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Billington, C.

Publications and source records attributed to Billington, C..

2 recordsLinked to original sources

A Telomere-to-telomere genome of the hibernating fat-tailed dwarf lemur (Cheirogaleus medius)

Madagascars dwarf lemurs (genus Cheirogaleus) are the only obligate-hibernating primates and closest relative to humans capable of hibernation. Endemic to the increasingly fragmented dry forests of Madagascar, the fat tailed dwarf lemur (Cheirogaleus medius) represents a unique model for understanding primate physiology and tropical hibernation. Here we present FatTail1, a highly contiguous diploid genome assembly generated from a male C. medius at the Duke Lemur Center using Oxford Nanopore Technologies PromethION sequencing. The assembly spans 2.3 Gb, with an N50 of 103Mb, L50 of 10, and a BUSCO completeness score of over 99%. In addition to a complete mitogenome, we generated allele-specific DNA methylation profiles and annotated 23,925 genes using NCBIs EGAPX. FatTail1 exceeds the gap-free contiguity of previously published strepsirrhine genomes, representing the first telomere-to-telomere genome of a Strepsirrhine primate, and providing a foundation for future studies of primate hibernation, epigenetic regulation, and conservation genomics. ARTICLE SUMMARYDwarf lemurs are the only primates and closest relative to humans capable of months-long hibernation, making them an important model for understanding metabolic adaptations with relevance to human physiology. Here we present FatTail1, the first telomere-to-telomere genome assembly of a strepsirrhine primate, generated from a fat-tailed dwarf lemur (Cheirogaleus medius) using Oxford Nanopore Technologies PromethION sequencing. In addition to a highly complete nuclear genome, we assembled the mitogenome, identified allele-specific DNA methylation profiles and annotated 23,925 genes. FatTail1 exceeds the gap-free contiguity of previously published strepsirrhine genomes and provides an improved genomic resource for studies of hibernation, comparative genomics, epigenetic regulation, evolutionary biology, and conservation of this threatened primate.

genomics↗

A novel variant in ADPRS disrupts ARH3 stability and subcellular localization in childrenwith neurodegeneration and respiratory failure

PurposeADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS). MethodsGenetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change. ResultsThe ARH3H182R variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3H182R additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3H182R resulted in accumulation of mono-ADP ribosylated species in cells. ConclusionsThe childrens clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.

molecular biology↗