Is it time to change the reference genome?

Ballouz, Sara; Dobin, Alexander; Gillis, Jesse

doi:10.1186/s13059-019-1774-4

Cited by 164 publications

(127 citation statements)

References 75 publications

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“…Because we compared graph-based mapping to the most-widely used linear mapping approach, we did not tune BWA mem. Our results show that a bovine breed-specific consensus sequence also improves linear mapping which corroborates recent findings in humans [5,27]. Because the adjusted consensus reference is also a linear sequence, tools that rely on a linear representation of the reference sequence can be used for read mapping and variant discovery.…”

Section: Discussionsupporting

confidence: 87%

“…Previous studies reported that linear mapping may be more accurate using population-specific than universal linear reference sequences [5,27,28]. In order to construct bovine linear consensus reference sequences, we replaced the alleles of the chromosome 25 ARS-UCD1.2 reference sequence with corresponding major alleles at 67,142 and 73,011 variants that were detected in 82 BSW and 288 cattle from four breeds, respectively.…”

Section: Linear Mapping Accuracy Using a Consensus Reference Sequencementioning

confidence: 99%

“…Recently generated de novo assemblies exceed in quality and continuity all current reference sequences [3,4]. However, modifications and amendments to existing linear reference sequences causes shifts in their coordinates that require large efforts from the genomics community to make data compatible with updated reference sequences [5].…”

Section: Introductionmentioning

confidence: 99%

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Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery

Crysnanto

Pausch

2019

Preprint

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BackgroundThe current bovine genomic reference sequence was assembled from the DNA of a Hereford cow.The resulting linear assembly lacks diversity because it does not contain allelic variation. Lack of diversity is a drawback of linear references that causes reference allele bias. High nucleotide diversity and the separation of individuals by hundreds of breeds make cattle ideally suited to investigate the optimal composition of variation-aware references. ResultsWe augment the bovine linear reference sequence (ARS-UCD1.2) with variants filtered for allele frequency in dairy (Brown Swiss, Holstein) and dual-purpose (Fleckvieh, Original Braunvieh) cattle breeds to construct either breed-specific or pan-genome reference graphs using the vg toolkit. We find that read mapping is more accurate to variation-aware than linear references if pre-selected variants are used to construct the genome graphs. Graphs that contain random variants do not improve read mapping over the linear reference sequence. Breed-specific augmented and pangenome graphs enable almost similar mapping accuracy improvements over the linear reference.We construct a whole-genome graph that contains the Hereford-based reference sequence and 14 million alleles that have alternate allele frequency greater than 0.03 in the Brown Swiss cattle breed.We show that our novel variation-aware reference facilitates accurate read mapping and unbiased sequence variant genotyping for SNPs and Indels. ConclusionsWe developed the first variation-aware reference graph for an agricultural animal: https://doi.org/10.5281/zenodo.3570312. Our novel reference structure improves sequence read mapping and variant genotyping over the linear reference. Our work is a first step towards the transition from linear to variation-aware reference structures in species with high genetic diversity and many sub-populations.

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Section: Discussionsupporting

confidence: 87%

Section: Linear Mapping Accuracy Using a Consensus Reference Sequencementioning

confidence: 99%

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Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery

Crysnanto

Pausch

2019

Preprint

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“…The sampling of more individuals from multiple African populations can further reveal the genetic diversity in Africa and can thereby substantiate our understanding of allelic diversity in IG loci. The recent completion of the African reference genome (69) can put this divergence in a different perspective, particularly when compared with the more narrow diversity of the European reference genomes (71, 72).…”

Section: Discussionmentioning

confidence: 99%

Population matched (PM) germline allelic variants of immunoglobulin (IG) loci: New pmIG database to better understandIGrepertoire and selection processes in disease and vaccination

Khatri

Berkowska

Akker

et al. 2020

Preprint

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At the population level, immunoglobulin (IG) loci harbor inter-individual allelic variants in the many different germline IG variable (V), Diversity (D) and Joining (J) genes of the IG heavy (IGH), IG kappa (IGK) and IG lambda (IGL) loci, which together form the genetic basis of the highly diverse antigen-specific B-cell receptors. These inter-individual allelic variants can be shared between or be specific to human populations. The current IG databases IMGT, VBASE2 and IgPdb hold information about germline alleles, most of which are partial sequences, obtained from a mixture of human (B-cell) samples, many with sequence errors and/or acquired (non-germline) IG variations, induced by somatic hypermutation (SHM) during antigen-specific B-cell responses. We systematically identified true germline alleles (without SHM) from 26 different human populations around the world, profiled by the “1000 Genomes data”. Our resource is uniquely enriched with complete IG allele sequences and their frequencies across human populations. We identified 409 IGHV, 179 IGKV, and 199 IGLV germline alleles supported by at least seven haplotypes (= minimum of four individuals), after removal of potential false-positives, based on using other genomic databases, i.e. ENSEMBL, TopMed, ExAC, ProjectMine. Remarkably, the positions of the identified variant nucleotides of the different alleles are not at random (as observed in case of SHM), but show striking patterns, restricted to limited nucleotide positions, the same as found in other IG data bases, suggesting over-time evolutionary selection processes. The identification of these specific patterns provides extra evidence that the identified variant nucleotides are not sequencing errors, but genuine allelic variants. The diversity of germline allelic variants in IGH and IGL loci is the highest in Africans, while the IGK locus is most diverse in Europeans. We also report on the presence of recombination signal sequences (RSS) in V pseudogenes, explaining their usage in V(D)J rearrangements. We propose that this new set of genuine germline IG sequences can serve as a new population-matched IG (pmIG) database for better understanding B-cell repertoire and B-cell receptor selection processes in disease and vaccination within and between different human populations. The database in format of fasta is available via GitHub (https://github.com/InduKhatri/pmIG). Contribution to the Field Statement We present a catalogue of immunoglobulin (IG) germline-alleles of unprecedented completeness and accuracy from 26 different human populations belonging to five different large ethnicities (Source: 1000 Genomes). We identified the population distribution of several known germline alleles and identified multiple new alleles, especially in African populations, indicative of high allelic diversity of IG genes in Africa. Strikingly, the identified variant nucleotides of the different alleles are not at random, but show striking patterns, restricted to limited nucleotide positions, the same as found in ot...

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“…Geographic and local population genetic stratification and variation complicate the ability to diagnose and treat medical conditions [32] (for additional exposition, see Addendum A.1). The predictive utility of GWAS and GWAS PRSs also varies broadly if the risk score is applied to a population other than the one for which the score was initially determined [33][34][35]. At the same time, there are many indications of the commonality of causal gene variants for polygenic diseases among geographically distinct populations [36,37], while admixed populations present an intermediate liability to diseases [38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

Oliynyk

2019

Preprint

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With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early-to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk, however the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If gene therapies that prevent heritable diseases were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

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Is it time to change the reference genome?

Cited by 164 publications

References 75 publications

Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery

Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery

Population matched (PM) germline allelic variants of immunoglobulin (IG) loci: New pmIG database to better understandIGrepertoire and selection processes in disease and vaccination

Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

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