Gene Copy‐Number Changes in Evolution

Abstract

High‐throughput genomics have revealed widespread copy‐number differences within and among populations of species belonging to diverse taxonomic groups. Experimental evolution in model organisms with minimal natural selection demonstrates that genome‐wide empirical estimates of the spontaneous rates of gene duplication and deletion are extremely high and contribute to the abundance of copy‐number variation (CNV). CNVs are, on average, deleterious with respect to fitness, but their high spontaneous rates of origin can also facilitate rapid adaptation to novel environmental challenges. Duplications and deletions constitute opposing forces that shape genome complexity and size. Gene duplications are the ultimate source of new genes that confer novel phenotypes, whereas deletions remove superfluous genetic material. Furthermore, CNVs can contribute to the evolution of genetic incompatibility and speciation. Future challenges for understanding the evolutionary potential of CNVs include elucidating the relative roles of genetic drift and natural selection for the maintenance of CNVs in populations.

Key Concepts

  • Gene duplications are naturally occurring mutations within genomes wherein genic material is duplicated, resulting in additional copies of the duplicated gene.
  • Gene deletions are mutations where genic material has been deleted, thereby reducing the number of copies of the deleted gene.
  • Gene duplications and deletions have resulted in extensive gene copy‐number variation (CNV) in populations across all domains of life.
  • The evolution of gene content and genome size is the net result of duplications adding new genetic material and contributing to the evolution of new genes, and deletions, which are continuously removing genetic information.
  • The study of copy‐number variants at single loci has a long history in population genetics, but a systematic analysis of CNVs across whole genomes became possible only after technical breakthroughs in DNA microarray technology and whole‐genome sequencing.
  • The rates of spontaneous gene duplication and deletion per gene are extraordinarily high and usually much higher than the nucleotide substitution rates.
  • Most CNVs in natural populations are deleterious.
  • Both duplications and deletions can contribute to adaptive genetic variation in natural and experimental populations.
  • The long‐term maintenance of duplicated genes, which contribute to the evolution of novel genes, can be achieved by both positive selection on gene copy‐number and subfunctionalisation resulting from the loss of partial functions of complementary gene copies.
  • Gene duplication and subfunctionalisation can contribute to reproductive isolation and speciation.
  • A comprehensive understanding of how CNVs contribute to the evolution of genomes will require a combination of high‐throughput genomics with analysis of the functional and fitness consequences of CNVs in experimental and natural populations.

Keywords: gene deletion; gene duplication; copy‐number variation; fitness; speciation; subfunctionalisation; neofunctionalisation; genome; evolution; mutation

Figure 1. Schematic displaying the contributions of copy‐number changes to genome size. Genome expansion occurs via the gain of new sequences by gene and genome (not shown) duplication. Genome contraction proceeds by loss of existing duplicate segments and deletions of unique DNA segments.
Figure 2. Rates of gene duplication estimated from (1) locus‐specific assays, (2) population frequencies of copy‐number variants, (3) bioinformatic analyses of initially sequenced genomes of model organisms and (4) empirical genome‐wide analyses of mutation accumulation experiments. Estimates of the duplication rate (duplication/gene/generation) vary several orders of magnitude across these studies employing different approaches and are represented on a logarithmic scale to facilitate comparison.
Figure 3. Rates of gene deletion estimated from (1) locus‐specific assays, (2) population frequencies of copy‐number variants and (3) empirical genome‐wide analyses of mutation accumulation experiments. Estimates of the deletion rate (deletion/gene/generation) vary several orders of magnitude across these studies employing different approaches and are represented on a logarithmic scale to facilitate comparison.
Figure 4. The origin of genetic incompatibility via reciprocal silencing of duplicate genes (adapted from Lynch and Force, ). Let us take an example of an ancestral gene comprising three functional regulatory regions (small, yellow squares) which control gene expression and the coding region (larger green rectangle). Duplication of the ancestral locus and associated regulatory regions yields structurally and functionally redundant duplicate loci A and B, each possessing the full repertoire of ancestral function. The ancestral population subsequently splits into two geographically isolated subpopulations: subpopulation 1 with duplicate copies A1 and B1, and subpopulation 2 with duplicate copies A2 and B2. Given the deleterious nature of most newly occurring mutations, each descendant subpopulation is expected to accumulate degenerative silencing (nonfunctionalizing) mutations at one of two duplicate loci. Although the mutations in themselves are deleterious (loss‐of‐function), they accumulate in a neutral fashion within each subpopulation due to the presence of genetic redundancy afforded by an extra gene copy that enables the maintenance of the full ancestral function irrespective of the accumulating mutations. This divergent resolution of the duplicate copies in the two subpopulations is represented in this schematic. Subpopulation 1 gains nonfunctionalizing mutations in the first and third regulatory regions of copy A1 and the second regulatory region of copy B1 (represented by white shaded boxes). However, within subpopulation 1, the presence of at least one functional copy of all three regulatory regions across the two duplicate copies maintains the ancestral expression. Likewise, although subpopulation 2 loses function of its first and second regulatory region in copy A2 and the third regulatory region in copy B2, the ancestral expression profile is preserved because of the presence of at least one functional version of all three regulatory regions between gene duplicates A2 and B2. Therefore, the nonfunctionalizing mutations are neutral with respect to fitness within each subpopulation. However, in a hybrid background, independent assortment of these alleles can result in the inheritance of nonfunctional modules across both duplicate copies, thereby leading to sterility or inviability. In this particular scenario, half of the F1 hybrid gametes are inviable and one‐eighth of the F2 hybrids will be double‐homozygotes for nonfunctional paralogs, leading to inviability or sterility if the ancestral gene function is necessary for fitness‐related traits. For example, F2 zygotes with genotype A1A1B2B2 lack a functional third regulatory region leading to loss of one ancestral subfunction. F2 zygotes with genotype A2A2B1B1 possess a silenced allele for the second regulatory region leading to loss of another ancestral subfunction.
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Further Reading

Alkan C, Coe BP and Eichler EE (2011) Genome structural variation discovery and genotyping. Nature Reviews Genetics 12: 363–376.

Conant GC and Wolfe KH (2008) Turning a hobby into a job: how duplicated genes find new functions. Nature Reviews Genetics 9: 938–950.

Hastings PJ, Lupski JR, Rosenberg SM and Ira G (2009) Mechanisms of change in gene copy number. Nature Reviews Genetics 10: 551–564.

Nair S, Nash D, Sudimack D, et al. (2007) Recurrent gene amplification and soft selective sweeps during evolution of multidrug resistance in malaria parasites. Molecular Biology and Evolution 24: 562–573.

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Bergthorsson, Ulfar, and Katju, Vaishali(May 2016) Gene Copy‐Number Changes in Evolution. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026319]