Cancers develop and progress as mutations accumulate, and with the advent of single-cell DNA and RNA sequencing, researchers can observe these mutations and their transcriptomic effects and predict proteomic changes with remarkable temporal and spatial precision. However, to connect genomic mutations with their transcriptomic and proteomic consequences, cells with either only DNA data or only RNA data must be mapped to a common domain. For this purpose, we present MaCroDNA, a method that uses maximum weighted bipartite matching of per-gene read counts from single-cell DNA and RNA-seq data. Using ground truth information from colorectal cancer data, we demonstrate the advantage of MaCroDNA over existing methods in accuracy and speed. Exemplifying the utility of single-cell data integration in cancer research, we suggest, based on results derived using MaCroDNA, that genomic mutations of large effect size increasingly contribute to differential expression between cells as Barrett’s esophagus progresses to esophageal cancer, reaffirming the findings of the previous studies.
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Holland, Barbara (Ed.)Abstract The evolutionary histories of individual loci in a genome can be estimated independently, but this approach is error-prone due to the limited amount of sequence data available for each gene, which has led to the development of a diverse array of gene tree error correction methods which reduce the distance to the species tree. We investigate the performance of two representatives of these methods: TRACTION and TreeFix. We found that gene tree error correction frequently increases the level of error in gene tree topologies by “correcting” them to be closer to the species tree, even when the true gene and species trees are discordant. We confirm that full Bayesian inference of the gene trees under the multispecies coalescent model is more accurate than independent inference. Future gene tree correction approaches and methods should incorporate an adequately realistic model of evolution instead of relying on oversimplified heuristics.more » « lessFree, publicly-accessible full text available June 1, 2024
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Kolodny, Rachel (Ed.)Phylogenomic studies of prokaryotic taxa often assume conserved marker genes are homologous across their length. However, processes such as horizontal gene transfer or gene duplication and loss may disrupt this homology by recombining only parts of genes, causing gene fission or fusion. We show using simulation that it is necessary to delineate homology groups in a set of bacterial genomes without relying on gene annotations to define the boundaries of homologous regions. To solve this problem, we have developed a graph-based algorithm to partition a set of bacterial genomes into Maximal Homologous Groups of sequences ( MHGs ) where each MHG is a maximal set of maximum-length sequences which are homologous across the entire sequence alignment. We applied our algorithm to a dataset of 19 Enterobacteriaceae species and found that MHGs cover much greater proportions of genomes than markers and, relatedly, are less biased in terms of the functions of the genes they cover. We zoomed in on the correlation between each individual marker and their overlapping MHGs, and show that few phylogenetic splits supported by the markers are supported by the MHGs while many marker-supported splits are contradicted by the MHGs. A comparison of the species tree inferred from marker genes with the species tree inferred from MHGs suggests that the increased bias and lack of genome coverage by markers causes incorrect inferences as to the overall relationship between bacterial taxa.more » « less
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Abstract Motivation Single-nucleotide variants (SNVs) are the most common variations in the human genome. Recently developed methods for SNV detection from single-cell DNA sequencing data, such as SCIΦ and scVILP, leverage the evolutionary history of the cells to overcome the technical errors associated with single-cell sequencing protocols. Despite being accurate, these methods are not scalable to the extensive genomic breadth of single-cell whole-genome (scWGS) and whole-exome sequencing (scWES) data.
Results Here, we report on a new scalable method, Phylovar, which extends the phylogeny-guided variant calling approach to sequencing datasets containing millions of loci. Through benchmarking on simulated datasets under different settings, we show that, Phylovar outperforms SCIΦ in terms of running time while being more accurate than Monovar (which is not phylogeny-aware) in terms of SNV detection. Furthermore, we applied Phylovar to two real biological datasets: an scWES triple-negative breast cancer data consisting of 32 cells and 3375 loci as well as an scWGS data of neuron cells from a normal human brain containing 16 cells and approximately 2.5 million loci. For the cancer data, Phylovar detected somatic SNVs with high or moderate functional impact that were also supported by bulk sequencing dataset and for the neuron dataset, Phylovar identified 5745 SNVs with non-synonymous effects some of which were associated with neurodegenerative diseases.
