Biology subjects

Larsen, C. S.

Publications and source records attributed to Larsen, C. S..

5 recordsLinked to original sources

bioRxiv2026

A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

immunology↗

bioRxiv2024

An age-specific burial practice reflected in ancient DNA preservation in Neolithic Catalhöyük

Selective funerary practices can inform about social relationships in prehistoric societies but are often difficult to discern. Here we present evidence for an age-specific practice at the Neolithic site of Catalhoyuk in Anatolia, dating to the 7th millennium BCE. Among ancient DNA libraries produced from 362 petrous bone samples, those of subadults contained three times higher average human DNA than those of adults. This difference in organic preservation was also confirmed by FTIR analysis. Studying similar datasets from seven prehistoric and historical sites, we found a similar age-related difference in only one cemetery. We propose that the organic preservation difference with age was caused by the special treatment of chosen corpses before interment, such as defleshing or drying, which was more frequently applied to Catalhoyuk adults and promoted organic decay.

evolutionary biology↗

bioRxiv2024

Out-of-Anatolia: cultural and genetic interactions during the Neolithic expansion in the Aegean

Western Anatolia has been a crucial yet elusive element in the Neolithic expansion from the Fertile Crescent to Europe. Using 30 new palaeogenomes from Anatolia c.8000-6000 BCE we describe the early Holocene genetic landscape of Western Anatolia, which reveals population continuity since the late Upper Pleistocene. Our findings indicate that the Neolithisation of Western Anatolia in the 7th millennium BCE was a multifaceted process, characterised by the assimilation of Neolithic practices by indigenous groups and the influx of populations from the east, their admixed descendants eventually laying the foundations of Neolithic Southeast Europe. Intriguingly, the observed diversity in material culture among Aegean Early Neolithic communities correlates with their geographical distances but not their genetic differences, signifying a decoupling between cultural developments and genetic admixture processes.

genomics↗

bioRxiv2024

Female lineages and changing kinship patterns in Neolithic Catalhöyük

Arguments have long suggested that the advent of early farming in the Near East and Anatolia was linked to a Mother Goddess cult. However, evidence for a dominant female role in these societies has been scarce. We studied social organisation, mobility patterns and gendered practices in Neolithic Southwest Asia using 131 paleogenomes from Catalhoyuk East Mound (7100-5950 BCE), a major settlement in Central Anatolia with an uninterrupted occupation and an apparent egalitarian structure. In contrast to widespread genetic evidence for patrilocality in Neolithic Europe, the Catalhoyuk individuals revealed no indication of patrilocal mobility. Analysing genetic kin ties among individuals buried in the same house (co-burials) across 35 Catalhoyuk buildings, we identified close ties concentrated within buildings and among neighbours in Catalhoyuks Early period, akin to those in the preceding Pre-Pottery Neolithic in Southwest Asia. This pattern weakened over time: by the late 7th millennium BCE, subadults buried in the same building were rarely closely genetically related, despite sharing similar diets. Still, throughout the sites occupation, genetic connections within Catalhoyuk buildings were much more frequently connected via the maternal than the paternal line. We also identified differential funerary treatment of female subadults compared to those of males, with a higher frequency of grave goods associated with females. Our results reveal how kinship practices changed while key female roles persisted over one thousand years in a large Neolithic community in western Eurasia.

genomics↗

bioRxiv2018

Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins

Deficiency in the cytosolic DNA sensor RNA Polymerase III was recently described in children with severe varicella zoster infection in the CNS or lungs. Here we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurological deficits, cerebrospinal fluid with pleocytosis and intrathecal VZV antibody production, and magnetic resonance scan of the brain showing ischaemic lesions. We performed whole exome sequencing and identified a rare mutation in the Pol III subunit POLR3F. The identified R50W POLR3F mutation is predicted to be damaging by bioinformatics and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the PoL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, these cases add genetic and immunological evidence to the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans.\n\nAbbreviations

immunology↗