loss of DRC1 results in distinct axonemal defects and altered ciliary beat patterns.
Neil Hunter and colleagues show that RNF212 is essential for crossing-over during mammalian meiosis and functions to couple chromosome synapsis to the formation of crossover-specific recombination complexes. They further show that selective localization of RNF212 to a subset of recombination sites is a key step in the crossover designation process that serves to stabilize meiosis-specific recombination factors at these sites.
John Maris, Matthew Meyerson, Marco Marra and colleagues report results of a large-scale sequencing study of neuroblastoma. They observe a low median exonic mutation frequency and strikingly few recurrently mutated genes in these tumors, highlighting challenges for developing targeted therapeutic strategies based on frequently mutated oncogenic drivers.
Rameen Beroukhim, Ian Dunn, William Hahn and colleagues report genome and exome sequencing of meningiomas. They identified recurrent somatic mutations in AKT1 and SMO.
William Carroll and colleagues report the identification of mutations in NT5C2, encoding cytosolic 5′-nucleotidase II, which are specific for relapsed childhood acute lymphoblastic leukemia. The mutations confer increased enzymatic activity and resistance to treatment with nucleoside analog therapies in vitro.
William Newman, Gareth Evans and colleagues report that loss-of-function mutations in SMARCE1 cause an inherited disorder characterized by multiple spinal meningiomas. Tumors from individuals with SMARCE1 mutations showed loss of SMARCE1 protein, consistent with a tumor suppressor mechanism.
Anthony Bleyer, Eric Lander, Mark Daly and colleagues show that frameshift mutations in a large VNTR of MUC1 cause medullary cystic kidney disease type 1. Their discovery sheds light on the biology of this disease and highlights challenges in using massively parallel sequencing technologies to characterize certain types of sequence variants.
Andrew Wilkie and colleagues report that mutations in TCF12 cause coronal craniosynostosis. They found heterozygous mutations in 38 unrelated families.
George Mavrothalassitis, Andrew Wilkie and colleagues report the identification of mutations in ERF that cause a complex craniosynostosis disorder with multiple-suture synostosis, craniofacial dysmorphism, Chiari malformation and language delay. They also show that reduced dosage of Erf in mice causes craniosynostosis.
Caroline Klaver and colleagues report a meta-analysis for refractive error and myopia, including 37,382 individuals from 27 European studies and 8,376 individuals from 5 Asian studies, as part of the Consortium for Refractive Error and Myopia (CREAM).
Amr Sawalha and colleagues performed dense genotyping in the HLA locus followed by imputation to fine map genetic variants associated with Behçet's disease in this region. They report four independent genetic associations in the HLA region and localize the genetic association previously attributed to HLA-B*51 to a genetic variant between the HLA-B and MICA genes.
Julie Baker and colleagues report epigenome and transcriptome profiles of rat and mouse trophoblast stem cells and show that endogenous retroviruses serve as a genome-wide source of species-specific enhancer elements in the placenta.
Wenbo Ma and colleagues show that two effectors from the oomycete plant pathogen Phytophthora sojae suppress RNA silencing in plants by inhibiting the biogenesis of small RNAs. These findings show that some eukaryotic pathogens, like their prokaryotic and viral counterparts, have evolved virulence proteins that target host RNA silencing processes to promote infection.
Domesticated maize make 8–20 rows of kernels, whereas its ancestor teosinte makes 2 rows. David Jackson and colleagues report that variation at the FEA2 locus in maize influences kernel row number and kernels per ear, which are important crop yield traits.
