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The ATRX ATP-dependent chromatin remodelling/helicase protein associates with the DAXX histone chaperone to deposit histone H3.3 over repetitive DNA regions. Because ATRX-protein interactions impart functions, such as histone deposition, we used proximity-dependent biotinylation (BioID) to identify proximal associations for ATRX. The proteomic screen captured known interactors, such as DAXX, NBS1, and PML, but also identified a range of new associating proteins. To gauge the scope of their roles, we examined three novel ATRX-associating proteins that likely differed in function, and for which little data were available. We found CCDC71 to associate with ATRX, but also HP1 and NAP1, suggesting a role in chromatin maintenance. Contrastingly, FAM207A associated with proteins involved in ribosome biosynthesis and localized to the nucleolus. ATRX proximal associations with the SLF2 DNA damage response factor help inhibit telomere exchanges. We further screened for the proteomic changes at telomeres when ATRX, SLF2, or both proteins were deleted. The loss caused important changes in the abundance of chromatin remodelling, DNA replication, and DNA repair factors at telomeres. Interestingly, several of these have previously been implicated in alternative lengthening of telomeres. Altogether, this study expands the repertoire of ATRX-associating proteins and functions.

Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with >40 monogenic disorders1. Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2-20 bp motifs in 17,231 genomes of families with autism2,3 and population controls4. We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.

This double-blinded randomized Phase 3 study evaluated the immunogenicity and safety of CYFENDUS® vaccine (AV7909; Anthrax Vaccine Adsorbed, Adjuvanted) to support licensure for post-exposure prophylaxis following suspected or confirmed Bacillus anthracis exposure when administered with the recommended antibacterial drugs. Healthy adult participants (n = 3689) aged 18 to 65 were randomized to receive CYFENDUS vaccination (intramuscularly at 0, 2 weeks) or BioThrax® (Anthrax Vaccine Absorbed) [subcutaneously at 0, 2, 4 weeks]. Immunogenicity at Day 64 (seven weeks after the last CYFENDUS vaccine dose; five weeks after the last BioThrax vaccine dose) was evaluated using a 50 % neutralizing factor (NF50) threshold of protective immunogenicity generated by a toxin neutralizing antibody (TNA) assay, and by evaluating non-inferiority of CYFENDUS to BioThrax vaccination. Safety was assessed by physical exams, vital signs, solicited local injection site and systemic reactogenicity, and unsolicited adverse events (AEs). The prospectively defined success criteria were met for the primary immunogenicity endpoints. The lower bound of the two-sided 95 % confidence interval (CI) for the proportion of CYFENDUS participants with TNA NF50 ≥ 0.56 was above the pre-defined criterion of ≥40 % (95 % CI: 64.5 %, 68.1 %). The lower bound of the two-sided 95 % CI of the difference in the proportion of participants with TNA NF50 ≥ 0.29 in the CYFENDUS versus the BioThrax vaccine group was greater than the pre-defined non-inferiority criterion of −15 % as well as demonstrating statistical superiority (95 % CI: 20.0, 29.2 %), a closed hypothesis test supported by regulatory agencies in well-controlled clinical trials. The most common adverse events (AE) were injection site-related; most reported solicited reactogenicities and AEs were either Grade 1 or 2 severity. The study met the pre-defined endpoint criteria, demonstrating protective level of immune response and non-inferiority of CYFENDUS to BioThrax vaccination. The CYFENDUS vaccine was well-tolerated in healthy adults. Trial Registration:ClinicalTrials.gov Identifier: NCT03877926 •CYFENDUS has comparable safety profile to Anthrax Vaccine Absorbed (BioThrax) in healthy adults•CYFENDUS achieved protective antibody levels up to seven weeks after second vaccination•CYFENDUS-elicited immune response was non-inferior to that of BioThrax•Equivalent immunogenicity was observed across three consecutively manufactured CYFENDUS vaccine lots

