Advances in Human Genome Resolution: The Role of Pan-Genomic Strategies and Fine-Tuning Pre-trained Genomic Models

Abstract

The groundbreaking theory of DNA double helix structure has greatly promoted the development of molecular genetics, shaping and refining the genetic central dogma, thus enabling researchers to explore genotype-phenotype regulation at different levels. In particular, with the continued advancement of third-generation sequencing technology, an increasing number of highly accurate human genomes have been assembled, such as T2T-CHM13 and HG002. These high-quality genome sequences not only provide a more comprehensive human reference sequence, but also enable functional genomics studies within a unified coordinate system. To better explore and resolve the complex genetic information encompassed within human genome sequences, scientists have proposed novel research strategies, involving graphical pan-genome and pre-trained genomic models. The graphical pan-genomes provide population- level high-quality references, revealing the genomic diversity within populations and exploring the sequence complexity of specific regions, such as the KIR immune region. Concurrently, related studies of pre-trained models within the human genome offer new perspectives for interpreting sequence functions and delving into the hidden genetic codes, potentially leading to complete DNA decoding. Overall, graphical pan-genome and pre-trained genomic models represent two crucial strategies in genomics research, which will provide more new insights and make greater breakthroughs in the human genome. Together, these approaches have deepened our understanding of the human genome, fostered the development of bioinformatics ecosystems, and will contribute to the establishment and improvement of the entire field. Therefore, this review focuses on DNA sequencing, human genome assembly, high-quality pan-genome and pre-trained genomic large language models (LLMs), highlighting and summarizing the latest achievements and progress in human genome research, discussing existing challenges and providing future perspectives.