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Publications (10 of 11) Show all publications
Negro, S., Imsland, F., Valera, M., Molina, A., Sole, M. & Andersson, L. (2017). Association analysis of KIT, MITF, and PAX3 variants with white markings in Spanish horses. Animal Genetics, 48(3), 349-352
Open this publication in new window or tab >>Association analysis of KIT, MITF, and PAX3 variants with white markings in Spanish horses
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2017 (English)In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 48, no 3, p. 349-352Article in journal (Refereed) Published
Abstract [en]

Several variants in the KIT, PAX3 and MITF genes have previously been associated with white markings in horses. In this study, we examined eight variants of these genes in 70 Menorca Purebred horses (PRMe, only black solid-coloured horses) and 70 Spanish Purebred horses (PRE, different coat colour patterns) that were scored for the extent of white markings. A maximum-likelihood chi-square test, logistic regression model and ridge regression analyses showed that a missense mutation (p.Arg682His) in KIT was associated with white facial markings (P<0.05) and with total white markings (P<0.05) in PRMe horses. The relative contribution of this variant to white markings in PRMe horses was estimated at 47.6% (head) and 43.4% (total score). In PRE horses, this variant was also associated with hindlimb scores (P<0.05) with a relative contribution of 41.2%. The g.20147039C>T intronic variant located 29.9kb downstream from the transcription start site of the MITF gene was associated with less white markings on forelimbs (P<0.05) in PRMe horses, with a relative contribution of 63.9%, whereas in PRE horses this variant was associated with white facial markings (P<0.05), with a relative contribution of 63.9%. No significant associations were found for PAX3 variants in these breeds. These results show that KIT and MITF variants are involved in the white marking patterns of both PRMe and PRE horses, providing breeders with an opportunity to use genetic testing to aid in breeding for their desired level of white markings.

Keywords
Menorca Purebred, phenotypic variance, Purebred, SNP, white spotting
National Category
Genetics Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-322506 (URN)10.1111/age.12528 (DOI)000399953100010 ()28084638 (PubMedID)
Available from: 2017-05-30 Created: 2017-05-30 Last updated: 2017-05-30Bibliographically approved
Imsland, F., McGowan, K., Rubin, C.-J., Henegar, C., Sundström, E., Berglund, J., . . . Andersson, L. (2016). Regulatory mutations in TBX3 disrupt asymmetric hair pigmentation underlying Dun camouflage colour in horses. Nature Genetics, 48(2), 152-158
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, p. 152-158Article 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
Identifiers
urn:nbn:se:uu:diva-254473 (URN)10.1038/ng.3475 (DOI)000369043900012 ()26691985 (PubMedID)
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
Velie, B. D., Jaederkvist, K., Imsland, F., Viluma, A., Andersson, L. S., Mikko, S., . . . Lindgren, G. (2015). Frequencies of polymorphisms in myostatin vary in Icelandic horses according to the use of the horses. Animal Genetics, 46(4), 467-468
Open this publication in new window or tab >>Frequencies of polymorphisms in myostatin vary in Icelandic horses according to the use of the horses
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2015 (English)In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 46, no 4, p. 467-468Article in journal (Refereed) Published
National Category
Medical Genetics Animal and Dairy Science
Identifiers
urn:nbn:se:uu:diva-260811 (URN)10.1111/age.12315 (DOI)000358641800020 ()26095686 (PubMedID)
Funder
Swedish Research Council FormasCarl Tryggers foundation
Available from: 2015-08-31 Created: 2015-08-25 Last updated: 2018-01-11Bibliographically approved
Imsland, F. (2015). Monogenic Traits Associated with Structural Variants in Chicken and Horse: Allelic and Phenotypic Diversity of Visually Appealing Traits. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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. p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1124
Keywords
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
Jäderkvist, K., Holm, N., Imsland, F., Arnason, T., Andersson, L., Andersson, L. S. & Lindgren, G. (2015). The importance of the DMRT3 'Gait keeper' mutation on riding traits and gaits in Standardbred and Icelandic horses. Livestock Science, 176, 33-39
Open this publication in new window or tab >>The importance of the DMRT3 'Gait keeper' mutation on riding traits and gaits in Standardbred and Icelandic horses
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2015 (English)In: Livestock Science, ISSN 1871-1413, E-ISSN 1878-0490, Vol. 176, p. 33-39Article in journal (Refereed) Published
Abstract [en]

