De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations

Wong, Karen; Levy‐Sakin, Michal; Kwok, Pui‐Yan

doi:10.1038/s41467-018-05513-w

Cited by 76 publications

(85 citation statements)

References 46 publications

(51 reference statements)

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“…Finally, we ran our method on the well-known CEPH/HapMap NA12878 diploid genome (sequence coverage 52x) and compared it with a recently de novo assembly based method Wong et al (2018) which we will refer to as NUI-pipeline). We obtained high-coverage 10x Chromium Linked-Reads from the publicly available Genome In A Bottle (GIAB) data set (Zook et al (2018)).…”

Section: The Na12878 Diploid Genomementioning

confidence: 99%

“…In what follows, we introduce an integrated mapping-based and assembly-based method, which is significantly more accurate than existing short-read methods for novel insertion discovery. While our method is less efficient that existing short-read methods, it is indeed more efficient compared to the recent Linked-Read algorithms that use whole-genome de novo assembly such as (Weisenfeld et al (2017); Wong et al (2018)) because it uses only a very small fraction of informative Linked-Reads as we describe below. While long-read sequencing is technically impractical for large-scale screening of whole genomes, our Linked-Read method is able to characterize one of the most challenging classes of SVs with a reasonable additional cost to standard short-read sequencing.…”

Section: Introductionmentioning

confidence: 99%

“…Recently developed NUI-pipeline (Wong et al (2018)) calls novel sequence insertions specifically with 10X data. It assembles whole dataset with SuperNova assembler and aligns Figure 1: Schematic comparing novel insertion detection using standard short-reads with Linked-Reads.…”

Section: Introductionmentioning

confidence: 99%

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Detection and assembly of novel sequence insertions using Linked-Read technology

Meleshko

Marks

Williams

et al. 2019

Preprint

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Motivation: Emerging Linked-Read (aka read-cloud) technologies such as the 10x Genomics Chromium system have great potential for accurate detection and phasing of largescale human genome structural variations (SVs). By leveraging the long-range information encoded in Linked-Read sequencing, computational techniques are able to detect and characterize complex structural variations that are previously undetectable by short-read methods. However, there is no available Linked-Read method for detection and assembly of novel sequence insertions, DNA sequences present in a given sequenced sample but missing in the reference genome, without requiring whole genome de novo assembly. In this paper, we propose a novel integrated alignment-based and local-assembly-based algorithm, Novel-X, that effectively uses the barcode information encoded in Linked-Read sequencing datasets to improve detection of such events without the need of whole genome de novo assembly. We evaluated our method on two haploid human genomes, CHM1 and CHM13, sequenced on the 10x Genomics Chromium system. These genomes have been also characterized with high coverage PacBio long-reads recently. We also tested our method on NA12878, the wellknown HapMap CEPH diploid genome and the child genome in a Yoruba trio (NA19240) which was recently studied on multiple sequencing platforms. Detecting insertion events is very challenging using short reads and the only viable available solution is by long-read sequencing (e.g. PabBio or ONT). Our experiments, however, show that Novel-X finds many insertions that cannot be found by state of the art tools using short-read sequencing data but present in PacBio data. Since Linked-Read sequencing is significantly cheaper than long-read sequencing, our method using Linked-Reads enables routine large-scale screenings of sequenced genomes for novel sequence insertions.

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Section: The Na12878 Diploid Genomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Detection and assembly of novel sequence insertions using Linked-Read technology

Meleshko

Marks

Williams

et al. 2019

Preprint

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“…Many studies have pointed out that a single genome is inadequate for a variety of reasons, such as inherent bias towards the reference genome (Need and Goldstein 2009, Popejoy and Fullerton 2016, Ballouz et al 2019. The availability of reference genomes from multiple human populations would greatly aid attempts to find genetic causes of traits that are over-or under-represented in those populations, including susceptibility to disease (Wong et al 2018). Another drawback of relying on a single reference genome is that it almost certainly contains minor alleles at some loci, which in turn confounds studies focused on variant discovery and association of those variants with disease (Ferrarini et al 2015, Magi et al 2015, Barbitoff et al 2018, Wong et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Assembly and Annotation of an Ashkenazi Human Reference Genome

Shumate

Zimin

Sherman

et al. 2020

Preprint

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Here we describe the assembly and annotation of the genome of an Ashkenazi individual and the creation of a new, population-specific human reference genome. This genome is more contiguous and more complete than GRCh38, the latest version of the human reference genome, and is annotated with highly similar gene content. The Ashkenazi reference genome, Ash1, contains 2,973,118,650 nucleotides as compared to 2,937,639,212 in GRCh38. Annotation identified 20,157 protein-coding genes, of which 19,563 are >99% identical to their counterparts on GRCh38. Most of the remaining genes have small differences. 40 of the protein-coding genes in GRCh38 are missing from Ash1; however, all of these genes are members of multi-gene families for which Ash1 contains other copies. 11 genes appear on different chromosomes from their homologs in GRCh38. Alignment of DNA sequences from an unrelated Ashkenazi individual to Ash1 identified ~1 million fewer homozygous SNPs than alignment of those same sequences to the more-distant GRCh38 genome, illustrating one of the benefits of population-specific reference genomes.

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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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De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations

Cited by 76 publications

References 46 publications

Detection and assembly of novel sequence insertions using Linked-Read technology

Detection and assembly of novel sequence insertions using Linked-Read technology

Assembly and Annotation of an Ashkenazi Human Reference Genome

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

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