CYFENDUS® vaccine (Anthrax Vaccine Adsorbed, Adjuvanted) with the recommended antibacterial drugs is licensed for post-exposure prophylaxis (PEP) following suspected or confirmed Bacillus anthracis exposure. This pre-licensure study examined potential interaction of CYFENDUS vaccine with ciprofloxacin and doxycycline when administered concomitantly. In this Phase 2, open-label study, healthy adult participants (18 to 45 years of age; n = 210) were randomized to receive either ciprofloxacin+CYFENDUS vaccine, doxycycline+CYFENDUS vaccine, or CYFENDUS vaccine only. Pharmacokinetic (PK) parameters of antibacterials such as steady-state maximum concentration (Cmax) and area under the curve from 0 to 12 h (AUC0-12h) were assessed. Immunogenicity of the vaccine was evaluated using 50 % neutralizing factor (NF50) values generated by toxin neutralizing antibody (TNA) assay. Solicited reactogenicity and adverse events (AEs) were collected for safety evaluation. The PK endpoint was met for ciprofloxacin. The vaccine had no effect on PK with 90 % confidence intervals (CIs) of the mean ratios for AUC0-12h [90 % CI: 0.8895,1.0718] and Cmax [90 % CI: 0.8693,1.0838] contained within the predefined equivalence criteria [0.80, 1.25]. The PK endpoint was not met for doxycycline, wherein the 90 % of the mean ratios for AUC0-12h [90 % CI: 0.8187,1.0278] was within the equivalence criteria, but the lower bound of the 90 % CI for Cmax [90 % CI: 0.7841,1.0271] was below the equivalence limits [0.80, 1.25]; this impact on Cmax may be negligible to the extent that doxycycline efficacy is correlated with AUC. The immunogenicity endpoint was met, wherein the lower bound 95 % CIs for geometric mean ratio of TNA NF50 for the vaccine with ciprofloxacin (0.78) or doxycycline (0.81) to vaccine alone were above the non-inferiority margin (0.5). Most solicited reactogenicities and AEs were Grade 1 or 2 in severity. CYFENDUS vaccination with or without ciprofloxacin or doxycycline had an acceptable safety profile and co-administration did not affect the relevant PK and immunogenicity parameters. ClinicalTrials.gov Identifier: NCT04067011

Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders 1 . Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2–20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD) 2 , 3 and population control individuals 4 . We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN , which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1 . Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD. Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

Expansion of the C9orf72 repeat (GGGGCC)n is the most common cause of amyotrophic lateral sclerosis and fronto-temporal dementia. Here I characterize the unusual structures formed by the C9orf72 repeat in vitro, the effect of DNA methylation on these structures, and explore the effects of structure and methylation on protein interactions. With this foundation, we can begin to unravel therapeutic targets for ALS/FTD-targeted treatments that could arrest or even reverse disease progression such as structure-specific compounds that could be used to induce contractions or halt somatic expansion in affected tissues. Furthermore, I show that the C9orf72 expansion is in fact a cytogenetic folate-sensitive chromosomal fragile site (FSFS), similar to the ten cloned FSFS that each have been mapped to (CGG)n expansions, including FRAXA, the cause of fragile X syndrome (FXS) and a plethora of other diseases. Like other FSFS, C9orf72 repeat expansions predispose to chromosome breaks, gaps, elongated under-condensed regions, aberrant CpG methylation, unusual DNA structures, micronuclei, double-strand breaks, sister-chromatid exchanges, and lead to aberrant chromatin packaging. That the C9orf72 expansion is a fragile site now broadens the repeat sequences associated with FSFS, and sheds light on the varied genetic alterations, variable manifestations and multiple modes of pathogeneses that can arise at the C9orf72 locus, as observed with FXS.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and is linked to multiple diseases. (GGGGCC)n expansions ( Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immuno-stimulatory or damaged DNA is unknown. Here, we show Exp in pre-symptomatic and ALS-FTD patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33kb of as highly-compacted chromatin embedded in an 8.2Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one Exp patient contained highly-rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic Exp repeat instability and chromosomal fragility are sensitive to folate-deficiency. Age-dependent repeat instability, chromosomal fragility, and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic Exp mice, implicating Exp as the source. Our results highlight unappreciated effects of expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.