Sequencing and analysis of an Irish human genome.
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.
Tong
Pin
P
Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
Prendergast
James G D
JG
Lohan
Amanda J
AJ
Farrington
Susan M
SM
Cronin
Simon
S
Friel
Nial
N
Bradley
Dan G
DG
Hardiman
Orla
O
Evans
Alex
A
Wilson
James F
JF
Loftus
Brendan
B
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*
D018389:Codon, Nonsense
Annu Rev Med. 2010;61:437-55
20059347
Bioinformatics. 2009 Jul 15;25(14):1754-60
19451168
Genetics. 2009 Feb;181(2):701-10
19087964
Nature. 2007 Oct 18;449(7164):913-8
17943131
Nature. 2008 Nov 6;456(7218):53-9
18987734
Nat Rev Genet. 2010 Jul;11(7):499-511
20517342
Genome Res. 2009 Jun;19(6):1124-32
19420381
Nature. 2001 Feb 15;409(6822):860-921
11237011
Genetics. 2000 Jun;155(2):945-59
10835412
Gastroenterology. 2010 Mar;138(3):1102-11
19944697
Genetics. 1989 Nov;123(3):585-95
2513255
Genetics. 2003 Aug;164(4):1567-87
12930761
Genome Res. 2008 Jan;18(1):137-47
18025270
BMC Bioinformatics. 2008 Jan 31;9:77
18237431
Inflamm Bowel Dis. 2010 Jul;16(7):1108-17
20024904
Nature. 2008 Apr 17;452(7189):872-6
18421352
Am J Hum Genet. 2007 Nov;81(5):1084-97
17924348
Am J Hum Genet. 2000 Dec;67(6):1526-43
11078479
BMC Bioinformatics. 2009 Feb 03;10:48
19192299
Genome Res. 2008 Sep;18(9):1393-402
18562677
Curr Biol. 2010 Feb 23;20(4):R174-83
20178764
BMC Bioinformatics. 2006 Sep 12;7:409
16968531
Mol Biol Evol. 2009 Dec;26(12):2755-64
19713326
Nat Rev Genet. 2009 Oct;10(10):669-80
19736561
Genome Res. 2009 Feb;19(2):327-35
19029536
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
19474294
Genome Biol. 2006;7(8):R74
16904005
Science. 2005 Nov 11;310(5750):1016-8
16284177
PLoS Genet. 2010 Feb 05;6(2):e1000840
20140238
PLoS Biol. 2006 Mar;4(3):e72
16494531
Mol Biol Evol. 2008 May;25(5):997-1001
18296703
PLoS Genet. 2009 Jun;5(6):e1000529
19543373
Science. 2006 Jun 16;312(5780):1614-20
16778047
PLoS Biol. 2007 Sep 4;5(10):e254
17803354
Nature. 2010 Feb 18;463(7283):943-7
20164927
Genome Res. 2009 Sep;19(9):1622-9
19470904
Nature. 2008 Nov 6;456(7218):98-101
18758442
Mucosal Immunol. 2008 Mar;1(2):131-8
19079170
PLoS Genet. 2007 Jun;3(6):e90
17542651
Nucleic Acids Res. 1998 Jan 1;26(1):285-7
9399854
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D514-7
15608251
Nature. 2008 Nov 6;456(7218):60-5
18987735
Am J Hum Genet. 2004 Oct;75(4):693-702
15309688
Nature. 2009 Aug 20;460(7258):1011-5
19587683
Nat Methods. 2008 Jul;5(7):621-8
18516045
Am J Hum Genet. 1996 Jul;59(1):185-203
8659525
Nature. 2007 Oct 18;449(7164):851-61
17943122
N Engl J Med. 2009 Sep 10;361(11):1058-66
19657110
Genome Biol. 2006;7(7):112
17224040
Science. 2010 Jan 1;327(5961):78-81
19892942
Science. 2010 Apr 30;328(5978):636-9
20220176
Hum Mol Genet. 2008 Mar 1;17(5):768-74
18057069
Bioinformatics. 2009 Aug 15;25(16):2078-9
19505943
Nature. 2009 Oct 8;461(7265):747-53
19812666
Nat Genet. 1999 Oct;23(2):147
10508508
Genome Res. 2009 May;19(5):804-14
19265028
Nat Protoc. 2009;4(7):1073-81
19561590
Nat Genet. 2009 Oct;41(10):1083-7
19734901