A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response

2021 ◽  
Vol 53 (10) ◽  
pp. 1504-1516
Author(s):  
Yang Luo ◽  
Masahiro Kanai ◽  
Wanson Choi ◽  
Xinyi Li ◽  
Saori Sakaue ◽  
...  
Keyword(s):  
High Resolution ◽  
Fine Mapping ◽  
Host Response ◽  
Population Diversity ◽  
Reference Panel ◽  
Global Population

scholarly journals A high-resolution HLA reference panel capturing global population diversity enables multi-ethnic fine-mapping in HIV host response

2020 ◽  
Author(s):  
Yang Luo ◽  
Masahiro Kanai ◽  
Wanson Choi ◽  
Xinyi Li ◽  
Kenichi Yamamoto ◽  
...  
Keyword(s):  
High Resolution ◽  
Fine Mapping ◽  
Association Studies ◽  
Population Group ◽  
Population Diversity ◽  
Reference Panel ◽  
Whole Genome Sequencing Data ◽  
Genome Wide Association Studies ◽  
Sequencing Data ◽  
Hla Haplotypes

Defining causal variation by fine-mapping can be more effective in multi-ethnic genetic studies, particularly in regions such as the MHC with highly population-specific structure. To enable such studies, we constructed a large (N=21,546) high resolution HLA reference panel spanning five global populations based on whole-genome sequencing data. Expectedly, we observed unique long-range HLA haplotypes within each population group. Despite this, we demonstrated consistently accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in Admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT)). We jointly analyzed genome-wide association studies (GWAS) of HIV-1 viral load from EUR, AA and LAT populations. Our analysis pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide binding groove, explaining 12.9% of trait variance, and obviating effects of previously reported associations from population-specific HIV studies.

Population diversity of B-locus alleles observed by high-resolution DNA typing

1995 ◽  
Vol 45 (3) ◽  
pp. 153-168 ◽  
Author(s):  
M. Fernandez-Viña ◽  
A. M. Lazaro ◽  
Y. Sun ◽  
S. Miller ◽  
L. Forero ◽  
...  
Keyword(s):  
High Resolution ◽  
Dna Typing ◽  
Population Diversity ◽  
B Locus

Ready to clone: CNV detection and breakpoint fine-mapping in breast and ovarian cancer susceptibility genes by high-resolution array CGH

2016 ◽  
Vol 159 (3) ◽  
pp. 585-590 ◽  
Author(s):  
Karl Hackmann ◽  
Franziska Kuhlee ◽  
Elitza Betcheva-Krajcir ◽  
Anne-Karin Kahlert ◽  
Luisa Mackenroth ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Resolution ◽  
Fine Mapping ◽  
Array Cgh ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Breast And Ovarian Cancer ◽  
Cancer Susceptibility Genes ◽  
Cnv Detection

scholarly journals Examining the Impact of Imputation Errors on Fine-Mapping Using DNA Methylation QTL as a Model Trait

Genetics ◽  
2019 ◽  
Vol 212 (3) ◽  
pp. 577-586 ◽  
Author(s):  
V. Kartik Chundru ◽  
Riccardo E. Marioni ◽  
James G. D. Prendergast ◽  
Costanza L. Vallerga ◽  
Tian Lin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fine Mapping ◽  
Complex Traits ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Imputation Accuracy ◽  
Reference Panel ◽  
Whole Genome Sequence ◽  
Strong Linkage Disequilibrium ◽  
The Impact

Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models to test fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (Bayesian imputation-based association mapping, Bayesian sparse linear mixed model, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same individuals (n = 1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Project Phase 3 (1000G) reference panel (n = 2504 from 26 populations) giving a mean nonreference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel (n = 32,470 Europeans). These imputation errors had an impact on whether the CpG-SNP was included in the 95% credible set, with a difference of ∼23% and ∼7% between the WGS and the 1000G and HRC imputed datasets, respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary cis genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong linkage disequilibrium with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low-level biological trait with imputed genetic data has implications for the study of higher-order complex traits and disease.

scholarly journals Progress in Developing Inhibitors of SARS-CoV-2 3C-Like Protease

2020 ◽  
Vol 8 (8) ◽  
pp. 1250 ◽  
Author(s):  
Qingxin Li ◽  
CongBao Kang
Keyword(s):  
High Resolution ◽  
World Health ◽  
Structural Basis ◽  
Valuable Insight ◽  
Structural Studies ◽  
Nonstructural Proteins ◽  
Enveloped Virus ◽  
Main Protease ◽  
Health Organization ◽  
Global Population

