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