title: Sequencing and analysis of an Irish human genome.
abstract: BACKGROUND
  Recent studies generating complete human sequences from Asian, African and European subgroups have revealed population-specific variation and disease susceptibility loci. Here, choosing a DNA sample from a population of interest due to its relative geographical isolation and genetic impact on further populations, we extend the above studies through the generation of 11-fold coverage of the first Irish human genome sequence.
  
  
  RESULTS
  Using sequence data from a branch of the European ancestral tree as yet unsequenced, we identify variants that may be specific to this population. Through comparisons with HapMap and previous genetic association studies, we identified novel disease-associated variants, including a novel nonsense variant putatively associated with inflammatory bowel disease. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. This analysis has implications for future re-sequencing studies and validates the imputation of Irish haplotypes using data from the current Human Genome Diversity Cell Line Panel (HGDP-CEPH). Finally, we identify gene duplication events as constituting significant targets of recent positive selection in the human lineage.
  
  
  CONCLUSIONS
  Our findings show that there remains utility in generating whole genome sequences to illustrate both general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that even armed with the resources of a small research group a number of similar initiatives geared towards answering specific biological questions will emerge.
authors.affiliation: Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Pin
authors.initials: P
authors.lastname: Tong
authors.forename: James G D
authors.initials: JG
authors.lastname: Prendergast
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lohan
authors.forename: Susan M
authors.initials: SM
authors.lastname: Farrington
authors.forename: Simon
authors.initials: S
authors.lastname: Cronin
authors.forename: Nial
authors.initials: N
authors.lastname: Friel
authors.forename: Dan G
authors.initials: DG
authors.lastname: Bradley
authors.forename: Orla
authors.initials: O
authors.lastname: Hardiman
authors.forename: Alex
authors.initials: A
authors.lastname: Evans
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Brendan
authors.initials: B
authors.lastname: Loftus
mesh_terms: D001483:Base Sequence; D002874:Chromosome Mapping; D018389:Codon, Nonsense; D020440:Gene Duplication; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005843:Geography; D006239:Haplotypes; D016045:Human Genome Project; D006801:Humans; D054643:INDEL Mutation; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D007494:Ireland; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense
references.citation: Annu Rev Med. 2010;61:437-55
references.pmid: 20059347
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Genetics. 2009 Feb;181(2):701-10
references.pmid: 19087964
references.citation: Nature. 2007 Oct 18;449(7164):913-8
references.pmid: 17943131
references.citation: Nature. 2008 Nov 6;456(7218):53-9
references.pmid: 18987734
references.citation: Nat Rev Genet. 2010 Jul;11(7):499-511
references.pmid: 20517342
references.citation: Genome Res. 2009 Jun;19(6):1124-32
references.pmid: 19420381
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Genetics. 2000 Jun;155(2):945-59
references.pmid: 10835412
references.citation: Gastroenterology. 2010 Mar;138(3):1102-11
references.pmid: 19944697
references.citation: Genetics. 1989 Nov;123(3):585-95
references.pmid: 2513255
references.citation: Genetics. 2003 Aug;164(4):1567-87
references.pmid: 12930761
references.citation: Genome Res. 2008 Jan;18(1):137-47
references.pmid: 18025270
references.citation: BMC Bioinformatics. 2008 Jan 31;9:77
references.pmid: 18237431
references.citation: Inflamm Bowel Dis. 2010 Jul;16(7):1108-17
references.pmid: 20024904
references.citation: Nature. 2008 Apr 17;452(7189):872-6
references.pmid: 18421352
references.citation: Am J Hum Genet. 2007 Nov;81(5):1084-97
references.pmid: 17924348
references.citation: Am J Hum Genet. 2000 Dec;67(6):1526-43
references.pmid: 11078479
references.citation: BMC Bioinformatics. 2009 Feb 03;10:48
references.pmid: 19192299
references.citation: Genome Res. 2008 Sep;18(9):1393-402
references.pmid: 18562677
references.citation: Curr Biol. 2010 Feb 23;20(4):R174-83
references.pmid: 20178764
references.citation: BMC Bioinformatics. 2006 Sep 12;7:409
references.pmid: 16968531
references.citation: Mol Biol Evol. 2009 Dec;26(12):2755-64
references.pmid: 19713326
references.citation: Nat Rev Genet. 2009 Oct;10(10):669-80
references.pmid: 19736561
references.citation: Genome Res. 2009 Feb;19(2):327-35
references.pmid: 19029536
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references.pmid: 19474294
references.citation: Genome Biol. 2006;7(8):R74
references.pmid: 16904005
references.citation: Science. 2005 Nov 11;310(5750):1016-8
references.pmid: 16284177
references.citation: PLoS Genet. 2010 Feb 05;6(2):e1000840
references.pmid: 20140238
references.citation: PLoS Biol. 2006 Mar;4(3):e72
references.pmid: 16494531
references.citation: Mol Biol Evol. 2008 May;25(5):997-1001
references.pmid: 18296703
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373
references.citation: Science. 2006 Jun 16;312(5780):1614-20
references.pmid: 16778047
references.citation: PLoS Biol. 2007 Sep 4;5(10):e254
references.pmid: 17803354
references.citation: Nature. 2010 Feb 18;463(7283):943-7
references.pmid: 20164927
references.citation: Genome Res. 2009 Sep;19(9):1622-9
references.pmid: 19470904
references.citation: Nature. 2008 Nov 6;456(7218):98-101
references.pmid: 18758442
references.citation: Mucosal Immunol. 2008 Mar;1(2):131-8
references.pmid: 19079170
references.citation: PLoS Genet. 2007 Jun;3(6):e90
references.pmid: 17542651
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):285-7
references.pmid: 9399854
references.citation: Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
references.pmid: 15608251
references.citation: Nature. 2008 Nov 6;456(7218):60-5
references.pmid: 18987735
references.citation: Am J Hum Genet. 2004 Oct;75(4):693-702
references.pmid: 15309688
references.citation: Nature. 2009 Aug 20;460(7258):1011-5
references.pmid: 19587683
references.citation: Nat Methods. 2008 Jul;5(7):621-8
references.pmid: 18516045
references.citation: Am J Hum Genet. 1996 Jul;59(1):185-203
references.pmid: 8659525
references.citation: Nature. 2007 Oct 18;449(7164):851-61
references.pmid: 17943122
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: Genome Biol. 2006;7(7):112
references.pmid: 17224040
references.citation: Science. 2010 Jan 1;327(5961):78-81
references.pmid: 19892942
references.citation: Science. 2010 Apr 30;328(5978):636-9
references.pmid: 20220176
references.citation: Hum Mol Genet. 2008 Mar 1;17(5):768-74
references.pmid: 18057069
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943
references.citation: Nature. 2009 Oct 8;461(7265):747-53
references.pmid: 19812666
references.citation: Nat Genet. 1999 Oct;23(2):147
references.pmid: 10508508
references.citation: Genome Res. 2009 May;19(5):804-14
references.pmid: 19265028
references.citation: Nat Protoc. 2009;4(7):1073-81
references.pmid: 19561590
references.citation: Nat Genet. 2009 Oct;41(10):1083-7
references.pmid: 19734901