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Analysis of Candidate Genes for Lineage-Specific Expression Changes in Humans and Primates
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
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2014 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 8, 3596-3606 p.Article in journal (Refereed) Published
Abstract [en]

RUNX2, a gene involved in skeletal development, has previously been shown to be potentially affected by positive selection during recent human evolution. Here we have used antibody-based proteomics to characterize potential differences in expression patterns of RUNX2 interacting partners during primate evolution. Tissue microarrays consisting of a large set of normal tissues from human and macaque were used for protein profiling of 50 RUNX2 partners with immunohistochemistry. Eleven proteins (AR, CREBBP, EP300, FGF2, HDAC3, JUN, PRKD3, RUNX1, SATB2, TCF3, and YAP1) showed differences in expression between humans and macaques. These proteins were further profiled in tissues from chimpanzee, gorilla, and orangutan, and the corresponding genes were analyzed with regard to genomic features. Moreover, protein expression data were compared with previously obtained RNA sequencing data from six different organs. One gene (TCF3) showed significant expression differences between human and macaque at both the protein and RNA level, with higher expression in a subset of germ cells in human testis compared with macaque. In conclusion, normal tissues from macaque and human showed differences in expression of some RUNX2 partners that could be mapped to various defined cell types. The applied strategy appears advantageous to characterize the consequences of altered genes selected during evolution.

Place, publisher, year, edition, pages
2014. Vol. 13, no 8, 3596-3606 p.
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-186271DOI: 10.1021/pr500045fISI: 000339983600010OAI: oai:DiVA.org:uu-186271DiVA: diva2:572817
Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2015-11-20Bibliographically approved
In thesis
1. Tissue Microarrays for Analysis of Expression Patterns
Open this publication in new window or tab >>Tissue Microarrays for Analysis of Expression Patterns
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are essential building blocks in every living cell, and since the complete human genome was sequenced in 2004, researchers have attempted to map the human proteome, which is the functional representation of the genome. One such initiative is the Human Protein Atlas programme (HPA), which generates monospecific antibodies towards all human proteins and uses these for high-throughput tissue profiling on tissue microarrays (TMAs). The results are publically available at the website www.proteinatlas.org.

In this thesis, TMAs were used for analysis of expression patterns in various research areas. Different search queries in the HPA were tested and evaluated, and a number of potential biomarkers were identified, e.g. proteins exclusively expressed in islets of Langerhans, but not in exocrine glandular cells or other abdominal organs close to pancreas. The identified candidates were further analyzed on TMAs with pancreatic tissues from normal and diabetic individuals, and colocalization studies with insulin and glucagon revealed that several of the investigated proteins (DGCR2, GBF1, GPR44 and SerpinB10) appeared to be beta cell specific. Moreover, a set of proteins differentially expressed in lung cancer stroma was further analyzed on a clinical lung cancer cohort in the TMA format, and one protein (CD99) was significantly associated with survival. In addition, TMAs with tissue samples from different species were generated, e.g. for mapping of influenza virus attachment in various human and avian tissues. The results showed that the gull influenza virus H16N3 attached to human respiratory tract and eye, suggesting possible transmission of the virus between gull and human. TMAs were also used for analysis of protein expression differences between humans and other primates, and two proteins (TCF3 and SATB2) proved to be significantly differentially expressed on the human lineage at both the protein level and the RNA level.  

In conclusion, this thesis exemplifies the potential of the TMA technology, which can be used for analysis of expression patterns in a large variety of research fields, such as biomarker discovery, influenza virus research or further understanding of human evolution.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 62 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 846
Tissue microarrays, Antibody-based proteomics, Immunohistochemistry, Biomarker discovery, Diabetes, Lung cancer, Influenza virus, Evolution
National Category
Endocrinology and Diabetes Infectious Medicine Cancer and Oncology Medical Genetics
Research subject
urn:nbn:se:uu:diva-186272 (URN)978-91-554-8551-1 (ISBN)
Public defence
2013-01-25, Rudbeck hall, Rudbeck laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Available from: 2012-12-21 Created: 2012-11-28 Last updated: 2013-02-11Bibliographically approved

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Lindskog, CeciliaPontén, Fredrik
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Science for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and Pathology
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