From the reference human genome to human pangenome: Premise, promise and challenge.

The Reference Human Genome remains the single most important resource for mapping genetic variations and assessing their impact. However, it is monophasic, incomplete and not representative of the variation that exists in the population. Given the extent of ethno-geographic diversity and the consequent diversity in clinical manifestations of these variations, population specific references were developed overtime. The dramatically plummeting cost of sequencing whole genomes and the advent of third generation long range sequencers allowing accurate, error free, telomere-to-telomere assemblies of human genomes present us with a unique and unprecedented opportunity to develop a more composite standard reference consisting of a collection of multiple genomes that capture the maximal variation existing in the population, with the deepest annotation possible, enabling a realistic, reliable and actionable estimation of clinical significance of specific variations. The Human Pangenome Project thus is a logical next step promising a more accurate and global representation of genomic variations. The pangenome effort must be reciprocally complemented with precise variant discovery tools and exhaustive annotation to ensure unambiguous clinical assessment of the variant in ethno-geographical context. Here we discuss a broad roadmap, the challenges and way forward in developing a universal pangenome reference including data visualization techniques and integration of prior knowledge base in the new graph based architecture and tools to submit, compare, query, annotate and retrieve relevant information from the pangenomes. The biggest challenge, however, will be the ethical, legal and social implications and the training of human resource to the new reference paradigm.