Biology subjects

Wenger, A.

Publications and source records attributed to Wenger, A..

8 recordsLinked to original sources

bioRxiv2025

Extensive and differential platinum chemotherapy mutagenesis in children

Childhood cancer survivors often develop long-term adverse effects, which may be caused by direct mutagenesis of cytotoxic agents. Some of these agents generate distinctive DNA imprints (mutational signatures), as exemplified by platinum chemotherapeutics. Here, we examined chemotherapy mutagenesis in paediatric tissues by deploying a duplex sequencing method (NanoSeq), which enables mutation calling from single DNA molecules. We surveyed whole genomes of paediatric liver, blood and other tissues, obtained from surgical resections and at post-mortem. Platinum signatures pervaded all tissues extensively, elevating mutation burdens of paediatric tissues to levels seen in adults. Remarkably, we found a tissue-specific mutational signature in the liver. We examined the functional potential of mutations by gene focused NanoSeq, which revealed that platinum agents cause a vast repertoire of cancer causing variants across normal tissues, such as leukaemogenic mutations in blood. This finding may conceivably link cancer treatment in childhood to mutation-driven long term sequelae.

cancer biology↗

bioRxiv2025

Identifying Priority Stepping Stone Reefs to Maintain Global Networks of Connected Coral Reefs

Conserving coral reef climate refugia is a key conservation strategy to address climate change. Yet, the accelerating impacts of coral bleaching and other anthropogenic pressures can jeopardize refugia persistence. The dispersal of coral larvae can increase long-term reef persistence through metapopulation dynamics if connected reefs can share beneficial adaptations to bleaching and facilitate demographic recovery. Here, we modelled reef connectivity using a network approach to identify present-day coral larval dispersal networks of predicted climate refugia and then determined locations of stepping stone reefs that can be used to connect these global networks of refugia. We identify 10 key locations of coral reef stepping stones in Indonesia, Mozambique, Glorioso Islands, and Malaysia that may ensure that 84,564km2 of refugia could remain connected together even if other (non-refugia) reefs become degraded. Global coral reef conservation efforts should consider prioritizing these stepping stones to build more redundancy and resilience into future-proofing conservation strategies.

ecology↗

bioRxiv2025

Single cell transcriptional evolution of myeloid leukaemia of Down syndrome

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukaemia (ML-DS). Unusually for a childhood leukaemia, ML-DS arises from a preleukaemic state, termed transient abnormal myelopoiesis (TAM), via a conserved sequence of mutations. Here, we examined the relationship between the genetic and transcriptional evolution of ML-DS from natural variation; a rich collection of primary patient samples and fetal tissues with a range of constitutional karyotypes. We distilled transcriptional consequences of each genetic step in ML-DS evolution, utilising single cell mRNA sequencing, complemented by phylogenetic analyses in progressive disease. We found that transcriptional changes induced by the TAM-defining GATA1 mutations are retained in, and account for most of the ML-DS transcriptome. The GATA1 transcriptome pervaded all stages of ML-DS, including progressive disease that had undergone genetic evolution. Our approach delineates the transcriptional evolution of ML-DS and provides an analytical blueprint for distilling consequences of mutations within their pathophysiological context.

cancer biology↗

bioRxiv2023

Repair of DNA double-strand breaks leaves heritable impairment to genome function

Upon DNA breakage, a genomic locus undergoes alterations in 3-D chromatin architecture to facilitate signaling and repair. While cells possess mechanisms to repair damaged DNA, it is unknown whether the surrounding chromatin is restored to its naive state. We show that a single DNA double-strand break (DSB) within a topologically-associated domain (TAD) harboring conformation-sensitive genes causes lasting chromatin alterations, which persist after completion of DNA repair and feature structural changes, chromatin compaction and loss of local RNA species. Unexpectedly, these newly-acquired features of post-repair chromatin are transmitted to daughter cells and manifest as heritable impairments of gene expression. These findings uncover a hitherto concealed dimension of DNA breakage, which we term post-repair chromatin fatigue, and which confers heritable impairment of gene function beyond DNA repair.

