Trends in Genetics
Volume 14, Issue 2, 1 February 1998, Pages 46-49
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Genetic redundancy in vertebrates: polyploidy and persistence of genes encoding multidomain proteins

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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 phenotype2, 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.

Section snippets

Loss-of-function mutants affecting protein domains

The human X-linked genetic disease fragile X syndrome is usually caused by trinucleotide repeat amplification leading to loss of expression of the RNA-binding protein FMR1 (Ref. [4]). However, a particularly severe phenotype was found to result from a single point mutation (Ile304Asn) in an FMR1 KH domain[5], which has been shown by NMR to destabilize the domain tertiary structure[6], thereby abolishing its RNA-binding function. A similar phenomenon, in which a KH domain-specific

Dominant-negative phenotypes and gene persistence

We have considered two examples of gene families where point mutations that damage part of the protein have a stronger phenotype than null mutants caused by loss of gene expression. Both these gene families encode multidomain proteins (Appendix A). Classically, duplicated genes with full redundancy are expected to reduce to a single copy over time, through the stochastic accumulation of mutations that damage one of the genes1, 14. The half-life for dispensable genes in vertebrates has been

Serial polyploidy

Compared with Drosophila, there is much more functional redundancy in mouse (and other vertebrates), and concomitantly the multigene families appear to be generally larger. In mouse and human there are many examples of highly related paralogous gene groupings with up to four members18, 19. These include the SRC and LYN kinase groups, the Hox gene clusters, the MYC and MyoD transcription factors, and so on. Genome analyses are steadily revealing quadruplicated segments with colinear gene orders

Acknowledgements

We thank K. Wolfe, D. Shields and many colleagues at EMBL in the structures, gene expression and cell differentiation programmes for commenting on the ideas in this manuscript.

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