Previous studies have shown that a single base-pair mutation, a change from cytosine (C) to adenine (A), in the DMRT3 gene affects both the ability to show ambling and lateral gaits in a wide range of horse breeds, as well as racing performance and trotting technique in Standardbred and Nordic trotters. The variant allele is present in gaited breeds but is absent, or found at a very low frequency, in breeds used for Western-European style riding and flat racing, like the Swedish Warmblood and Thoroughbreds as well as in draught horses. This indicates that the variant allele might have a negative effect on certain riding performance traits in horses. Therefore, one aim of this study was to investigate whether the DMRT3 variant affects canter in Standardbred trotters, and to test if heterozygous horses (CA) were better suited for Western-European style riding than homozygous horses (M). Riding traits were studied in 115 Standardbred horses, and a similar study was also performed with data from 55 Nordic trotters. The results showed that CA Standardbreds had significantly better balance in canter, both collected and extended canter, than M horses. The CA horses also got significantly higher scores for transitions in collected canter. For the rhythm we found no significant differences between the genotypes. In the Nordic trotters we were unable to establish any significant difference for canter ability. Another aim of this study was to investigate the effect of the variant allele on riding abilities and gaits in the Icelandic horse (n=446). Practically all horse breeds considered to be three-gaited have a CC genotype, in contrast Icelandic CC horses can show tolt We therefore tested whether the variant influenced how difficult it was to initiate tolt training for these horses. It was also investigated whether the variant affects which gaits Icelandic horses choose, both at liberty and during initial training. Icelandic CC horses were significantly more difficult to train to tolt compared to CA and AA horses. The M Icelandic horses showed the lateral gaits tolt and pace significantly more frequent, both at liberty and during initial training, than CA or CC horses. The majority of the Icelandic CC and CA horses chose trot at liberty and during initial training.

Keywords
DMR73, Gaits, Icelandic horse, Riding traits, Standardbred
National Category
Animal and Dairy Science
Identifiers
urn:nbn:se:uu:diva-256826 (URN)10.1016/j.livsci.2015.03.025 (DOI)000355365200004 ()
Note

Correction in: Livestock Science, 2015, Volume: 180, Pages: 268-268, DOI: 10.1016/j.livsci.2015.08.005

Available from: 2015-06-26 Created: 2015-06-26 Last updated: 2017-12-04Bibliographically approved
Promerová, M., Andersson, L. S., Juras, R., Penedo, M. C., Reissmann, M., Tozaki, T., . . . Andersson, L. (2014). Worldwide frequency distribution of the 'Gait keeper' mutation in the DMRT3 gene. Animal Genetics, 45(2), 274-282
Open this publication in new window or tab >>Worldwide frequency distribution of the 'Gait keeper' mutation in the DMRT3 gene
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2014 (English)In: Animal Genetics, ISSN 0268-9146, E-ISSN 1365-2052, Vol. 45, no 2, p. 274-282Article in journal (Refereed) Published
Abstract [en]

For centuries, domestic horses have represented an important means of transport and served as working and companion animals. Although their role in transportation is less important today, many horse breeds are still subject to intense selection based on their pattern of locomotion. A striking example of such a selected trait is the ability of a horse to perform additional gaits other than the common walk, trot and gallop. Those could be four-beat ambling gaits, which are particularly smooth and comfortable for the rider, or pace, used mainly in racing. Gaited horse breeds occur around the globe, suggesting that gaitedness is an old trait, selected for in many breeds. A recent study discovered that a nonsense mutation in DMRT3 has a major impact on gaitedness in horses and is present at a high frequency in gaited breeds and in horses bred for harness racing. Here, we report a study of the worldwide distribution of this mutation. We genotyped 4396 horses representing 141 horse breeds for the DMRT3 stop mutation. More than half (2749) of these horses also were genotyped for a SNP situated 32kb upstream of the DMRT3 nonsense mutation because these two SNPs are in very strong linkage disequilibrium. We show that the DMRT3 mutation is present in 68 of the 141 genotyped horse breeds at a frequency ranging from 1% to 100%. We also show that the mutation is not limited to a geographical area, but is found worldwide. The breeds with a high frequency of the stop mutation (>50%) are either classified as gaited or bred for harness racing.

Keywords
ambling, domestication, horse, locomotion, pace, running walk
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-224333 (URN)10.1111/age.12120 (DOI)000332140000014 ()
Note

De två första författarna delar första författarskapet.

