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Monogenic Traits Associated with Structural Variants in Chicken and Horse: Allelic and Phenotypic Diversity of Visually Appealing Traits
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1124
Keyword [en]
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
URN: urn:nbn:se:uu:diva-259621ISBN: 978-91-554-9295-3OAI: oai:DiVA.org:uu-259621DiVA: diva2:845131
Public defence
2015-09-25, room B42, at the BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2015-09-04 Created: 2015-08-10 Last updated: 2015-10-01
List of papers
1. The Rose-comb Mutation in Chickens Constitutes a Structural Rearrangement Causing Both Altered Comb Morphology and Defective Sperm Motility
Open this publication in new window or tab >>The Rose-comb Mutation in Chickens Constitutes a Structural Rearrangement Causing Both Altered Comb Morphology and Defective Sperm Motility
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2012 (English)In: PLOS Genetics, ISSN 1553-7404, Vol. 8, no 6, e1002775- p.Article in journal (Refereed) Published
Abstract [en]

Rose-comb, a classical monogenic trait of chickens, is characterized by a drastically altered comb morphology compared to the single-combed wild-type. Here we show that Rose-comb is caused by a 7.4 Mb inversion on chromosome 7 and that a second Rose-comb allele arose by unequal crossing over between a Rose-comb and wild-type chromosome. The comb phenotype is caused by the relocalization of the MNR2 homeodomain protein gene leading to transient ectopic expression of MNR2 during comb development. We also provide a molecular explanation for the first example of epistatic interaction reported by Bateson and Punnett 104 years ago, namely that walnut-comb is caused by the combined effects of the Rose-comb and Pea-comb alleles. Transient ectopic expression of MNR2 and SOX5 (causing the Pea-comb phenotype) occurs in the same population of mesenchymal cells and with at least partially overlapping expression in individual cells in the comb primordium. Rose-comb has pleiotropic effects, as homozygosity in males has been associated with poor sperm motility. We postulate that this is caused by the disruption of the CCDC108 gene located at one of the inversion breakpoints. CCDC108 is a poorly characterized protein, but it contains a MSP (major sperm protein) domain and is expressed in testis. The study illustrates several characteristic features of the genetic diversity present in domestic animals, including the evolution of alleles by two or more consecutive mutations and the fact that structural changes have contributed to fast phenotypic evolution.

National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-178136 (URN)10.1371/journal.pgen.1002775 (DOI)000305961000037 ()
Available from: 2012-07-30 Created: 2012-07-30 Last updated: 2015-10-01Bibliographically approved
2. Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses
Open this publication in new window or tab >>Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses
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2012 (English)In: BMC Genomics, ISSN 1471-2164, Vol. 13, 365- p.Article in journal (Refereed) Published
Abstract [en]

Background: Greying with age in horses is an autosomal dominant trait, associated with loss of hair pigmentation, melanoma and vitiligo-like depigmentation. We recently identified a 4.6 kb duplication in STX17 to be associated with the phenotype. The aims of this study were to investigate if the duplication in Grey horses shows copy number variation and to exclude that any other polymorphism is uniquely associated with the Grey mutation.

Results: We found little evidence for copy number expansion of the duplicated sequence in blood DNA from Grey horses. In contrast, clear evidence for copy number expansions was indicated in five out of eight tested melanoma tissues or melanoma cell lines. A tendency of a higher copy number in aggressive tumours was also found. Massively parallel resequencing of the similar to 350 kb Grey haplotype did not reveal any additional mutations perfectly associated with the phenotype, confirming the duplication as the true causative mutation. We identified three SNP alleles that were present in a subset of Grey haplotypes within the 350 kb region that shows complete linkage disequilibrium with the causative mutation. Thus, these three nucleotide substitutions must have occurred subsequent to the duplication, consistent with our interpretation that the Grey mutation arose more than 2,000 years before present.

Conclusions: These results suggest that the mutation acts as a melanoma-driving regulatory element. The elucidation of the mechanistic features of the duplication will be of considerable interest for the characterization of these horse melanomas as well as for the field of human melanoma research.

STX17, Melanoma, Hair greying, Copy number variation, Melanocytes
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-183233 (URN)10.1186/1471-2164-13-365 (DOI)000308940000001 ()
Available from: 2012-10-25 Created: 2012-10-23 Last updated: 2015-10-01Bibliographically approved
3. Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses
Open this publication in new window or tab >>Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses
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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.

National Category
Genetics Cell Biology
urn:nbn:se:uu:diva-254473 (URN)10.1038/ng.3475 (DOI)000369043900012 ()26691985 (PubMedID)
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: 2016-03-02Bibliographically approved

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