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Functional Genomics of Bone Metabolism: Novel Candidate Genes Identified by Studies in Chicken Models
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Osteoporosis is a disease that leads to decreased bone mineral density (BMD), an altered bone micro-architecture and fragile bones. The disease is highly heritable and numerous genes are thought to be involved, making it difficult to identify the causative genetic elements.

Animal models, mainly intercrosses between laboratory strains of mice, have been succesfully used to map genes affecting these traits, but may not mirror the multifactorial genetic etiology of highly complex traits such as osteoporosis.

Over the course of tens of thousand years humans have kept domestic animals whose phenotypic repertoires have been tailored to meet our needs. Wild-type red junglefowl (RJ) and domestic White Leghorn (WL) chicken differ for several bone traits.

In this thesis Quantitative Trait Loci (QTL) mapping was used to trace the inheritance of bone traits in two separate intercrosses between RJ and WL. In these studies we identified several QTL that contributed to differences in BMD, bone size and biomechanical strength of bone. In a comparison of QTL identified in the two intercrosses it was observed that nine QTL had overlapping genomic positions, implicating these loci as important to bone phenotypic variation in chicken.

In two separate studies, microarray technology was used to compare global gene expression in bone tissue from RJ and WL. In these studies, differential expression was observed for 779 and 560 genes, respectively. Many differentially expressed genes were co-localized with QTL, which implicates them as QTL-candidates.

Results presented in this thesis link several genomic regions and genes to variation in bone traits. Increased knowledge about these identified genes and regions will contribute to a better understanding of the mechanisms underlying inter-individual differences in bone metabolism, both in chicken and man.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 70
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 314
Keywords [en]
Molecular medicine, QTL, Bone, Osteoporosis, Gene expression, Microarray, Domestication
Keywords [sv]
Molekylärmedicin
Identifiers
URN: urn:nbn:se:uu:diva-8498ISBN: 978-91-554-7110-1 (print)OAI: oai:DiVA.org:uu-8498DiVA, id: diva2:171513
Public defence
2008-03-28, Enghoffsalen, Uppsala Akademiska Sjukhus, Ingårng 50, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-03-06 Created: 2008-03-06Bibliographically approved
List of papers
1. Quantitative Trait Loci for BMD and Bone Strength in an Intercross Between Domestic and Wildtype Chickens
Open this publication in new window or tab >>Quantitative Trait Loci for BMD and Bone Strength in an Intercross Between Domestic and Wildtype Chickens
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2007 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 22, no 3, p. 375-384Article in journal (Refereed) Published
Abstract [en]

With chicken used as a model species, we used QTL analysis to examine the genetic contribution to bone traits. We report the identification of four QTLs for femoral traits: one for bone strength, one for endosteal circumference, and two affecting mineral density of noncortical bone. Introduction: BMD is a highly heritable phenotype, governed by elements at numerous loci. In studies examining the genetic contribution to bone traits, many loci have been identified in humans and in other species. The goal of this study was to identify quantitative trait loci (QTLs) controlling BMD and bone strength in an intercross between wildtype and domestic chickens. Materials and Methods: A set of 164 markers, covering 30 chromosomes (chr.), were used to genotype 337 F 2-individuals from an intercross of domesticated white Leghorn and wildtype red junglefowl chicken. DXA and pQCT were used to measure BMD and bone structure. Three-point bending tests and torsional strength tests were performed to determine the biomechanical strength of the bone. QTLs were mapped using forward selection for loci with significant marginal effects. Results: Four QTLs for femoral bone traits were identified in QTL analysis with body weight included as a covariate. A QTL on chr. 1 affected female noncortical BMD (LOD 4.6) and is syntenic to human 12q21-12q23. Also located on chr. 1, a locus with synteny to human 12q 13-1.4 affected endosteal circumference (LOD 4.6). On chr. 2, a QTL corresponding to human 5p13-p15, 7p12, 18q12, 18q21, and 9q22-9q31 affected BMD in females; noncortical (LOD 4.0) and metaphyseal (LOD 7.0) BMD by pQCT and BMD by DXA (LOD 5.9). A QTL located on chr. 20 (LOD 5.2) affected bone biomechanical strength and had sex-dependent effects. In addition to the significant QTLs, 10 further loci with suggestive linkage to bone traits were identified. Conclusions: Four QTLs were identified: two for noncortical BMD, one for endosteal circumference, and one affecting bone biomechanical strength. The future identification of genes responsible for these QTLs will increase the understanding of vertebrate skeletal biology.

Keywords
chicken, quantitative trait loci, BMD, biomechanics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96811 (URN)10.1359/jbmr.061203 (DOI)000244619400005 ()17181401 (PubMedID)
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2017-12-14Bibliographically approved
2. Differential gene expression in femoral bone from red junglefowl and domestic chicken, differing for bone phenotypic traits
Open this publication in new window or tab >>Differential gene expression in femoral bone from red junglefowl and domestic chicken, differing for bone phenotypic traits
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2007 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 8, p. 208-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Osteoporosis is frequently observed among aging hens from egg-producing strains (layers) of domestic chicken. White Leghorn (WL) has been intensively selected for egg production and it manifests striking phenotypic differences for a number of traits including several bone phenotypes in comparison with the wild ancestor of chicken, the red junglefowl (RJ). Previously, we have identified four Quantitative Trait Loci (QTL) affecting bone mineral density and bone strength in an intercross between RJ and WL. With the aim of further elucidating the genetic basis of bone traits in chicken, we have now utilized cDNA-microarray technology in order to compare global RNA-expression in femoral bone from adult RJ and WL (five of each sex and population). RESULTS: When contrasting microarray data for all WL-individuals to that of all RJ-individuals we observed differential expression (False discovery rate adjusted p-values < 0.015) for 604 microarray probes. In corresponding male and female contrasts, differential expression was observed for 410 and 270 probes, respectively. Altogether, the three contrasts between WL and RJ revealed differential expression of 779 unique transcripts, 57 of which are located to previously identified QTL-regions for bone traits. Some differentially expressed genes have previously been attributed roles in bone metabolism and these were: WNT inhibitory factor 1 (WIF1), WD repeat-containing protein 5 (WDR5) and Syndecan 3 (SDC3). Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all 15 had lower expression in WL. CONCLUSION: We report the identification of 779 differentially expressed transcripts, several residing within QTL-regions for bone traits. Among differentially expressed transcripts, those encoding structural ribosomal proteins were highly enriched and all had lower expression levels in WL. In addition, transcripts encoding four translation initiation and translation elongation factor proteins also had lower expression levels in WL, possibly indicating perturbation of protein biosynthesis pathways between the two populations. Information derived from this study could be relevant to the bone research field and may also aid in further inference of genetic changes accompanying animal domestication.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-96812 (URN)10.1186/1471-2164-8-208 (DOI)000248481100001 ()17605776 (PubMedID)
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2017-12-14Bibliographically approved
3. Candidate genes for several bone QTL in chicken revealed by gene expression analysis
Open this publication in new window or tab >>Candidate genes for several bone QTL in chicken revealed by gene expression analysis
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-96813 (URN)
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2011-06-30Bibliographically approved
4. A high proportion of bone trait QTL coincides in two separate intercrosses between wild-type and domestic chicken – suggestive evidence for domestication effects
Open this publication in new window or tab >>A high proportion of bone trait QTL coincides in two separate intercrosses between wild-type and domestic chicken – suggestive evidence for domestication effects
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-96814 (URN)
Available from: 2008-03-06 Created: 2008-03-06 Last updated: 2011-06-30Bibliographically approved

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