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ABSTRACT Genomes usually contain some non-repetitive sequences that are missing from the reference genome and occur only in a population subset. Such non-repetitive, non-reference (NRNR)

sequences have remained largely unexplored in terms of their characterization and downstream analyses. Here we describe 3,791 breakpoint-resolved NRNR sequence variants called using PopIns

from whole-genome sequence data of 15,219 Icelanders. We found that over 95% of the 244 NRNR sequences that are 200 bp or longer are present in chimpanzees, indicating that they are

ancestral. Furthermore, 149 variant loci are in linkage disequilibrium (_r_2 > 0.8) with a genome-wide association study (GWAS) catalog marker, suggesting disease relevance. Additionally,

we report an association (_P_ = 3.8 × 10−8, odds ratio (OR) = 0.92) with myocardial infarction (23,360 cases, 300,771 controls) for a 766-bp NRNR sequence variant. Our results underline the

importance of including variation of all complexity levels when searching for variants that associate with disease. Access through your institution Buy or subscribe This is a preview of

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HUMAN GENOMES Article Open access 14 September 2023 A DRAFT HUMAN PANGENOME REFERENCE Article Open access 10 May 2023 A DEEP POPULATION REFERENCE PANEL OF TANDEM REPEAT VARIATION Article

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Article  PubMed  PubMed Central  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * deCODE Genetics/Amgen, Inc., Reykjavik, Iceland Birte Kehr, Anna

Helgadottir, Pall Melsted, Hakon Jonsson, Hannes Helgason, Adalbjörg Jonasdottir, Aslaug Jonasdottir, Asgeir Sigurdsson, Arnaldur Gylfason, Gisli H Halldorsson, Snaedis Kristmundsdottir, 

Hilma Holm, Unnur Thorsteinsdottir, Patrick Sulem, Agnar Helgason, Daniel F Gudbjartsson, Bjarni V Halldorsson & Kari Stefansson * Berlin Institute of Health, Berlin, Germany Birte Kehr

* School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland Pall Melsted, Hannes Helgason & Daniel F Gudbjartsson * Faculty of Medicine, School of Health

Sciences, University of Iceland, Reykjavik, Iceland Gudmundur Thorgeirsson, Unnur Thorsteinsdottir & Kari Stefansson * Department of Internal Medicine, Landspitali–National University

Hospital, Reykjavik, Iceland Gudmundur Thorgeirsson & Hilma Holm * Department of Clinical Biochemistry, Landspitali–National University Hospital, Reykjavik, Iceland Isleifur Olafsson *

Department of Anthropology, University of Iceland, Reykjavik, Iceland Agnar Helgason * School of Science and Engineering, Reykjavik University, Reykjavik, Iceland Bjarni V Halldorsson

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this author inPubMed Google Scholar CONTRIBUTIONS B.K., P.M., B.V.H. and K.S. designed the experiments. B.K., P.M., A.G., S.K., D.F.G. and B.V.H. implemented the methodology and analyzed the

call set. B.K., A. Helgadottir, H. Holm, P.S., D.F.G. and B.V.H. interpreted the association results. B.K., H. Helgason and G.H.H. analyzed gene expression. Aslaug Jonasdottir, Adalbjorg

Jonasdottir, and A.S. performed PCR verification and Sanger sequencing. U.T. oversaw the operations of the genotyping facilities. G.T., I.O., H. Holm and U.T. were responsible for phenotype

data acquisition. B.K. prepared tables and figures. B.K., H.J., A. Helgason and B.V.H. wrote the manuscript. All authors reviewed and approved the final manuscript. K.S. supervised the

study. CORRESPONDING AUTHORS Correspondence to Bjarni V Halldorsson or Kari Stefansson. ETHICS DECLARATIONS COMPETING INTERESTS B.K., A. Helgadottir, P.M., H.J., H. Helgason, Adalbjorg

Jonasdottir, Aslaug Jonasdottir, A.S., A.G., G.H.H., S.K., H. Holm, P.S., U.T., A. Helgason, D.F.G., B.V.H. and K.S. are all employees of deCODE Genetics/Amgen, Inc. INTEGRATED SUPPLEMENTARY

INFORMATION SUPPLEMENTARY FIGURE 1 PRIMER PAIRS DESIGNED FOR THE FIVE CATEGORIES OF NRNR SEQUENCE VARIANTS FOR VALIDATION BY SANGER SEQUENCING. For the categories “INS > 200” and “DEL

> INS”, two or three primer pairs were designed including at least one for each allele. For “INS < 200”, only a single primer pair was designed that may amplify in both alleles. For

“Different contig” always three and for “Singleton” always two primer pairs were designed. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figure 1, Supplementary

Tables 2, 7 and 8, and Supplementary Note (PDF 1950 kb) SUPPLEMENTARY DATA 1: NRNR SEQUENCES ANCHORED BY IMPUTED NRNR MARKERS. Sequences are given in FASTA format. (TXT 2129 kb)

SUPPLEMENTARY DATA 2: NRNR SEQUENCES ANCHORED BY FIXED NRNR MARKERS. Fixed are those markers that were predicted to have 100% frequency in Iceland. Sequences are given in FASTA format. (TXT

288 kb) SUPPLEMENTARY TABLE 1 List of imputed NRNR markers. (XLSX 623 kb) SUPPLEMENTARY TABLE 3 Details of Sanger sequencing validation experiments. (XLSX 65 kb) SUPPLEMENTARY TABLE 4 List

of fixed NRNR markers. (XLSX 48 kb) SUPPLEMENTARY TABLE 5 Overlap of NRNR markers with known variants and sequences. (XLSX 358 kb) SUPPLEMENTARY TABLE 6 Correlation with the GWAS catalog.

(XLSX 84 kb) SUPPLEMENTARY TABLE 9 Conversion to GenBank sequences. (XLSX 163 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Kehr, B., Helgadottir,

A., Melsted, P. _et al._ Diversity in non-repetitive human sequences not found in the reference genome. _Nat Genet_ 49, 588–593 (2017). https://doi.org/10.1038/ng.3801 Download citation *

Received: 10 October 2016 * Accepted: 03 February 2017 * Published: 27 February 2017 * Issue Date: April 2017 * DOI: https://doi.org/10.1038/ng.3801 SHARE THIS ARTICLE Anyone you share the

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