Reviews & Analysis

Pigmentation traits are known risk factors for skin cancer. Now, three new studies provide insights into the genetic factors underlying these effects, and the results reveal a surprisingly complex picture of the relationship between pigmentation traits and disease risk.

An earlier report of high-frequency ESR1 amplification in breast cancer is now challenged by correspondence from four groups. This discussion of whether or not there is something 'FISHy' about ESR1 amplification highlights the difficulty of validating such observations, leaving the frequency and clinical significance of ESR1 amplification in breast cancer an open question.

Genetic studies of age-related macular degeneration (AMD), the most prevalent blinding condition among the elderly, have had both great success and deep controversy. A new study now begins to resolve contradictory views over two candidate genes at a major AMD locus on chromosome 10q26 by suggesting a functional variant in one of these genes.

The tremendous regenerative power of the intestinal epithelium has attracted considerable attention to the crypt as a model for adult stem cell biology. A new study now identifies the Polycomb group protein Bmi1 as a specific marker of intestinal stem cells in vivo.

Wnt ligands are secreted glycoproteins with critical roles in organogenesis, cancer initiation and progression, and maintenance of stem cell pluripotency. A new study strengthens considerably our understanding of the role of Wnt signaling in progenitor cells of the lung epithelium during development and injury.

Genome-wide association studies in Crohn's disease have convincingly identified multiple risk variants. Two new studies in ulcerative colitis, a related inflammatory bowel disease, now reveal a glimpse of the overlapping spectrum of risk variants, highlighting both the commonalities and the unique features of these disorders.

A new paper reports an individual with the major features of Prader-Willi syndrome (PWS) and a microdeletion in 15q11–q13 removing a cluster of small nucleolar RNAs (snoRNAs). This report provides virtually conclusive evidence that PWS is caused by loss of expression of the C/D box HBII-85 snoRNAs.

Gene fusions arising from translocations make an important contribution to the development of cancer. A new study uses high-throughput sequencing to characterize such fusions at an unprecedented level of resolution.

Digital clubbing has been recognized since the time of the ancient Greeks as a sign of systemic disease. Now, a new study identifies a role for prostaglandin E2 in the pathogenesis of digital clubbing observed in familial hypertrophic osteoarthropathy.

The X chromosome has been thought to be mostly silent after meiosis in males. A new study reports that this is not the case for a set of multicopy genes often arranged in giant palindromes and highly expressed in spermatids.

Principal component analysis (PCA) has been a useful tool for analysis of genetic data, particularly in studies of human migration. A new study finds evidence that the observed geographic gradients, traditionally thought to represent major historical migrations, may in fact have other interpretations.

Genome-wide association studies have identified many variants affecting susceptibility to disease. Now, three studies use this approach to study adult height variation in a combined sample size of ∼63,000 individuals and report a total of 54 validated variants influencing this trait.

Recessive loss-of-function mutations in genes involved in renal NaCl handling cause rare diseases characterized by salt wasting and reduced blood pressure of variable severity. A new study shows that the carrier state for rare inactivating mutations in three genes involved in NaCl transport in the kidney is associated with a significant blood pressure reduction and a reduced risk of hypertension in the general population.

Gene expression can be an indicator of cellular state, and studies characterizing variation in gene expression have been useful on the cellular level. Two new studies now provide the first direct demonstration of the successful use of the multidimensionality of gene expression to dissect the genetic architecture of complex diseases.

The progression of carcinomas to high-grade malignancies is accompanied by profound histological changes in the tumor-associated stroma. Although previous studies have suggested that mesenchymal cells of the stroma undergo genetic alterations during this progression, a new study now provides evidence that strongly contradicts this theory of stromal cell coevolution.

When cytochrome c is released from mitochondria, it interacts with Apaf-1 to activate death-promoting caspases. Now, a gain-of-function mutation affecting cytochrome c with enhanced caspase-stimulatory activity is shown to have no other consequences for human health than a subclinical thrombocytopenia, showing that, in most settings, enhanced cytochrome c activity per se is not sufficient to disturb normal tissue homeostasis.