A Maximum Parsimony Principle for Multichromosomal Complex Genome Rearrangements

Motivation. Complex genome rearrangements, such as chromothripsis and chromoplexy, are common in cancer and have also been reported in individuals with various developmental and neurological disorders. These mutations are proposed to involve simultaneous breakage of the genome at many loci and rejoining of these breaks that produce highly rearranged genomes. Since genome sequencing measures only the novel adjacencies present at the time of sequencing, determining whether a collection of novel adjacencies resulted from a complex rearrangement is a complicated and ill-posed problem. Current heuristics for this problem often result in the inference of complex rearrangements that affect many chromosomes. Results. We introduce a model for complex rearrangements that builds upon the methods developed for analyzing simple genome rearrangements such as inversions and translocations. While nearly all of these existing methods use a maximum parsimony assumption of minimizing the number of rearrangements, we propose an alternative maximum parsimony principle based on minimizing the number of chromosomes involved in a rearrangement scenario. We show that our model leads to inference of more plausible sequences of rearrangements that better explain a complex congenital rearrangement in a human genome and chromothripsis events in 22 cancer genomes

Genome Halving and Aliquoting Under the Copy Number Distance

Large-scale genome rearrangements occur frequently in species evolution and cancer evolution. While the computation of evolutionary distances is tractable for balanced rearrangements, such as inversions and translocations, computing distances involving duplications and deletions is much more difficult. In the recently proposed Copy Number Distance (CND) model, a genome is represented as a Copy Number Profile (CNP), a sequence of integers, and the CND between two CNPs is the length of a shortest sequence of deletions and amplifications of contiguous segments that transforms one CNP into the other. In addition to these segmental events, genomes also undergo global events such as Whole Genome Duplication (WGD) or polyploidization that multiply the entire genome content. These global events are common and important in both species and cancer evolution. In this paper, we formulate the genome halving problem of finding a closest preduplication CNP that has undergone a WGD and evolved into a given CNP under the CND model. We also formulate the analogous genome aliquoting problem of finding the closest prepolyploidzation CNP under the CND distance. We give a linear time algorithm for the halving distance and a quadratic time dynamic programming algorithm for the aliquoting distance. We implement these algorithms and show that they produce reasonable solutions on simulated CNPs

Energy decisions reframed as justice and ethical concerns

All too often, energy policy and technology discussions are limited to the domains of engineering and economics. Many energy consumers, and even analysts and policymakers, confront and frame energy and climate risks in a moral vacuum, rarely incorporating broader social justice concerns. Here, to remedy this gap, we investigate how concepts from justice and ethics can inform energy decision-making by reframing five energy problems — nuclear waste, involuntary resettlement, energy pollution, energy poverty and climate change — as pressing justice concerns. We conclude by proposing an energy justice framework centred on availability, affordability, due process, transparency and accountability, sustainability, equity and responsibility, which highlights the futurity, fairness and equity dimensions of energy production and use. The structure of the global energy system and the pending consequences of climate change are among the central justice issues of our time, with profound implications for human happiness, welfare, freedom, equity and due process1. One global study distinguishing between ‘experienced’ and ‘imposed’ effects of climate change — essentially separating out primary emitters from those suffering from climate change — concluded that people in rich countries impose 200–300 times more health damage on others than they experience themselves as a result of their nation's historical emissions2. Others argue that the costs of climate change will befall the weakest and least developed countries as well as the poorest in developed nations, while the benefits, if there are any, will probably be accrued by the rich and powerful3. Meanwhile, serious environmental burdens can arise from having too much energy (from waste, over-consumption and pollution4) or from not having enough (from lack of access to modern forms of energy, under-consumption and poverty). With increasing wealth, these environmental burdens shift in terms of severity, geographic scope and temporal reach. For instance, a decline in household environmental risks through enhanced access to modern energy services, clean water and better healthcare coincides with an increase in global risks such as climate change and other forms of transboundary environmental pollution. While solutions to some problems, such as poverty, obviously require an increase in energy consumption, solutions to other problems, such as climate change, might well require a decrease in energy consumption. Clearly, the current fossil fuel-based global energy system has many benefits but also many disadvantages, including significant health burdens that shorten lives, undermine the conditions for happiness and impede a more just and equitable society. Yet most of us confront and frame such climate and energy risks within a moral vacuum. It has been argued that our moral systems are ill-equipped to handle the complexity and expansiveness of modern-day energy and climate problems5,6, and that individuals will work to avoid feelings of responsibility for climate change or energy insecurity; some will even have optimistic biases, downgrading any negative information they receive and counterbalancing it with almost irrational exuberance7. In this Perspective, we argue that concepts from ethics and justice provide an important structure to think about, and approach, the world's climate and energy dilemmas. We reframe five contemporary energy problems — nuclear waste, involuntary resettlement, energy pollution, energy poverty and climate change — as justice and ethics concerns. We then synthesize justice elements into a common framework that energy decision-makers can utilize to create a more just and equitable energy future. By ‘decision-makers’, we refer not only to the more traditional notion of policymakers and regulators, but also ordinary students, jurists, homeowners, businesspersons, investors and consumers — essentially, anyone that makes decisions or choices about energy conversion and use8. Admittedly, we take an anthropocentric perspective based on social justice principles, though there are certainly justice claims that arise with how humans interact with non-human forms of life. Some have called this human-centered approach ‘cosmopolitan justice’, as it acknowledges that all ethnic groups belong to a single community based on a collective morality9. Many scholars have taken up modern manifestations of these ideals, and have advanced the core arguments presented in Table 110,​11,​12,​13,​14,​15,​16,​17,​18,​19. These arguments underscore how all human beings have equal moral worth and, as we will argue, are deserving of ‘energy justice’

Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine

High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein sequence or structure. Finally, we review techniques to identify recurrent combinations of somatic mutations, including approaches that examine mutations in known pathways or protein-interaction networks, as well as de novo approaches that identify combinations of mutations according to statistical patterns of mutual exclusivity. These techniques, coupled with advances in high-throughput DNA sequencing, are enabling precision medicine approaches to the diagnosis and treatment of cancer

STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection.

UnlabelledSTING (stimulator of interferon [IFN] genes) initiates type I IFN responses in mammalian cells through the detection of microbial nucleic acids. The membrane-bound obligate intracellular bacterium Chlamydia trachomatis induces a STING-dependent type I IFN response in infected cells, yet the IFN-inducing ligand remains unknown. In this report, we provide evidence that Chlamydia synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite not previously identified in Gram-negative bacteria, and that this metabolite is a prominent ligand for STING-mediated activation of IFN responses during infection. We used primary mouse lung fibroblasts and HEK293T cells to compare IFN-β responses to Chlamydia infection, c-di-AMP, and other type I IFN-inducing stimuli. Chlamydia infection and c-di-AMP treatment induced type I IFN responses in cells expressing STING but not in cells expressing STING variants that cannot sense cyclic dinucleotides but still respond to cytoplasmic DNA. The failure to induce a type I IFN response to Chlamydia and c-di-AMP correlated with the inability of STING to relocalize from the endoplasmic reticulum to cytoplasmic punctate signaling complexes required for IFN activation. We conclude that Chlamydia induces STING-mediated IFN responses through the detection of c-di-AMP in the host cell cytosol and propose that c-di-AMP is the ligand predominantly responsible for inducing such a response in Chlamydia-infected cells.ImportanceThis study shows that the Gram-negative obligate pathogen Chlamydia trachomatis, a major cause of pelvic inflammatory disease and infertility, synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite that thus far has been described only in Gram-positive bacteria. We further provide evidence that the host cell employs an endoplasmic reticulum (ER)-localized cytoplasmic sensor, STING (stimulator of interferon [IFN] genes), to detect c-di-AMP synthesized by Chlamydia and induce a protective IFN response. This detection occurs even though Chlamydia is confined to a membrane-bound vacuole. This raises the possibility that the ER, an organelle that innervates the entire cytoplasm, is equipped with pattern recognition receptors that can directly survey membrane-bound pathogen-containing vacuoles for leaking microbe-specific metabolites to mount type I IFN responses required to control microbial infections