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PNAS Papers on Earth BioGenome Project, SETX Knockouts, Pig Model of Cystic Fibrosis

Editor's Note: Some of the articles described below are not yet available at the PNAS site but are scheduled to be posted this week.

A series of papers slated to appear in PNAS this week spell out the rationale for, and progress of, the Earth BioGenome Project — a decade-long eukaryotic species sequencing project that kicked off in 2018. The collection includes an introductory perspectives piece that touches on COVID-19 pandemic impacts on the EGP effort, for example, while other articles discuss specific EBP projects and the development of recommended standards for sample collection, sequencing, and more. "Every eukaryotic species is the product of millions of years of evolution," the EGP team writes. "Recorded in their genomes are secrets that can fundamentally change our understanding of the evolution of life on Earth — and its very existence and essence — and may lead to radical new approaches for mitigating the effects of climate change on biodiversity, improving agriculture, growing a sustainable global bioeconomy, saving species, and repairing ecosystems, and preventing future pandemics."

A team from the UK and Australia presents findings from a genomic and transcriptomic analysis of cells from human patients and mice missing the senataxin-coding SETX gene, which has been implicated in a progressive neurodegenerative disease called "ataxia with oculomotor apraxia 2" (AOA2) and amyotrophic lateral sclerosis 4. Using RNA sequencing, chromatin immunoprecipitation sequencing, CRISPR-Cas9 gene editing, and other approaches, the researchers saw signs that SETX typically helps to ward off transcriptional stress, while its absence contributes to chromosome fragility and genomic instability. "[O]ur findings indicate that AOA2 is a transcription stress-related disorder and that SETX is necessary to preserve the integrity of transcription," they report, noting that "[f]uture studies will provide invaluable insights that will allow us to piece together the relationships between transcription stress and human disease."

University of Iowa researchers compare single-cell gene expression, cell type, spatial, and other features found in pig models of cystic fibrosis (CF) and wild type pigs, focusing on submucosal glands that produce lung protecting mucus that is known for becoming abnormal mucus that contributes to disease features during CF. The team's single-cell transcriptome, immunohistochemistry, and other experiments provided a look at shared and cell type-specific processes in the submucosal gland cells, while uncovering similar cell type and messenger RNA transcript profiles in submucosal gland cells from pigs with or without CF. "Normal and cystic fibrosis submucosal glands were similar, suggesting that disease is due to loss of anion secretion rather than an intrinsic cell defect," the authors note.