Reviews & Analysis

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.

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.

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.

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.

Two studies in this issue identify the landscape of somatic mutations in Burkitt lymphoma and highlight the pathogenic and clinical relevance of inactivating mutations of ID3, an inhibitor of the TCF3 transcription factor.

A new study shows that loss of the lariat debranching enzyme Dbr1 suppresses TDP-43 toxicity. The accumulated intronic lariat RNAs, which are normally degraded after splicing, likely act as decoys to sequester TDP-43 away from binding to and disrupting functions of other RNAs.

Powerful genomic technologies, such as exome sequencing, are providing new insights into the genetics underlying Mendelian traits. A new study identifies a role for digenic inheritance and an epigenetic modifier in facioscapulohumeral muscular dystrophy type 2.

Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion.

Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1.

Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications.

A new exome sequencing study of individuals with hepatocellular carcinoma (HCC) reveals imprints of mutagenic exposure and identifies new genes contributing to tumorigenesis. This work joins several recent publications reporting whole-genome, exome and RNA sequencing in HCC, which together provide a comprehensive genomic landscape and new insights into the etiology of liver cancer.

Gene expression is under partial genetic regulation, which may vary between different cell types and tissues. A new study finds that there is substantial but incomplete overlap among regulatory variants located near the regulated genes in three human tissues.

Genomic characterization efforts in small-cell lung cancer have been complicated by the paucity of high-quality surgical resection specimens for this aggressive lung cancer subtype that is usually diagnosed at unresectable stages in small biopsies or cytology specimens. Now, two papers report genomic analyses of small-cell lung cancer, highlighting subsets of tumors driven by amplification of FGFR1, SOX2 or MYC family members or by a MYCL1 fusion oncogene, among many other recurrent alterations.

Plasmodium vivax has received less attention and study than Plasmodium falciparum, due in part to difficulties in culturing this pathogen. Whole-genome sequencing of both P. vivax and Plasmodium cynomolgi and characterization of genetic variation in these species provide a genetic toolbox for tertian malaria and new insights into the monkey malaria clade.

Shigella sonnei is an important cause of bacterial dysentery in the developed world and has also recently emerged in transitional countries. Phylogenetic analysis based on whole-genome sequencing of a global sample has detailed the recent evolutionary history of this pathogen and shed light on the genetic changes associated with this epidemiological shift.

The cloning of Dolly the sheep was a remarkable demonstration of the oocyte's ability to reprogram a specialized nucleus. However, embryos derived from such somatic cell nuclear transfer (SCNT) very rarely result in live births—a fate that may be linked to observed epigenetic defects. A new genome-wide study shows that epigenetic reprogramming in SCNT embryos does not fully recapitulate the natural DNA demethylation events occurring at fertilization, resulting in aberrant methylation at some promoters and repetitive elements that may contribute to developmental failure.

A combination of in vitro and in vivo models with validation in human tumors has identified AXL activation as a new mechanism of acquired resistance to EGFR inhibitors in non–small cell lung cancer. The identification of this mechanism, alongside the current development of specific AXL inhibitors, provides the rationale for further studies that may improve treatment for EGFR inhibitor–resistant patients.

Two new studies show that haploinsufficiency for TGFB2 causes a familial syndrome of thoracic aortic aneurysms and dissections with other clinical features that overlap the Marfan, Loeys-Dietz spectrum of syndromes. Their finding of loss-of-function mutations in yet another transforming growth factor (TGF)-β pathway gene reinforces the seeming paradox of observed increases in the downstream TGF-β signaling pathway.

Two new studies report mutations in FAN1 and three other genome-stability genes that tie the DNA damage response to progressive kidney failure and the dysfunction of several other organs. These findings provide clues to the underlying causes of tissue decline and may add a series of genes to the growing list of genome maintenance factors that protect against premature aging.