Home LiteratureArticle Details
PMID: 23435088 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Using population admixture to help complete maps of the human genome.

Nature genetics ·Vol. 45 ·No. 4 ·2013-04-00 ·Pages 406-14, 414e1-2

Genovese G, Handsaker RE, Li H, Altemose N, Lindgren AM, Chambert K, Pasaniuc B, Price AL, Reich D, Morton CC, Pollak MR, Wilson JG, McCarroll SA

Abstract

Tens of millions of base pairs of euchromatic human genome sequence, including many protein-coding genes, have no known location in the human genome. We describe an approach for localizing the human genome's missing pieces using the patterns of genome sequence variation created by population admixture. We mapped the locations of 70 scaffolds spanning 4 million base pairs of the human genome's unplaced euchromatic sequence, including more than a dozen protein-coding genes, and identified 8 new large interchromosomal segmental duplications. We find that most of these sequences are hidden in the genome's heterochromatin, particularly its pericentromeric regions. Many cryptic, pericentromeric genes are expressed at the RNA level and have been maintained intact for millions of years while their expression patterns diverged from those of paralogous genes elsewhere in the genome. We describe how knowledge of the locations of these sequences can inform disease association and genome biology studies.

MeSH Terms
Chromosome Mapping Computational Biology Euchromatin/genetics Evolution, Molecular Gene Duplication Genetic Variation/genetics Genetics, Population Genome, Human Heterochromatin/genetics Humans In Situ Hybridization, Fluorescence
Chemicals
Euchromatin Heterochromatin
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Genovese Giulio
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Handsaker Robert E
Li Heng
Altemose Nicolas
Lindgren Amelia M
Chambert Kimberly
Pasaniuc Bogdan
Price Alkes L
Reich David
Morton Cynthia C
Pollak Martin R
Wilson James G
McCarroll Steven A
References (63)
63 references, click to expand
  1. Rare chromosomal deletions and duplications increase risk of schizophrenia.
    Nature. 2008 Sep 11;455(7210):237-41 PMID: 18668038
  2. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  3. A high-resolution recombination map of the human genome.
    Nat Genet. 2002 Jul;31(3):241-7 PMID: 12053178
  4. Initial impact of the sequencing of the human genome.
    Nature. 2011 Feb 10;470(7333):187-97 PMID: 21307931
  5. BAGE genes generated by juxtacentromeric reshuffling in the Hominidae lineage are under selective pressure.
    Genomics. 2003 Apr;81(4):391-9 PMID: 12676563
  6. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes.
    N Engl J Med. 2008 Oct 16;359(16):1685-99 PMID: 18784092
  7. Sensitive detection of chromosomal segments of distinct ancestry in admixed populations.
    PLoS Genet. 2009 Jun;5(6):e1000519 PMID: 19543370
  8. Integrative genomics viewer.
    Nat Biotechnol. 2011 Jan;29(1):24-6 PMID: 21221095
  9. A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss.
    Am J Hum Genet. 2010 May 14;86(5):797-804 PMID: 20451170
  10. Construction of a genetic linkage map in man using restriction fragment length polymorphisms.
    Am J Hum Genet. 1980 May;32(3):314-31 PMID: 6247908
  11. An integrated map of genetic variation from 1,092 human genomes.
    Nature. 2012 Nov 1;491(7422):56-65 PMID: 23128226
  12. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease.
    Circ Res. 2004 Jun 11;94(11):1429-35 PMID: 15117819
  13. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis.
    Cell. 2010 Jan 8;140(1):88-98 PMID: 20074522
  14. A map of human genome variation from population-scale sequencing.
    Nature. 2010 Oct 28;467(7319):1061-73 PMID: 20981092
  15. Fast and accurate long-read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2010 Mar 1;26(5):589-95 PMID: 20080505
  16. A second-generation linkage map of the human genome.
    Nature. 1992 Oct 29;359(6398):794-801 PMID: 1436057
  17. Admixture mapping comes of age.
    Annu Rev Genomics Hum Genet. 2010;11:65-89 PMID: 20594047
  18. GenBank.
    Nucleic Acids Res. 2011 Jan;39(Database issue):D32-7 PMID: 21071399
  19. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale.
    Nat Genet. 2011 Mar;43(3):269-76 PMID: 21317889
  20. False positive peaks in ChIP-seq and other sequencing-based functional assays caused by unannotated high copy number regions.
