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1. Accurate and efficient cell lineage tree inference from noisy single cell data: the maximum likelihood perfect phylogeny approach

   https://doi.org/10.1093/bioinformatics/btz676  

   Wu, Yufeng (August 2019, Bioinformatics)

   Schwartz, Russell (Ed.)

   Abstract Motivation Cells in an organism share a common evolutionary history, called cell lineage tree. Cell lineage tree can be inferred from single cell genotypes at genomic variation sites. Cell lineage tree inference from noisy single cell data is a challenging computational problem. Most existing methods for cell lineage tree inference assume uniform uncertainty in genotypes. A key missing aspect is that real single cell data usually has non-uniform uncertainty in individual genotypes. Moreover, existing methods are often sampling based and can be very slow for large data. Results In this article, we propose a new method called ScisTree, which infers cell lineage tree and calls genotypes from noisy single cell genotype data. Different from most existing approaches, ScisTree works with genotype probabilities of individual genotypes (which can be computed by existing single cell genotype callers). ScisTree assumes the infinite sites model. Given uncertain genotypes with individualized probabilities, ScisTree implements a fast heuristic for inferring cell lineage tree and calling the genotypes that allow the so-called perfect phylogeny and maximize the likelihood of the genotypes. Through simulation, we show that ScisTree performs well on the accuracy of inferred trees, and is much more efficient than existing methods. The efficiency of ScisTree enables new applications including imputation of the so-called doublets. Availability and implementation The program ScisTree is available for download at: https://github.com/yufengwudcs/ScisTree. Supplementary information Supplementary data are available at Bioinformatics online. 

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2. Sparse Convolutional Denoising Autoencoders for Genotype Imputation

   https://doi.org/10.3390/genes10090652  

   Chen, Junjie; Shi, Xinghua (September 2019, Genes)

   Genotype imputation, where missing genotypes can be computationally imputed, is an essential tool in genomic analysis ranging from genome wide associations to phenotype prediction. Traditional genotype imputation methods are typically based on haplotype-clustering algorithms, hidden Markov models (HMMs), and statistical inference. Deep learning-based methods have been recently reported to suitably address the missing data problems in various fields. To explore the performance of deep learning for genotype imputation, in this study, we propose a deep model called a sparse convolutional denoising autoencoder (SCDA) to impute missing genotypes. We constructed the SCDA model using a convolutional layer that can extract various correlation or linkage patterns in the genotype data and applying a sparse weight matrix resulted from the L1 regularization to handle high dimensional data. We comprehensively evaluated the performance of the SCDA model in different scenarios for genotype imputation on the yeast and human genotype data, respectively. Our results showed that SCDA has strong robustness and significantly outperforms popular reference-free imputation methods. This study thus points to another novel application of deep learning models for missing data imputation in genomic studies. 

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3. Matrix (factorization) reloaded: flexible methods for imputing genetic interactions with cross-species and side information

   https://doi.org/10.1093/bioinformatics/btaa818  

   Fan, Jason; Li, Xuan Cindy; Crovella, Mark; Leiserson, Mark D (December 2020, Bioinformatics)

   null (Ed.)

   Abstract Motivation Mapping genetic interactions (GIs) can reveal important insights into cellular function and has potential translational applications. There has been great progress in developing high-throughput experimental systems for measuring GIs (e.g. with double knockouts) as well as in defining computational methods for inferring (imputing) unknown interactions. However, existing computational methods for imputation have largely been developed for and applied in baker’s yeast, even as experimental systems have begun to allow measurements in other contexts. Importantly, existing methods face a number of limitations in requiring specific side information and with respect to computational cost. Further, few have addressed how GIs can be imputed when data are scarce. Results In this article, we address these limitations by presenting a new imputation framework, called Extensible Matrix Factorization (EMF). EMF is a framework of composable models that flexibly exploit cross-species information in the form of GI data across multiple species, and arbitrary side information in the form of kernels (e.g. from protein–protein interaction networks). We perform a rigorous set of experiments on these models in matched GI datasets from baker’s and fission yeast. These include the first such experiments on genome-scale GI datasets in multiple species in the same study. We find that EMF models that exploit side and cross-species information improve imputation, especially in data-scarce settings. Further, we show that EMF outperforms the state-of-the-art deep learning method, even when using strictly less data, and incurs orders of magnitude less computational cost. Availability Implementations of models and experiments are available at: https://github.com/lrgr/EMF. Supplementary information Supplementary data are available at Bioinformatics online. 

