Origins and evolution of three multidomain gene families concerned with basic cellular and developmental processes in eukaryotes.

摘要

Duplicate genes are the principal substrates for innovative tinkering during evolution. In eukaryotes a special case of tinkering is the acquisition of domain(s) after gene duplication. Domain acquisition results in the formation of multigene families that code for multidomain proteins. These families often diverge extensively, acquire new functions, and follow different modes of evolution. To understand the mode of evolution of such families, I studied the evolutionary relationships of three different gene families: the FORMIN, the BTK/TEC, and the DANGER.;FORMIN proteins promote the assembly and elongation of actin filaments. My study showed that the FORMIN gene apparently originated at the advent of eukaryotes and probably was duplicated before the divergence of plants and animals. The FORMIN gene family followed the birth-and-death model of evolution and experienced multiple lineage-specific genomic rearrangements which led to acquisition of various different domains. On the basis of their domain organization, FORMIN proteins can be classified into three different types, A, B, and C. Type A FORMIN proteins have the typical Formin Homology 2 domain but lack any other known domain in their N- and C-terminal regions. Type B FORMIN proteins have N-and C-terminal domains, which interact in an intramolecular manner and inactivate the FORMIN function. Type C FORMIN proteins have various non-homologous N- and/or C-terminal domains. Type B FORMIN appeared in the common ancestor of unikonts. The presence of type B FORMIN genes in two parasitic bikonts is explained by either parallel evolution or horizontal gene transfer. This study provides insights into the diversification process of a eukaryote-specific regulator of the cytoskeleton. The lineage-specific diversification of FORMIN genes probably points to unique adaptations.;The BTK/TEC genes code for multidomain proteins that phosphorylate tyrosine residues. In mammals the BTK/TEC proteins play a key role in signal transduction in cells involved in adaptive immunity. My study showed that the BTK/TEC gene appeared before the divergence of animals and choanoflagellates. This gene was duplicated at least three times before the emergence of bony fish. In mammals the N- and C-terminal domains of these kinases---PH and SH1 respectively---are conserved. In contrast, the SH3 and SH2 domains and their flanking linker sequences (denoted as the SSL region) are highly diverged. Because the SSL region of paralogous BTK/TEC proteins has not differentiated with respect to its protein ligands, I hypothesized that this region binds to lipids and has differentiated with respect to this function. I determined that the SSL region has the capacity to bind to lipids. I also verified the functional differentiation hypothesis by showing that the SSL region of paralogous BTK/TEC genes has different lipid-binding profiles. Natural mutations in the SSL region of the BTK gene, which cause a hereditary immunodeficiency in mice and humans, alter the lipid-binding profile of the BTK protein. My study revealed a new function for the BTK/TEC kinases. It also suggested a link between the lipid-binding function and the regulation/function of B-cells.;The DANGER gene family is a highly divergent multigene family that appeared before the origin of animals. Early during animal evolution the DANGER gene duplicated multiple times and diversified extensively. Protostomes lost many DANGER genes, whereas deuterostomes kept them and further increased their numbers. The DANGER proteins are probably involved in cell development and differentiation. DANGER proteins are comprised of micro-domains which show different levels of sequence divergence. The N-terminal micro-domain was probably acquired by exon shuffling and enabled some DANGER proteins to function in different cellular compartments or to be secreted. Other mechanisms of sequence divergence of DANGER proteins include amino acid replacement, intron gain/and loss, and recombination. v