Segmental Duplications And Evolution

The paradigm of segmental duplications as mediators of chromosomal rearrangement in a growing list of recurrent microdeletion/microduplication syndromes indicates their potential as catalysts of structural chromosome rearrangement. However, with the recent availability of DNA sequence from several mammalian species, it is now clear that segmental duplications are also a major driving force in karyotype evolution and speciation.

Comparative analysis of orthologous regions has provided strong evidence for a duplication-driven mechanism underlying chromosomal evolution. In several cases, analysis of evolutionary breakpoints of translocation or inversions between humans and other primates has revealed the presence of duplicated sequences at the sites of rearrangement (51-54). Indeed, cross-species analysis using array comparative genomic hybridization (CGH) has shown a significant association of segmental duplications and sites of large scale rearrangement between the great apes, suggesting that the genomic architecture plays an important role in mediating evolutionary rearrangements (55). Furthermore, recent comparative analyses of breaks in synteny between the genomes of humans and mice also show a highly significant enrichment of duplicated sequences at the sites of breakage (56,57). Although definitive evidence showing that these duplicated sequences are the cause, and not a consequence, of the rearrangements, they strongly support a nonrandom model in which chromosomal evolution is driven by the duplication architecture of the genome.

However, segmental duplications may also play an important role in genome evolution in other ways besides mediating large-scale rearrangement (Fig. 4). Many duplications contain either partial or complete gene sequences, and their proliferation can, therefore, create additional copies of transcripts that have the potential to evolve independently from one another. It has been suggested that such duplication removes the pressure for conservation of function that would normally constrain translational change, and that gene duplication may, therefore, be one of the major forces involved in generating proteome diversity. Although it is true that the majority of such duplication events will create nonfunctional pseudogenes owing to the loss of crucial exons, regulatory elements, or the accumulation of deleterious mutations, several important examples exist of genes that have acquired novel functions following duplication events. These include the evolution of trichromatic color vision in the apes and monkeys

Fig. 4. Mechanisms of duplication-driven evolution: (A) gene evolution by complete duplication provides a period of relaxed selection, allowing the resultant copies to diverge and potentially acquire novel function. Two alternative models have been proposed: (1) the classical model of 'mutation during redundancy" proposes that advantageous mutation in one duplicated copy leads to gain of function (67) and (2) an alternative model, termed "duplication-degeneration-complementation," that suggests deleterious mutations occur in both copies, leaving each with partial functions that complement one another (67). (B) The creation of novel fusion transcripts by the juxtaposition of exons of independent origin, or alternatively insertion of novel exon(s) into an existing gene. (C) A hypothetical duplication-mediated chromosomal rearrangement that occurs as a result of an interchro-mosomal duplication followed by nonallelic homologous recombination. (Reproduced in part with permission from ref. 68.)

Fig. 4. Mechanisms of duplication-driven evolution: (A) gene evolution by complete duplication provides a period of relaxed selection, allowing the resultant copies to diverge and potentially acquire novel function. Two alternative models have been proposed: (1) the classical model of 'mutation during redundancy" proposes that advantageous mutation in one duplicated copy leads to gain of function (67) and (2) an alternative model, termed "duplication-degeneration-complementation," that suggests deleterious mutations occur in both copies, leaving each with partial functions that complement one another (67). (B) The creation of novel fusion transcripts by the juxtaposition of exons of independent origin, or alternatively insertion of novel exon(s) into an existing gene. (C) A hypothetical duplication-mediated chromosomal rearrangement that occurs as a result of an interchro-mosomal duplication followed by nonallelic homologous recombination. (Reproduced in part with permission from ref. 68.)

(58,59) and novel immunological functions of the eosinophil proteins ECP and EDN (60), demonstrating the ability of whole gene duplication to drive rapid phenotypic change. Similarly, gene duplication provides an opportunity for the daughter genes to achieve functional specialization in response to environmental pressures, acting as novel substrates for adaptive evolution (61).

Segmental duplications may also lead to the modification or creation of new genes by a number of different mechanisms. Novel exons may be inserted into an existing gene, a mechanism termed exon shuffling, as has been reported for the fibrinolytic factors (62). Alternatively, the juxtaposition of segmental duplications containing different exonic structures has the potential to join two independent transcriptional units, thereby creating novel fusion transcripts lacking in functional constraints and able to evolve rapidly. Examples of these include POM-ZP3 (63), PMCHL1-PMCHL2 (64), CECR7 (46), KIAA0187 (34), and USP6 (65). Segmental duplications can also frequently lead to the creation of novel splice variants in existing genes. Indeed, analysis of alternatively spliced genes has shown that as many as 10% of all splice variants may have arisen from an initial intragenic duplication event (66).

Finally, a recent survey of segmental duplications in the human genome found that approx 6% of transcribed exons are located in recently duplicated sequence (2). Genes associated with immunity and defense, membrane surface interactions, drug detoxification, and growth and development were preferentially enriched, suggesting that gene duplication plays a major role in the evolution of these functions. Thus, in contrast to the popular conception in which single nucleotide polymorphisms and small mutations are the major method of evolutionary change, larger genomic rearrangements may instead represent the driving force behind much of recent primate evolution, facilitated by the presence of abundant highly homologous duplicated sequences throughout the genome (68).

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