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Large Deletions at the SHOX Locus in the Pseudoautosomal Region Are Associated with Skeletal Atavism in Shetland Ponies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
Swedish Univ Agr Sci, Dept Anim Breeding & Genet, S-75007 Uppsala, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2016 (English)In: G3: Genes, Genomes, Genetics, ISSN 2160-1836, E-ISSN 2160-1836, Vol. 6, no 7, 2213-2223 p.Article in journal (Refereed) Published
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Text
Abstract [en]

Skeletal atavism in Shetland ponies is a heritable disorder characterized by abnormal growth of the ulna and fibula that extend the carpal and tarsal joints, respectively. This causes abnormal skeletal structure and impaired movements, and affected foals are usually killed. In order to identify the causal mutation we subjected six confirmed Swedish cases and a DNA pool consisting of 21 control individuals to whole genome resequencing. We screened for polymorphisms where the cases and the control pool were fixed for opposite alleles and observed this signature for only 25 SNPs, most of which were scattered on genome assembly unassigned scaffolds. Read depth analysis at these loci revealed homozygosity or compound heterozygosity for two partially overlapping large deletions in the pseudoautosomal region (PAR) of chromosome X/Y in cases but not in the control pool. One of these deletions removes the entire coding region of the SHOX gene and both deletions remove parts of the CRLF2 gene located downstream of SHOX. The horse reference assembly of the PAR is highly fragmented, and in order to characterize this region we sequenced bacterial artificial chromosome (BAC) clones by single-molecule real-time (SMRT) sequencing technology. This considerably improved the assembly and enabled size estimations of the two deletions to 1602180 kb and 60280 kb, respectively. Complete association between the presence of these deletions and disease status was verified in eight other affected horses. The result of the present study is consistent with previous studies in humans showing crucial importance of SHOX for normal skeletal development.

Place, publisher, year, edition, pages
2016. Vol. 6, no 7, 2213-2223 p.
Keyword [en]
SMRT sequencing, skeletal atavism, SHOX, PAR
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-300547DOI: 10.1534/g3.116.029645ISI: 000379590200041PubMedID: 27207956OAI: oai:DiVA.org:uu-300547DiVA: diva2:951710
Available from: 2016-08-10 Created: 2016-08-09 Last updated: 2017-11-28Bibliographically approved
In thesis
1. Exploring genetic diversity in natural and domestic populations through next generation sequencing
Open this publication in new window or tab >>Exploring genetic diversity in natural and domestic populations through next generation sequencing
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Studying genetic diversity in natural and domestic populations is of major importance in evolutionary biology. The recent advent of next generation sequencing (NGS) technologies has dramatically changed the scope of these studies, enabling researchers to study genetic diversity in a whole-genome context. This thesis details examples of studies using NGS data to: (i) characterize evolutionary forces shaping the genome of the Atlantic herring, (ii) detect the genetic basis of speciation and domestication in the rabbit, and, (iii) identify mutations associated with skeletal atavism in Shetland ponies.

The Atlantic herring (Clupea harengus) is the most abundant teleost species inhabiting the North Atlantic. Herring has seasonal reproduction and is adapted to a wide range of salinity (3-35‰) throughout the Baltic Sea and Atlantic Ocean. By using NGS data and whole-genome screening of 20 populations, we revealed the underlying genetic architecture for both adaptive features. Our results demonstrated that differentiated genomic regions have evolved by natural selection and genetic drift has played a subordinate role.

The European rabbit (Oryctolagus cuniculus) is native to the Iberian Peninsula, where two rabbit subspecies with partial reproductive isolation have evolved. We performed whole genome sequencing to characterize regions of reduced introgression. Our results suggest key role of gene regulation in triggering genetic incompatibilities in the early stages of reproductive isolation. Moreover, we studied gene expression in testis and found misregulation of many genes in backcross progenies that often show impaired male fertility. We also scanned whole genome of wild and domestic populations and identified differentiated regions that were enriched for non-coding conserved elements. Our results indicated that selection has acted on standing genetic variation, particularly targeting genes expressed in the central nervous system. This finding is consistent with the tame behavior present in domestic rabbits, which allows them to survive and reproduce under the stressful non-natural rearing conditions provided by humans.

In Shetland ponies, abnormally developed ulnae and fibulae characterize a skeletal deformity known as skeletal atavism. To explore the genetic basis of this disease, we scanned the genome using whole genome resequencing data. We identified two partially overlapping large deletions in the pseudoautosomal region (PAR) of the sex chromosomes that remove the entire coding sequence of the SHOX gene and part of CRLF2 gene. Based on this finding, we developed a diagnostic test that can be used as a tool to eradicate this inherited disease in horses.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1301
Keyword
Ecological adaptation, seasonal reproduction, Atlantic herring, domestication, speciation, rabbit, skeletal atavism, Shetland ponies, NGS, SMRT sequencing, genome, transcriptome, assembly, structural variation, genetic diversity, HCE, TSHR, SHOX, CRLF2
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-315032 (URN)978-91-554-9821-4 (ISBN)
Public defence
2017-03-30, B42, BMC, Husarg. 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Funder
EU, European Research Council
Available from: 2017-03-09 Created: 2017-02-08 Last updated: 2017-04-03

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Rafati, NimaFeng, ChungangPettersson, JessicaAmeur, AdamAndersson, LeifRubin, Carl-Johan

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