Cancer type‐dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types

Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co‐occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re‐wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another.     

Genetic mosaic analysis indicates that the bulb region of coat hair follicles contains a resident population of several active multipotent epithelial lineage progenitors.

The hair follicle represents an excellent model system for exploring the properties of lineage-forming units in a dynamic epithelium containing multiple cell types. During its growth (anagen) phase, the proximal-distal axis of the mouse coat hair (pelage) follicle provides a historical record of all epithelial lineages generated from its resident stem cell population. An unresolved question in the field is whether the bulb region of anagen pelage follicles contains multipotential progenitors and whether their individual contribution to cellular census fluctuates over time. To address this issue, chimeric follicles were harvested in midanagen from three types of genetic mosaic mouse models. Analysis of the distribution of genotypic markers, including digital three-dimensional reconstruction of serially sectioned chimeric follicles, revealed that on average the bulb contains four or fewer active progenitors, each capable of giving rise to all six follicular epithelial fates. Moreover, analysis of mosaic pelage, as well as cultured whisker follicles provided evidence that bulb-associated progenitors can give rise to expanding descendant clones during midanagen, leading to the conclusion that the bulb contains dormant or symmetrically dividing stem cells. This latter feature resembles the behavior of hematopoietic stem cells after bone marrow transplantation, and raises the question of whether this property may be shared by stem cells in other self-renewing epithelia.     

Characterization of Bovine Atrial Angiotensin-Converting Enzyme

Bovine atrial angiotensin-converting enzyme (ACE) was purified to electrophoretic homogeneity. The purification procedure included ion-exchange chromatography on DEAE-Toyopearl 650M, affinity chromatography on lisinopril-agarose and gel filtration on Sephadex G-100. The bovine atrial ACE exhibited similar sensitivities to inhibition by lisinopril and captopril as lung ACE (the K _i values for the atrial and lung enzymes differed insignificantly). However, the kinetic parameters of hydrolysis of some synthetic tripeptide substrates (FA-Phe-Gly-Gly, FA-Phe-Phe-Arg, Cbz-Phe-His-Leu, Hip-His-Leu) catalyzed by bovine atrial and lung ACE varied to a greater extent. The enzymes were also characterized by some differences in activation by chloride, nitrate, and sulfate anions. These data support the hypothesis of tissue specificity of ACEs.     

A statistical power analysis of the 'internal reference' technique for comparing growth and growth depensation of tilapia strains

Experiments were conducted to compare the growth and growth compensation of three strains of juvenile Oreochromis niloticus . Ten full sib families (10 replicates) per strain were split and grown under crowded and uncrowded conditions for 3 weeks (the treatment). Both treatments were then grown an additional 12 weeks under less crowded conditions (the compensation). Standard length measurements were made at the end of crowding and the end of compensation. Each replicate included a size-matched control population of a fourth (red) reference strain. ANCOVA with the reference strain used as a cofactor revealed significant strain effects on specific growth throughout the experiment. The reference strain removed most of the random among-replicate error variance as shown by an increase of r 2 from 0.06 to 0.91 when it was included in the statistical models. If the reference fish had not been used, approximately 450 replicate families would have been needed to achieve the sensitivity of the present experiment (a difference of 7% among strains significant at P =0.05). We conclude that the CLSU strain grows significantly more slowly than the Israel and NIFI strains under the experimental conditions, that the crowding effect was essentially eliminated after 12 weeks of compensation, and that the reference strain greatly improved the resolution of the strain-testing experiment.     

Penetrance rate estimation in autosomal dominant conditions

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.