Algorithms for constructing more accurate and inclusive phylogenetic trees

Despite the unprecedented outpouring of molecular sequence data in phylogenetics, the current understanding of the tree of life is still incomplete. The widespread applications of phylogenies, ranging from drug design to biodiversity conservation, repeatedly remind us of the need for more accurate and inclusive phylogenies. My thesis addresses some of the underlying challenges, by presenting theoretical and empirical results, as well as algorithms for a range of phylogenetic optimization problems. In the first part of this thesis, I develop a heuristic method for the NP-hard unrooted Robinson-Foulds (RF) supertree problem, and show that it yields more accurate supertrees than those obtained from Matrix Representation with Parsimony (MRP) and rooted RF heuristic. In the second, I present an RF distance measure based approach (MulRF) for inferring a species tree from the input multi-copy gene trees, through a generalization of RF distance to multi-labeled trees. Through simulation, I show that this approach, which is independent of gene tree discordance mechanisms, produces more accurate species trees than existing methods when incongruence is caused by gene tree error, duplications and losses, and/or lateral gene transfer. Next, I perform a simulation study to evaluate the performance of Gene Tree Parsimony (GTP) under duplication and duplication and loss cost models and compare it to MulRF method. The objective is to study the effects of various types of sampling (e.g., gene tree and sequence sampling), gene tree error, and duplication and loss rates on the accuracy of the phylogenetic estimates by GTP and MulRF. Next, I present efficient error correction algorithms for gene tree reconciliation based on duplication, duplication and loss, and deep coalescence. In the end, I present NP-completeness proofs for two problems whose complexity was previously unknown

Inferring Species Trees from Incongruent Multi-Copy Gene Trees Using the Robinson-Foulds Distance

We present a new method for inferring species trees from multi-copy gene trees. Our method is based on a generalization of the Robinson-Foulds (RF) distance to multi-labeled trees (mul-trees), i.e., gene trees in which multiple leaves can have the same label. Unlike most previous phylogenetic methods using gene trees, this method does not assume that gene tree incongruence is caused by a single, specific biological process, such as gene duplication and loss, deep coalescence, or lateral gene transfer. We prove that it is NP-hard to compute the RF distance between two mul-trees, but it is easy to calculate the generalized RF distance between a mul-tree and a singly-labeled tree. Motivated by this observation, we formulate the RF supertree problem for mul-trees (MulRF), which takes a collection of mul-trees and constructs a species tree that minimizes the total RF distance from the input mul-trees. We present a fast heuristic algorithm for the MulRF supertree problem. Simulation experiments demonstrate that the MulRF method produces more accurate species trees than gene tree parsimony methods when incongruence is caused by gene tree error, duplications and losses, and/or lateral gene transfer. Furthermore, the MulRF heuristic runs quickly on data sets containing hundreds of trees with up to a hundred taxa.Comment: 16 pages, 11 figure

Recent advances of biosensors in biomedical sciences

This review discusses recent advances in biosensor technology which draw on the disciplines of physics, chemistry, biochemistry and electronics. We first show that a biosensor consists of three components, a biological detection system, a transducer and an output system. Biological receptors are reviewed, followed by a detailed discussion of transducers, optical, electrochemical, piezoelectric, and others which involve interesting physics and show particular promise for commercial biosensors, are discussed thoroughly. New developments in biosensor design are appearing at a high rate as these devices play increasingly important roles in daily life. We describe a new technology, the Ibis T5000, for the identification of pathogens in clinical and environmental samples; a novel ion channel switch biosensor (ICSB), offers a rapid and sensitive immunodiagnostic for viral detection at point-of care; Chip-NMR, new diagnostic platforms have been developed to measure biomolecule abundance with high sensitivity; Graphene has attracted strong scientific and technological interest in recent years. Finally, future trends in biosensor development are discussed. In this context, bioelectronics, miniaturization, and especially biotechnology seem to be growing areas that will have a marked influence on the development of new biosensing strategies in the next future

Efficient error correction algorithms for gene tree reconciliation based on duplication, duplication and loss, and deep coalescence

<p>Abstract</p> <p>Background</p> <p>Gene tree - species tree reconciliation problems infer the patterns and processes of gene evolution within a species tree. Gene tree parsimony approaches seek the evolutionary scenario that implies the fewest gene duplications, duplications and losses, or deep coalescence (incomplete lineage sorting) events needed to reconcile a gene tree and a species tree. While a gene tree parsimony approach can be informative about genome evolution and phylogenetics, error in gene trees can profoundly bias the results.</p> <p>Results</p> <p>We introduce efficient algorithms that rapidly search local Subtree Prune and Regraft (SPR) or Tree Bisection and Reconnection (TBR) neighborhoods of a given gene tree to identify a topology that implies the fewest duplications, duplication and losses, or deep coalescence events. These algorithms improve on the current solutions by a factor of <it>n </it>for searching SPR neighborhoods and <it>n</it>²for searching TBR neighborhoods, where <it>n </it>is the number of taxa in the given gene tree. They provide a fast error correction protocol for ameliorating the effects of gene tree error by allowing small rearrangements in the topology to improve the reconciliation cost. We also demonstrate a simple protocol to use the gene rearrangement algorithm to improve gene tree parsimony phylogenetic analyses.</p> <p>Conclusions</p> <p>The new gene tree rearrangement algorithms provide a fast method to address gene tree error. They do not make assumptions about the underlying processes of genome evolution, and they are amenable to analyses of large-scale genomic data sets. These algorithms are also easily incorporated into gene tree parsimony phylogenetic analyses, potentially producing more credible estimates of reconciliation cost.</p

iGTP: A software package for large-scale gene tree parsimony analysis

<p>Abstract</p> <p>Background</p> <p>The ever-increasing wealth of genomic sequence information provides an unprecedented opportunity for large-scale phylogenetic analysis. However, species phylogeny inference is obfuscated by incongruence among gene trees due to evolutionary events such as gene duplication and loss, incomplete lineage sorting (deep coalescence), and horizontal gene transfer. Gene tree parsimony (GTP) addresses this issue by seeking a species tree that requires the minimum number of evolutionary events to reconcile a given set of incongruent gene trees. Despite its promise, the use of gene tree parsimony has been limited by the fact that existing software is either not fast enough to tackle large data sets or is restricted in the range of evolutionary events it can handle.</p> <p>Results</p> <p>We introduce iGTP, a platform-independent software program that implements state-of-the-art algorithms that greatly speed up species tree inference under the duplication, duplication-loss, and deep coalescence reconciliation costs. iGTP significantly extends and improves the functionality and performance of existing gene tree parsimony software and offers advanced features such as building effective initial trees using stepwise leaf addition and the ability to have unrooted gene trees in the input. Moreover, iGTP provides a user-friendly graphical interface with integrated tree visualization software to facilitate analysis of the results.</p> <p>Conclusions</p> <p>iGTP enables, for the first time, gene tree parsimony analyses of thousands of genes from hundreds of taxa using the duplication, duplication-loss, and deep coalescence reconciliation costs, all from within a convenient graphical user interface.</p

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe