For compressing similar genomes, specialized tools will do better. AGC [1] can compress 620k SARS-CoV-2 genomes (19 GB uncompressed) into tens of MB. More impor

For compressing similar genomes, specialized tools will do better. AGC [1] can compress 620k SARS-CoV-2 genomes (19 GB uncompressed) into tens of MB. More importantly, AGC allows you to extract individual sequences without decompressing the entire file. In addition, zstd/xz wouldn't have a big enough dictionary to compress multiple human genomes efficiently. AGC can compress 300 GB human assemblies to 1.5 GB, a 200-fold compression ratio. I agree for sequence reads, zstd is better than gzip in almost every aspect. The only problem is that zstd is not as widely available. Many Linux distros don't ship zstd by default but on managed clusters, common users don't have the root permission to install zstd system-wide. It is worth mentioning that many mainstream bioinformatics tools can read FASTQ over pipes. You can use something like mytool <(zstd -dc in.fastq.zst) > output.txt # bash; also works on multiple zstd input files zstd -dc in.fastq.zst | mytool - > output.txt # general; for multiple input files, use mkfifo Those who prefer zstd can use it now. [1] https://www.biorxiv.org/content/10.1101/2022.04.07.487441v1 https://www.biorxiv.org/content/10.1101/2022.04.07.487441v1