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Pan-genomics in the human genome era

Abstract

Since the early days of the genome era, the scientific community has relied on a single ‘reference’ genome for each species, which is used as the basis for a wide range of genetic analyses, including studies of variation within and across species. As sequencing costs have dropped, thousands of new genomes have been sequenced, and scientists have come to realize that a single reference genome is inadequate for many purposes. By sampling a diverse set of individuals, one can begin to assemble a pan-genome: a collection of all the DNA sequences that occur in a species. Here we review efforts to create pan-genomes for a range of species, from bacteria to humans, and we further consider the computational methods that have been proposed in order to capture, interpret and compare pan-genome data. As scientists continue to survey and catalogue the genomic variation across human populations and begin to assemble a human pan-genome, these efforts will increase our power to connect variation to human diversity, disease and beyond.

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Fig. 1: Core and dispensable genomes.
Fig. 2: Graphical representations of pan-genomes.
Fig. 3: Addition of variants increases alignment ambiguity.
Fig. 4: Two-step alignment method.
Fig. 5: Variant discovery from a pan-genome reference.

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Acknowledgements

This work was supported in part by the National Institutes of Health under grants R01-HL129239, R01-HG006677 and R35-GM130151.

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R.M.S. researched data for the article. Both authors wrote the manuscript.

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Correspondence to Rachel M. Sherman.

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Glossary

Reference genomes

A reference genome is a genome sequence that is used as the representative for the species — typically, the most polished and complete sequence available for the species.

Long-read sequencing

Sequencing reads on the order of 5–10 kb (Pacific Biosciences) or longer, in some cases up to 1–2 Mb in length (Oxford Nanopore Technologies). Long reads are more expensive to generate and have higher error than short reads (100–250 bp in length).

Core genome

The genes or sequence shared between all individuals of a species (or other grouping).

Dispensable genome

The genes or sequence not shared between all individuals of a species (or other grouping). Everything that is not a part of the core genome is part of the dispensable genome, and vice versa.

Singleton

A sequence found only in a single individual in the study population or group.

Transcriptome

The sequences of only the exon regions, typically inferred by sequencing RNA transcripts rather than DNA directly.

Alignment

The process of computationally lining up sequencing reads to a genome (typically a reference) in order to determine where they are likely to have originated from in the genome.

Assembly

The process of overlapping sequencing reads from many copies of a genome in order to piece together short sequences into longer sequences. Assembly is often performed for a whole genome, particularly when no reference is available for alignment, but it can be performed locally, as well as on regions or subsets of reads.

Haplotype

A sequence on one of the two homologous chromosomes of an organism’s diploid genome. In humans, haplotypes are considered in contrast to using a single sequence to represent that sequence on both homologous copies of a chromosome.

Admixed

An individual with genetic ancestry from multiple distinct populations.

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Sherman, R.M., Salzberg, S.L. Pan-genomics in the human genome era. Nat Rev Genet 21, 243–254 (2020). https://doi.org/10.1038/s41576-020-0210-7

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