Genetic Admixture in the Culturally Unique Peranakan Chinese Population in Southeast Asia

10.1093/molbev/msab187Molecular Biology and Evolution38104463-447

Single-cell genomic profiling of acute myeloid leukemia for clinical use: A pilot study

10.3892/ol.2017.5669ONCOLOGY LETTERS1331625-163

Effects of extended pharmacological disruption of zebrafish embryonic heart biomechanical environment on cardiac function, morphology, and gene expression

10.1002/dvdy.378Developmental Dynamics250121759-177

Computationally defined and in vitro validated putative genomic safe harbour loci for transgene expression in human cells

Selection of the target site is an inherent question for any project aiming for directed transgene integration. Genomic safe harbour (GSH) loci have been proposed as safe sites in the human genome for transgene integration. Although several sites have been characterised for transgene integration in the literature, most of these do not meet criteria set out for a GSH and the limited set that do have not been characterised extensively. Here, we conducted a computational analysis using publicly available data to identify 25 unique putative GSH loci that reside in active chromosomal compartments. We validated stable transgene expression and minimal disruption of the native transcriptome in three GSH sites in vitro using human embryonic stem cells (hESCs) and their differentiated progeny. Furthermore, for easy targeted transgene expression, we have engineered constitutive landing pad expression constructs into the three validated GSH in hESCs

Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Background: In Western cohorts, the prevalence of incidental findings (IFs) or incidentalome, referring to variants in genes that are unrelated to the patient's primary condition, is between 0.86% and 8.8%. However, data on prevalence and type of IFs in Asian population is lacking. Methods: In 2 cohorts of individuals with genomic sequencing performed in Singapore (total n = 377), we extracted and annotated variants in the 56 ACMG-recommended genes and filtered these variants based on the level of pathogenicity. We then analyzed the precise distribution of IFs, class of genes, related medical conditions, and potential clinical impact. Results: We found a total of 41,607 variants in the 56 genes in our cohort of 377 individuals. After filtering for rare and coding variants, we identified 14 potential variants. After reviewing primary literature, only 4 out of the 14 variants were classified to be pathogenic, while an additional two variants were classified as likely pathogenic. Overall, the cumulative prevalence of IFs (pathogenic and likely pathogenic variants) in our cohort was 1.6%. Conclusion: The cumulative prevalence of IFs through genomic sequencing is low and the incidentalome may not be a significant barrier to implementation of genomics for personalized medicine

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Funder: DH | NIHR | Efficacy and Mechanism Evaluation Programme (NIHR Efficacy and Mechanism Evaluation Programme); doi: https://doi.org/10.13039/501100001922Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Royal Society-Newton Advanced Research Fellow (NA170257/FF-2018-033Funder: Japan Society for the Promotion of Science KAKENHI grants 17K08680Funder: DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme); doi: https://doi.org/10.13039/501100001923Funder: NIHR Translational ResearchFunder: Biomedical Research Council, SingaporeFunder: the European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 694913Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref no. 18K07414Funder: European Research Council under the European Union’s Horizon 2020 research and innovation program. Grant agreement No. 633983Funder: Japan Society for the Promotion of Science KAKENHI grants. Grant ref. 18K07049 and 15K15113 Ministry of Education, Culture, Sports, Science and Technology-Supported Program for the Strategic Research Foundation at Private Universities 2015-19Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production

Large-Scale Whole-Genome Sequencing of Three Diverse Asian Populations in Singapore

Because of Singapore's unique history of immigration, whole-genome sequence analysis of 4,810 Singaporeans provides a snapshot of the genetic diversity across East, Southeast, and South Asia.</p