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

Abstract

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.

Human Pangenomics: Promises and Challenges of a Distributed Genomic Reference

“…The concept of pangenome has recently been extended to higher-order organisms, and is being applied most notably to the human species [ 49 , 50 , 51 , 52 ]. By extension, the notion of a pangenome is based on the idea that different cell types can be regarded as “species” in their own right, each with a unique constitution of genetic material [ 18 , 53 ].…”

Pangenome graph layout by Path-Guided Stochastic Gradient Descent

“…Reference genomes are widely used in genetics, serving as a foundation for a variety of analyses, including gene annotation, read mapping, and variant detection (Singh et al, 2022). However, this linear model is becoming obsolete given the accessibility to hundreds or even thousands of high-quality genomes.…”

“…A single genome can not fully represent the genetic diversity of any species, resulting in reference bias (Ballouz et al, 2019). In contrast, a pangenome models the entire set of genomic elements of a given population (Tettelin et al, 2008;Computational Pan-Genomics Consortium, 2018;Eizenga et al, 2020;Sherman and Salzberg, 2020). Pangenomes can be represented as a sequence graph incorporating sequences as nodes and their relationships as edges (Hein, 1989).…”

Haplotype-aware sequence alignment to pangenome graphs

“…Pangenome graphs represent the maximum possible diversity that exists in the population [55]. A variety of methods have been developed that use pangenome graphs for common applications including genotyping, variant calling, haplotype reconstruction, etc.…”

“…Pangenome graphs represent the maximum possible diversity that exists in the population [52]. Efforts toward using pangenome graphs have been further catalyzed by the advent of long and accurate reads.…”