Haplotype-resolved assembly of diploid genomes without parental data

Cheng, Haoyu; Jarvis, Erich D.; Fédrigo, Olivier; Koepfli, Klaus‐Peter; Urban, Lara; Gemmell, Neil J.; Li, Heng

doi:10.1038/s41587-022-01261-x

Cited by 289 publications

(231 citation statements)

References 20 publications

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“…Similarly, the trio and a non-trio version of hifiasm followed by the scaffolding approach used here for HPRC-HG002 have been adopted by other large-scale sequencing projects, such as the VGP, the Earth Biogenome Project (EBP), and the Darwin Tree of Life Project (DToL). Improvements have also been made to some of the other assembly algorithms since the versions tested here 27,52,53,54 . But thus far, the trio-graph-based approach with trio-based scaffolding still yields the best combination of the highest quality metrics.…”

Section: A Look Towards the Futurementioning

confidence: 99%

“…Towards this end, using Hi-C or Strand-seq data for haplotype phasing are promising alternatives, as both data types contain within-chromosome haplotype information of an individual. To date, three methods have successfully used Hi-C, including FALCON Phase 21 , hifiasm (Hi-C) 53 and pstools 55 , and another has used Strand-Seq 52 to generate maternal and paternal phased long-read based human genome assemblies with fewer switch errors, including on HG002. As with trio binning, these approaches appear to work best when phasing is integrated with the assembly process, but further improvements are necessary to match or surpass the quality metrics seen with a parental trio-graph-based approach used here.…”

Section: Mainmentioning

confidence: 99%

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Automated assembly of high-quality diploid human reference genomes

Jarvis

Formenti

Rhie

et al. 2022

Preprint

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The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has greatly benefited society. However, it still has many gaps and errors, and does not represent a biological human genome since it is a blend of multiple individuals. Recently, a high-quality telomere-to-telomere reference genome, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a duplicate genome, and is thus nearly homozygous. To address these limitations, the Human Pangenome Reference Consortium (HPRC) recently formed with the goal of creating a collection of high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity. Here, in our first scientific report, we determined which combination of current genome sequencing and automated assembly approaches yields the most complete, accurate, and cost-effective diploid genome assemblies with minimal manual curation. Approaches that used highly accurate long reads and parent-child data to sort haplotypes during assembly outperformed those that did not. Developing a combination of all the top performing methods, we generated our first high-quality diploid reference assembly, containing only ~4 gaps (range 0-12) per chromosome, most within + 1% of CHM13 length. Nearly 1/4th of protein coding genes have synonymous amino acid changes between haplotypes, and centromeric regions showed the highest density of variation. Our findings serve as a foundation for assembling near-complete diploid human genomes at the scale required for constructing a human pangenome reference that captures all genetic variation from single nucleotides to large structural rearrangements.

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Section: A Look Towards the Futurementioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Automated assembly of high-quality diploid human reference genomes

Jarvis

Formenti

Rhie

et al. 2022

Preprint

Self Cite

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“…The ability of hifiasm, and to a lesser extent Shasta with diploid-aware polishing, to assemble phased haplotypes from purebred individuals also avoids ethical and logistical concerns regarding the higher heterozygosity crosses previously targeted (Koren et al, 2018). In situations where parental data is unavailable, accurate haplotype phasing is still possible with supplementary data on the offspring (Cheng, Jarvis, et al, 2021;Porubsky et al, 2020). Our results show that HiFi reads alone are sufficient for contig-level phasing for higher heterozygosity individuals like the GxP (Supplementary Figure 7).…”

Section: Discussionmentioning

confidence: 83%

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Leonard

Crysnanto

Fang

et al. 2021

Preprint

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Advantages of pangenomes over linear reference assemblies for genome research have recently been established. However, potential effects of sequence platform and assembly approach, or of combining assemblies created by different approaches, on pangenome construction have not been investigated. Ten haplotype-resolved assemblies of three bovine trios representing increasing levels of heterozygosity were generated that each demonstrate a substantial improvement in contiguity and accuracy over the current Bos taurus reference genome, with more telomere and centromere content and an average 2.5x increase in NG50 and 11x decrease in base errors. Downsampling analysis demonstrated that diploid coverage as low as 20x for HiFi or 60x for ONT was sufficient to produce two haplotype-resolved assemblies meeting the standards set by the Vertebrate Genome Project. The assemblies were integrated into structural variant-based pangenomes that demonstrated significant consensus regardless of sequence platform, assembler algorithm, or coverage. Inspecting pangenome topologies identified approximately 900 structural variants overlapping with coding sequences; this approach revealed variants affecting QRICH2, PRDM9, HSPA1A, TAS2R46 and GC that have potential to affect phenotype.

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“…Furthermore, reconstruction of the haplotype in the 200 kb region surrounding HBB suggested that the HbS mutations were derived from three subpopulations within Africa (West, West-Central, and East Africa), indicating that there is not a founder population for the sickle cell mutation [37]. However, newer technologies such as PacBio and Oxford Nanopore long-read sequencing along with Hi-C [40], as well as recent efforts in the Telomere-to-Telomere (T2T) sequencing project and developing a repository of diverse whole genomes may provide further insights [41].…”

Section: Connection Between Rmc and Sickle Hemoglobinopathiesmentioning

confidence: 99%

Recent Advances in Renal Medullary Carcinoma

Hong

2022

IJMS

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Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field.

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Haplotype-resolved assembly of diploid genomes without parental data

Cited by 289 publications

References 20 publications

Automated assembly of high-quality diploid human reference genomes

Automated assembly of high-quality diploid human reference genomes

Structural variant-based pangenome construction has low sensitivity to variability of haplotype-resolved bovine assemblies

Recent Advances in Renal Medullary Carcinoma

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