Availability and implementation Phylovar is implemented in Python and is publicly available at https://github.com/NakhlehLab/Phylovar.
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Coalescent methods are proven and powerful tools for population genetics, phylogenetics, epidemiology, and other fields. A promising avenue for the analysis of large genomic alignments, which are increasingly common, is coalescent hidden Markov model (coalHMM) methods, but these methods have lacked general usability and flexibility. We introduce a novel method for automatically learning a coalHMM and inferring the posterior distributions of evolutionary parameters using black-box variational inference, with the transition rates between local genealogies derived empirically by simulation. This derivation enables our method to work directly with three or four taxa and through a divide-and-conquer approach with more taxa. Using a simulated data set resembling a human–chimp–gorilla scenario, we show that our method has comparable or better accuracy to previous coalHMM methods. Both species divergence times and population sizes were accurately inferred. The method also infers local genealogies, and we report on their accuracy. Furthermore, we discuss a potential direction for scaling the method to larger data sets through a divide-and-conquer approach. This accuracy means our method is useful now, and by deriving transition rates by simulation, it is flexible enough to enable future implementations of various population models.more » « less
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Abstract Species tree inference from multilocus data has emerged as a powerful paradigm in the postgenomic era, both in terms of the accuracy of the species tree it produces as well as in terms of elucidating the processes that shaped the evolutionary history. Bayesian methods for species tree inference are desirable in this area as they have been shown not only to yield accurate estimates, but also to naturally provide measures of confidence in those estimates. However, the heavy computational requirements of Bayesian inference have limited the applicability of such methods to very small data sets. In this article, we show that the computational efficiency of Bayesian inference under the multispecies coalescent can be improved in practice by restricting the space of the gene trees explored during the random walk, without sacrificing accuracy as measured by various metrics. The idea is to first infer constraints on the trees of the individual loci in the form of unresolved gene trees, and then to restrict the sampler to consider only resolutions of the constrained trees. We demonstrate the improvements gained by such an approach on both simulated and biological data.more » « less
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Abstract Motivation Reticulate evolutionary histories, such as those arising in the presence of hybridization, are best modeled as phylogenetic networks. Recently developed methods allow for statistical inference of phylogenetic networks while also accounting for other processes, such as incomplete lineage sorting. However, these methods can only handle a small number of loci from a handful of genomes.
Results In this article, we introduce a novel two-step method for scalable inference of phylogenetic networks from the sequence alignments of multiple, unlinked loci. The method infers networks on subproblems and then merges them into a network on the full set of taxa. To reduce the number of trinets to infer, we formulate a Hitting Set version of the problem of finding a small number of subsets, and implement a simple heuristic to solve it. We studied their performance, in terms of both running time and accuracy, on simulated as well as on biological datasets. The two-step method accurately infers phylogenetic networks at a scale that is infeasible with existing methods. The results are a significant and promising step towards accurate, large-scale phylogenetic network inference.
Availability and implementation We implemented the algorithms in the publicly available software package PhyloNet (https://bioinfocs.rice.edu/PhyloNet).
Supplementary information Supplementary data are available at Bioinformatics online.
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Abstract Phylogenetic networks provide a powerful framework for modeling and analyzing reticulate evolutionary histories. While polyploidy has been shown to be prevalent not only in plants but also in other groups of eukaryotic species, most work done thus far on phylogenetic network inference assumes diploid hybridization. These inference methods have been applied, with varying degrees of success, to data sets with polyploid species, even though polyploidy violates the mathematical assumptions underlying these methods. Statistical methods were developed recently for handling specific types of polyploids and so were parsimony methods that could handle polyploidy more generally yet while excluding processes such as incomplete lineage sorting. In this article, we introduce a new method for inferring most parsimonious phylogenetic networks on data that include polyploid species. Taking gene tree topologies as input, the method seeks a phylogenetic network that minimizes deep coalescences while accounting for polyploidy. We demonstrate the performance of the method on both simulated and biological data. The inference method as well as a method for evaluating evolutionary hypotheses in the form of phylogenetic networks are implemented and publicly available in the PhyloNet software package. [Incomplete lineage sorting; minimizing deep coalescences; multilabeled trees; multispecies network coalescent; phylogenetic networks; polyploidy.]
