The design and construction of reference pangenome graphs with minigraph

Li, Heng; Feng, Xiaowen; Chu, Chong

doi:10.1186/s13059-020-02168-z

Cited by 297 publications

(380 citation statements)

References 73 publications

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“…This can help distinguish stabilizing versus fragile motifs (Braida et al 2010) , or resolve some of the problem of missing heritability by discovering new associations between motif and disease (Song, Lowe, and Kingsley 2018) . Finally, this work is a part of ongoing pangenome graph analysis (Paten et al 2017;Li, Feng, and Chu 2020) , and represents an approach to generating pangenome graphs in loci that have difficult multiple sequence alignments or degenerate graph topologies. Additional methods may be developed to harmonize danbing-tk RPGGs with genome-wide pangenome graphs constructed from other methods.…”

Section: Discussionmentioning

confidence: 99%

Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

Chaisson

2020

Preprint

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Variable number tandem repeats (VNTR) are genetic loci composed of consecutive repeats of short segments of DNA, with hypervariable repeat count and composition across individuals. Many genes have coding VNTR sequences, and noncoding VNTR variants are associated with a wide spectrum of clinical disorders such as Alzheimer's disease, bipolar disorder and colorectal cancer. The identification of VNTR length and composition provides the basis for downstream analysis such as expression quantitative trait loci discovery and genome wide association studies. Disease studies that use high-throughput short read sequencing do not resolve the repeat structures of many VNTR loci because the VNTR sequence is missing from the reference or is too repetitive to map. We solve the VNTR mapping problem for short reads by representing a collection of genomes with a repeat-pangenome graph, a data structure that encodes both the population diversity and repeat structure of VNTR loci. We developed software to build a repeat-pangenome using haplotype-resolved single-molecule sequencing assemblies, and to estimate VNTR length and sequence composition based on the alignment of short read sequences to the graph. Using long-read assemblies as ground truth, we are able to determine which VNTR loci may be accurately profiled using repeat-pangenome graph analysis with short reads. This enabled measuring the global diversity of VNTR sequences in the 1000-Genomes Project, and the discovery of expression quantitative trait loci in the Genotype-Tissue Expression Project. This analysis reveals loci that have significant differences in length and repeat composition between continental populations. Furthermore, the repeat pangenome graph analysis establishes an association between previously inaccessible variation and gene expression. Taken together, these indicate that measuring VNTR sequence diversity with repeat-pangenome graphs will be a critical component of future studies on human diversity and disease.

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Section: Discussionmentioning

confidence: 99%

Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

Chaisson

2020

Preprint

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“…Using the bubble popping algorithm of gfatools 21 , we identified 68,328 structural variations present in the multi-assembly graph. To reveal true alleles within these structural variations, we traversed all possible paths through the bubbles (i.e., alleles) and retained only those that were supported by at least one assembly ( Supplementary Fig.…”

Section: Structural Variation Discovery From the Multi-assembly Graphmentioning

confidence: 99%

“…We used minigraph 21 The genetic distance among the six assemblies was estimated using Mash (version 2.2) 22 .…”

Section: Construction Of the Multi-assembly Graphmentioning

confidence: 99%

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Novel functional sequences uncovered through a bovine multi-assembly graph

Crysnanto

Leonard

Fang

et al. 2021

Preprint

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Linear reference genomes are typically assembled from single individuals. They are unable to reflect the genetic diversity of populations and lack millions of bases. To overcome such limitations and make non-reference sequences amenable to genetic investigations, we build a multi-assembly graph from six reference-quality assemblies from taurine cattle and their close relatives. We uncover 70,329,827 bases that are missing in the bovine linear reference genome. The missing sequences encode novel transcripts that are differentially expressed between individual animals. Reads which were previously poorly or unmapped against the bovine reference genome now align accurately to the non-reference sequences. We show that the non-reference sequences contain polymorphic sites that segregate within and between breeds of cattle. Our efforts to uncover novel functional sequences from a multi-assembly graph pave the way towards the transition to a more representative bovine reference genome.

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“…The incorporation of thousands of individuals into a single reference will avoid “reference bias”, and mapping reads to such a pan-genome will improve variant calling, especially in regions with a high density of complex variants [ 107 ]. While many of the proposed pan-genome implementations represent genomes as graphs with shared and private variants, some of the new approaches have proposed elegant ways of creating pan-genome graphs while preserving linear coordinates [ 108 ]. In the future, ultra-long accurate reads, coupled with complete reference pan-genomes, will enable the full understanding of the underlying functional variation hidden in the repetitive parts of the genome.…”

Section: Futurementioning

confidence: 99%

Probably Correct: Rescuing Repeats with Short and Long Reads

Čechová

2020

Genes

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Ever since the introduction of high-throughput sequencing following the human genome project, assembling short reads into a reference of sufficient quality posed a significant problem as a large portion of the human genome—estimated 50–69%—is repetitive. As a result, a sizable proportion of sequencing reads is multi-mapping, i.e., without a unique placement in the genome. The two key parameters for whether or not a read is multi-mapping are the read length and genome complexity. Long reads are now able to span difficult, heterochromatic regions, including full centromeres, and characterize chromosomes from “telomere to telomere”. Moreover, identical reads or repeat arrays can be differentiated based on their epigenetic marks, such as methylation patterns, aiding in the assembly process. This is despite the fact that long reads still contain a modest percentage of sequencing errors, disorienting the aligners and assemblers both in accuracy and speed. Here, I review the proposed and implemented solutions to the repeat resolution and the multi-mapping read problem, as well as the downstream consequences of reference choice, repeat masking, and proper representation of sex chromosomes. I also consider the forthcoming challenges and solutions with regards to long reads, where we expect the shift from the problem of repeat localization within a single individual to the problem of repeat positioning within pangenomes.

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The design and construction of reference pangenome graphs with minigraph

Cited by 297 publications

References 73 publications

Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

Profiling variable-number tandem repeat variation across populations using repeat-pangenome graphs

Novel functional sequences uncovered through a bovine multi-assembly graph

Probably Correct: Rescuing Repeats with Short and Long Reads

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