Biology subjects

Brew, J.

Publications and source records attributed to Brew, J..

6 recordsLinked to original sources

bioRxiv2026

Complete timing of copy-number amplification histories reveals whole-genome duplication dynamics and coincident oncogene amplification bursts

Copy-number amplifications drive cancer evolution through increased oncogene dosage. Mutations acquired before a gain are co-amplified, so their multiplicity places successive gains on a molecular timescale. This principle has been used to time individual gains and whole-genome duplication (WGD), but possible gain histories multiply rapidly with copy number, confining existing methods to low copy-number states or predefined scenarios and leaving oncogene-bearing amplifications unresolved. Here we describe a mathematical framework to systematically enumerate every allele-specific gain route to a copy-number state and derive an analytical timing for each gain, implemented in a method called Tau. Across pan-cancer genomes, punctuated multichromosomal events account for roughly three-quarters of clonal gains. Most are WGD, acquired early and often repeated within a doubling-prone subset, but a distinct, predominantly monoallelic class recurs on tumor-type-specific chromosomes, representing a coordinated mode separate from doubling. Strikingly, the highest copy-number states are reached not gradually but in abrupt bursts that cluster around WGD and contain more gains than doubling alone can produce, recurring at oncogenes. WGD is therefore not a passive doubling but a window in which localized oncogene amplification becomes far more frequent. By resolving the order of gains and the mutational processes shifting between them, Tau establishes punctuated amplification as a pervasive mode of cancer genome evolution.

bioinformatics↗

bioRxiv2025

Benchmarking of duplex sequencing approaches to reveal somatic mutation landscapes

Detecting somatic mutations in normal tissues is challenging due to sequencing errors and the low allele fractions of post-zygotic variants. Duplex sequencing greatly reduces errors and can detect mutations at any allele fraction, but systematic, cross-platform comparisons are lacking. We present a comprehensive benchmarking of six duplex sequencing technologies used by the SMaHT Network: CODEC, CompDuplex-seq, HiDEF-seq, NanoSeq, ppmSeq, and VISTA-seq. We evaluated their performance using cord blood DNA, a tumor-normal cell line mixture, and homogenates from six human tissues. Each method shows distinct profiles in genomic footprint, sensitivity, and cost. Despite differences in library construction and sequencing platforms, estimates of mutation rates and mutational signatures are highly concordant. Integration with ultra-deep whole-genome sequencing shows that duplex approaches sensitively capture mutations and signatures beyond embryonic or clonally expanded variants. These results provide a foundation for selecting duplex methods and interpreting their data, enabling scalable single-molecule analyses of somatic mutation landscapes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/692823v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@123b221org.highwire.dtl.DTLVardef@83ba0aorg.highwire.dtl.DTLVardef@2b0ab0org.highwire.dtl.DTLVardef@1cae35e_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2025

A comprehensive view of somatic mosaicism by single-cell DNA analysis

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

genomics↗

bioRxiv2024

Perinatal Reduction of Genetically Aberrant Neurons from Human Cerebral Cortex

Human neurons are postmitotic and long-lived, requiring precise genomic regulation to maintain function over a lifetime. Normal neuronal function is highly dependent on gene dosage, with copy number variants (CNVs) and heterozygous point mutations associated with a host of neurodevelopmental and neuropsychiatric conditions [1-5]. Here, we investigated the landscape of somatic CNVs arising in fetal human brains, and how they change over development, to understand the processes that generate normal neuronal genomes. We sequenced 2,158 single neurons from human postmortem brain using two distinct single cell whole genome sequencing (scWGS) approaches. Tn5-transposase based (TbA) scWGS of 1,327 neurons from 16 individuals ranging in age from gestational week 14 to 90 years old resulted in 8,765 CNVs. Primary template amplification (PTA) was used to assess for CNV from 831 neurons from 12 individuals. Up to 46% of neurons in prenatal cortex showed aberrant genomes, characterized by widespread CNVs of multiple chromosomes, but this proportion reduces by 4-5 fold after birth across the two scWGS approaches (p=7.5x10-6, Fisher meta-analysis). We identified micronuclei in the developing cortex in situ, reflecting chromosomal material missegregated during neurodevelopment [6-8]. Neurons with widespread CNVs were eliminated in the perinatal period, while neurons with smaller CNV burden slowly declined during postnatal aging. CNVs in surviving neurons were depleted for genes that are dosage-sensitive or involved in neurodevelopmental disorders (p<0.05), suggesting selective elimination of neurons with CNVs involving these critical genes. We surveyed 44,861 nuclei with 10X Genomics scATAC/RNAseq and determined that neurons with high CNV burdens also showed abnormal expression of synaptic gene sets, suggesting that abnormal synaptic gene regulation contributes to neuronal elimination. Elimination of defective neuronal genomes during synaptogenesis may represent a critical process of genome quality control and a vulnerable target of factors that contribute to neurodevelopmental disease.

neuroscience↗

bioRxiv2023

Noncoding genetic variation in ISPD distinguishes gamecocks from nongame chickens

Chickens were domesticated >4,000 years ago, probably first for fighting them and only later as a source of food. Fighting chickens, commonly known as gamecocks, continue to be bred throughout the world, but the genetic relationships among geographically diverse gamecocks and with nongame chickens are not known. Here, we sequenced the genomes of 44 geographically diverse gamecocks and of 62 nongame chickens representing a variety of breeds. We combined these sequences with published genomes to generate the most diverse chicken genomes dataset yet assembled, at 307 samples. We found that gamecocks do not form a homogeneous group, yet they share genetic similarities that distinguish them from nongame chickens. Such similarities are likely the result of a common origin before their local diversification into, or mixing with, nongame chickens. Particularly noteworthy is a variant in an intron of ISPD, an extreme outlier present at a frequency of 90% in gamecocks but only 4% in nongame chickens. The ISPD locus has the strongest signal of selection in gamecocks, suggesting it is important for fighting performance. Because ISPD variants that are highly prevalent in gamecocks are still segregating in nongame chickens, selective breeding may help reduce its frequency in farm conditions in which aggression is not a desired trait. Altogether, our work provides genomic resources for agricultural genetics, uncovers a common origin for gamecocks from around the world and what distinguishes them genetically from chickens bred for purposes other than fighting, and points to ISPD as the most important locus related to fighting performance.

evolutionary biology↗

bioRxiv2018

Modelling the distribution of Aedes aegypti and Aedes albopictus using climate, host density and interspecies competitive effects

Florida faces the challenge of repeated introduction and autochthonous transmission of arboviruses transmitted by Aedes aegypti and Aedes albopictus. Empirically-based predictive models of the spatial distribution of these species would aid surveillance and vector control efforts. To predict the occurrence and abundance of these species, we fit mixed-effects zero-inflated negative binomial regression to a mosquito surveillance dataset with records from more than 200,000 trap days, covering 73% of the land area and ranging from 2004 to 2018 in Florida. We found an asymmetrical competitive interaction between adult populations of Aedes aegypti and Aedes albopictus for the sampled sites. Wind speed was negatively associated with the occurrence and abundance of both vectors. Our model predictions show high accuracy (72.9% to 94.5%) in the validation tests leaving out a random 10% subset of sites and data from 2018, suggesting a potential for predicting the distribution of the two Aedes vectors.

ecology↗