Linkage Disequilibrium in Targeted Sequencing

We propose an approach for optimizing the development of gene diagnostic panels, which is based on the construction of non-equilibrium linkage maps. In the process of gene selection we essentially use genome-wide association analysis (GWAS). Whole-genome analysis of associations makes it possible to reveal the relationship of genomic variants with the studied phenotype. However, the nucleotide variants that showed the highest degree of association can only be statistically associated with the phenotype, not being the true cause of the phenotype. In this case, they may be in the block of linked inheritance with nucleotide variants that really affect the manifestation of the phenotype. The construction of maps of non-equilibrium linkage of nucleotides makes it possible to optimally determine the boundaries of linkage blocks, in which the desired variants fall. The aim of this study was to optimize the demarcation of genomic loci to create targeted panels aimed at predicting susceptibility to SARS-CoV-2 and the severity of COVID-19. The proposed method for selecting loci for a target panel, taking into account nonequilibrium linkage, makes it possible to use the phenomenon of nonequilibrium linkage in order to maximally cover the regions involved in the development of the phenotype, while simultaneously minimizing the length of these regions, and, at the same time, the cost of sequencing.

[1]  Alexander F. Wilson,et al.  Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis , 2022, Genes.

[2]  Eurie L. Hong,et al.  Whole-genome sequencing reveals host factors underlying critical COVID-19 , 2022, Nature.

[3]  M. Guo,et al.  CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1 , 2022, eBioMedicine.

[4]  B. Mahboub,et al.  Genome-wide association study of hospitalized COVID-19 patients in the United Arab Emirates , 2021, EBioMedicine.

[5]  J. Todd,et al.  Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus , 2021, Nature Genetics.

[6]  Neville E. Sanjana,et al.  Integrative approach identifies SLC6A20 and CXCR6 as putative causal genes for the COVID-19 GWAS signal in the 3p21.31 locus , 2021, Genome biology.

[7]  Nicholette D. Palmer,et al.  A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response , 2021, Nature Genetics.

[8]  Mattia G. Bergomi,et al.  Mapping the human genetic architecture of COVID-19 , 2021, Nature.

[9]  S. Pääbo,et al.  A genomic region associated with protection against severe COVID-19 is inherited from Neandertals , 2021, Proceedings of the National Academy of Sciences.

[10]  Ira M. Hall,et al.  High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios , 2021, Cell.

[11]  S. Semiz.  SIT1 transporter as a potential novel target in treatment of COVID-19 , 2021, Biomolecular concepts.

[12]  Marina C. Gonsales,et al.  Genetic variability in COVID-19-related genes in the Brazilian population , 2020, bioRxiv.

[13]  Shan-Shan Dong,et al.  LDBlockShow: a fast and convenient tool for visualizing linkage disequilibrium and haplotype blocks based on variant call format files , 2020, bioRxiv.

[14]  A. Rahimi,et al.  Genetics and genomics of SARS-CoV-2: A review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection , 2020, Genomics.

[15]  Barbara B. Shih,et al.  Genetic mechanisms of critical illness in COVID-19 , 2020, Nature.

[16]  S. Villapol.  Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome , 2020, Translational Research.

[17]  S. Pääbo,et al.  The major genetic risk factor for severe COVID-19 is inherited from Neanderthals , 2020, bioRxiv.

[18]  J. Erdmann,et al.  Genomewide Association Study of Severe Covid-19 with Respiratory Failure , 2020, The New England journal of medicine.

[19]  I. Amit,et al.  Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19 , 2020, Nature Medicine.

[20]  Jing Zhao,et al.  Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia , 2020, The New England journal of medicine.

[21]  Findlay Bewicke-Copley,et al.  Applications and analysis of targeted genomic sequencing in cancer studies , 2019, Computational and structural biotechnology journal.

[22]  Dahui Qin.  Next-generation sequencing and its clinical application , 2019, Cancer biology & medicine.

[23]  D. Schaid,et al.  From genome-wide associations to candidate causal variants by statistical fine-mapping , 2018, Nature Reviews Genetics.

[24]  A. F. Wilson,et al.  A variant associated with sagittal nonsyndromic craniosynostosis alters the regulatory function of a non‐coding element , 2017, American journal of medical genetics. Part A.

[25]  Cisca Wijmenga,et al.  The MHC locus and genetic susceptibility to autoimmune and infectious diseases , 2017, Genome Biology.

[26]  T. Kitamoto,et al.  Targeted next-generation sequencing and fine linkage disequilibrium mapping reveals association of PNPLA3 and PARVB with the severity of nonalcoholic fatty liver disease , 2014, Journal of Human Genetics.

[27]  Alexander F. Wilson,et al.  A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9 , 2012, Nature Genetics.

[28]  Marylyn D. Ritchie,et al.  A comparison of cataloged variation between International HapMap Consortium and 1000 Genomes Project data , 2012, J. Am. Medical Informatics Assoc..

[29]  Jinko Graham,et al.  LDheatmap: An R Function for Graphical Display of Pairwise Linkage Disequilibria Between Single Nucleotide Polymorphisms , 2006 .

[30]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[31]  Simon C. Potter,et al.  An overview of Ensembl. , 2004, Genome research.

[32]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[33]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.