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Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
HudsonAlpha Institute for Biotechnology / Department of Genetics, Stanford University School of Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Department of Genetics, Stanford University School of Medicine.
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2016 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 2, 152-158 p.Article in journal (Refereed) Published
Abstract [en]

Dun is a wild-type coat color in horses characterized by pigment dilution with a striking pattern of dark areas termed primitive markings. Here we show that pigment dilution in Dun horses is due to radially asymmetric deposition of pigment in the growing hair caused by localized expression of the T-box 3 (TBX3) transcription factor in hair follicles, which in turn determines the distribution of hair follicle melanocytes. Most domestic horses are non-dun, a more intensely pigmented phenotype caused by regulatory mutations impairing TBX3 expression in the hair follicle, resulting in a more circumferential distribution of melanocytes and pigment granules in individual hairs. We identified two different alleles (non-dun1 and non-dun2) causing non-dun color. non-dun2 is a recently derived allele, whereas the Dun and non-dun1 alleles are found in ancient horse DNA, demonstrating that this polymorphism predates horse domestication. These findings uncover a new developmental role for T-box genes and new aspects of hair follicle biology and pigmentation.

Place, publisher, year, edition, pages
2016. Vol. 48, no 2, 152-158 p.
National Category
Genetics Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-254473DOI: 10.1038/ng.3475ISI: 000369043900012PubMedID: 26691985OAI: oai:DiVA.org:uu-254473DiVA: diva2:844993
Funder
Knut and Alice Wallenberg FoundationNIH (National Institute of Health)Swedish Research Council, 80576801Swedish Research Council, 70374401Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2015-08-10 Created: 2015-06-08 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Monogenic Traits Associated with Structural Variants in Chicken and Horse: Allelic and Phenotypic Diversity of Visually Appealing Traits
Open this publication in new window or tab >>Monogenic Traits Associated with Structural Variants in Chicken and Horse: Allelic and Phenotypic Diversity of Visually Appealing Traits
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Domestic animals have rich phenotypic diversity that can be explored to advance our understanding of the relationship between molecular genetics and phenotypic variation. Since the advent of second generation sequencing, it has become easier to identify structural variants and associate them with phenotypic outcomes. This thesis details studies on three such variants associated with monogenic traits.

The first studies on Rose-comb in the chicken were published over a century ago, seminally describing Mendelian inheritance and epistatic interaction in animals. Homozygosity for the otherwise dominant Rose-comb allele was later associated with reduced rooster fertility. We show that a 7.38 Mb inversion is causal for Rose-comb, and that two alleles exist for Rose-comb, R1 and R2. A novel genomic context for the gene MNR2 is causative for the comb phenotype, and the bisection of the gene CCDC108 is associated with fertility issues. The recombined R2 allele has intact CCDC108, and normal fertility.

The dominant phenotype Greying with Age in horses was previously associated with an intronic duplication in STX17. By utilising second generation sequencing we have examined the genomic region surrounding the duplication in detail, and excluded all other discovered variants as causative for Grey.

Dun is the ancestral coat colour of equids, where the individual is mostly pale in colour, but carries intensely pigmented primitive markings, most notably a dorsal stripe. Dun is a dominant trait, and yet most domestic horses are non-dun in colour and intensely pigmented. We show that Dun colour is established by radially asymmetric expression of the transcription factor TBX3 in hair follicles. This results in a microscopic spotting phenotype on the level of the individual hair, giving the impression of pigment dilution. Non-dun colour is caused by two different alleles, non-dun1 and non-dun2, both of which disrupt the TBX3-mediated regulation of pigmentation. Non-dun1 is associated with a SNP variant 5 kb downstream of TBX3, and non-dun2 with a 1.6 kb deletion that overlaps the non-dun1 SNP. Homozygotes for non-dun2 show a more intensely pigmented appearance than horses with one or two non-dun1 alleles. We have also shown by genotyping of ancient DNA that non-dun1 predates domestication.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1124
Keyword
Structural variation, Pigmentation, Domestication, Equids, MNR2, CCDC108, STX17, TBX3, Grey, Dun, non-dun, Rose-comb, Chicken, Genetic mapping, Phenotyping
National Category
Genetics Genetics and Breeding
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-259621 (URN)978-91-554-9295-3 (ISBN)
Public defence
2015-09-25, room B42, at the BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-09-04 Created: 2015-08-10 Last updated: 2015-10-01

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Imsland, FreyjaRubin, Carl-JohanSundström, ElisabethBerglund, JonasLindblad-Toh, KerstinAndersson, Leif

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Imsland, FreyjaRubin, Carl-JohanSundström, ElisabethBerglund, JonasLindblad-Toh, KerstinAndersson, Leif
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