Generative Language Models on Nucleotide Sequences of Human Genes

Language models, primarily transformer-based ones, obtained colossal success in NLP. To be more precise, studies like BERT in NLU and works such as GPT-3 for NLG are very crucial. DNA sequences are very close to natural language in terms of structure, so if the DNA-related bioinformatics domain is concerned, discriminative models, like DNABert, exist. Yet, the generative side of the coin is mainly unexplored to the best of our knowledge. Consequently, we focused on developing an autoregressive generative language model like GPT-3 for DNA sequences. Because working with whole DNA sequences is challenging without substantial computational resources, we decided to carry out our study on a smaller scale, focusing on nucleotide sequences of human genes, unique parts in DNA with specific functionalities, instead of the whole DNA. This decision did not change the problem structure a lot due to the fact that both DNA and genes can be seen as 1D sequences consisting of four different nucleotides without losing much information and making too much simplification. First of all, we systematically examined an almost entirely unexplored problem and observed that RNNs performed the best while simple techniques like N-grams were also promising. Another beneficial point was learning how to work with generative models on languages we do not understand, unlike natural language. How essential using real-life tasks beyond the classical metrics such as perplexity is observed. Furthermore, checking whether the data-hungry nature of these models can be changed through selecting a language with minimal vocabulary size, four owing to four different types of nucleotides, is examined. The reason for reviewing this was that choosing such a language might make the problem easier. However, what we observed in this study was it did not provide that much of a change in the amount of data needed

Scalable Profiling and Visualization for Characterizing Microbiomes

Metagenomics is the study of the combined genetic material found in microbiome samples, and it serves as an instrument for studying microbial communities, their biodiversities, and the relationships to their host environments. Creating, interpreting, and understanding microbial community profiles produced from microbiome samples is a challenging task as it requires large computational resources along with innovative techniques to process and analyze datasets that can contain terabytes of information. The community profiles are critical because they provide information about what microorganisms are present in the sample, and in what proportions. This is particularly important as many human diseases and environmental disasters are linked to changes in microbiome compositions. In this work we propose novel approaches for the creation and interpretation of microbial community profiles. This includes: (a) a cloud-based, distributed computational system that generates detailed community profiles by processing large DNA sequencing datasets against large reference genome collections, (b) the creation of Microbiome Maps: interpretable, high-resolution visualizations of community profiles, and (c) a machine learning framework for characterizing microbiomes from the Microbiome Maps that delivers deep insights into microbial communities. The proposed approaches have been implemented in three software solutions: Flint, a large scale profiling framework for commercial cloud systems that can process millions of DNA sequencing fragments and produces microbial community profiles at a very low cost; Jasper, a novel method for creating Microbiome Maps, which visualizes the abundance profiles based on the Hilbert curve; and Amber, a machine learning framework for characterizing microbiomes using the Microbiome Maps generated by Jasper with high accuracy. Results show that Flint scales well for reference genome collections that are an order of magnitude larger than those used by competing tools, while using less than a minute to profile a million reads on the cloud with 65 commodity processors. Microbiome maps produced by Jasper are compact, scalable representations of extremely complex microbial community profiles with numerous demonstrable advantages, including the ability to display latent relationships that are hard to elicit. Finally, experiments show that by using images as input instead of unstructured tabular input, the carefully engineered software, Amber, can outperform other sophisticated machine learning tools available for classification of microbiomes

Synthetic biology routes to bio-artificial intelligence

The design of synthetic gene networks (SGNs) has advanced to the extent that novel genetic circuits are now being tested for their ability to recapitulate archetypal learning behaviours first defined in the fields of machine and animal learning. Here, we discuss the biological implementation of a perceptron algorithm for linear classification of input data. An expansion of this biological design that encompasses cellular 'teachers' and 'students' is also examined. We also discuss implementation of Pavlovian associative learning using SGNs and present an example of such a scheme and in silico simulation of its performance. In addition to designed SGNs, we also consider the option to establish conditions in which a population of SGNs can evolve diversity in order to better contend with complex input data. Finally, we compare recent ethical concerns in the field of artificial intelligence (AI) and the future challenges raised by bio-artificial intelligence (BI)

Using signal processing, evolutionary computation, and machine learning to identify transposable elements in genomes

