Biology subjects

Townsend, J. P.

Publications and source records attributed to Townsend, J. P..

25 records · Page 2Linked to original sources

bioRxiv2019

Evolutionary analyses guide selection of model systems to investigate proto-oncogene function in ALK and LTK

Model systems to investigate oncogene-driven cancer have played an essential role in the development of therapies for cancer. However, not all systems are appropriate for all therapeutic targets. Knowing where and when proto-oncogenes and their interactors originated in evolutionary history is key to understanding which organisms can serve as models. Here we investigate two tyrosine kinase receptors that underlie tumorigenesis in cancer: anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK). In Drosophila melanogaster, Caenorhabitis elegans, and Homo sapiens, the discovery of putative ligands Jeb, Hen-1, and AUG has the potential to accelerate the development of novel therapeutics. However, homology of these ligands and receptors is unclear. We performed an exhaustive search for their homologs spanning the metazoan tree of life. Jeb and Hen-1 were restricted to species that diverged prior to the origin of all vertebrates. No non-vertebrate species had ligands orthologous to AUG. Instead, an ancestral receptor tyrosine kinase and AUG gene were present in early vertebrates and are still solitary in lamprey; we demonstrate that the early embryonic expression of AUG in lamprey parallels its expression in model mammal systems. The presence of ALK and LTK in jawed vertebrates is an evolutionary innovation, as is a previously unrecognized functional convergence within ALK and LTK occurring between actinopterygians and sarcopterygians. Our results provide the phylogenetic context necessary for the selection of model organisms that will provide informative investigations of the biology of these critically important tyrosine kinase receptors, enabling successful therapeutic development.\n\nSignificanceThe anaplastic lymphoma kinase ALK can be oncogenically altered to become a driver of several malignancies, including non-small-cell lung cancer and anaplastic large-cell lymphomas. The development of therapeutics targeting this gene depend on the discovery of its interacting partner ligands in relevant model organisms. ALK is found across most major animal groups including mammals, fishes, and invertebrates. Correspondly, several candidate ligands for ALK and its duplicate LTK have been advanced by research in model species. However their homology to the human ligands and therefore their potential to guide therapeutic development is unknown. Our comparative evolutionary analysis revealed which model organisms had functional receptor-ligand pairings that are informative regarding the role of these genes in human tumorigenesis.

cancer biology↗

bioRxiv2019

Identifying Combinations of Cancer Drivers in Individual Patients.

Identifying the subset of genetic alterations present in individual tumors that are essential and collectively sufficient for cancer initiation and progression would advance the development of effective personalized treatments. We present CRSO for inferring the combinations of alterations, i.e., rules, that cooperate to drive tumor formation in individual patients. CRSO prioritizes rules by integrating patient-specific passenger probabilities for individual alterations along with information about the recurrence of particular combinations throughout the population. We present examples in glioma, liver cancer and melanoma of significant differences in patient outcomes based on rule assignments that are not identifiable by consideration of individual alterations.

bioinformatics↗

bioRxiv2019

Unmatched level of molecular convergence among deeply divergent complex multicellular fungi

Convergent evolution is pervasive in nature, but it is poorly understood how various constraints and natural selection limit the diversity of evolvable phenotypes. Here, we report that, despite >650 million years of divergence, the same genes have repeatedly been co-opted for the development of complex multicellularity in the two largest clades of fungi--the Ascomycota and Basidiomycota. Co-opted genes have undergone duplications in both clades, resulting in >81% convergence across shared multicellularity-related families. This convergence is coupled with a rich repertoire of multicellularity-related genes in ancestors that predate complex multicellular fungi, suggesting that the coding capacity of early fungal genomes was well suited for the repeated evolution of complex multicellularity. Our work suggests that evolution may be predictable not only when organisms are closely related or are under similar selection pressures, but also if the genome biases the potential evolutionary trajectories organisms can take, even across large phylogenetic distances.

evolutionary biology↗

bioRxiv2018

Sexual stage-induced long noncoding RNAs in the filamentous fungus Fusarium graminearum

