Biology subjects

Kaiser, V. B.

Publications and source records attributed to Kaiser, V. B..

5 recordsLinked to original sources

bioRxiv2025

Genetic background sets the trajectory of cancer evolution

Human cancers are heterogeneous. Their genomes evolve from genetically diverse germlines in complex and dynamic environments, including exposure to potential carcinogens. This heterogeneity of humans, our environmental exposures, and subsequent tumours makes it challenging to understand the extent to which cancer evolution is predictable. Addressing this limitation, we re-ran early tumour evolution hundreds of times in diverse, inbred mouse strains, capturing genetic variation comparable to and beyond that found in human populations. The sex, environment, and carcinogenic exposures were all controlled and tumours comprehensively profiled with whole genome and transcriptome sequencing. Within a strain, there was a high degree of consistency in the mutational landscape, a limited range of driver mutations, and all strains converged on the acquisition of a MAPK activating mutation with similar transcriptional disruption of that pathway. Despite these similarities in the phenotypic state of tumours, different strains took markedly divergent paths to reach that state. This included pronounced biases in the precise driver mutations, the strain specific occurrence of whole genome duplication, and differences in subclonal selection that reflected both cancer susceptibility and tumour growth rate. These results show that interactions between the germline genome and the environment are highly deterministic for the trajectory of tumour genome evolution, and even modest genetic divergence can substantially alter selection pressures during cancer development, influencing both cancer risk and the biology of the tumour that develops.

genomics↗

bioRxiv2024

Stage-resolved chromatin conformation dynamics during human meiosis

BackgroundDuring meiosis, the mammalian genome is organised within chromatin loops, which facilitate synapsis, crossing over and chromosome segregation, setting the stage for recombination events and the generation of genetic diversity. Chromatin looping is thought to play a major role in the establishment of cross overs during prophase I of meiosis, in diploid early primary spermatocytes. However, chromatin conformation dynamics during human meiosis are difficult to study experimentally, due to the transience of each cell division and the difficulty of obtaining stage-resolved cell populations. Here, we employed a machine learning framework trained on single cell ATAC-seq and RNA-seq data to predict CTCF-anchored looping during spermatogenesis, including cell types at different stages of meiosis. ResultsWe find dramatic changes in genome-wide looping patterns throughout meiosis: compared to pre-and-post meiotic germline cell types, loops in meiotic early primary spermatocytes are more abundant, more variable between individual cells, and more evenly spread throughout the genome. In preparation for the first meiotic division, loops also include longer stretches of DNA, encompassing more than half of the total genome. These loop structures then influence the rate of recombination initiation and resolution as cross overs. In contrast, in later mature sperm stages, we find evidence of genome compaction, with loops being confined to the telomeric ends of the chromosomes. ConclusionOverall, we find that chromatin loops do not orchestrate the gene expression dynamics seen during spermatogenesis, but loops do play important roles in recombination, influencing the positions of DNA breakage and cross over events.

genomics↗

bioRxiv2021

Mutational bias in spermatogonia impacts the anatomy of regulatory sites in the human genome

Mutation in the germline is the ultimate source of genetic variation, but little is known about the influence of germline chromatin structure on mutational processes. Using ATAC-seq, we profile the open chromatin landscape of human spermatogonia, the most proliferative cell-type of the germline, identifying transcription factor binding sites (TFBSs) and PRDM9-binding sites, a subset of which will initiate meiotic recombination. We observe an increase in rare structural variant (SV) breakpoints at PRDM9-bound sites, implicating meiotic recombination in the generation of structural variation. Many germline TFBSs, such as NRF, are also associated with increased rates of SV breakpoints, apparently independent of recombination. Singleton short insertions (>=5 bp) are highly enriched at TFBSs, particularly at sites bound by testis active TFs, and their rates correlate with those of structural variant breakpoints. Short insertions often duplicate the TFBS motif, leading to clustering of motif sites near regulatory regions in this male-driven evolutionary process. Increased mutation loads at germline TFBSs disproportionately affect neural enhancers with activity in spermatogonia, potentially altering neurodevelopmental regulatory architecture. Local chromatin structure in spermatogonia is thus pervasive in shaping both evolution and disease.

genomics↗

bioRxiv2019

Pervasive lesion segregation shapes cancer genome evolution

Cancers arise through the acquisition of oncogenic mutations and grow through clonal expansion1, 2. Here we reveal that most mutagenic DNA lesions are not resolved as mutations within a single cell-cycle. Instead, DNA lesions segregate unrepaired into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterise this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can generate multiple alternative alleles in successive cell divisions, thereby increasing both multi-allelic and combinatorial genetic diversity. The phasing of lesions enables the accurate measurement of strand biased repair processes, the quantification of oncogenic selection, and the fine mapping of sister chromatid exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

cancer biology↗

bioRxiv2017

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline.

Chromatin loops form a basic unit of interphase nuclear organisation, providing contacts between regulatory regions and target promoters, and forming higher level patterns defining self interacting domains. Recent studies have shown that mutations predicted to alter chromatin loops and domains are frequently observed in tumours and can result in the upregulation of oncogenes, but the combinations of selection and mutational bias underlying these observations remains unknown. Here, we explore the unusual mutational landscape associated with chromatin loop anchor points (LAPs), which are located at the base of chromatin loops and form a kinetic trap for cohesin. We show that LAPs are strongly depleted for single nucleotide variants (SNVs) in tumours, which is consistent with their relatively early replication timing. However, despite low SNV rates, LAPs emerge as sites of evolutionary innovation showing enrichment for structural variants (SVs). They harbour an excess of SV breakpoints in cancers, are prone to double strand breaks in somatic cells, and are bound by DNA repair complex proteins. Recurrently disrupted LAPs are often associated with genes annotated with functions in cell cycle transitions. An unexpectedly large fraction of LAPs (16%) also overlap known meiotic recombination hotspot (HSs), and are enriched for the core PRDM9 binding motif, suggesting that LAPs have been foci for diversity generated during recent human evolution. We suggest that the unusual chromatin structure at LAPs underlies the elevated SV rates observed, marking LAPs as sites of regulatory importance but also genomic fragility.

genomics↗