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<p>Conventional genome mapping-based approaches systematically overlook genetic variation, particularly in regions that substantially differ from the reference. To explore this hidden variation, here we examine unmapped and poorly mapped reads from the genomes of 640 human individuals from South Asian populations in the 1000 Genomes Project and the Simons Genome Diversity Project. We assemble tens of megabases of non-redundant sequence in tens of thousands of large contigs, a significant portion of which is present in both South Asian and other populations. We demonstrate that much of this sequence is not discovered by traditional variant discovery approaches even when using complete genomes and pangenomes. Across 20,000 placed contigs, we find 8215 intersections with 106 protein coding genes and over 15,000 placements within 1 kbp of a known GWAS hit. We use long-read data from a subset of samples to validate the majority of their assembled sequences, align RNA-seq data to identify hundreds of unplaced contigs with transcriptional potential, and query existing nucleotide databases to infer the origins of the remaining unplaced sequences. Our results highlight the limitations of even the most complete reference genomes and provide a model for understanding the distribution of hidden variation in any human population.</p>

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Assembling unmapped reads reveals hidden variation in South Asian genomes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Arun Das,
  • Arjun Biddanda,
  • Rajiv C. McCoy,
  • Michael C. Schatz

摘要

Conventional genome mapping-based approaches systematically overlook genetic variation, particularly in regions that substantially differ from the reference. To explore this hidden variation, here we examine unmapped and poorly mapped reads from the genomes of 640 human individuals from South Asian populations in the 1000 Genomes Project and the Simons Genome Diversity Project. We assemble tens of megabases of non-redundant sequence in tens of thousands of large contigs, a significant portion of which is present in both South Asian and other populations. We demonstrate that much of this sequence is not discovered by traditional variant discovery approaches even when using complete genomes and pangenomes. Across 20,000 placed contigs, we find 8215 intersections with 106 protein coding genes and over 15,000 placements within 1 kbp of a known GWAS hit. We use long-read data from a subset of samples to validate the majority of their assembled sequences, align RNA-seq data to identify hundreds of unplaced contigs with transcriptional potential, and query existing nucleotide databases to infer the origins of the remaining unplaced sequences. Our results highlight the limitations of even the most complete reference genomes and provide a model for understanding the distribution of hidden variation in any human population.