MOTIVATION: Sequence simulations along phylogenetic trees play an important role in numerous molecular evolution studies such as benchmarking algorithms for ancestral sequence reconstruction, multiple sequence alignment, and phylogeny inference. They are also used in phylogenetic model-selection tasks, including the inference of selective forces. Recently, Approximate Bayesian Computation (ABC)-based approaches have been developed for inferring parameters of complex evolutionary models, which rely on massive generation of simulated data. For all these applications, computationally efficient sequence simulators are essential. RESULTS: In this study, we investigate fast algorithms for simulating sequences along a phylogenetic tree, focusing on accelerating the speed-limiting component of the simulation process: handling insertion and deletion (indel) events. We demonstrate that data structures which efficiently store indel events along a tree can substantially accelerate the simulation process compared to a naive approach. To illustrate the utility of this efficient simulator, we integrated it into an ABC-based algorithm for inferring indel model parameters and applied it to study indel dynamics within Chiroptera. AVAILABILITY AND IMPLEMENTATION: The source code for the different simulation algorithms, alongside the data used, is available at: https://github.com/nimrodSerokTAU/evo-sim. The simulator has also been integrated into SpartaABC, a website for the inference of indel parameters, accessible at: https://spartaabc.tau.ac.il/.

MOTIVATION: Multiple sequence alignments (MSAs) are extensively used in biology, from phylogenetic reconstruction to structure and function prediction. Here, we suggest an out-of-the-box approach for the inference of MSAs, which relies on algorithms developed for processing natural languages. We show that our artificial intelligence (AI)-based methodology can be trained to align sequences by processing alignments that are generated via simulations, and thus different aligners can be easily generated for datasets with specific evolutionary dynamics attributes. We expect that natural language processing (NLP) solutions will replace or augment classic solutions for computing alignments, and more generally, challenging inference tasks in phylogenomics. RESULTS: The MSA problem is a fundamental pillar in bioinformatics, comparative genomics, and phylogenetics. Here, we characterize and improve BetaAlign, the first deep learning aligner, which substantially deviates from conventional algorithms of alignment computation. BetaAlign draws on NLP techniques and trains transformers to map a set of unaligned biological sequences to an MSA. We show that our approach is highly accurate, comparable and sometimes better than state-of-the-art alignment tools. We characterize the performance of BetaAlign and the effect of various aspects on accuracy; for example, the size of the training data, the effect of different transformer architectures, and the effect of learning on a subspace of indel-model parameters (subspace learning). We also introduce a new technique that leads to improved performance compared to our previous approach. Our findings further uncover the potential of NLP-based methods for sequence alignment, highlighting that AI-based algorithms can substantially challenge classic approaches in phylogenomics and bioinformatics. AVAILABILITY AND IMPLEMENTATION: Datasets used in this work are available on HuggingFace (Wolf et al. Transformers: state-of-the-art natural language processing. In: Proceedings of the 2020 Conference on Empirical Methods in Natural Language Processing: System Demonstrations. p.38-45. 2020) at: https://huggingface.co/dotan1111. Source code is available at: https://github.com/idotan286/SimulateAlignments.

MOTIVATION: Deep-learning models are transforming biological research, including many bioinformatics and comparative genomics algorithms, such as sequence alignments, phylogenetic tree inference, and automatic classification of protein functions. Among these deep-learning algorithms, models for processing natural languages, developed in the natural language processing (NLP) community, were recently applied to biological sequences. However, biological sequences are different from natural languages, such as English, and French, in which segmentation of the text to separate words is relatively straightforward. Moreover, biological sequences are characterized by extremely long sentences, which hamper their processing by current machine-learning models, notably the transformer architecture. In NLP, one of the first processing steps is to transform the raw text to a list of tokens. Deep-learning applications to biological sequence data mostly segment proteins and DNA to single characters. In this work, we study the effect of alternative tokenization algorithms on eight different tasks in biology, from predicting the function of proteins and their stability, through nucleotide sequence alignment, to classifying proteins to specific families. RESULTS: We demonstrate that applying alternative tokenization algorithms can increase accuracy and at the same time, substantially reduce the input length compared to the trivial tokenizer in which each character is a token. Furthermore, applying these tokenization algorithms allows interpreting trained models, taking into account dependencies among positions. Finally, we trained these tokenizers on a large dataset of protein sequences containing more than 400 billion amino acids, which resulted in over a 3-fold decrease in the number of tokens. We then tested these tokenizers trained on large-scale data on the above specific tasks and showed that for some tasks it is highly beneficial to train database-specific tokenizers. Our study suggests that tokenizers are likely to be a critical component in future deep-network analysis of biological sequence data. AVAILABILITY AND IMPLEMENTATION: Code, data, and trained tokenizers are available on https://github.com/technion-cs-nlp/BiologicalTokenizers.