Jürg Spring

Genetic redundancy in vertebrates: polyploidy and persistence of genes encoding multidomain proteins

Abstract We were interested to read the recent article by Cooke and co-workers in Trends in Genetics discussing redundant gene expression in metazoans[1]. It would certainly be helpful to gain some understanding of this curious phenomenon, given the burgeoning list of mouse gene knockouts with no apparent phenotype[2, 3]. Here we should like to contribute to the debate by putting forward a rather different perspective, which obviates the highly questionable need to propose active selection for redundant gene function in vertebrate development[1]. There is evidence to suggest that selection operates to reject deleterious point mutations in redundant genes encoding multidomain proteins, while the redundancy itself appears to be a historical consequence of polyploidy in the vertebrate common ancestor. We develop the argument by first considering some relevant properties of three disparate multigene families encoding proteins belonging to the KH domain, SRC and HOX groups, and then draw some general conclusions.

Genome duplication strikes back

The human genome contains up to four paralogs of many Drosophila genes. Two rounds of whole-genome duplication followed by substantial gene loss could explain this pattern easily, but this hypothesis has often been questioned. Mounting evidence from the human genome sequence now confirms at least one genome duplication during early chordate evolution.

A TOXIN HOMOLOGY DOMAIN IN AN ASTACIN-LIKE METALLOPROTEINASE OF THE JELLYFISH PODOCORYNE CARNEA WITH A DUAL ROLE IN DIGESTION AND DEVELOPMENT

Abstract Metalloproteinases of the astacin family such as tolloid play major roles in animal morphogenesis. Cnidarians are thought to be evolutionary simple organisms and, therefore, a metalloproteinase from the marine hydrozoan Podocoryne carnea was analysed to evaluate the role of this conserved gene familiy at the base of animal evolution. Surprisingly, the proteinase domain of Podocornyne PMP1 is more similar to human meprin than to HMP1 from another hydrozoan, the freshwater polyp Hydra vulgaris. However, PMP1 and HMP1 both contain a small C-terminal domain with six cysteines that distinguishes them from other astacin-like molecules. Similar domains have been described only recently from sea anemone toxins specific for potassium channels. This toxin homology (Tox1) domain is clearly distinct from epidermal growth factor (EGF)-like domains or other cysteine-rich modules and terminates with the characteristic pattern CXXXCXXC with three out of six cysteines in the last eight residues of the protein. PMP1 is transiently expressed at various sites of morphogenetic activity during medusa bud development. In the adult medusa, however, expression is concentrated to the manubrium, the feeding organ, where the PMP1 gene is highly induced upon feeding. These disparate expression patterns suggest a dual role of PMP1 comparable to tolloid in development and, like astacin in the crayfish, also for food digestion. The Tox1 domain of PMP1 could serve as a toxin to keep the pray paralysed after ingestion, but as a sequence module such Tox1 domains with six cysteines are neither restricted to cnidarians nor to toxins.

Distinct expression patterns of the two T-box homologues Brachyury and Tbx2/3 in the placozoan Trichoplax adhaerens

Trichoplax adhaerens is the only species known from the phylum Placozoa with one of the simplest metazoan body plans. In the small disc-like organism an upper and a lower epithelium can be distinguished with a less compact third cell layer in between. When Trichoplax was first described in 1883, the relation of these three cell layers with ectoderm, endoderm and mesoderm of higher animals was discussed. Still, little is known about embryonic development of Trichoplax, however, genes thought to be specific for mesoderm in bilaterian animals turned out to be already present in non-bilaterians. Searching for a Brachyury homologue, two members of the T-box gene family were isolated from Trichoplax, Brachyury and a Tbx2/3 homologue. The T-box genes encode a transcription factor family characterized by the DNA-binding T-box domain. T-box genes have been found in all metazoans so far investigated, but in contrast to other transcription factors such as the homeobox family, T-box genes are not present in plants or fungi. The distinct expression patterns of two T-box genes in Trichoplax point to non-redundant functions already present at the beginning of animal evolution. Since the expression patterns derived by in situ hybridization do not overlap with anatomical structures, it can be concluded that this simple animal has more than the four cell types described in the literature. This hidden complexity and the unresolved position in relation to Porifera, Cnidaria, Ctenophora and Bilateria highlight the necessity of the inclusion of Trichoplax in studies of comparative evolutionary and developmental biology.