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4. SAILER: scalable and accurate invariant representation learning for single-cell ATAC-seq processing and integration

   https://doi.org/10.1093/bioinformatics/btab303  

   Cao, Yingxin; Fu, Laiyi; Wu, Jie; Peng, Qinke; Nie, Qing; Zhang, Jing; Xie, Xiaohui (July 2021, Bioinformatics)

   null (Ed.)

   Abstract Motivation Single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) provides new opportunities to dissect epigenomic heterogeneity and elucidate transcriptional regulatory mechanisms. However, computational modeling of scATAC-seq data is challenging due to its high dimension, extreme sparsity, complex dependencies and high sensitivity to confounding factors from various sources. Results Here, we propose a new deep generative model framework, named SAILER, for analyzing scATAC-seq data. SAILER aims to learn a low-dimensional nonlinear latent representation of each cell that defines its intrinsic chromatin state, invariant to extrinsic confounding factors like read depth and batch effects. SAILER adopts the conventional encoder-decoder framework to learn the latent representation but imposes additional constraints to ensure the independence of the learned representations from the confounding factors. Experimental results on both simulated and real scATAC-seq datasets demonstrate that SAILER learns better and biologically more meaningful representations of cells than other methods. Its noise-free cell embeddings bring in significant benefits in downstream analyses: clustering and imputation based on SAILER result in 6.9% and 18.5% improvements over existing methods, respectively. Moreover, because no matrix factorization is involved, SAILER can easily scale to process millions of cells. We implemented SAILER into a software package, freely available to all for large-scale scATAC-seq data analysis. Availability and implementation The software is publicly available at https://github.com/uci-cbcl/SAILER. Supplementary information Supplementary data are available at Bioinformatics online. 

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5. A beginner's guide to low‐coverage whole genome sequencing for population genomics

   https://doi.org/10.1111/mec.16077  

   Lou, Runyang Nicolas; Jacobs, Arne; Wilder, Aryn P.; Therkildsen, Nina Overgaard (August 2021, Molecular Ecology)

   Abstract Low‐coverage whole genome sequencing (lcWGS) has emerged as a powerful and cost‐effective approach for population genomic studies in both model and nonmodel species. However, with read depths too low to confidently call individual genotypes, lcWGS requires specialized analysis tools that explicitly account for genotype uncertainty. A growing number of such tools have become available, but it can be difficult to get an overview of what types of analyses can be performed reliably with lcWGS data, and how the distribution of sequencing effort between the number of samples analysed and per‐sample sequencing depths affects inference accuracy. In this introductory guide to lcWGS, we first illustrate how the per‐sample cost for lcWGS is now comparable to RAD‐seq and Pool‐seq in many systems. We then provide an overview of software packages that explicitly account for genotype uncertainty in different types of population genomic inference. Next, we use both simulated and empirical data to assess the accuracy of allele frequency, genetic diversity, and linkage disequilibrium estimation, detection of population structure, and selection scans under different sequencing strategies. Our results show that spreading a given amount of sequencing effort across more samples with lower depth per sample consistently improves the accuracy of most types of inference, with a few notable exceptions. Finally, we assess the potential for using imputation to bolster inference from lcWGS data in nonmodel species, and discuss current limitations and future perspectives for lcWGS‐based population genomics research. With this overview, we hope to make lcWGS more approachable and stimulate its broader adoption. 

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