The tree roots at an ancestral genome size of approximately 1x = 0.2 pg. Arabidopsis thaliana (1C = 0.16 pg; approximately 157 Mbp) has the smallest genome size in Brassicaceae studied here and apparently represents an evolutionary decrease in genome size. Two other branches that represent probable evolutionary decreases in genome size terminate in Lepidium virginicum and Brassica rapa. Branches in the phylogenetic tree that represent probable evolutionary increases in genome size terminate in Arabidopsis halleri, A. lyrata, Arabis hirsuta, Capsella rubella, Caulanthus heterophyllus, Crucihimalaya, Lepidium sativum, Sisymbrium and Thlaspi arvense. Branches within one clade containing Brassica were identified that represent two ancient ploidy events (2x to 4x and 4x to 6x) that were predicted from published comparative mapping studies.
SUMMARY Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the three year old proband with severe myoclonic epilepsy of infancy (SMEI). We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neuro-cardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Our findings demonstrate the importance of comprehensive high resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo SNPs and CNVs in the SCN1A and KCNA1 genes respectively is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.
Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development. Mutations in the filamin A gene are frequent in familial cases with X‐linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations. We evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes. Following SEEG explantation, we collected trace tissue adherent to the electrodes and extracted the DNA. Whole‐exome sequencing performed in a Clinical Laboratory Improvement Amendments–approved genetic diagnostic laboratory uncovered a de novo heterozygous pathogenic variant in novel candidate PNH gene MEN1 (multiple endocrine neoplasia type 1; c.1546dupC, p.R516PfsX15). The variant was absent in an earlier exome profiling of the venous blood–derived DNA. The MEN1 gene encodes the ubiquitously expressed, nuclear scaffold protein menin, a known tumor suppressor gene with an established role in the regulation of transcription, proliferation, differentiation, and genomic integrity. Our study contributes a novel candidate gene in PNH generation and a novel practical approach that integrates electrophysiological and genetic explorations of epilepsy.
Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of epilepsy-related mortality, and the analysis of mouse SUDEP models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signaling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of SUDEP. Most monogenic models of SUDEP invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioral seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human SUDEP and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in SUDEP cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying SUDEP risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of SUDEP risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.
Vα24-invariant natural killer T cells (NKTs) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L– cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, while Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression promoted NKT expansion and limited exhaustion following serial tumor challenge and was sufficient to induce a central memory–like transcriptional program in NKTs. In mice, NKTs expressing a GD2-specific chimeric-antigen receptor (CAR) with LEF1 demonstrated superior control of neuroblastoma xenograft tumors compared to control CAR-NKTs. These results identify LEF1 as a transcriptional activator of the NKT central memory program and advance development of NKT cell–based immunotherapy.
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