Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-kB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-kB signalling, and we observed mutual exclusivity among tumours with somatic NF-kB pathway aberrations and LMP1-overexpression, suggesting that NF-kB activation is selected for by both somatic and viral events during NPC pathogenesis.

Although massively parallel sequencing approaches have been widely used to study genomic variation, simple alignment of short reads to a reference genome cannot be used to investigate the full range of structural variation and phased diploid architecture, which are important for precision medicine. By contrast, the single-molecule real-time (SMRT) sequencing platform produces long reads that can resolve repetitive structures effectively. We integrated this technology with several other sequencing approaches to construct a high-quality

The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world's population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the GenomeAsia 100K Project. This includes a whole-genome sequencing reference dataset from 1,739 individuals of 219 population groups and 64 countries across Asia. We catalogue genetic variation, population structure, disease associations and founder effects. We also explore the use of this dataset in imputation, to facilitate genetic studies in populations across Asia and worldwide.

Imprinting control regions (ICRs) are known to repress genes by utilizing one of two mechanisms, CTCF‐mediated insulation or the transcription of non‐coding RNAs (ncRNAs). The KvDMR1 ICR contains both the promoter for the Kcnq1ot1 ncRNA and two CTCF‐binding sites located within sequences exhibiting repressive activity in enhancer‐blocking assays. Deletion of KvDMR1 results in ubiquitous biallelic expression of eight maternal‐specific genes in distal chromosome 7. Here we report that while truncation of the Kcnq1ot1 transcript results in the loss of imprinted expression of these genes in the placenta, it does not affect imprinted expression of Cdkn1c in a subset of embryonic tissues despite universal loss of paternal‐specific methylation at Cdkn1c. Consistent with tissue‐specific loss of imprinted expression, growth deficiency of these mutant mice was less severe than that observed previously in mice with deletion of KvDMR1. This study demonstrates that the KvDMR1 locus can silence Cdkn1c by a mechanism independent of Kcnq1ot1 transcription, perhaps by CTCF‐associated repression, making it the first example of an ICR capable of silencing the same gene by two distinct mechanisms.