First draft of a human pangenome(Nature Biotechnology)

The first draft of a human pangenome reference — a collection that aims to eventually represent as many as possible of the DNA sequences found across our species — is published in Nature this week. The research combines genetic material from a population of 47 genetically diverse individuals to provide a more complete image of the human genome.

The human reference genome has been the backbone of human genomics since its draft release in 2001. However, a single genome cannot represent the genetic diversity present within the human species, due to the presence of structural variants and alternative alleles, some of which were not present in the original reference genome.

In a collection of three papers, the Human Pangenome Reference Consortium presents the first draft human pangenome reference and findings from two studies that use this reference as a basis for new genetic research. The pangenome was developed from a cohort of 47 ancestrally diverse individuals and adds 119 million base pairs and 1,115 gene duplications (mutations in which a region of DNA containing a gene is duplicated) to the current reference human genome (GRCh38). Use of this draft increased the number of structural variants detected by 104% compared to GRCh38, providing a more complete picture of genetic diversity within the human genome.

Two companion papers present associated findings using the human pangenome draft. In the first companion paper, Evan Eichler and colleagues developed a map of single-nucleotide variations (SNVs) within segmental duplications (blocks of DNA that occur at more than one site in a genome and share a high level of sequence identity), characterising millions of previously unmapped SNVs and mutational properties that differ from unique DNA. Erik Garrison and colleagues observe patterns of recombination between the short arms of heterologous acrocentric (where the centromere is located near one end of the chromosome) chromosomes, providing observational evidence for a mechanism of DNA exchange between these chromosomes that had previously been speculated on but not observed, due to the lack of suitable data.

These results are only an interim stage of the envisioned human pangenome, which aims to capture genetic diversity of 350 individuals. Arya Massarat and Melissa Gymrek highlight the importance of these advancements in an accompanying News & Views Forum but note that continued improvements are needed to overcome some remaining challenges, such as the need for even more diverse sampling. “This will ultimately make it easier to discover genetic variants that mediate physical and clinical traits, and — it is to be hoped — will eventually lead to better health outcomes for many people”, they write.

A fourth paper will also publish in Nature Biotechnology.

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