The recent increase in genomic data is revealing a novel perspective of gene loss as a pervasive source of genetic variation in all life kingdoms.
Gene loss depends on gene dispensability, which in turn is affected by changes in mutational robustness and environmental conditions.
Patterns of gene loss are not stochastic but show biases that are associated with gene functions and genomic positions.
Although many gene losses are neutral and fixed by genetic drift, many examples support the idea that gene loss can be an adaptive evolutionary force that is especially effective when organisms are faced with abrupt environmental challenges.
The future mapping of all instances of gene loss in the tree of life will provide valuable information for many fields of biology, including evolutionary biology and translational medicine.
Population genomics might expose ongoing processes of gene loss in natural populations, revealing actual values of gene dispensability and identifying adaptive gene losses with potential interest in biomedicine.
The recent increase in genomic data is revealing an unexpected perspective of gene loss as a pervasive source of genetic variation that can cause adaptive phenotypic diversity. This novel perspective of gene loss is raising new fundamental questions. How relevant has gene loss been in the divergence of phyla? How do genes change from being essential to dispensable and finally to being lost? Is gene loss mostly neutral, or can it be an effective way of adaptation? These questions are addressed, and insights are discussed from genomic studies of gene loss in populations and their relevance in evolutionary biology and biomedicine.
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Ohno, S. Evolution by Gene Duplication (Springer, 1970).
Force, A. et al. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545 (1999).
Kortschak, R. D., Samuel, G., Saint, R. & Miller, D. J. EST analysis of the cnidarian Acropora millepora reveals extensive gene loss and rapid sequence divergence in the model invertebrates. Curr. Biol. 13, 2190–2195 (2003).
Technau, U. et al. Maintenance of ancestral complexity and non-metazoan genes in two basal cnidarians. Trends Genet. 21, 633–639 (2005).
Putnam, N. H. et al. Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317, 86–94 (2007). The sequencing of the anemone genome changed the view of animal evolution, revealing that ancient metazoan genomes were complex and that gene losses have been pervasive throughout animal lineages.
Kusserow, A. et al. Unexpected complexity of the Wnt gene family in a sea anemone. Nature 433, 156–160 (2005).
Szathmary, E., Jordan, F. & Pal, C. Molecular biology and evolution. Can genes explain biological complexity? Science 292, 1315–1316 (2001).
Simakov, O. et al. Insights into bilaterian evolution from three spiralian genomes. Nature 493, 526–531 (2013).
Sea Urchin Genome Sequencing Consortium et al. The genome of the sea urchin Strongylocentrotus purpuratus. Science 314, 941–952 (2006).
Putnam, N. H. et al. The amphioxus genome and the evolution of the chordate karyotype. Nature 453, 1064–1071 (2008).
Dehal, P. et al. The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298, 2157–2167 (2002).
Cañestro, C., Bassham, S. & Postlethwait, J. H. Seeing chordate evolution through the Ciona genome sequence. Genome Biol. 4, 208–211 (2003).
Cañestro, C., Yokoi, H. & Postlethwait, J. H. Evolutionary developmental biology and genomics. Nat. Rev. Genet. 8, 932–942 (2007).
Edvardsen, R. B. et al. Remodelling of the homeobox gene complement in the tunicate Oikopleura dioica. Curr. Biol. 15, R12–R13 (2005).
Denoeud, F. et al. Plasticity of animal genome architecture unmasked by rapid evolution of a pelagic tunicate. Science 330, 1381–1385 (2010).
Srivastava, M. et al. The Amphimedon queenslandica genome and the evolution of animal complexity. Nature 466, 720–726 (2010).
Fortunato, S. A. et al. Calcisponges have a ParaHox gene and dynamic expression of dispersed NK homeobox genes. Nature 514, 620–623 (2014).
King, N. et al. The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451, 783–788 (2008).
Suga, H. et al. The Capsaspora genome reveals a complex unicellular prehistory of animals. Nat. Commun. 4, 2325 (2013).
Ryan, J. F. et al. The homeodomain complement of the ctenophore Mnemiopsis leidyi suggests that Ctenophora and Porifera diverged prior to the ParaHoxozoa. Evodevo 1, 9 (2010).
Mendivil Ramos, O., Barker, D. & Ferrier, D. E. Ghost loci imply Hox and ParaHox existence in the last common ancestor of animals. Curr. Biol. 22, 1951–1956 (2012).
Lynch, M. Streamlining and simplification of microbial genome architecture. Annu. Rev. Microbiol. 60, 327–349 (2006).
Moya, A., Pereto, J., Gil, R. & Latorre, A. Learning how to live together: genomic insights into prokaryote-animal symbioses. Nat. Rev. Genet. 9, 218–229 (2008).
McCutcheon, J. P. & Moran, N. A. Extreme genome reduction in symbiotic bacteria. Nat. Rev. Microbiol. 10, 13–26 (2012).
Wolf, Y. I. & Koonin, E. V. Genome reduction as the dominant mode of evolution. BioEssays 35, 829–837 (2013).
Librado, P., Vieira, F. G., Sanchez-Gracia, A., Kolokotronis, S. O. & Rozas, J. Mycobacterial phylogenomics: an enhanced method for gene turnover analysis reveals uneven levels of gene gain and loss among species and gene families. Genome Biol. Evol. 6, 1454–1465 (2014).
