Our research has these primary aims:
1) To resolve the evolution of important gene families in vertebrates, particularly gene families expressed in the nervous system and in the endocrine system. Thousands of vertebrate gene families expanded in two genome doublings (tetraploidizations) that took place approximately 500 million years ago. These events explain a great deal of the complexity of the vertebrates, and also explain functional overlap for members of many gene families. We use sequence analyses and chromosome comparisons across species to distinguish orthologous and paralogous genes. The results have important implications for our understanding of how functions arise and change during evolution. We are primarily investigating gene families for neuropeptides, receptors, ion channels, and genes involved in vision. We have resolved the evolution of a number of complicated gene families, including the following:
- Neuropeptide Y-family peptides and receptors
- Opioid peptides and receptors
- Oxtyocin-vasopressin receptors
- Voltage-gated sodium channels
- TGF (transforming growth factor) beta receptors
- Visual opsins
- Transducins (G proteins in vision)
- Glutamate receptors (ion channels)
- GABA-A receptors
- Nicotinic acetylcholine receptors
- Muscarinic acetylcholine receptors
Genes expressed in the eye are being investigated in zebrafish to see how duplicates may differ from each other. We have found several examples how gene duplication results in specialization of the duplicates, for instance in the developmental onset of expression and in the distribution of the products across the retina.
A main project presently is to investigate the evolution of gene families involved in learning and long-term memory. Preliminary results show that many of these gene families received new members in the early vertebrate tetraploidizations, notably glutamate receptors of both the AMPA type and the NMDA type. These findings suggest that much of the machinery for long-term memory existed already in the earliest vertebrates.
2) To characterize the NPY (neuropeptide Y) system of peptides and G-protein-coupled receptors, and their closest relatives, with regard to ligand-receptor interactions and receptor regulation of importance for appetite regulation. Molecular modelling is combined with mutagenesis and expression for functional characterization.
We also investigate how genetic variation in one of the receptor genes correlates with body mass index and obesity. We have found that an appetite-regulating gene displays extensive copy number variation in humans, ranging from 2-8 copies, and that higher copy number correlates with higher body mass index.
Christina Bergqvist, research engineer
Helen Haines, PhD student
Julia E. Pedersen, PhD
Fengjiao Chen, postdoc
- Sundström, G., Dreborg, S., and Larhammar, D. Concomitant duplications of opioid peptide and receptor genes before the origin of jawed vertebrates. PLoS One, May 6; 5(5):e10512 (2010). PMID: 20463905.
- Xu, B., Fällmar, H., Boukharta, L., Gutiérrez-de-Terán, H., Pruner, J., Lundell, I., Mohell, N., Åqvist, J., and Larhammar, D. Mutagenesis and computational modeling of the human G protein-coupled receptor Y2 for neuropeptide Y and peptide YY. Biochemistry 52, 7987-7998 (2013). PMID: 24111902.
- Lagman, D., Ocampo Daza, D., Widmark, J., Abalo, X. M., Sundström, G., and Larhammar, D. The vertebrate ancestral repertoire of visual opsins, transducin alpha subunits and oxytocin/vasopressin receptors was established by duplication of their shared genomic region in the two rounds of early vertebrate genome duplications. BMC Evol. Biol. 13, 238 (2013). PMID: 24180662.
- Lagman, D., Franzén, I. E., Eggert, J., Larhammar, D. and Abalo, X. M. Evolution and expression of phosphodiesterase 6 genes unveils vertebrate novelty to control photosensitivity. BMC Evol. Biol., 16:124 (2016). PMID: 27296292.
- Ocampo Daza, D. and Larhammar, D. Evolution of the receptors for growth hormone, prolactin, erythropoietin and thrombopoietin in relation to the vertebrate tetraploidizations. Gen. Comp. Endocrinol. 2017, in press.