Volume 43 Issue 3, March 2011

Expression of oncogenes in otherwise normal cells often leads to the activation of anti-oncogenic pathways through a poorly understood process described as 'oncogenic stress'. A new study implicates the Jnk pathway signaling in the activation of p53 in response to both K-Ras and Neu oncogene expression.

A new study uses genome-wide SNP genotypes to identify a subset of children undergoing therapy for acute lymphoblastic leukemia that are at increased risk for relapse. Borrowing from the classical approach of admixture mapping, the work shows how genome-wide assessment of genetic ancestry can be used as a biomarker for disease outcome.

Follow-up studies of a Crohn's disease risk locus encompassing IRGM have revealed unexpected complexity. A new study shows that a synonymous variant in the IRGM coding region alters a binding site for miR-196 and modulates IRGM-dependent autophagy, adding to the list of possible mechanisms by which this locus influences disease risk.

Rulla Tamimi and colleagues report a meta-analysis of five genome-wide association studies for percent mammographic density. They identify an associated locus at ZNF365, which has also been associated with susceptibility to breast cancer.

Nicholas Katsanis and colleagues show that biallelic mutations in TTC21B, encoding the retrograde intraflagellar transport protein IFT139, are associated with diverse ciliopathy phenotypes in humans. They further show that pathogenic alleles of TTC21B are present in as many as 5% of ciliopathy cases, supporting an oligogenic model of disease.

Phil Beales and colleagues show that mutations in the lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome, a disorder that includes craniofacial defects, learning disability and other developmental phenotypes. They also present evidence that the COLEC11 gene product serves as a guidance cue for neural crest cell migration.

Antonio Giraldez and colleagues report that miRNA-mediated regulation of the sdf1 chemokine signaling pathway in zebrafish provides genetic robustness to germ cell migration.

Josef Penninger and colleagues show that deletion of the stress kinase MKK7 in mouse models of lung and mammary tumors accelerates tumor onset and reduces overall survival. The study suggests that MKK7 is a sensor of oncogenic stress.

Geneviève Almouzni and colleagues report that SUMOylation promotes de novo targeting of HP1α to pericentric heterochromatin in mouse. They identify long nuclear non-coding transcripts at major satellite repeats and show that they specifically associate with SUMO-modified HP1 proteins.

Richard Wilson and colleagues report the genome sequence of Trichinella spiralis, a food-borne parasitic nematode that diverged early in the evolution of the phylum Nematoda. T. spiralis is the most common cause of human trichinellosis.

Mary Relling and colleagues explore the effects of ancestry on the pharmacogenomics of relapse in acute lymphoblastic leukemia. They found that Native American ancestry was associated with risk of relapse but that differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy.

Paul Hofman and colleagues show that a synonymous variant in IRGM, previously associated with risk of Crohn's disease, alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy. These findings implicate this synonymous polymorphism as a likely causal variant underlying the association of IRGM with Crohn's disease.

John Rioux and colleagues report results of a large genome-wide association meta-analysis and follow-up study of ulcerative colitis. They identify 29 new risk loci for this inflammatory disease and show that many risk loci are shared between ulcerative colitis and Crohn's disease.

Patrick Gaffney and colleagues perform a fine-mapping study of the TNFAIP3 region in systemic lupus erythematosus using individuals from diverse ancestral populations. They identify a putative causal variant in a region of high conservation and regulatory potential that is associated with reduced TNFAIP3 expression.

Massimo Zeviani and colleagues report mutations in TTC19 cause mitochondrial defects and progressive encephalopathy in humans. Adult flies lacking TTC19 function also display signs of neurological impairment.

John Stamatoyannopoulos, Gordon Hager and colleagues report that up to 95% of induced de novo genomic binding by the glucocorticoid receptor is targeted to pre-existing foci of accessible chromatin.

Steven McCarroll and colleagues report an analytical framework for characterizing genome deletion polymorphism in populations, applied here to the low coverage genome sequences of 168 individuals from the 1000 Genomes Project. Their population-aware analysis enables structural inference with greater accuracy than previous methods.