Available from: 2014-05-14 Created: 2014-05-09 Last updated: 2017-12-05Bibliographically approved
Sundström, E., Imsland, F., Mikko, S., Wade, C., Sigurdsson, S., Pielberg, G. R., . . . Andersson, L. (2012). Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses. BMC Genomics, 13, 365
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, E-ISSN 1471-2164, Vol. 13, p. 365-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.

Keywords
STX17, Melanoma, Hair greying, Copy number variation, Melanocytes
National Category
Medical and Health Sciences
Identifiers
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: 2017-12-07Bibliographically approved
Andersson, L. S., Larhammar, M., Memic, F., Wootz, H., Schwochow, D., Rubin, C.-J., . . . Kullander, K. (2012). Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature, 488(7413), 642-646
Open this publication in new window or tab >>Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
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2012 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 488, no 7413, p. 642-646Article in journal (Refereed) Published
Abstract [en]

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-181404 (URN)10.1038/nature11399 (DOI)000308095100053 ()
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved
Boije, H., Harun-Or-Rashid, M., Lee, Y.-J., Imsland, F., Bruneau, N., Vieaud, A., . . . Hallböök, F. (2012). Sonic Hedgehog-Signalling Patterns the Developing Chicken Comb as Revealed by Exploration of the Pea-comb Mutation. PLoS ONE, 7(12), e50890
Open this publication in new window or tab >>Sonic Hedgehog-Signalling Patterns the Developing Chicken Comb as Revealed by Exploration of the Pea-comb Mutation
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e50890-Article in journal (Refereed) Published
Abstract [en]

The genetic basis and mechanisms behind the morphological variation observed throughout the animal kingdom is stillrelatively unknown. In the present work we have focused on the establishment of the chicken comb-morphology byexploring the Pea-comb mutant. The wild-type single-comb is reduced in size and distorted in the Pea-comb mutant. Peacombis formed by a lateral expansion of the central comb anlage into three ridges and is caused by a mutation in SOX5,which induces ectopic expression of the SOX5 transcription factor in mesenchyme under the developing comb. Analysis ofdifferential gene expression identified decreased Sonic hedgehog (SHH) receptor expression in Pea-comb mesenchyme. Byexperimentally blocking SHH with cyclopamine, the wild-type single-comb was transformed into a Pea-comb-likephenotype. The results show that the patterning of the chicken comb is under the control of SHH and suggest that ectopicSOX5 expression in the Pea-comb change the response of mesenchyme to SHH signalling with altered combmorphogenesis as a result. A role for the mesenchyme during comb morphogenesis is further supported by the recentfinding that another comb-mutant (Rose-comb), is caused by ectopic expression of a transcription factor in combmesenchyme. The present study does not only give knowledge about how the chicken comb is formed, it also adds to ourunderstanding how mutations or genetic polymorphisms may contribute to inherited variations in the human face.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-187458 (URN)10.1371/journal.pone.0050890 (DOI)000312588200079 ()
Available from: 2012-12-07 Created: 2012-12-06 Last updated: 2017-12-07Bibliographically approved
Wang, Y., Gao, Y., Imsland, F., Gu, X., Feng, C., Liu, R., . . . Li, N. (2012). The Crest Phenotype in Chicken Is Associated with Ectopic Expression of HOXC8 in Cranial Skin. PLoS ONE, 7(4), e34012
Open this publication in new window or tab >>The Crest Phenotype in Chicken Is Associated with Ectopic Expression of HOXC8 in Cranial Skin
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34012-Article in journal (Refereed) Published
Abstract [en]

The Crest phenotype is characterised by a tuft of elongated feathers atop the head. A similar phenotype is also seen in several wild bird species. Crest shows an autosomal incompletely dominant mode of inheritance and is associated with cerebral hernia. Here we show, using linkage analysis and genome-wide association, that Crest is located on the E22C19W28 linkage group and that it shows complete association to the HOXC-cluster on this chromosome. Expression analysis of tissues from Crested and non-crested chickens, representing 26 different breeds, revealed that HOXC8, but not HOXC12 or HOXC13, showed ectopic expression in cranial skin during embryonic development. We propose that Crest is caused by a cis-acting regulatory mutation underlying the ectopic expression of HOXC8. However, the identification of the causative mutation(s) has to await until a method becomes available for assembling this chromosomal region. Crest is unfortunately located in a genomic region that has so far defied all attempts to establish a contiguous sequence.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-177634 (URN)10.1371/journal.pone.0034012 (DOI)000305341600018 ()
Available from: 2012-07-17 Created: 2012-07-17 Last updated: 2017-12-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9452-5566

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