Biology subjects

Campbell, K. J.

Publications and source records attributed to Campbell, K. J..

5 recordsLinked to original sources

bioRxiv2022

Population structure and inbreeding in wild house mice (Mus musculus) at different geographic scales

House mice (Mus musculus) have spread globally as a result of their commensal relationship with humans. In the form of laboratory strains, both inbred and outbred, they are also among the most widely-used model organisms in biomedical research. Although the general outlines of house mouse dispersal and population structure are well known, details have been obscured by either limited sample size or small numbers of markers. Here we examine ancestry, population structure and inbreeding using SNP microarray genotypes in a cohort of 814 wild mice spanning five continents and all major subspecies of Mus, with a focus on M. m. domesticus. We find that the major axis of genetic variation in M. m. domesticus is a south-to-north gradient within Europe and the Mediterranean. The dominant ancestry component in North America, Australia, New Zealand and various small offshore islands is of northern European origin. Next we show that inbreeding is surprisingly pervasive and highly variable, even between nearby populations. By inspecting the length distribution of homozygous segments in individual genomes, we find that inbreeding in commensal populations is mostly due to consanguinity. Our results offer new insight into the natural history of an important model organism for medicine and evolutionary biology.

genetics↗

bioRxiv2021

Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage

Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centres upon the control of minority MOMP, a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP, and its associated DNA damage, by enabling homogenous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.

cell biology↗

bioRxiv2019

Locally Fixed Alleles: A method to localize gene drive to island populations

Invasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the \"Locally Fixed Alleles\" approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to multiple genomic alleles becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.

evolutionary biology↗

bioRxiv2018

Regulation of checkpoint kinase signalling and tumorigenesis by the NF-κB regulated gene, CLSPN

Inhibition of the tumour promoting activities of NF-{kappa}B by cell signalling pathways has been proposed as a natural mechanism to limit the development of cancer. However, there has been a lack of evidence for these effects in vivo. Here we report that RelAT505A mice, where a CHK1 targeted Thr505 phosphosite is mutated to alanine, display earlier onset of MYC driven lymphoma than wild type littermates. We describe a positive feedback loop in which the NF-{kappa}B subunits RelA and c-Rel, in a manner dependent upon RelA Thr505 phosphorylation, drive the expression of the ATR checkpoint kinase regulator Claspin in response to DNA replication stress in cancer cells. This in turn is required for maintenance of CHK1 activity. Loss of a single allele of the Clspn gene in mice is sufficient to drive earlier tumorigenesis and low levels of CLSPN mRNA expression are associated with worse survival in some forms of human cancer. We propose that loss of this pathway early in tumorigenesis promotes cancer development through increased genomic instability. However, in malignant cancer cells it can help promote their addiction to the checkpoint kinase signalling required for the maintenance of genomic integrity. Importantly, disruption of this pathway leads to resistance of cells to treatment with CHK1 inhibitors. Claspin expression could therefore act as a biomarker for responsiveness of patients to CHK1 inhibitors and provide a potential pathway for the development of tumour resistance.

cancer biology↗

bioRxiv2018

Genetic characterization of invasive house mouse populations on small islands

House mice (Mus musculus) have dispersed to nearly every major landmass around the globe as a result of human activity. They are a highly successful invasive species, but their presence can be devastating for native ecosystems. This is particularly true on small offshore islands where mouse populations may grow unchecked by predators. Here we use genome-wide SNP genotypes to examine ancestry and population structure on two islands of ecological interest - Southeast Farallon Island, near San Francisco, CA; and Floreana Island in the Galapagos - in the context of a total cohort of 520 mice with diverse geographic origins, as a first step towards genetically-based eradication campaigns. We show that Farallon and Floreana mice, like those from previously-studied islands in both the Atlantic and Pacific Oceans, are of admixed European ancestry. We find that these populations are on average more inbred than mainland ones and passed through a strong colonization bottleneck with little subsequent genetic exchange. Finally we show that rodenticide resistance alleles present in parts of Europe are absent from all island populations studied. Our results add nuance to previous studies of island populations based on mitochondrial sequences or small numbers of microsatellites and will be useful for future eradication and monitoring efforts.

genetics↗