TopHap: rapid inference of key phylogenetic structures from common haplotypes in large genome collections with limited diversity

Motivation: Building reliable phylogenies from very large collections of sequences with a limited number of phylogenetically informative sites is challenging because sequencing errors and recurrent/backward mutations interfere with the phylogenetic signal, confounding true evolutionary relationships. Massive global efforts of sequencing genomes and reconstructing the phylogeny of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains exemplify these difficulties since there are only hundreds of phylogenetically informative sites but millions of genomes. For such datasets, we set out to develop a method for building the phylogenetic tree of genomic haplotypes consisting of positions harboring common variants to improve the signal-to-noise ratio for more accurate and fast phylogenetic inference of resolvable phylogenetic features. Results: We present the TopHap approach that determines spatiotemporally common haplotypes of common variants and builds their phylogeny at a fraction of the computational time of traditional methods. We develop a bootstrap strategy that resamples genomes spatiotemporally to assess topological robustness. The application of TopHap to build a phylogeny of 68 057 SARS-CoV-2 genomes (68KG) from the first year of the pandemic produced an evolutionary tree of major SARS-CoV-2 haplotypes. This phylogeny is concordant with the mutation tree inferred using the co-occurrence pattern of mutations and recovers key phylogenetic relationships from more traditional analyses. We also evaluated alternative roots of the SARS-CoV-2 phylogeny and found that the earliest sampled genomes in 2019 likely evolved by four mutations of the most recent common ancestor of all SARS-CoV-2 genomes. An application of TopHap to more than 1 million SARS-CoV-2 genomes reconstructed the most comprehensive evolutionary relationships of major variants, which confirmed the 68KG phylogeny and provided evolutionary origins of major and recent variants of concern.

Automated summary

This study developed a method called TopHap that uses common variant positions to determine spatiotemporally common haplotypes and builds their phylogeny in a fraction of the computational time of traditional methods. Applying TopHap to 68,057 SARS-CoV-2 genomes produced an evolutionary tree of major haplotypes that was consistent with other traditional analyses. The study also evaluated alternative roots of the SARS-CoV-2 phylogeny and discovered that the earliest sampled genomes likely evolved from the most recent common ancestor through four mutations. Additionally, applying TopHap to over 1 million SARS-CoV-2 genomes reconstructed the most comprehensive evolutionary relationships of major variants, confirming the 68KG phylogeny and providing evolutionary origins of major and recent variants of concern.