The present invention discloses a gene sequencing data compression preprocessing, compression and decompression method, a system, and a computer-readable medium. The preprocessing method implementation steps include: obtaining reference genome data; obtaining a mapping relationship between a short string K-mer and a prediction character c to obtain a prediction data model P1 containing any short string K-mer in the positive strand and negative strand of a reference genome and the prediction character c in a corresponding adjacent bit. The compression and decompression methods relate to performing compression/decompression on the basis of the prediction data model P1. The system is a computer system including a program for executing the previous method. The computer-readable medium includes a computer program for executing the previous method. The present invention can be oriented towards lossless gene sequencing data compression, provides fully effective information for a high-performance lossless compression and decompression algorithm for gene sequencing data.