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Bestrophin 1 together with its three homologues forms a phylogenetically highly conserved family of proteins.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>A bioinformatics study was performed to investigate the phylogenetic relationship among the bestrophin family members and to statistically evaluate sequence conservation and functional divergence. Phylogenetic tree assembly with all available eukaryotic bestrophin sequences suggests gene duplication events in the lineage leading to the vertebrates. A common N-terminal topology which includes four highly conserved transmembrane domains is shared by the members of the four paralogous groups of vertebrate bestrophins and has been constrained by purifying selection. Pairwise comparison shows that altered functional constraints have occurred at specific amino acid positions after phylogenetic diversification of the paralogues. Most notably, significant functional divergence was found between bestrophin 4 and the other family members, as well as between bestrophin 2 and bestrophin 3. Site-specific profiles were established by posterior probability analysis revealing significantly divergent clusters mainly in two hydrophilic loops and a region immediately adjacent to the last predicted transmembrane domain. Strikingly, codons 279 and 347 of human bestrophin 4 reveal high divergence when compared to the paralogous positions strongly indicating the functional importance of these residues for the bestrophin 4 protein. None of the functionally divergent amino acids were found to reside within obvious sequences patterns or motifs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our study highlights the molecular evolution of the bestrophin family of transmembrane proteins and indicates amino acid residues likely relevant for distinct functional properties of the paralogues. These findings may provide a starting point for further experimental verifications.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2148-8-72","type":"journal-article","created":{"date-parts":[[2008,2,29]],"date-time":"2008-02-29T07:14:45Z","timestamp":1204269285000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Molecular evolution and functional divergence of the bestrophin protein family"],"prefix":"10.1186","volume":"8","author":[{"given":"Vladimir M","family":"Milenkovic","sequence":"first","affiliation":[]},{"given":"Thomas","family":"Langmann","sequence":"additional","affiliation":[]},{"given":"Rainer","family":"Schreiber","sequence":"additional","affiliation":[]},{"given":"Karl","family":"Kunzelmann","sequence":"additional","affiliation":[]},{"given":"Bernhard HF","family":"Weber","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2008,2,28]]},"reference":[{"key":"641_CR1","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1006\/geno.1997.4989","volume":"46","author":"EL Sonnhammer","year":"1997","unstructured":"Sonnhammer EL, Durbin R: Analysis of protein domain families in Caenorhabditis elegans. 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