Distinct positions of genetic and oral histories: Perspectives from India.

Over the past decade, genomic data have contributed to several insights on global human population histories. These studies have been met both with interest and critically, particularly by populations with oral histories that are records of their past and often reference their origins. While several studies have reported concordance between oral and genetic histories, there is potential for tension that may stem from genetic histories being prioritized or used to confirm community-based knowledge and ethnography, especially if they differ. To investigate the interplay between oral and genetic histories, we focused on the southwestern region of India and analyzed whole-genome sequence data from 156 individuals identifying as Bunt, Kodava, Nair, and Kapla. We supplemented limited anthropological records on these populations with oral history accounts from community members and historical literature, focusing on references to non-local origins such as the ancient Scythians in the case of Bunt, Kodava, and Nair, members of Alexander the Great's army for the Kodava, and an African-related source for Kapla. We found these populations to be genetically most similar to other Indian populations, with the Kapla more similar to South Indian tribal populations that maximize a genetic ancestry related to Ancient Ancestral South Indians. We did not find evidence of additional genetic sources in the study populations than those known to have contributed to many other present-day South Asian populations. Our results demonstrate that oral and genetic histories may not always provide consistent accounts of population origins and motivate further community-engaged, multi-disciplinary investigations of non-local origin stories in these communities.

False Alarms in Consumer Genomics Add to Public Fear and Potential Health Care Burden.

We have entered an era of direct-to-consumer (DTC) genomics. Patients have relayed many success stories of DTC genomics about finding causal mutations of genetic diseases before showing any symptoms and taking precautions. However, consumers may also take unnecessary medical actions based on false alarms of "pathogenic alleles". The severity of this problem is not well known. Using publicly available data, we compared DTC microarray genotyping data with deep-sequencing data of 5 individuals and manually checked each inconsistently reported single nucleotide variants (SNVs). We estimated that, on average, a person would have ~5 "pathogenic" alleles reported due to wrongly reported genotypes if using a 23andMe genotyping microarray. We also found that the number of wrongly classified "pathogenic" alleles per person is at least as significant as those due to wrongly reported genotypes. We show that the scale of the false alarm problem could be large enough that the medical costs will become a burden to public health.

The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.

The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eµ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eµ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

Iron Hack - A symposium/hackathon focused on porphyrias, Friedreich's ataxia, and other rare iron-related diseases.

Background: Basic and clinical scientific research at the University of South Florida (USF) have intersected to support a multi-faceted approach around a common focus on rare iron-related diseases. We proposed a modified version of the National Center for Biotechnology Information's (NCBI) Hackathon-model to take full advantage of local expertise in building "Iron Hack", a rare disease-focused hackathon. As the collaborative, problem-solving nature of hackathons tends to attract participants of highly-diverse backgrounds, organizers facilitated a symposium on rare iron-related diseases, specifically porphyrias and Friedreich's ataxia, pitched at general audiences. Methods: The hackathon was structured to begin each day with presentations by expert clinicians, genetic counselors, researchers focused on molecular and cellular biology, public health/global health, genetics/genomics, computational biology, bioinformatics, biomolecular science, bioengineering, and computer science, as well as guest speakers from the American Porphyria Foundation (APF) and Friedreich's Ataxia Research Alliance (FARA) to inform participants as to the human impact of these diseases. Results: As a result of this hackathon, we developed resources that are relevant not only to these specific disease-models, but also to other rare diseases and general bioinformatics problems. Within two and a half days, "Iron Hack" participants successfully built collaborative projects to visualize data, build databases, improve rare disease diagnosis, and study rare-disease inheritance. Conclusions: The purpose of this manuscript is to demonstrate the utility of a hackathon model to generate prototypes of generalizable tools for a given disease and train clinicians and data scientists to interact more effectively.

Silencing of HDAC6 as a therapeutic target in chronic lymphocytic leukemia.

Although the treatment paradigm for chronic lymphocytic leukemia (CLL) is rapidly changing, the disease remains incurable, except with allogeneic bone marrow transplantation, and resistance, relapsed disease, and partial responses persist as significant challenges. Recent studies have uncovered roles for epigenetic modification in the regulation of mechanisms contributing to malignant progression of CLL B cells. However, the extent to which epigenetic modifiers can be targeted for therapeutic benefit in CLL patients remains poorly explored. We report for the first time that expression of epigenetic modifier histone deacetylase 6 (HDAC6) is upregulated in CLL patient samples, cell lines, and euTCL1 transgenic mouse models compared with HDAC6 in normal controls. Genetic silencing of HDAC6 conferred survival benefit in euTCL1 mice. Administration of isoform-specific HDAC6 inhibitor ACY738 in the euTCL1 aging and adoptive transfer models deterred proliferation of CLL B cells, delayed disease onset via disruption of B-cell receptor signaling, and sensitized CLL B cells to apoptosis. Furthermore, coadministration of ACY738 and ibrutinib displayed synergistic cell kill against CLL cell lines and improved overall survival compared with either single agent in vivo. These results demonstrate for the first time the therapeutic efficacy of selective HDAC6 inhibition in preclinical CLL models and suggest a rationale for the clinical development of HDAC6 inhibitors for CLL treatment, either alone or in combination with Bruton tyrosine kinase inhibition.

Born This Way: Using Intrinsic Disorder to Map the Connections between SLITRKs, TSHR, and Male Sexual Orientation.

Recently, genome-wide association study reveals a significant association between specific single nucleotide polymorphisms (SNPs) in men and their sexual orientation. These SNPs (rs9547443 and rs1035144) reside in the intergenic region between the SLITRK5 and SLITRK6 genes and in the intronic region of the TSHR gene and might affect functionality of SLITRK5, SLITRK6, and TSHR proteins that are engaged in tight control of key developmental processes, such as neurite outgrowth and modulation, cellular differentiation, and hormonal regulation. SLITRK5 and SLITRK6 are single-pass transmembrane proteins, whereas TSHR is a heptahelical G protein-coupled receptor (GPCR). Mutations in these proteins are associated with various diseases and are linked to phenotypes found at a higher rate in homosexual men. A bioinformatics analysis of SLITRK5, SLITRK6, and TSHR proteins is conducted to look at their structure, protein interaction networks, and propensity for intrinsic disorder. It is assumed that this information might improve understanding of the roles that SLITRK5, SLITRK6, and TSHR play within neuronal and thyroidal tissues and give insight into the phenotypes associated with male homosexuality.