The FTO Gene, Implicated in Human Obesity, Is Found Only in Vertebrates and Marine Algae

Human obesity is a main cause of morbidity and mortality. Recently, several studies have demonstrated an association between the FTO gene locus and early onset and severe obesity. To date, the FTO gene has only been discovered in vertebrates. We identified FTO homologs in the complete genome sequences of various evolutionary diverse marine eukaryotic algae, ranging from unicellular photosynthetic picoplankton to a multicellular seaweed. However, FTO homologs appear to be absent from all other completely sequenced genomes of plants, fungi, and invertebrate animals. Although the biological roles of these marine algal FTO homologs are still unknown, these genes will be useful for exploring basic protein features and could hence help unravel the function of the FTO gene in vertebrates and its inferred link with obesity in humans.

T-box and homeobox genes from the ctenophore Pleurobrachia pileus : Comparison of Brachyury, Tbx2/3 and Tlx in basal metazoans and bilaterians

Most animals are classified as Bilateria and only four phyla are still extant as outgroups, namely Porifera, Placozoa, Cnidaria and Ctenophora. These non‐bilaterians were not considered to have a mesoderm and hence mesoderm‐specific genes. However, the T‐box gene Brachyury could be isolated from sponges, placozoans and cnidarians. Here, we describe the first Brachyury and a Tbx2/3 homologue from a ctenophore. In addition, analysing T‐box and homeobox genes under comparable conditions in all four basal phyla lead to the discovery of novel T‐box genes in sponges and cnidarians and a Tlx homeobox gene in the ctenophore Pleurobrachia pileus . The conservation of the T‐box and the homeobox genes suggest that distinct subfamilies with different roles in bilaterians were already split in non‐bilaterians.

Major transitions in evolution by genome fusions: from prokaryotes to eukaryotes, metazoans, bilaterians and vertebrates

The major transitions in human evolution from prokaryotes toeukaryotes, from protozoans to metazoans, from the first animals tobilaterians and finally from a primitive chordate to vertebrates wereall accompanied by increases in genome complexity. Rare fusion ofdivergent genomes rather than continuous single gene duplications couldexplain these jumps in evolution. The origin of eukaryotes was proposedto be due to a symbiosis of Archaea and Bacteria. Symbiosis is clearlyseen as the source for mitochondria. A fundamental difference of highereukaryotes is the cycle from haploidy to diploidy, a well-regulatedgenome duplication. Of course, self-fertilization exists, but thepotential of sex increases with the difference of the haploid stages,such as the sperm and the egg. What should be the advantage of havingtwo identical copies of a gene? Still, genes duplicate all the time andeven genomes duplicate rather often. In plants, polyploidy is wellrecognized, but seems to be abundant in fungi and even in animals, too.However, hybridization, rather than autopolyploidy, seems to be thepotential mechanism for creating something new. The problem withchimaeric, symbiotic or reticulate evolution events is that they blurphylogenetic lineages. Unrecognized paralogous genes or random loss ofone of the paralogs in different lineages can lead to falseconclusions. Horizontal genome transfer, genome fusion or hybridizationmight be only truly innovative combined with rare geologicaltransitions such as change to an oxygen atmosphere, snowball Earthevents or the Cambrian explosion, but correlates well with the majortransitions in evolution.

Identification of the Drosophila melanogaster homolog of the human spastin gene

The human SPG4 locus encodes the spastin gene, which is responsible for the most prevalent form of autosomal dominant hereditary spastic paraplegia (AD-HSP), a neurodegenerative disorder. Here we identify the predicted gene product CG5977 as the Drosophila homolog of the human spastin gene, with much higher sequence similarities than any other related AAA domain protein in the fly. Furthermore we report a new potential transmembrane domain in the N-terminus of the two homologous proteins. During embryogenesis, the expression pattern of Drosophila spastin becomes restricted primarily to the central nervous system, in contrast to the ubiquitous expression of the vertebrate spastin genes. Given this nervous system-specific expression, it will be important to determine if Drosophila spastin loss-of-function mutations also lead to neurodegeneration.