Volume 45 Issue 1, January 2013

A major challenge for genomics is to provide clinical benefits to the genetically diverse human population. Genome science has achieved a catalog of mutations and informative SNPs. Next-generation sequencing is rapidly delivering thousands of complete human genomes, but understanding and applying genomic knowledge remains a daunting undertaking. These challenges and opportunities for genomic medicine were central themes of the Golden Helix Symposium held in Turin, Italy, 18–21 April 2012.

A new study reports whole-genome sequencing of a large collection of healthcare-associated C. difficile isolates, followed by comparative genomics and phylogenetic analyses. This work provides insight into the emergence of the current C. difficile epidemic 027/BI/NAP1 clone, which can be separated into two lineages on the basis of both SNPs and larger genetic changes mediated by mobile elements.

Cancer stem cells are thought to share many characteristics with their normal stem cell counterparts, raising concerns about the ability to selectively target them. A new study shows that Dclk1 marks cancer, but not normal, stem cells in the intestine and that targeting this population results in adenoma collapse without affecting normal tissue.

Two new studies explore the origin of domesticated fruit species through whole-genome sequencing of modern representatives and comparative analysis of closely related subspecies. Analysis of the watermelon and sweet orange genomes detects the absence of recent duplication events and leads to insights into traits related to their domestication.

Victor Velculescu, Michael Hogarty and colleagues report whole-genome and exome sequences of neuroblastoma, the most common solid tumor in children. They identify recurrent somatic mutations in the chromatin-remodeling genes ARID1A and ARID1B.

Carlo Gambacorti-Passerini and colleagues identify recurrent SETBP1 mutations in atypical chronic myeloid leukemia. The mutations, which cluster in a small region of SETBP1, are associated with high white blood cell counts and poor prognosis.

Panos Deloukas, Nilesh Samani and colleagues report a large-scale association analysis using the Metabochip array in 63,746 coronary artery disease cases and 130,681 controls. They identify 15 susceptibility loci, refine previous associations and use network analysis to highlight biological pathways.

Duanqing Pei and colleagues show that BMP signaling to histone H3 lysine 9 methylation is a barrier to reprogramming somatic cells into induced pluripotent cells (iPSCs) and that its removal promotes the formation of fully reprogrammed iPSCs from pre-iPSCs. pre-iPSCs exhibit pluripotent properties but do not activate the core pluripotent network.

Maize oil is an important food and energy source. Now, Jianbing Yan and colleagues report a genome-wide association study in maize for maize kernel oil composition. They analyzed 368 maize lines with 1.06 million SNPs genome-wide and found 74 loci associated with maize kernel oil concentration and fatty acid composition.

Zhangjun Fei and colleagues report the draft genome of a Chinese elite watermelon inbred line 97103 and resequencing of 20 diverse accessions that represent the three subspecies of Citrullus lunatus. Comparative genome-wide analyses identify the extent of genetic diversity and population structure of watermelon germplasm.

Yijun Ruan and colleagues report the draft genome of the sweet orange, Citrus sinensis. Their data suggests sweet orange originated from a cross between pummelo and mandarin.

Fuwen Wei, Jun Wang and colleagues report whole-genome sequencing of 34 wild giant pandas. Their population genetic analysis provides insights into demographic history and local adaptation.

Long Yu and colleagues report a genome-wide association study for hepatitis B virus–related hepatocellular carcinoma (HBV-HCC). They report that genetic variants in STAT4 and HLA-DQ genes confer risk of HBV-HCC.

Rachel Freathy and colleagues report results of a large-scale genome-wide association study of birth weight. They identify four loci newly associated with this trait and find overlap between birth weight–associated loci and those influencing adult height and metabolism.

Heinz Jungbluth and colleagues report the identification of mutations in EPG5 that cause Vici syndrome, characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. EPG5 encodes a regulator of autophagy, and the identified mutations cause defective autophagosomal function.

Laurie Ozelius and colleagues identify mutations in GNAL in families with primary torsion dystonia, a movement disorder characterized by repetitive twisting muscle contractions and postures. GNAL encodes Gα_olf, a stimulatory G protein α subunit.

Rajesh Thakker and colleagues show that missense mutations affecting codon 15 of AP2S1 cause familial hypocalciuric hypercalcemia type 3, a disorder of calcium homeostasis. AP2S1 encodes a protein involved in clathrin-mediated endocytosis, and the mutations probably cause disease by disrupting internalization of the calcium-sensing receptor CaSR.

Hiroshi Seno and colleagues report that Dclk1 selectively marks intestinal tumor stem cells. They further show that specific ablation of these cells in a mouse tumor model results in a pronounced regression of polyps without apparent damage to normal intestinal tissue.

David Sabatini and colleagues report an insertional mutagenesis screen in haploid cells for resistance to the cancer drug candidate 3-bromopyruvate (3-BrPA). They find that SLC16A1, the gene that encodes MCT1, is frequently inactivated. MCT1 expression is required and sufficient for 3-BrPA uptake by cancer cells and may be used to predict cancers that are sensitive to 3-BrPA.

Trevor Lawley and colleagues report whole-genome sequencing of a large global collection of Clostridium difficile, the most common cause of healthcare-associated infection in the developed world. Their phylogenetic analysis traces the spread of this pathogen through healthcare-associated epidemics worldwide.