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral outbreak started in late 2019 and rapidly became a serious health threat to the global population. COVID-19 was declared a pandemic by the World Health Organization in March 2020. Several therapeutic options have been adopted to prevent the spread of the virus. Although vaccines have been developed, antivirals are still needed to combat the infection of this virus. SARS-CoV-2 is an enveloped virus, and its genome encodes polyproteins that can be processed into structural and nonstructural proteins. Maturation of viral proteins requires cleavages by proteases. Therefore, the main protease (3 chymotrypsin-like protease (3CLpro) or Mpro) encoded by the viral genome is an attractive drug target because it plays an important role in cleaving viral polyproteins into functional proteins. Inhibiting this enzyme is an efficient strategy to block viral replication. Structural studies provide valuable insight into the function of this protease and structural basis for rational inhibitor design. In this review, we describe structural studies on the main protease of SARS-CoV-2. The strategies applied in developing inhibitors of the main protease of SARS-CoV-2 and currently available protein inhibitors are summarized. Due to the availability of high-resolution structures, structure-guided drug design will play an important role in developing antivirals. The availability of high-resolution structures, potent peptidic inhibitors, and diverse compound scaffolds indicate the feasibility of developing potent protease inhibitors as antivirals for COVID-19.

Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity

2019 ◽  
Vol 21 (5) ◽  
pp. 1806-1817 ◽  
Author(s):  
Wei-Yang Bai ◽  
Xiao-Wei Zhu ◽  
Pei-Kuan Cong ◽  
Xue-Jun Zhang ◽  
J Brent Richards ◽  
...  
Keyword(s):  
Chinese Population ◽  
Large Scale ◽  
Imputation Accuracy ◽  
European Population ◽  
Han Chinese ◽  
Population Diversity ◽  
Genotype Imputation ◽  
Reference Panel ◽  
Systematic Evaluation ◽  
Han Chinese Population

Abstract Here, 622 imputations were conducted with 394 customized reference panels for Han Chinese and European populations. Besides validating the fact that imputation accuracy could always benefit from the increased panel size when the reference panel was population specific, the results brought two new thoughts. First, when the haplotype size of the reference panel was fixed, the imputation accuracy of common and low-frequency variants (Minor Allele Frequency (MAF) > 0.5%) decreased while the population diversity of the reference panel increased, but for rare variants (MAF < 0.5%), a small fraction of diversity in panel could improve imputation accuracy. Second, when the haplotype size of the reference panel was increased with extra population-diverse samples, the imputation accuracy of common variants (MAF > 5%) for the European population could always benefit from the expanding sample size. However, for the Han Chinese population, the accuracy of all imputed variants reached the highest when reference panel contained a fraction of an extra diverse sample (8–21%). In addition, we evaluated the imputation performances in the existing reference panels, such as the Haplotype Reference Consortium (HRC), 1000 Genomes Project Phase 3 and the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE). For the European population, the HRC panel showed the best performance in our analysis. For the Han Chinese population, we proposed an optimum imputation reference panel constituent ratio if researchers would like to customize their own sequenced reference panel, but a high-quality and large-scale Chinese reference panel was still needed. Our findings could be generalized to the other populations with conservative genome; a tool was provided to investigate other populations of interest (https://github.com/Abyss-bai/reference-panel-reconstruction).

scholarly journals An ultra-high density linkage map and QTL mapping for sex and growth-related traits of common carp (Cyprinus carpio)

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Wenzhu Peng ◽  
Jian Xu ◽  
Yan Zhang ◽  
Jianxin Feng ◽  
Chuanju Dong ◽  
...  
Keyword(s):  
High Resolution ◽  
Linkage Map ◽  
Common Carp ◽  
Fine Mapping ◽  
Genetic Linkage ◽  
Genetic Linkage Map ◽  
High Density ◽  
Sex Dimorphism ◽  
Qtl Fine Mapping ◽  
High Density Linkage Map

Abstract High density genetic linkage maps are essential for QTL fine mapping, comparative genomics and high quality genome sequence assembly. In this study, we constructed a high-density and high-resolution genetic linkage map with 28,194 SNP markers on 14,146 distinct loci for common carp based on high-throughput genotyping with the carp 250 K single nucleotide polymorphism (SNP) array in a mapping family. The genetic length of the consensus map was 10,595.94 cM with an average locus interval of 0.75 cM and an average marker interval of 0.38 cM. Comparative genomic analysis revealed high level of conserved syntenies between common carp and the closely related model species zebrafish and medaka. The genome scaffolds were anchored to the high-density linkage map, spanning 1,357 Mb of common carp reference genome. QTL mapping and association analysis identified 22 QTLs for growth-related traits and 7 QTLs for sex dimorphism. Candidate genes underlying growth-related traits were identified, including important regulators such as KISS2, IGF1, SMTLB, NPFFR1 and CPE. Candidate genes associated with sex dimorphism were also identified including 3KSR and DMRT2b. The high-density and high-resolution genetic linkage map provides an important tool for QTL fine mapping and positional cloning of economically important traits, and improving common carp genome assembly.

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