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Biology subjects

Gilbertson, R.

Publications and source records attributed to Gilbertson, R..

3 recordsLinked to original sources

Genomics reveals population structure despite high connectivity of common sole, Solea solea, and European plaice, Pleuronectes platessa, in the Celtic Sea and western English Channel.

Despite being two of the most commercially important flatfish (order Pleuronectiformes) in Europe, little is known of the population structure of common sole Solea solea and European plaice Pleuronectes platessa. To address this gap, we generated full-genome resequencing data for 244 sole and 189 plaice in the Celtic Sea and western English Channel region to analyse both neutral and adaptive loci and quantify population processes, such as reproductive isolation or adaptive differentiation in each species. For sole, there was no evidence of reproductive isolation or population structure at neutral loci. There was, however, adaptive differentiation as adaptive loci indicated two subpopulations, with separation in the western English Channel. This is consistent with previous studies using RAD-seq and gene-linked SNPs. For plaice, there was no evidence of population structure at either neutral or adaptive loci in the Celtic Seas and Western English Channel region. However, when considering a larger geographical area and utilising previously published genomic data, three distinct populations of plaice were identified (Iceland; North Sea, Kattegat and Western Baltic; Celtic Sea and western English Channel), with clear reproductive isolation indicated by neutral loci and adaptive differentiation indicated by adaptive loci. Moreover, three large chromosomal inversions were identified, which differed in their frequency between regions. These large structural variants represent putative key regions for adaptive differentiation. This study shows the benefit from quantifying neutral and adaptive loci to better understand population structure and genetic diversity of commercially important fish.

evolutionary biology↗

Single-cell Atlas of Human Fetal Cerebellum Decoding Medulloblastoma Origin and Oncogenesis

Medulloblastoma (MB) is the most common malignant childhood brain tumor1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3,4 or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

cancer biology↗

KCNQ gene family members act as both tumor suppressors and oncogenes in gastrointestinal cancers

Voltage sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large scale analysis of 1594 patients with GI cancers coupled with in vitro models we find KCNQ family genes are mutated in ~30% of patients, and play therapeutically targetable roles in GI cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation, and its resultant effects on cadherins junctions. This also highlights novel roles for KCNQ3 in non-excitable tissues. We additionally discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors, and that inhibition of KCNQ activity reduces proliferation of GI cancer. These findings reveal a novel and exploitable role for potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GI cancers may exist through KCNQ inhibitors. SIGNIFICANCEKCNQ channels modulate the WNT pathway and MYC signalling, and drive growth of gastrointestinal cancers. Available drugs modulate these pathways and offer therapeutic potential in gastrointestinal cancer.

cancer biology↗