Genome sequencing is one of the key applications in healthcare and has a great potential to realize precision medicine and personalized healthcare. However, its computing process is very time consuming. Even pre-processing the raw sequence data of a whole genome for a single person to the analysis ready data can take several days on a single-core CPU.In this paper, we propose to accelerate the performance of the widely used Genome Analysis ToolKit (GATK) using FPGAs. More specifically, we focus on the algorithm and hardware co-design for the Base Quality Score Re-calibration (BQSR) step in GATK, which is an important and time-consuming step to correct systematic errors made by a sequencing machine. Prior studies did not consider hardware acceleration for BQSR because it requires a large amount of memory with random access and has a lot of control flow. To address these challenges, we first adapt the algorithm to resolve the random memory access conflicts to achieve a fully pipelined accelerator design and reduce its dataset size. Second, we leverage the newly introduced large-capacity UltraRAM (URAM) in Xilinx UltraScale+ FPGAs to butter BQSR's large dataset on chip, and further optimize its operating frequency. Finally, we also explore the coarse-grained pipeline and parallelism to improve the overall performance of the BQSR accelerator. Compared to the latest software implementation of BQSR on GATK 4.1, running on single-thread and 56-thread CPUs (14nm Xeon E5-2680 v4), our FPGA accelerator running on Xilinx 16nmUltraScale+VCUl525 board achieves up to 40. 7x and 8. 5x speedups, respectively.