SPLASH: A statistical, reference-free genomic algorithm unifies biological discovery

Kaitlin Chaung; Tavor Z Baharav; George Henderson; Ivan N Zheludev; Peter L Wang; Julia Salzman

doi:10.1016/j.cell.2023.10.028

SPLASH: A statistical, reference-free genomic algorithm unifies biological discovery

Cell. 2023 Dec 7;186(25):5440-5456.e26. doi: 10.1016/j.cell.2023.10.028.

Authors

Kaitlin Chaung¹, Tavor Z Baharav², George Henderson¹, Ivan N Zheludev³, Peter L Wang¹, Julia Salzman⁴

Affiliations

¹ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.
² Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA.
³ Department of Biochemistry, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Biomedical Data Science, Stanford University, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University, Stanford, CA 94305, USA; Department of Statistics (by courtesy), Stanford University, Stanford, CA 94305, USA; Department of Biology (by courtesy), Stanford University, Stanford, CA 94305, USA. Electronic address: julia.salzman@stanford.edu.

Abstract

Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale. We show that SPLASH identifies complex mutation patterns in SARS-CoV-2, discovers regulated RNA isoforms at the single-cell level, detects the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a unifying approach to genomic analysis that enables expansive discovery without metadata or references.

Keywords: RNA-seq; computational biology; genetics; genomics; reference-free; single-cell RNA-seq; splicing; statistics.

MeSH terms

Algorithms*
Genome
Genomics*
HLA Antigens / genetics
Humans
Sequence Analysis, RNA
Single-Cell Analysis

Substances

HLA Antigens

Grants and funding

R35 GM139517/GM/NIGMS NIH HHS/United States