Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

Maja L Arendt; Malin Melin; Noriko Tonomura; Michele Koltookian; Celine Courtay-Cahen; Netty Flindall; Joyce Bass; Kim Boerkamp; Katherine Megquir; Lisa Youell; Sue Murphy; Colleen McCarthy; Cheryl London; Gerard R Rutteman; Mike Starkey; Kerstin Lindblad-Toh

doi:10.1371/journal.pgen.1005647

Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

Maja L Arendt, Malin Melin, Noriko Tonomura, Michele Koltookian, Celine Courtay-Cahen, Netty Flindall, Joyce Bass, Kim Boerkamp, Katherine Megquir, Lisa Youell, Sue Murphy, Colleen McCarthy, Cheryl London, Gerard R Rutteman, Mike Starkey, Kerstin Lindblad-Toh

26 Citations (Scopus)

Abstract

Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

Original language	English
Article number	e1005647
Journal	PLOS Genetics
Volume	11
Issue number	11
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1005647
Publication status	Published - Nov 2015
Externally published	Yes

Keywords

Alternative Splicing
Animals
Dog Diseases/genetics
Dogs
GTP-Binding Protein alpha Subunit, Gi2/genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Germ-Line Mutation
Mastocytoma/genetics
Polymorphism, Single Nucleotide

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Arendt, M. L., Melin, M., Tonomura, N., Koltookian, M., Courtay-Cahen, C., Flindall, N., Bass, J., Boerkamp, K., Megquir, K., Youell, L., Murphy, S., McCarthy, C., London, C., Rutteman, G. R., Starkey, M., & Lindblad-Toh, K. (2015). Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours. PLOS Genetics, 11(11), Article e1005647. https://doi.org/10.1371/journal.pgen.1005647

Arendt, ML, Melin, M, Tonomura, N, Koltookian, M, Courtay-Cahen, C, Flindall, N, Bass, J, Boerkamp, K, Megquir, K, Youell, L, Murphy, S, McCarthy, C, London, C, Rutteman, GR, Starkey, M & Lindblad-Toh, K 2015, 'Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours', PLOS Genetics, vol. 11, no. 11, e1005647. https://doi.org/10.1371/journal.pgen.1005647

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title = "Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours",

abstract = "Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT. ",

keywords = "Alternative Splicing, Animals, Dog Diseases/genetics, Dogs, GTP-Binding Protein alpha Subunit, Gi2/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Mastocytoma/genetics, Polymorphism, Single Nucleotide",

author = "Arendt, {Maja L} and Malin Melin and Noriko Tonomura and Michele Koltookian and Celine Courtay-Cahen and Netty Flindall and Joyce Bass and Kim Boerkamp and Katherine Megquir and Lisa Youell and Sue Murphy and Colleen McCarthy and Cheryl London and Rutteman, {Gerard R} and Mike Starkey and Kerstin Lindblad-Toh",

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T1 - Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

AU - Arendt, Maja L

AU - Melin, Malin

AU - Tonomura, Noriko

AU - Koltookian, Michele

AU - Courtay-Cahen, Celine

AU - Flindall, Netty

AU - Bass, Joyce

AU - Boerkamp, Kim

AU - Megquir, Katherine

AU - Youell, Lisa

AU - Murphy, Sue

AU - McCarthy, Colleen

AU - London, Cheryl

AU - Rutteman, Gerard R

AU - Starkey, Mike

AU - Lindblad-Toh, Kerstin

PY - 2015/11

Y1 - 2015/11

N2 - Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

AB - Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

KW - Alternative Splicing

KW - Animals

KW - Dog Diseases/genetics

KW - Dogs

KW - GTP-Binding Protein alpha Subunit, Gi2/genetics

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Germ-Line Mutation

KW - Mastocytoma/genetics

KW - Polymorphism, Single Nucleotide

U2 - 10.1371/journal.pgen.1005647

DO - 10.1371/journal.pgen.1005647

M3 - Journal article

C2 - 26588071

SN - 1553-7390

VL - 11

JO - PLOS Genetics

JF - PLOS Genetics

IS - 11

M1 - e1005647

ER -

Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

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Keywords

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