About half of the human genome consists of transposable elements (TE's), sequences that have many copies of themselves distributed throughout the genome. All genomes, from bacterial to human, contain TE's. TE's affect genome function by either creating proteins directly or affecting genome regulation. They serve as molecular fossils, giving clues to the evolutionary history of the organism. TE's are often challenging to identify because they are fragmentary or heavily mutated. In this thesis, novel features for the detection and study of TE's are developed. These features are of two types. The first type are statistical features based on the Fourier transform used to assess reading frame use. These features measure how different the reading frame use is from that of a random sequence, which reading frames the sequence is using, and the proportion of use of the active reading frames. The second type of feature, called side effect machine (SEM) features, are generated by finite state machines augmented with counters that track the number of times the state is visited. These counters then become features of the sequence. The number of possible SEM features is super-exponential in the number of states. New methods for selecting useful feature subsets that incorporate a genetic algorithm and a novel clustering method are introduced. The features produced reveal structural characteristics of the sequences of potential interest to biologists. A detailed analysis of the genetic algorithm, its fitness functions, and its fitness landscapes is performed. The features are used, together with features used in existing exon finding algorithms, to build classifiers that distinguish TE's from other genomic sequences in humans, fruit flies, and ciliates. The classifiers achieve high accuracy (> 85%) on a variety of TE classification problems. The classifiers are used to scan large genomes for TE's. In addition, the features are used to describe the TE's in the newly sequenced ciliate, Tetrahymena thermophile to provide information for biologists useful to them in forming hypotheses to test experimentally concerning the role of these TE's and the mechanisms that govern them

Extreme Scale De Novo Metagenome Assembly

Metagenome assembly is the process of transforming a set of short, overlapping, and potentially erroneous DNA segments from environmental samples into the accurate representation of the underlying microbiomes's genomes. State-of-the-art tools require big shared memory machines and cannot handle contemporary metagenome datasets that exceed Terabytes in size. In this paper, we introduce the MetaHipMer pipeline, a high-quality and high-performance metagenome assembler that employs an iterative de Bruijn graph approach. MetaHipMer leverages a specialized scaffolding algorithm that produces long scaffolds and accommodates the idiosyncrasies of metagenomes. MetaHipMer is end-to-end parallelized using the Unified Parallel C language and therefore can run seamlessly on shared and distributed-memory systems. Experimental results show that MetaHipMer matches or outperforms the state-of-the-art tools in terms of accuracy. Moreover, MetaHipMer scales efficiently to large concurrencies and is able to assemble previously intractable grand challenge metagenomes. We demonstrate the unprecedented capability of MetaHipMer by computing the first full assembly of the Twitchell Wetlands dataset, consisting of 7.5 billion reads - size 2.6 TBytes.Comment: Accepted to SC1

One-Class Classification: Taxonomy of Study and Review of Techniques

One-class classification (OCC) algorithms aim to build classification models when the negative class is either absent, poorly sampled or not well defined. This unique situation constrains the learning of efficient classifiers by defining class boundary just with the knowledge of positive class. The OCC problem has been considered and applied under many research themes, such as outlier/novelty detection and concept learning. In this paper we present a unified view of the general problem of OCC by presenting a taxonomy of study for OCC problems, which is based on the availability of training data, algorithms used and the application domains applied. We further delve into each of the categories of the proposed taxonomy and present a comprehensive literature review of the OCC algorithms, techniques and methodologies with a focus on their significance, limitations and applications. We conclude our paper by discussing some open research problems in the field of OCC and present our vision for future research.Comment: 24 pages + 11 pages of references, 8 figure

Exploiting structural and topological information to improve prediction of RNA-protein binding sites

The breast and ovarian cancer susceptibility gene BRCA1 encodes a multifunctional tumor suppressor protein BRCA1, which is involved in regulating cellular processes such as cell cycle, transcription, DNA repair, DNA damage response and chromatin remodeling. BRCA1 protein, located primarily in cell nuclei, interacts with multiple proteins and various DNA targets. It has been demonstrated that BRCA1 protein binds to damaged DNA and plays a role in the transcriptional regulation of downstream target genes. As a key protein in the repair of DNA double-strand breaks, the BRCA1-DNA binding properties, however, have not been reported in detail