Bioframe: operations on genomic intervals in Pandas dataframes.

MOTIVATION: Genomic intervals are one of the most prevalent data structures in computational genome biology, and used to represent features ranging from genes, to DNA binding sites, to disease variants. Operations on genomic intervals provide a language for asking questions about relationships between features. While there are excellent interval arithmetic tools for the command line, they are not smoothly integrated into Python, one of the most popular general-purpose computational and visualization environments. RESULTS: Bioframe is a library to enable flexible and performant operations on genomic interval dataframes in Python. Bioframe extends the Python data science stack to use cases for computational genome biology by building directly on top of two of the most commonly-used Python libraries, NumPy and Pandas. The bioframe API enables flexible name and column orders, and decouples operations from data formats to avoid unnecessary conversions, a common scourge for bioinformaticians. Bioframe achieves these goals while maintaining high performance and a rich set of features. AVAILABILITY AND IMPLEMENTATION: Bioframe is open-source under MIT license, cross-platform, and can be installed from the Python Package Index. The source code is maintained by Open2C on GitHub at https://github.com/open2c/bioframe.

Pairtools: From sequencing data to chromosome contacts.

The field of 3D genome organization produces large amounts of sequencing data from Hi-C and a rapidly-expanding set of other chromosome conformation protocols (3C+). Massive and heterogeneous 3C+ data require high-performance and flexible processing of sequenced reads into contact pairs. To meet these challenges, we present pairtools-a flexible suite of tools for contact extraction from sequencing data. Pairtools provides modular command-line interface (CLI) tools that can be flexibly chained into data processing pipelines. The core operations provided by pairtools are parsing of.sam alignments into Hi-C pairs, sorting and removal of PCR duplicates. In addition, pairtools provides auxiliary tools for building feature-rich 3C+ pipelines, including contact pair manipulation, filtration, and quality control. Benchmarking pairtools against popular 3C+ data pipelines shows advantages of pairtools for high-performance and flexible 3C+ analysis. Finally, pairtools provides protocol-specific tools for restriction-based protocols, haplotype-resolved contacts, and single-cell Hi-C. The combination of CLI tools and tight integration with Python data analysis libraries makes pairtools a versatile foundation for a broad range of 3C+ pipelines.

Cooltools: Enabling high-resolution Hi-C analysis in Python.

Chromosome conformation capture (3C) technologies reveal the incredible complexity of genome organization. Maps of increasing size, depth, and resolution are now used to probe genome architecture across cell states, types, and organisms. Larger datasets add challenges at each step of computational analysis, from storage and memory constraints to researchers' time; however, analysis tools that meet these increased resource demands have not kept pace. Furthermore, existing tools offer limited support for customizing analysis for specific use cases or new biology. Here we introduce cooltools (https://github.com/open2c/cooltools), a suite of computational tools that enables flexible, scalable, and reproducible analysis of high-resolution contact frequency data. Cooltools leverages the widely-adopted cooler format which handles storage and access for high-resolution datasets. Cooltools provides a paired command line interface (CLI) and Python application programming interface (API), which respectively facilitate workflows on high-performance computing clusters and in interactive analysis environments. In short, cooltools enables the effective use of the latest and largest genome folding datasets.

Crumpled polymer with loops recapitulates key features of chromosome organization.

Chromosomes are exceedingly long topologically-constrained polymers compacted in a cell nucleus. We recently suggested that chromosomes are organized into loops by an active process of loop extrusion. Yet loops remain elusive to direct observations in living cells; detection and characterization of myriads of such loops is a major challenge. The lack of a tractable physical model of a polymer folded into loops limits our ability to interpret experimental data and detect loops. Here, we introduce a new physical model - a polymer folded into a sequence of loops, and solve it analytically. Our model and a simple geometrical argument show how loops affect statistics of contacts in a polymer across different scales, explaining universally observed shapes of the contact probability. Moreover, we reveal that folding into loops reduces the density of topological entanglements, a novel phenomenon we refer as "the dilution of entanglements". Supported by simulations this finding suggests that up to ~ 1 - 2Mb chromosomes with loops are not topologically constrained, yet become crumpled at larger scales. Our theoretical framework allows inference of loop characteristics, draws a new picture of chromosome organization, and shows how folding into loops affects topological properties of crumpled polymers.