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1.
Sci Adv ; 9(32): eadg6319, 2023 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-37556544

RESUMO

Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.


Assuntos
População do Leste Asiático , Estudo de Associação Genômica Ampla , Humanos , Genoma Humano , Polimorfismo de Nucleotídeo Único , Genótipo , Receptores Acoplados a Proteínas G/genética
2.
Hum Genomics ; 15(1): 58, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454617

RESUMO

BACKGROUND: Low-pass sequencing (LPS) has been extensively investigated for applicability to various genetic studies due to its advantages over genotype array data including cost-effectiveness. Predicting the risk of complex diseases such as Parkinson's disease (PD) using polygenic risk score (PRS) based on the genetic variations has shown decent prediction accuracy. Although ultra-LPS has been shown to be effective in PRS calculation, array data has been favored to the majority of PRS analysis, especially for PD. RESULTS: Using eight high-coverage WGS, we assessed imputation approaches for downsampled LPS data ranging from 0.5 × to 7.0 × . We demonstrated that uncertain genotype calls of LPS diminished imputation accuracy, and an imputation approach using genotype likelihoods was plausible for LPS. Additionally, comparing imputation accuracies between LPS and simulated array illustrated that LPS had higher accuracies particularly at rare frequencies. To evaluate ultra-low coverage data in PRS calculation for PD, we prepared low-coverage WGS and genotype array of 87 PD cases and 101 controls. Genotype imputation of array and downsampled LPS were conducted using a population-specific reference panel, and we calculated risk scores based on the PD-associated SNPs from an East Asian meta-GWAS. The PRS models discriminated cases and controls as previously reported when both LPS and genotype array were used. Also strong correlations in PRS models for PD between LPS and genotype array were discovered. CONCLUSIONS: Overall, this study highlights the potentials of LPS under 1.0 × followed by genotype imputation in PRS calculation and suggests LPS as attractive alternatives to genotype array in the area of precision medicine for PD.


Assuntos
Predisposição Genética para Doença , Herança Multifatorial/genética , Doença de Parkinson/genética , Sequenciamento Completo do Genoma/estatística & dados numéricos , Adulto , Idoso , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
3.
Genome Med ; 11(1): 64, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640730

RESUMO

Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversity of Korean (n = 850) and Mongolian (n = 384) ancestries that were not present in the 1000 Genomes Project Phase 3 (1KGP3). We combined and re-phased the genotypes from NARD and 1KGP3 to construct a union set of haplotypes. This approach established a robust imputation reference panel for Northeast Asians, which yields the greatest imputation accuracy of rare and low-frequency variants compared with the existing panels. NARD imputation panel is available at https://nard.macrogen.com/ .


Assuntos
Povo Asiático/genética , Genética Populacional , Genoma Humano , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/normas , Frequência do Gene , Genótipo , Humanos , Padrões de Referência
4.
Nature ; 538(7624): 243-247, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27706134

RESUMO

Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.


Assuntos
Povo Asiático/genética , Mapeamento de Sequências Contíguas , Genoma Humano/genética , Genômica , Haplótipos/genética , Análise de Sequência de DNA , Alelos , Cromossomos Artificiais Bacterianos/genética , Citocromo P-450 CYP2D6/genética , Diploide , Variação Genética/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Medicina de Precisão , Padrões de Referência , República da Coreia
5.
Nat Commun ; 4: 2433, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24045858

RESUMO

Tigers and their close relatives (Panthera) are some of the world's most endangered species. Here we report the de novo assembly of an Amur tiger whole-genome sequence as well as the genomic sequences of a white Bengal tiger, African lion, white African lion and snow leopard. Through comparative genetic analyses of these genomes, we find genetic signatures that may reflect molecular adaptations consistent with the big cats' hypercarnivorous diet and muscle strength. We report a snow leopard-specific genetic determinant in EGLN1 (Met39>Lys39), which is likely to be associated with adaptation to high altitude. We also detect a TYR260G>A mutation likely responsible for the white lion coat colour. Tiger and cat genomes show similar repeat composition and an appreciably conserved synteny. Genomic data from the five big cats provide an invaluable resource for resolving easily identifiable phenotypes evident in very close, but distinct, species.


Assuntos
Genoma/genética , Leões/genética , Panthera/genética , Tigres/genética , Adaptação Fisiológica/genética , Sequência de Aminoácidos , Animais , Variação Genética , Dados de Sequência Molecular , Mutação/genética , Densidade Demográfica , Sintenia/genética
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