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From the Human Genome Organization (HUGO) onward, there has been a desire to get together to talk about using our shared genomic heritage to improve human health and development. We now have all the organizations we need and should collaborate on multiple practical demonstrations of the usefulness of genomic knowledge—be it human, animal or plant—for human health.
Relapsed neuroblastoma is common, frequently lethal and poorly studied and poses a major treatment challenge. Two new studies shed light on the genomic landscape of recurrent neuroblastoma and demonstrate profound differences between the disease at diagnosis and relapse.
Copy number variation (CNV) at several genomic loci has been associated with different human traits and diseases, but in many cases the findings could not be replicated. A new study provides insights into the degree of variation present at the amylase locus and calls into question a previous association between amylase copy number and body mass index.
A major challenge in human genetics is pinpointing which non-coding genetic variants affect gene expression and disease risk. A new study in this issue describes a broadly applicable approach for this task that explicitly models cell type–specific regulatory motifs and generates variant effect predictions that are more accurate and interpretable than those of alternative tools.
Matthew Nelson and colleagues investigate how well genetic evidence for disease susceptibility predicts drug mechanisms. They find a correlation between gene products that are successful drug targets and genetic loci associated with the disease treated by the drug and predict that selecting genetically supported targets could increase the success rate of drugs in clinical development.
Hajime Okita and colleagues show that clear-cell sarcoma of the kidney (CCSK) is characterized by recurrent in-frame, internal tandem duplications in BCOR. They detected BCOR alterations in all 20 CCSK tumors analyzed but not in any other pediatric renal tumors, suggesting a specific role for these in-frame duplications in driving CCSK oncogenesis.
John Maris, Jan Molenaar, Gudrun Schleiermacher and colleagues performed whole-genome sequencing of 23 paired diagnostic and relapsed neuroblastomas, showing enrichment for mutations in the RAS-MAPK signaling pathway. These mutations render neuroblastoma cell lines susceptible to MEK inhibition.
Alexander Schramm, Johannes Schulte and colleagues characterize 16 paired samples from patients with neuroblastoma at diagnosis and relapse using whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis. Their data show the frequency, identity and evolution of genetic alterations in neuroblastoma.
Richard Gilbertson and colleagues report an in vivo screen of 84 candidate oncogenes and 39 candidate tumor-suppressor genes in ependymoma mouse models. The validated targets are involved in vesicle trafficking, DNA modification and cholesterol biosynthesis.
Simon Gayther and colleagues report 3 new risk variants for mucinous ovarian carcinoma (MOC) on the basis of an analysis of 1,644 MOC cases and 21,693 controls. They confirm an eQTL association between the HOXD9 promoter and risk SNPs at 2q31.1 using chromosome conformation capture analysis and show that HOXD9 overexpression associates with neoplastic transformation.
Soumya Raychaudhuri and colleagues present a detailed analysis of the association between the HLA region and type 1 diabetes risk. They find that variants at three amino acid positions in HLA-DQβ1 and HLA-DRβ1 account for a large fraction of the association signal, acting through a combination of additive and interaction effects.
Hannes Helgason, Kari Stefansson and colleagues report an association study of gastric cancer susceptibility based on whole-genome sequencing in the Icelandic population. They find that loss-of-function variants in ATM confer risk of gastric cancer.
Alison Klein and colleagues report a genome-wide meta-analysis to identify loci associated with pancreatic cancer risk. They identify associated variants at 17q25.1, 3q29, 7p13 and 2p13.3.
Regie Lyn Santos-Cortez and colleagues identify a duplication variant within A2ML1 that cosegregates with otitis media in an indigenous Filipino pedigree. They also identify seven additional A2ML1 variants in otitis-prone children.
Steven McCarroll, Joel Hirschhorn and colleagues identify eight common structural forms of the human amylase locus. They measured amylase gene copy number in ~3,500 individuals and detected no association with BMI and obesity.
Stephan Zuchner, Taosheng Huang and colleagues show that recessive mutations in SLC25A46 cause optic atrophy with additional neurological symptoms. They further show that SLC25A46 encodes a modified mitochondrial solute transporter linked to mitochondrial dynamics.
Pierre Coulombe and colleagues show that the autoimmune regulator Aire is induced in tumor keratinocytes in a keratin 17 (K17)-dependent manner and promotes skin tumorigenesis in mice. They further show that K17 and Aire colocalize in the nucleus and bind a subset of proinflammatory genes, providing a molecular explanation for the K17-dependent amplification of inflammatory responses in diseased epithelia.
Jianxin Ma and colleagues report the identification of a gene variant selected for during the domestication of soybean that causes permeable seed coats, in contrast to the hard seed coats of its wild ancestors. The identified gene, GmHs1-1, is predicted to encode a calcineurin-like metallophosphatase, although its cellular function remains unknown.
Jiayang Li, Xudong Zhu, Qian Qian and colleagues report cloning of the Grain Length on Chromosome 7 (GL7) locus in rice and identify a copy number variant that increases grain length and improves grain quality. They demonstrate how interactions with other grain length–related genes may be used to improve breeding.
Xiangdong Fu and colleagues show that variation in GW7 influences rice grain shape and yield. They further show that GW7 expression is directly regulated by OsSPL16, a transcription factor encoded by the grain-width locus GW8.
Michael Beer and colleagues report a metric based on a regulatory region annotation method, gkm-SVM, and use this to predict the effects of regulatory variants from sequencing and DNase I–hypersensitive site data. They apply their method to autoimmune disease GWAS data and report several new predictions for causal SNPs.