Long noncoding RNA (lncRNA) plays important roles in morphological differentiation and development in eukaryotes. In filamentous fungi, however, little is known about lncRNAs and their roles in sexual development. Here we describe sexual stage-induced lncRNAs during the formation of perithecia, the sexual fruiting bodies of Fusarium graminearum. We have identified 547 lncRNAs whose expression was developmental stage-specific, with about 40% of which peaked during the development of asci, the sac-like structures containing meiospores. A large fraction of the lncRNAs were found to be antisense to mRNAs, forming 300 sense-antisense pairs. Although small RNAs (sRNAs) were produced from these overlapping loci, most of the antisense lncRNAs appeared not to be involved in gene silencing pathways. Genome-wide analysis of sRNA clusters identified many silenced loci at the meiotic stage. However, we found transcriptionally-active sRNA clusters, many of which were associated with lncRNAs. Also, we observed that many antisense lncRNAs and their respective sense transcripts were induced in parallel as the perithecia matured. To identify regulatory components for lncRNA expression, we analyzed mutants defective in the nonsense-mediated decay (NMD) pathway. A subset of the lncRNAs appeared to be targeted by the NMD before the perithecia formation, suggesting a suppressive role of the NMD in lncRNA expression during vegetative stage. This research provides fundamental genomic resources that will spur further investigations on developmental lncRNAs that may play important roles in shaping the fungal fruiting bodies.

developmental biology↗

bioRxiv2017

Effect sizes of somatic mutations in cancer

A major goal of cancer biology is determination of the relative importance of the genomic alterations that confer selective advantage to cancer cells. Tumor sequence surveys have frequently ranked the importance of substitutions to cancer growth by P value or a false-discovery conversion thereof. However, P values are thresholds for belief, not metrics of effect. Their frequent misuse as metrics of effect has often been vociferously decried. Here, we estimate the effect sizes of all recurrent single nucleotide variants in 23 cancer types, quantifying relative importance within and between driver genes. Some of the variants with the highest effect size, such as EGFR L858R in lung adenocarcinoma and BRAF V600E in primary skin cutaneous melanoma, have yielded remarkable therapeutic responses. Quantification of cancer effect sizes has immediate importance to the prioritization of clinical decision-making by tumor boards, selection and design of clinical trials, pharmacological targeting, and basic research prioritization.

cancer biology↗

bioRxiv2017

The Moran coalescent in a discrete one-dimensional spatial model

Among many organisms, offspring are constrained to occur at sites adjacent to their parents. This applies to plants and animals with limited dispersal ability, to colonies of microbes in biofilms, and to other genetically heterogeneous aggregates of cells, such as cancerous tumors. The spatial structure of such populations leads to greater relatedness among proximate individuals while increasing the genetic divergence between distant individuals. In this study, we analyze a Moran coa-lescent in a one-dimensional spatial model where a randomly selected individual dies and is replaced by the progeny of an adjacent neighbor in every generation. We derive a recursive system of equations using the spatial distance among haplotypes as a state variable to compute coalescent probabilities and coalescent times. The coalescent probabilities near the branch termini are smaller than in the unstructured Moran model (except for t = 1, where they are equal), corresponding to longer branch lengths and greater expected pairwise coalescent times. The lower terminal coalescent probabilities result from a spatial separation of lineages, i.e. a coalescent event between a haplotype and its neighbor in one spatial direction at time t cannot co-occur with a coalescent event with a haplotype in the opposite direction at t + 1. The concomitant increased pairwise genetic distance among randomly sampled haplotypes in spatially constrained populations could lead to incorrect inferences of recent diversifying selection or of population bottlenecks when analyzed using an unconstrained coalescent model as a null hypothesis.

genetics↗

bioRxiv2017

The likelihood of heterogeneity or additional mutation in KRAS or associated oncogenes to compromise targeting of oncogenic KRAS G12C

Activating mutations in RAS genes are associated with approximately 20% of all human cancers. New targeted therapies show preclinical promise in inhibiting the KRAS G12C variant, however, concerns exist regarding the effectiveness of such therapies in vivo given the possibilities of existing intratumor heterogeneity or de novo mutation leading to treatment resistance. We performed deep sequencing of 27 KRAS G12 positive lung tumors and found no evidence of other oncogenic mutations within KRAS or within commonly mutated downstream genes that could confer resistance at the time of treatment. Furthermore, we estimate the de novo mutation rate in KRAS position 12 and in genes downstream of KRAS. We find that mutations that confer resistance are about as likely to occur downstream of KRAS as within KRAS. Moreover, we present an approach for estimation of the selection intensity for these point mutations that explains their high prevalence in tumors. Our approach predicts that BRAF V600E would provide the highest fitness advantage for de novo resistant subclones. Overall, our findings suggest that resistance to targeted therapy of KRAS G12C positive tumors is unlikely to be present at the time of treatment and, among the de novo mutations likely to confer resistance, mutations in BRAF, a gene with targeted inhibitors presently available, result in subclones with the highest fitness advantage.\n\nOne Sentence SummaryMutations conferring resistance to KRAS G12C targeted therapy are unlikely to be present at the time of resection, and the likely mechanisms of evolved resistance are predicted be ones that are responsive to therapies that are in development or that are already available.

cancer biology↗