Volume 47 Issue 5, May 2015

A new study identifies SPRY4 as a tumor suppressor in acute myeloid leukemia and shows that loss of SPRY4 acts as an alternative mechanism to drive RAS signaling. In addition, a paradigm of cooperativity in which combined loss of multiple negative regulators of the RAS pathway supplants the need for RAS mutations is suggested.

A hallmark of CpG islands is their unmethylated state, and determining how DNA methylation can invade these elements is therefore important for understanding developmental gene regulation and disease. A new study shows that FBXL10, a protein commonly altered by mutation in leukemia, is part of a mechanism that blocks methylation of CpG islands.

Kari Stefansson and colleagues report the whole-genome sequencing of 2,636 individuals from Iceland to a median of 20× coverage, providing a valuable genomic resource for this population isolate. They characterize patterns of genetic variation and population structure and demonstrate the usefulness of this resource for genetic discovery for several disease phenotypes.

Stacy Steinberg, Hreinn Stefansson, Thorlakur Jonsson and colleagues found that rare variants predicted to alter the function of ABCA7 are associated with risk of Alzheimer's disease. The association was found in Iceland and replicated in northern Europe and the United States.

Patrick Sulem, Hannes Helgason and colleagues identify homozygous and compound heterozygous loss-of-function variants of minor allele frequency <2% in 7.7% of the genotyped Icelandic population. Under transmission of some of these variants from heterozygous parents provides evidence that they are actually deleterious.

Agnar Helgason and colleagues report the point mutation rate for the male-specific euchromatic sequence of the Y chromosome based on 753 Icelandic males. They find that the non-recombining portions of the Y chromosome mutate at a faster rate than palindromic regions, suggesting that gene conversion acts to correct mutations in palindromic sequences.

Seishi Ogawa, Atsushi Natsume and colleagues report analyses of large sets of sequence data of grade II and III gliomas. They find three distinct subtypes of grade II and III gliomas characterized by discrete mutation profiles and distinct clinical behaviors.

Alexander Meissner and colleagues use CRISPR/Cas9 genome editing to inactivate the DNA methyltransferases DNMT1, DNMT3A and DNMT3B in human embryonic stem cells (ESCs). They find an essential role for DNMT1 in human ESCs and generate genome-wide maps of the DNA methylation changes that occur following inactivation of these enzymes.

Timothy Bestor and colleagues disrupt the Fbxl10 gene in mice, which leads to dense de novo DNA methylation of promoters that are co-occupied by both FBXL10 and by Polycomb repressive complexes. They conclude that FBXL10 protects Polycomb-bound genes from hypermethylation.

Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty transposon mutagenesis screen in mice carrying a melanocyte-specific inducible Braf^V600E allele. Analysis of transposon insertion sites identified candidate genetic drivers of melanoma.

Gabrielle Kardon and colleagues present a detailed study of diaphragm development in mice. They show that migration of connective tissue fibroblasts derived from the pleuroperitoneal folds controls diaphragm morphogenesis and that mosaic ablation of Gata4 in this cell population results in defects resembling human congenital diaphragmatic hernias.

Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tumors.

Christine Garcia and colleagues use exome sequencing to identify genetic risk factors for familial pulmonary fibrosis. They observe an excess of rare damaging variants in PARN and RTEL1 in probands with pulmonary fibrosis and show that these variants cosegregate with disease in the affected families.

Anders Molven and colleagues show that a recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. The hybrid allele is associated with approximately fivefold-higher risk of disease, and it encodes a protein with reduced lipolytic activity and prominent intracellular accumulation.

Sergey Nejentsev and colleagues identify intronic variants in ASAP1 that associate with susceptibility to tuberculosis. They show that ASAP1 is downregulated in dendritic cells infected with Mycobacterium tuberculosis, impairing their migration and matrix degradation abilities.

Joseph Gleeson and colleagues report that biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy marked by lysosome-autophagosome dysfunction. Their findings suggest a role for SNX14 in mediating lysosome-autophagosome fusion.

Jorge Di Paola, Christopher Porter, Walter Kahr and colleagues report germline mutations in the transcriptional repressor gene ETV6 in three families with thrombocytopenia and elevated red blood cell volume. All three mutations affect the ability of ETV6 to repress transcription of a reporter construct, and the two protein-altering mutations affect megakaryocyte development.

Scott Lowe and colleagues investigate regulation of Ras signaling during leukemogenesis and show that negative regulators Spry4 and Nf1 prevent transformation to aggressive acute myeloid leukemia in mice.

Hunter Fraser and colleagues generate atlases of imprinted gene expression across many mouse and human tissues. They find that imprinted genes are enriched for co-expression in pairs of maternally and paternally expressed genes, consistent with an evolutionary signature of parental conflict.

John Storey and colleagues report a statistical test for genetic association for use with data from structured populations. They demonstrate the use of this test on both simulated data and empirical data from the Northern Finland Birth Cohort, from which they identify significant loci not detected by other methods.

Xiaoming Liu and Yun-Xin Fu present a model-flexible method for inferring changes in population size over time on the basis of the composite likelihood of SNP frequencies. They apply the method to 1000 Genomes Project data to infer changes in human population size on the timescale of 10,000 to 200,000 years ago.

The largest-ever set of human genomes from a single population and the consequent insights into mutation, evolution, gene function and disease predisposition are reported in four linked papers. These results provide a strategy for the analysis of the full spectrum of genetic variation in any population and raise questions about how society should implement the knowledge gained. Produced with support from Illumina.