Protein tandem duplication

The following sections explore nature s use of domain swapping to evolve new function. These include the formation of multifunctional proteins, tandem duplication, domain recruitment, and cicular permutation (Fig. 1). The evolution of several enzymes in the purine (Fig. 2) and pyrimidine (Fig. 3) de novo biosynthetic pathways, as well as other enzymes, are discussed as illustrative examples. 

Fig. 1. Schematics of evolutionary mechanisms of domain swapping in nature. Multifunctional proteins arise from the fusion of the genes coding for individual enzymes. Often the individual domains of multifunctional proteins catalyze successive steps in metabolic pathways. In tandem duplication, a gene is duplicated and the 3 end of one copy is fused in-frame to the 5 end of the second copy. In domain recruitment, a functional unit (whole gene or gene fragment) from one gene is either inserted within or fused to an end of a second gene. Circular permuted genes are believed to arise via tandem duplication followed by introduction of new start and stop codons (Ponting el at, 1995).

Circular permutation of a protein results in the relocation of its N- and C-termini within the existing structural framework. Initiated by a tandem duplication of a precursor gene, one mechanistic model proposes an in-frame fusion of the original termini, followed by the generation of a new start codon in the first repeat and a termination site in the second. In support of the model, tandem duplications are observed in prosaposins [29] and DNA methyltransferases [30], both genes for which circular per-mutated variants are also known. 

Homeologous recombination (recombination between partially homologous sequences) has been successfully used to produce novel antibiotics and functional hybrid proteins in Streptomyces [64-66], If partially homologous sequences are placed in tandem and in the same orientation [67,68], general recombination leads to excision of the duplicated genes as well as of the sequences lying between... 

Besides duplicated protein-coding genes and tandemly repeated genes, eukaryotic cells contain multiple copies of other DNA sequences in the genome, generally referred to as repetitious DNA (see Table 10-1). Of the two main types of repetitious DNA, the less prevalent is simple-sequence DNA, which constitutes about 3 percent of the human genome and is composed of perfect or nearly perfect repeats of relatively short sequences. The more common type of repetitious DNA, composed of much longer sequences, is discussed in Section 10.3. 

Kearns-Sayre syndrome Onset before 20 years of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and one of the following cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins. Deletion of contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation. 

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