    Bioinformatics. 2011 Aug 1;27(15):2144-6 PMID: 21690102
  21. The structure and evolution of centromeric transition regions within the human genome.
    Nature. 2004 Aug 19;430(7002):857-64 PMID: 15318213
  22. Recent segmental duplications in the human genome.
    Science. 2002 Aug 9;297(5583):1003-7 PMID: 12169732
  23. Physical and genetic mapping of the human X chromosome centromere: repression of recombination.
    Genome Res. 1998 Feb;8(2):100-10 PMID: 9477338
  24. Human-specific duplication and mosaic transcripts: the recent paralogous structure of chromosome 22.
    Am J Hum Genet. 2002 Jan;70(1):83-100 PMID: 11731936
  25. Integration of cytogenetic landmarks into the draft sequence of the human genome.
    Nature. 2001 Feb 15;409(6822):953-8 PMID: 11237021
  26. Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT).
    PLoS Genet. 2011 Jun;7(6):e1002108 PMID: 21738479
  27. A whole-genome admixture scan finds a candidate locus for multiple sclerosis susceptibility.
    Nat Genet. 2005 Oct;37(10):1113-8 PMID: 16186815
  28. Segmental duplications and the evolution of the primate genome.
    Nat Rev Genet. 2002 Jan;3(1):65-72 PMID: 11823792
  29. The diploid genome sequence of an individual human.
    PLoS Biol. 2007 Sep 4;5(10):e254 PMID: 17803354
  30. Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.
    Nat Genet. 2008 Dec;40(12):1466-71 PMID: 19029900
  31. An assessment of the sequence gaps: unfinished business in a finished human genome.
    Nat Rev Genet. 2004 May;5(5):345-54 PMID: 15143317
  32. Characterization of missing human genome sequences and copy-number polymorphic insertions.
    Nat Methods. 2010 May;7(5):365-71 PMID: 20440878
  33. A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011 May;43(5):491-8 PMID: 21478889
  34. Building the sequence map of the human pan-genome.
    Nat Biotechnol. 2010 Jan;28(1):57-63 PMID: 19997067
  35. Modernizing reference genome assemblies.
    PLoS Biol. 2011 Jul;9(7):e1001091 PMID: 21750661
  36. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data.
    Bioinformatics. 2011 Nov 1;27(21):2987-93 PMID: 21903627
  37. A 360-kb interchromosomal duplication of the human HYDIN locus.
    Genomics. 2006 Dec;88(6):762-771 PMID: 16938426
  38. The landscape of recombination in African Americans.
    Nature. 2011 Jul 20;476(7359):170-5 PMID: 21775986
  39. Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals.
    Nat Genet. 2011 Jul 03;43(8):745-52 PMID: 21725310
  40. The 200-kb segmental duplication on human chromosome 21 originates from a pericentromeric dissemination involving human chromosomes 2, 18 and 13.
    Gene. 2003 Jul 17;312:51-9 PMID: 12909340
  41. Toward resolution of cardiovascular health disparities in African Americans: design and methods of the Jackson Heart Study.
    Ethn Dis. 2005 Autumn;15(4 Suppl 6):S6-4-17 PMID: 16320381
  42. Segmental duplications: organization and impact within the current human genome project assembly.
    Genome Res. 2001 Jun;11(6):1005-17 PMID: 11381028
  43. Limitations of next-generation genome sequence assembly.
    Nat Methods. 2011 Jan;8(1):61-5 PMID: 21102452
  44. Genomic structure of a copy of the human TPTE gene which encompasses 87 kb on the short arm of chromosome 21.
    Hum Genet. 2000 Aug;107(2):127-31 PMID: 11030409
  45. The sequence of the human genome.
    Science. 2001 Feb 16;291(5507):1304-51 PMID: 11181995
  46. A second generation human haplotype map of over 3.1 million SNPs.
    Nature. 2007 Oct 18;449(7164):851-61 PMID: 17943122
  47. Candidate gene association resource (CARe): design, methods, and proof of concept.
    Circ Cardiovasc Genet. 2010 Jun;3(3):267-75 PMID: 20400780
  48. High-quality draft assemblies of mammalian genomes from massively parallel sequence data.
    Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1513-8 PMID: 21187386
  49. Recent duplication, domain accretion and the dynamic mutation of the human genome.
    Trends Genet. 2001 Nov;17(11):661-9 PMID: 11672867
  50. Hundreds of variants clustered in genomic loci and biological pathways affect human height.
    Nature. 2010 Oct 14;467(7317):832-8 PMID: 20881960
  51. Initial sequencing and analysis of the human genome.
    Nature. 2001 Feb 15;409(6822):860-921 PMID: 11237011
  52. The sequence and analysis of duplication-rich human chromosome 16.
    Nature. 2004 Dec 23;432(7020):988-94 PMID: 15616553
  53. Interchromosomal segmental duplications of the pericentromeric region on the human Y chromosome.