cell biology↗

bioRxiv2023

Resolving the unsolved: Comprehensive assessment of tandem repeats at scale

Tandem repeat (TR) variation is associated with gene expression changes and over 50 rare monogenic diseases. Recent advances in sequencing have enabled accurate, long reads that can characterize the full-length sequence and methylation profile of TRs. However, despite these advances in sequencing technology, computational methods to fully profile tandem repeats across the genome do not exist. To address this gap, we introduce tools for tandem repeat genotyping (TRGT), visualization and an accompanying TR database. TRGT accurately resolves the length and sequence composition of TR regions in the human genome. Assessing 937,122 TRs, TRGT showed a Mendelian concordance of 99.56%, allowing a single repeat unit difference. In six samples with known repeat expansions, TRGT detected all repeat expansions while also identifying methylation signals, mosaicism, and providing finer resolution of repeat length. Additionally, we release a database with allele sequences and methylation levels for 937,122 TRs across 100 genomes.

genomics↗

bioRxiv2021

The global rarity of intact coastal regions

Management of the land-sea interface is considered essential for global conservation and sustainability objectives, as coastal regions maintain natural processes that support biodiversity and the livelihood of billions of people. However, assessments of coastal regions have focused on either strictly the terrestrial or marine realm, and as a consequence, we still have a poor understanding of the overall state of Earths coastal regions. Here, by integrating the terrestrial human footprint and marine cumulative human impact maps, we provide a global assessment of the anthropogenic pressures affecting coastal areas. Just 15.5% of coastal areas globally can be considered having low anthropogenic pressure, mostly found in Canada, Russia, and Greenland. Conversely, 47.9% of coastal regions are heavily impacted by humanity with most countries (84.1%) having >50% of their coastal regions degraded. Nearly half (43.3%) of protected areas across coastal regions are exposed to high human pressures. In order to meet global sustainability objectives, we identify those nations that must undertake greater actions to preserve and restore coastal regions so as to ensure global sustainable development objectives can be met.

ecology↗

bioRxiv2021

A global map of human pressures on tropical coral reefs

As human activities on the worlds oceans intensify, mapping human pressures is essential to develop appropriate conservation strategies and prioritize investments with limited resources. Here, we map non-climatic pressures on coral reefs using the latest quantitative data layers on fishing, nitrogen and sediment pollution, coastal and industrial development, and tourism. Across 54,596 coral reef pixels worldwide, we identify the top-ranked local pressure and estimate a cumulative pressure index mapped at 0.05-degree ([~]5 km) resolution. Fishing was the most common top-ranked pressure followed by water pollution (nutrients and sediments), although there is substantial variation by regions. We also find that local pressures are similar inside and outside a proposed global portfolio of coral reef climate refugia. We provide the best available information to inform critical conservation strategies and ensure local pressures are effectively managed to increase the likelihood of the persistence of coral reefs to climate change.

ecology↗

bioRxiv2017

Tracing the influence of land-use change on water quality and coral reefs using a Bayesian model

Coastal ecosystems can be degraded by poor water quality. Tracing the causes of poor water quality back to land-use change is necessary to target catchment management for coastal zone management. However, existing models for tracing the sources of pollution require extensive data-sets which are not available for many of the worlds coral reef regions that may have severe water quality issues. Here we develop a hierarchical Bayesian model that uses freely available satellite data to infer the connection between land-uses in catchments and water clarity in coastal oceans. We apply the model to estimate the influence of land-use change on water clarity in Fiji. We tested the models predictions against underwater surveys, finding that predictions of poor water quality are consistent with observations of high siltation and low coverage of sediment-sensitive coral genera. The model thus provides a means to link land-use change to declines in coastal water quality.

ecology↗