Genome-wide association analysis reveals QTL and candidate mutations involved in white spotting in cattle.
Journal
Genetics, selection, evolution : GSE
ISSN: 1297-9686
Titre abrégé: Genet Sel Evol
Pays: France
ID NLM: 9114088
Informations de publication
Date de publication:
08 Nov 2019
08 Nov 2019
Historique:
received:
11
12
2018
accepted:
25
10
2019
entrez:
10
11
2019
pubmed:
11
11
2019
medline:
11
3
2020
Statut:
epublish
Résumé
White spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein-Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein-Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date. Using imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region. Our findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics.
Sections du résumé
BACKGROUND
BACKGROUND
White spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein-Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein-Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date.
RESULTS
RESULTS
Using imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region.
CONCLUSIONS
CONCLUSIONS
Our findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics.
Identifiants
pubmed: 31703548
doi: 10.1186/s12711-019-0506-2
pii: 10.1186/s12711-019-0506-2
pmc: PMC6839108
doi:
Substances chimiques
Microphthalmia-Associated Transcription Factor
0
PAX3 Transcription Factor
0
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
62Références
Nat Genet. 2011 May;43(5):405-13
pubmed: 21516082
Am J Hum Genet. 2007 Nov;81(5):1084-97
pubmed: 17924348
Nat Genet. 1994 Nov;8(3):256-63
pubmed: 7874168
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Anim Genet. 2009 Oct;40(5):623-9
pubmed: 19456317
PLoS One. 2012;7(5):e36346
pubmed: 22567150
Development. 1997 Jun;124(12):2377-86
pubmed: 9199364
Hum Genet. 2000 Jul;107(1):1-6
pubmed: 10982026
Anim Genet. 2013 Dec;44(6):763-5
pubmed: 23659293
Fly (Austin). 2012 Apr-Jun;6(2):80-92
pubmed: 22728672
PLoS One. 2014 Aug 12;9(8):e104363
pubmed: 25116146
Pigment Cell Melanoma Res. 2008 Dec;21(6):627-45
pubmed: 18983540
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Pigment Cell Res. 2004 Jun;17(3):215-24
pubmed: 15140066
Nat Commun. 2014 Dec 18;5:5861
pubmed: 25519203
Nat Genet. 2007 Nov;39(11):1321-8
pubmed: 17906626
BMC Genomics. 2017 Dec 15;18(1):968
pubmed: 29246110
Hum Mol Genet. 2000 Aug 12;9(13):1907-17
pubmed: 10942418
Nat Methods. 2018 Jun;15(6):461-468
pubmed: 29713083
Nat Commun. 2018 Jul 17;9(1):2648
pubmed: 30018292
Mamm Genome. 1999 Mar;10(3):283-8
pubmed: 10051325
PLoS One. 2011;6(12):e28857
pubmed: 22174915
Development. 2015 Apr 1;142(7):1387
pubmed: 25804742
J Investig Dermatol Symp Proc. 2001 Nov;6(1):99-104
pubmed: 11764295
Nat Genet. 1998 Mar;18(3):283-6
pubmed: 9500554
Sci Rep. 2017 Sep 13;7(1):11466
pubmed: 28904385
Mamm Genome. 2005 Nov;16(11):893-902
pubmed: 16284805
N Z Vet J. 2010 Feb;58(1):1-5
pubmed: 20200568
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Genetics. 2009 Jul;182(3):923-6
pubmed: 19398771
Anim Genet. 2009 Dec;40(6):975-7
pubmed: 19531114
Bioinformatics. 2012 Jun 15;28(12):1647-9
pubmed: 22543367
Am J Hum Genet. 2016 Dec 1;99(6):1388-1394
pubmed: 27889061
Hum Mutat. 2010 Apr;31(4):391-406
pubmed: 20127975
PLoS One. 2015 Oct 23;10(10):e0141225
pubmed: 26496443
PLoS Genet. 2012;8(4):e1002653
pubmed: 22511888
Nucleic Acids Res. 2018 Jan 4;46(D1):D754-D761
pubmed: 29155950
Cell Res. 2008 Dec;18(12):1163-76
pubmed: 19002157
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Genome Res. 2011 Jun;21(6):974-84
pubmed: 21324876
Nat Genet. 2014 Jul;46(7):748-52
pubmed: 24880339
Int J Mol Sci. 2016 Jul 15;17(7):
pubmed: 27428965
Nucleic Acids Res. 2018 Jan 4;46(D1):D836-D842
pubmed: 29092072
Anim Genet. 2019 Feb;50(1):27-32
pubmed: 30506810
Nature. 2012 Feb 01;482(7383):81-4
pubmed: 22297974
Cytogenet Genome Res. 2007;119(3-4):225-30
pubmed: 18253033
Anim Genet. 2013 Aug;44(4):450-3
pubmed: 23418861
Sci Rep. 2016 May 05;6:25376
pubmed: 27146958
Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20
pubmed: 23315928
Nucleic Acids Res. 2017 Jan 4;45(D1):D635-D642
pubmed: 27899575
Eur J Hum Genet. 2012 May;20(5):584-7
pubmed: 22258527
Anim Genet. 2012 Jun;43(3):250-6
pubmed: 22486495
Nat Protoc. 2009;4(7):1073-81
pubmed: 19561590
Genet Sel Evol. 2019 Nov 8;51(1):62
pubmed: 31703548
PLoS Genet. 2010 Sep 23;6(9):e1001139
pubmed: 20927186