    Genome Res. 2005 Feb;15(2):195-204 PMID: 15653831
  54. Finishing the euchromatic sequence of the human genome.
    Nature. 2004 Oct 21;431(7011):931-45 PMID: 15496913
  55. Large recurrent microdeletions associated with schizophrenia.
    Nature. 2008 Sep 11;455(7210):232-6 PMID: 18668039
  56. Diversity of human copy number variation and multicopy genes.
    Science. 2010 Oct 29;330(6004):641-6 PMID: 21030649
  57. Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication.
    Cell. 2012 May 11;149(4):912-22 PMID: 22559943
  58. A genetic linkage map of the human genome.
    Cell. 1987 Oct 23;51(2):319-37 PMID: 3664638
  59. Islands of euchromatin-like sequence and expressed polymorphic sequences within the short arm of human chromosome 21.
    Genome Res. 2007 Nov;17(11):1690-6 PMID: 17895424
  60. New approaches to disease mapping in admixed populations.
    Nat Rev Genet. 2011 Jun 28;12(8):523-8 PMID: 21709689
  61. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
    Nat Genet. 2008 Oct;40(10):1253-60 PMID: 18776909
  62. Recombination rates in admixed individuals identified by ancestry-based inference.
    Nat Genet. 2011 Jul 20;43(9):847-53 PMID: 21775992
  63. Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome.
    Cytogenet Genome Res. 2006;115(3-4):205-14 PMID: 17124402
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2565
Published
2013-04-00
Epub
2013-00-24
Pages
406-14, 414e1-2
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3683849
Subset
IM
Grants
NHLBI NIH HHS · HHSN268201100009I · United States
NHLBI NIH HHS · N01-HC48049 · United States
NHLBI NIH HHS · HHSN268201100011I · United States
NHLBI NIH HHS · N01-HC-95159 · United States
NHLBI NIH HHS · R01-HL-071251 · United States
NHLBI NIH HHS · N01-HC-95171 · United States
NHLBI NIH HHS · HHSN268201100007I · United States
NHLBI NIH HHS · R01-HL-071051 · United States
NIGMS NIH HHS · RC1 GM091332-01 · United States
NHLBI NIH HHS · HHSN268201100012C · United States
NIDDK NIH HHS · R01DK54931 · United States
NHLBI NIH HHS · N02-HL-6-4278 · United States
NIDDK NIH HHS · R01 DK054931 · United States
NHLBI NIH HHS · R01-HL-071252 · United States
NHLBI NIH HHS · R01 HL071251 · United States
NHLBI NIH HHS · N01-HC48050 · United States
NHLBI NIH HHS · R01-HL-071258 · United States
NHLBI NIH HHS · HHSN268201100010C · United States
NHLBI NIH HHS · R01 HL071259 · United States
NIGMS NIH HHS · R01 GM100233 · United States
NHLBI NIH HHS · HHSN268201100008C · United States
NHLBI NIH HHS · HHSN268201100005G · United States
NHLBI NIH HHS · R01 HL071252 · United States
NHLBI NIH HHS · HHSN268201100008I · United States
NHLBI NIH HHS · N01HC48049 · United States
NIGMS NIH HHS · RC1 GM091332 · United States
NHLBI NIH HHS · HHSN268201100007C · United States
NHLBI NIH HHS · N01-HC48048 · United States
NCRR NIH HHS · RR-024156 · United States
NHLBI NIH HHS · R01-HL-071250 · United States
NHLBI NIH HHS · N01HC95169 · United States
NHLBI NIH HHS · R01 HL071250 · United States
NHLBI NIH HHS · HHSN268201100011C · United States
NHGRI NIH HHS · R01 HG006399 · United States
NCRR NIH HHS · UL1 RR024156 · United States
NHLBI NIH HHS · R01 HL071051 · United States
NHLBI NIH HHS · N01HC95170 · United States
NHLBI NIH HHS · HHSN268201100006C · United States
NIMHD NIH HHS · R01 MD007092 · United States
NHLBI NIH HHS · R01-HL-071259 · United States
NHLBI NIH HHS · N01HC95095 · United States
NHLBI NIH HHS · N01-HC48047 · United States
NHLBI NIH HHS · N01-HC-95169 · United States
NHLBI NIH HHS · HHSN268201100005I · United States
NHLBI NIH HHS · N01HC95159 · United States
NHLBI NIH HHS · R01-HL-071205 · United States
NHGRI NIH HHS · R01 HG006855 · United States
NHLBI NIH HHS · N01HC65226 · United States
NHLBI NIH HHS · N01HC48050 · United States
NHLBI NIH HHS · N01-HC-95172 · United States
NHLBI NIH HHS · HHSN268201100009C · United States
NHLBI NIH HHS · N01HC48047 · United States
NHLBI NIH HHS · HHSN268201100005C · United States
NHLBI NIH HHS · N01HC95171 · United States
NHLBI NIH HHS · R01 HL071205 · United States
NHLBI NIH HHS · N01-HC-95170 · United States
NHLBI NIH HHS · R01 HL071258 · United States
NHLBI NIH HHS · N01HC48048 · United States
NHLBI NIH HHS · N01-HC95095 · United States
NHLBI NIH HHS · N01-HC-65226 · United States
NHLBI NIH HHS · N01HC95172 · United States
External Links
PubMed source DOI: 10.1038/ng.2565 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2