Spatial transcriptomics (ST) encompasses rich multi-modal information related to cell state and organization. Precisely identifying spatial domains with consistent gene expression patterns and histological features is a critical task in ST analysis, which requires comprehensive integration of multi-modal information. Here, we propose TriCLFF, a contrastive learning-based multi-modal feature fusion framework, to effectively integrate spatial associations, gene expression levels, and histological features in a unified manner. Leveraging an advanced feature fusion mechanism, our proposed TriCLFF framework outperforms existing state-of-the-art methods in terms of accuracy and robustness across four datasets (mouse brain anterior, mouse olfactory bulb, human dorsolateral prefrontal cortex, and human breast cancer) from different platforms (10x Visium and Stereo-seq) for spatial domain identification. TriCLFF also facilitates the identification of finer-grained structures in breast cancer tissues and detects previously unknown gene expression patterns in the human dorsolateral prefrontal cortex, providing novel insights for understanding tissue functions. Overall, TriCLFF establishes an effective paradigm for integrating spatial multi-modal data, demonstrating its potential for advancing ST research. The source code of TriCLFF is available online at https://github.com/HBZZ168/TriCLFF.

Copy number variants (CNVs) play important roles in human disease and evolution. With the rapid development of next-generation sequencing technologies, many tools have been developed for inferring CNVs based on whole-exome sequencing (WES) data. However, as a result of the sparse distribution of exons in the genome, the limitations of the WES technique, and the nature of high-level signal noises in WES data, the efficacy of these variants remains less than desirable. Thus, there is need for the development of an effective tool to achieve a considerable power in WES CNVs discovery. In the present study, we describe a novel method, Estimation by Read Depth (RD) with Single-nucleotide variants from exome sequencing data (ERDS-exome). ERDS-exome employs a hybrid normalization approach to normalize WES data and to incorporate RD and single-nucleotide variation information together as a hybrid signal into a paired hidden Markov model to infer CNVs from WES data. Based on systematic evaluations of real data from the 1000 Genomes Project using other state-of-the-art tools, we observed that ERDS-exome demonstrates higher sensitivity and provides comparable or even better specificity than other tools. ERDS-exome is publicly available at: https://erds-exome.github.io.

BACKGROUND: Numerous essential algorithms and methods, including entropy-based quantitative methods, have been developed to analyze complex DNA sequences since the last decade. Exons and introns are the most notable components of DNA and their identification and prediction are always the focus of state-of-the-art research. RESULTS: In this study, we designed an integrated entropy-based analysis approach, which involves modified topological entropy calculation, genomic signal processing (GSP) method and singular value decomposition (SVD), to investigate exons and introns in DNA sequences. We optimized and implemented the topological entropy and the generalized topological entropy to calculate the complexity of DNA sequences, highlighting the characteristics of repetition sequences. By comparing digitalizing entropy values of exons and introns, we observed that they are significantly different. After we converted DNA data to numerical topological entropy value, we applied SVD method to effectively investigate exon and intron regions on a single gene sequence. Additionally, several genes across five species are used for exon predictions. CONCLUSIONS: Our approach not only helps to explore the complexity of DNA sequence and its functional elements, but also provides an entropy-based GSP method to analyze exon and intron regions. Our work is feasible across different species and extendable to analyze other components in both coding and noncoding region of DNA sequences.

BACKGROUND: During procedures for conducting multiple sequence alignment, that is so essential to use the substitution score of pairwise alignment. To compute adaptive scores for alignment, researchers usually use Hidden Markov Model or probabilistic consistency methods such as partition function. Recent studies show that optimizing the parameters for hidden Markov model, as well as integrating hidden Markov model with partition function can raise the accuracy of alignment. The combination of partition function and optimized HMM, which could further improve the alignment's accuracy, however, was ignored by these researches. RESULTS: A novel algorithm for MSA called ProbPFP is presented in this paper. It intergrate optimized HMM by particle swarm with partition function. The algorithm of PSO was applied to optimize HMM's parameters. After that, the posterior probability obtained by the HMM was combined with the one obtained by partition function, and thus to calculate an integrated substitution score for alignment. In order to evaluate the effectiveness of ProbPFP, we compared it with 13 outstanding or classic MSA methods. The results demonstrate that the alignments obtained by ProbPFP got the maximum mean TC scores and mean SP scores on these two benchmark datasets: SABmark and OXBench, and it got the second highest mean TC scores and mean SP scores on the benchmark dataset BAliBASE. ProbPFP is also compared with 4 other outstanding methods, by reconstructing the phylogenetic trees for six protein families extracted from the database TreeFam, based on the alignments obtained by these 5 methods. The result indicates that the reference trees are closer to the phylogenetic trees reconstructed from the alignments obtained by ProbPFP than the other methods. CONCLUSIONS: We propose a new multiple sequence alignment method combining optimized HMM and partition function in this paper. The performance validates this method could make a great improvement of the alignment's accuracy.

Detecting copy number variants (CNVs) is an essential part in variant calling process. Here, we describe a novel method ERDS-pe to detect CNVs from whole-exome sequencing (WES) data. ERDS-pe first employs principal component analysis to normalize WES data. Then, ERDS-pe incorporates read depth signal and single-nucleotide variation information together as a hybrid signal into a paired hidden Markov model to infer CNVs from WES data. Experimental results on real human WES data show that ERDS-pe demonstrates higher sensitivity and provides comparable or even better specificity than other tools. ERDS-pe is publicly available at: https://github.com/microtan0902/erds-pe.

MOTIVATION: Whole-genome and -exome sequencing on parent-offspring trios is a powerful approach to identifying disease-associated genes by detecting de novo mutations in patients. Accurate detection of de novo mutations from sequencing data is a critical step in trio-based genetic studies. Existing bioinformatic approaches usually yield high error rates due to sequencing artifacts and alignment issues, which may either miss true de novo mutations or call too many false ones, making downstream validation and analysis difficult. In particular, current approaches have much worse specificity than sensitivity, and developing effective filters to discriminate genuine from spurious de novo mutations remains an unsolved challenge. RESULTS: In this article, we curated 59 sequence features in whole genome and exome alignment context which are considered to be relevant to discriminating true de novo mutations from artifacts, and then employed a machine-learning approach to classify candidates as true or false de novo mutations. Specifically, we built a classifier, named De Novo Mutation Filter (DNMFilter), using gradient boosting as the classification algorithm. We built the training set using experimentally validated true and false de novo mutations as well as collected false de novo mutations from an in-house large-scale exome-sequencing project. We evaluated DNMFilter's theoretical performance and investigated relative importance of different sequence features on the classification accuracy. Finally, we applied DNMFilter on our in-house whole exome trios and one CEU trio from the 1000 Genomes Project and found that DNMFilter could be coupled with commonly used de novo mutation detection approaches as an effective filtering approach to significantly reduce false discovery rate without sacrificing sensitivity. AVAILABILITY: The software DNMFilter implemented using a combination of Java and R is freely available from the website at http://humangenome.duke.edu/software.