Genomic Mosaicism of the Brain: Origin, Impact, and Utility.

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype-motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism.

Individual variation of the percentage of Y-chromosome bearing sperm content in human ejaculates.

The study aimed to determine the variation of Y-chromosome-bearing sperm content among individual ejaculates. A real-time polymerase chain reaction (qPCR) with unique primers was developed and used to calculate the percentage of Y-chromosome-bearing sperm in individual ejaculates from 50 randomly selected men. There was a significant difference in the overall mean ± SD between the proportion of Y-chromosome-bearing sperm and X-chromosome-bearing sperm (45.36 ± 7.88 vs. 54.42 ± 7.88). Of the 50 ejaculates, 17 had more than, and 14 had less than the 99% confidence interval of the mean of the Y-chromosome-bearing sperm (45.58 ± 2.87). These results suggest that the inconsistency in sperm-based sex-selection outcomes appears to be a function of differences in the ejaculates and highlights the need for further study in environmental and genetic factors contributing to X or Y bearing spermatozoan instability.Abbreviations: qPCR: real-time polymerase chain reaction; ROS: reactive oxygen species; DTT: dithiothreitol; SRY: sex-determining region Y.

Estrogen Receptor Alpha Signaling Is Responsible for the Female Sex Bias in the Loss of Tolerance and Immune Cell Activation Induced by the Lupus Susceptibility Locus Sle1b.

The dramatic female sex bias observed in human lupus is thought to be due, at least in part, to estrogens. Using mouse models, we have shown that estrogens, acting through estrogen receptor alpha (ERα) promote lupus development and contribute significantly to the female sex bias observed in this disease. C57Bl/6 (B6) mice carrying the lupus susceptibility locus Sle1 locus exhibit immune cell hyperactivation and loss of tolerance, and the action of Sle1 displays a strong female sex bias. Previously, we showed that disruption of ERα completely eliminates the female sex bias in the effects of Sle1. Here we report that ERα signaling selectively modulates the action of Sle1b, one of the three subloci that together constitute Sle1. We observed that disruption of ERα signaling attenuated T cell hyperactivation, formation of spontaneous germinal centers, loss of tolerance, and the development of anti-chromatin autoantibodies in B6.Sle1b female mice, but had no impact on these phenotypes in B6.Sle1b male mice. In fact, disruption of ERα completely abolished the female sex bias that is seen in each of these phenotypes in B6.Sle1b mice. Strikingly, Sle1b-induced B cell hyperactivation, a female sex-specific manifestation of Sle1b, was completely abrogated by disruption of ERα in B6.Sle1b females. Altogether, these results demonstrate that ERα signaling is responsible for the female sex bias in the actions of Sle1b, and is absolutely required for the female-specific B cell hyperactivation phenotype associated with this lupus susceptibility locus. By contrast, we found that ERα signaling had no impact on Sle1a, the other Sle1 sublocus that exerts effects that show a female sex bias.

UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells.

Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including mutations in the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5, with the majority of mutations within the HECT domain of the protein that can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B-cell maturation and activation, we generated a conditional mutant disrupting UBR5's C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and upregulation of proteins associated with messenger RNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B-cell maturation by stabilization of spliceosome components during B-cell development and suggests UBR5 mutations play a role in MCL transformation.

T Cell Lymphoma and Leukemia in Severe Combined Immunodeficiency Pigs following Bone Marrow Transplantation: A Case Report.

After the discovery of naturally occurring severe combined immunodeficiency (SCID) within a selection line of pigs at Iowa State University, we found two causative mutations in the Artemis gene: haplotype 12 (ART12) and haplotype 16 (ART16). Bone marrow transplants (BMTs) were performed to create genetically SCID and phenotypically immunocompetent breeding animals to establish a SCID colony for further characterization and research utilization. Of nine original BMT transfer recipients, only four achieved successful engraftment. At approximately 11 months of age, both animals homozygous for the ART16 mutation were diagnosed with T cell lymphoma. One of these ART16/ART16 recipients was a male who received a transplant from a female sibling; the tumors in this recipient consist primarily of Y chromosome-positive cells. The other ART16/ART16 animal also presented with leukemia in addition to T cell lymphoma, while one of the ART12/ART16 compound heterozygote recipients presented with a nephroblastoma at a similar age. Human Artemis SCID patients have reported cases of lymphoma associated with a "leaky" Artemis phenotype. The naturally occurring Artemis SCID pig offers a large animal model more similar to human SCID patients and may offer a naturally occurring cancer model and provides a valuable platform for therapy development.