No abstract

Mitochondrial DNA (mtDNA) mutations cause severe congenital diseases but may also be associated with healthy aging. MtDNA is stochastically replicated and degraded, and exists within organelles which undergo dynamic fusion and fission. The role of the resulting mitochondrial networks in the time evolution of the cellular proportion of mutated mtDNA molecules (heteroplasmy), and cell-to-cell variability in heteroplasmy (heteroplasmy variance), remains incompletely understood. Heteroplasmy variance is particularly important since it modulates the number of pathological cells in a tissue. Here, we provide the first wide-reaching theoretical framework which bridges mitochondrial network and genetic states. We show that, under a range of conditions, the (genetic) rate of increase in heteroplasmy variance and de novo mutation are proportionally modulated by the (physical) fraction of unfused mitochondria, independently of the absolute fission-fusion rate. In the context of selective fusion, we show that intermediate fusion/fission ratios are optimal for the clearance of mtDNA mutants. Our findings imply that modulating network state, mitophagy rate and copy number to slow down heteroplasmy dynamics when mean heteroplasmy is low could have therapeutic advantages for mitochondrial disease and healthy aging.

word count: 189 14 Text word count: 6,604 15 ABSTRACT 16Transposon-Directed Insertion-site Sequencing (TraDIS) is a high-throughput method 17 coupling transposon mutagenesis with short-fragment DNA sequencing. It is commonly used 18 to identify essential genes. Single gene deletion libraries are considered the gold standard for 19 identifying essential genes. Currently, the TraDIS method has not been benchmarked against 20 such libraries and therefore it remains unclear whether the two methodologies are 21 comparable. To address this, a high density transposon library was constructed in 22

Motivation The evolution of bacterial drug resistance and other features in biology, the progression of cancer and other diseases, and a wide range of broader questions can often be viewed as the sequential stochastic acquisition of binary traits (for example, genetic changes, symptoms, or characters). Using potentially noisy or incomplete data to learn the sequences by which such traits are acquired is a problem of general interest. The problem is complicated for large numbers of traits which may, individually or synergistically, influence the probability of further acquisitions both positively and negatively. Hypercubic inference approaches, based on hidden Markov models on a hypercubic transition network, address these complications, but previous Bayesian instances can consume substantial time for converged results, limiting their practical use. Results Here we introduce HyperHMM, an adapted Baum-Welch (expectation maximisation) algorithm for hypercubic inference with resampling to quantify uncertainty, and show that it allows orders-of-magnitude faster inference while making few practical sacrifices compared to previous hypercubic inference approaches. We show that HyperHMM allows any combination of traits to exert arbitrary positive or negative influence on the acquisition of other traits, relaxing a common limitation of only independent trait influences. We apply this approach to synthetic and biological datasets and discuss its more general application in learning evolutionary and progressive pathways. Availability and Implementation Code for inference and visualisation, and data for example cases, is freely available at https://github.com/StochasticBiology/hypercube-hmm. Supplementary Information Supplementary Information for this article is available online.

In this paper, a previously undescribed rock art style consisting of large human figures and animals with stroke-line infill is introduced. These depictions have been named Maliwawa Figures. They are primarily found in northwest Arnhem Land and to date have been recorded at 87 sites from Awunbarna (Mount Borradaile area) to the Namunidjbuk clan state of the Wellington Range. There are solitary figures and others arranged in compositions or scenes. We describe the features of this style, its distribution, subject matter and probable age. The results of a detailed analysis of all sites are discussed and a new, refined Arnhem Land rock art chronology is presented. It is concluded that Maliwawa Figures are most likely to date between 6,000 to 9,400 years of age and to be contemporaneous with Northern Running Figures and Yam Figures found at sites to the south.