The gene encoding the glycolytic enzyme triose-phosphate isomerase (TPI; EC 5.3.1.1) has been central to the long-standing controversy on the origin and evolutionary significance of spliceosomal introns by virtue of its pivotal support for the introns-early view, or exon theory of genes.Putative correlations between intron positions and TPI protein structure have led to the conjecture that the gene was assembled by exon shuffling, and five TPI intron positions are old by the criterion of being conserved between animals and plants. We have sequenced TPI genes from three diverse eukaryotes-the basidiomycete Coprinus cinereus, the nematode Caenorhabditis elegans, and the insect Heliothis virescens and have found introns at seven novel positions that disrupt previously recognized gene/protein structure correlations.The set of 21 TPI introns now known is consistent with a random model of intron insertion. Twelve of the 21 TPI introns appear to be of recent origin since each is present in but a single examined species. These results, together with their implication that as more TPI genes are sequenced more intron positions will be found, render TPI untenable as a paradigm for the introns-early theory and, instead, support the introns-late view that spliceosomal introns have been inserted into preexisting genes during eukaryotic evolution.The surprising discovery of spliceosomal introns in 1977 was soon followed by considerable speculation about their origin, evolution, and significance (1-3). Nearly 20 years later, the issue is very much alive and has long since become polarized into two opposing theories. The introns-early theory, or exon theory of genes, posits the presence of many introns in the common ancestor of all life, followed by massive, often complete, intron loss in many independent lineages (4, 5). Introns are thought to have functioned in the primordial assembly of protein genes by promoting the recombinational shuffling of short exons, each encoding 15-20 amino acid units of protein structure (6-8). The other theory, termed introns-late, posits that spliceosomal introns were not present in the common ancestor of life but, instead, arose and spread within eukaryotic evolution (9-11); therefore, these introns could not have played any role in ancient gene and protein assembly.A major part of the evidence in favor of the introns-early theory has been supplied by the ancient gene encoding the glycolytic enzyme triose-phosphate isomerase (TPI; EC 5.3.1.1; refs. 6-8 and 12). As soon as the first eukaryotic TPI gene was sequenced, a correspondence was noted between exons and secondary structural elements, with all six chicken introns falling at or near the ends of a-helices and (3-strands (13). More TPI intron positions were discovered in 1986 from a plant and a fungus (6). Five introns are located in the same positions in plant and animal TPI genes, indicating that these introns were in place prior to the presumably ancient divergence of these taxa (6). Since these new data did not support a straightf...
Background: As genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra-and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation. Methods: A primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidatesother muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype. Findings: Twenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation. Interpretation: Our multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases. Funding: The Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme "Integrated European Àomics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)".
Little is known about how the observed fat-specific pattern of 3D-spatial genome organisation is established. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope transmembrane protein Tmem120a disrupts fat genome organisation, thus causing a lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a−/− mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifest upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein encoding LMNA mutations. Our data indicate TMEM120A genome organisation functions affect many adipose functions and its loss may yield adiposity spectrum disorders, including a miRNA-based mechanism that could explain muscle hypertrophy in human lipodystrophy.
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