Volume 40 Issue 7, July 2008

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.

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.

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.

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.

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.

Lars Bertram and colleagues report the creation of an online database, SzGene, containing all published genetic association studies for schizophrenia. A series of meta-analyses reveals 24 variants in 16 genes to be associated with the disease with nominal significance, and four of these have strong epidemiological support.

Sulem et al. report two previously unknown loci associated with variation in pigmentation in Northern Europeans. In two separate studies, Brown et al. and Gudbjartsson et al. report that some variants affecting human pigmentation, including variants on 20q11.22 near ASIP, also confer risk of cutaneous melanoma and basal cell carcinoma.

Brown et al. report results of a genome-wide association study for melanoma. Their screen, which used a pooling strategy, identified common variants on 20q11.22 associated with melanoma susceptibility. In two separate studies, Sulem et al. and Gudbjartsson et al. report that the same region on 20q11.22, near ASIP, influences pigmentation and confers risk of cutaneous melanoma and basal cell carcinoma.

Tushar Bhangale, Mark Reider, and Deborah Nickerson report estimates of coverage and power by commercial genotyping arrays using a variation dataset for 76 genes resequenced as part of the SeattleSNPs program.

Jiri Bartek and colleagues find that a common variant reducing NAD(P)H:quinone oxidoreductase 1 activity is a potential predictor of response to epirubicin chemotherapy in women with breast cancer. Cell-based assays suggest three modes of action for the enzyme via the p53 and TNF–NF-κB pathways and by direct detoxification of reactive oxygen species.

Eric Schadt and colleagues report the construction of yeast regulatory networks from multiple sources of large-scale functional genomic data, and show that a network constructed from the integration of genotypic, transcription factor binding site, and protein–protein interaction data is the most predictive.

Edward Morrisey and colleagues show that mice lacking the transcription factor Gata6 in the lung epithelium have an increased number of bronchioalveolar stem cells during development and in the context of lung regeneration. Additional evidence suggests that a Gata6-Wnt pathway regulates the balance of stem cell expansion and epithelial differentiation in the lung.

Using Xenopus epidermis as a model, John Wallingford and colleagues show that the planar cell polarity protein Dishevelled, acting in concert with Inturned and Rho, controls the apical positioning of basal bodies. Subsequently, Dvl and Rho are also required for directional ciliary beating, suggesting that a common signaling apparatus governs both apical docking and planar polarization of basal bodies.

Maria Karayiorgou and colleagues report that de novo mutations in DNA copy number are strongly associated with nonfamilial cases of schizophrenia. The authors observed no such enrichment among familial cases, suggesting that this type of mutation contributes primarily to sporadic forms of the disease.

Gudbjartsson et al. report that variants near two genes, ASIP and TYR, are associated with risk of cutaneous melanoma and basal cell carcinoma. These loci are among several loci initially discovered for their role in human pigmentation, as reported by Sulem et al. In a separate study, Brown et al. independently discover an association between variants near ASIP and melanoma risk.

Bernhard Weber and colleagues identify a previously unknown insertion-deletion polymorphism in ARMS2 (LOC387715), a gene associated with age-related macular degeneration. The variant leads to rapid mRNA turnover of the ARMS2 transcript, suggesting a role for this gene in AMD.

Keji Zhao and colleagues report genome-wide maps of 18 histone lysine acetylations in human CD4⁺ T cells as detected by ChIP-sequencing. Analysis of the data along with genome-wide maps of histone lysine methylations revealed a common module of 17 modifications associated with 25% of genes.

Ben Tycko and colleagues report the identification of genotype-dependent allele-specific methylation at many loci through the use of genomic methylation-sensitive SNP array analysis. Using independent assays, they confirm allele-specific methylation at 16 SNP-tagged loci on various chromosomes.

Evan Eichler and colleagues assess copy number variation of the C57BL/6J duplicated regions in 15 mouse strains used for genetic association studies. They report that mice show comparable copy number polymorphism when compared to humans, but that it is more locally restricted, specifically to regions containing gene families associated with spermatogenesis, pregnancy, viviparity, pheromone signaling and the immune response.

Eugenio Sangiorgi and Mario Capecchi use lineage tracing in mice to identify Bmi1 as a specific marker of a stem cell population located at the +4 position of the small intestinal crypt. Their findings address a long-standing debate in the field and support the existence of two distinct intestinal stem cell populations near the crypt base.

George Daley and colleagues show that ectopic Ras activation diverts embryonic stem cells towards trophoblastic fates, and conversely, that inhibition of MAPK signaling reduces trophectoderm outgrowth from embryo explants. These results implicate Ras-MAPK signaling in this early and critical cell fate decision.