Loftus, B. et al. The genome of the protist parasite Entamoeba histolytica. Nature 433, 865–868 (2005).
Spanu, P. D. et al. Genome expansion and gene loss in powdery mildew fungi reveal tradeoffs in extreme parasitism. Science 330, 1543–1546 (2010).
Peyretaillade, E. et al. Extreme reduction and compaction of microsporidian genomes. Res. Microbiol. 162, 598–606 (2011).
De Smet, R. et al. Convergent gene loss following gene and genome duplications creates single-copy families in flowering plants. Proc. Natl Acad. Sci. USA 110, 2898–2903 (2013).
Koskiniemi, S., Sun, S., Berg, O. G. & Andersson, D. I. Selection-driven gene loss in bacteria. PLoS Genet. 8, e1002787 (2012).
Puigbo, P., Lobkovsky, A. E., Kristensen, D. M., Wolf, Y. I. & Koonin, E. V. Genomes in turmoil: quantification of genome dynamics in prokaryote supergenomes. BMC Biol. 12, 66 (2014).
Nelson-Sathi, S. et al. Origins of major archaeal clades correspond to gene acquisitions from bacteria. Nature 517, 77–80 (2015).
Wendel, J. F. Genome evolution in polyploids. Plant Mol. Biol. 42, 225–249 (2000).
Jiao, Y. & Paterson, A. H. Polyploidy-associated genome modifications during land plant evolution. Phil. Trans. R. Soc. B 369, 20130355 (2014).
Scannell, D. R., Butler, G. & Wolfe, K. H. Yeast genome evolution — the origin of the species. Yeast 24, 929–942 (2007).
Andersson, S. G. & Kurland, C. G. Reductive evolution of resident genomes. Trends Microbiol. 6, 263–268 (1998).
Papp, B., Notebaart, R. A. & Pal, C. Systems-biology approaches for predicting genomic evolution. Nat. Rev. Genet. 12, 591–602 (2011). This Review discusses gene dispensability in the context of systems biology and formulates the gene knockout paradox.
Korona, R. Gene dispensability. Curr. Opin. Biotechnol. 22, 547–551 (2011).
Acevedo-Rocha, C. G., Fang, G., Schmidt, M., Ussery, D. W. & Danchin, A. From essential to persistent genes: a functional approach to constructing synthetic life. Trends Genet. 29, 273–279 (2013).
Ritchie, M. D., Holzinger, E. R., Li, R., Pendergrass, S. A. & Kim, D. Methods of integrating data to uncover genotype–phenotype interactions. Nat. Rev. Genet. 16, 85–97 (2015).
Ohno, S. Dispensable genes. Trends Genet. 1, 160–164 (1985).
Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).
de Berardinis, V. et al. A complete collection of single-gene deletion mutants of Acinetobacter baylyi ADP1. Mol. Syst. Biol. 4, 174 (2008).
Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).
Kim, D. U. et al. Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nat. Biotechnol. 28, 617–623 (2010).
Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003).
Sonnichsen, B. et al. Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434, 462–469 (2005).
Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007).
White, J. K. et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell 154, 452–464 (2013).
Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
Wang, T. et al. Identification and characterization of essential genes in the human genome. Science 350, 1096–1101 (2015).
Osorio, J. Functional genomics: the genetic essence of human cells. Nat. Rev. Genet. 16, 683 (2015).
Deutscher, D., Meilijson, I., Kupiec, M. & Ruppin, E. Multiple knockout analysis of genetic robustness in the yeast metabolic network. Nat. Genet. 38, 993–998 (2006).
Felix, M. A. & Barkoulas, M. Pervasive robustness in biological systems. Nat. Rev. Genet. 16, 483–496 (2015).
Piskur, J., Sandrini, M. P., Knecht, W. & Munch-Petersen, B. Animal deoxyribonucleoside kinases: 'forward' and 'retrograde' evolution of their substrate specificity. FEBS Lett. 560, 3–6 (2004).
Wagner, A. Distributed robustness versus redundancy as causes of mutational robustness. BioEssays 27, 176–188 (2005). The author discusses the contribution of gene redundancy and distributed robustness to gene dispensability.
Papp, B., Pal, C. & Hurst, L. D. Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast. Nature 429, 661–664 (2004).
Blank, L. M., Kuepfer, L. & Sauer, U. Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast. Genome Biol. 6, R49 (2005).
Gu, Z. et al. Role of duplicate genes in genetic robustness against null mutations. Nature 421, 63–66 (2003).
Ihmels, J., Collins, S. R., Schuldiner, M., Krogan, N. J. & Weissman, J. S. Backup without redundancy: genetic interactions reveal the cost of duplicate gene loss. Mol. Syst. Biol. 3, 86 (2007).
Li, J., Yuan, Z. & Zhang, Z. The cellular robustness by genetic redundancy in budding yeast. PLoS Genet. 6, e1001187 (2010).
DeLuna, A. et al. Exposing the fitness contribution of duplicated genes. Nat. Genet. 40, 676–681 (2008).
Boone, C., Bussey, H. & Andrews, B. J. Exploring genetic interactions and networks with yeast. Nat. Rev. Genet. 8, 437–449 (2007).
Liu, G. et al. Gene essentiality is a quantitative property linked to cellular evolvability. Cell 163, 1388–1399 (2015).
Baryshnikova, A. et al. Quantitative analysis of fitness and genetic interactions in yeast on a genome scale. Nat. Methods 7, 1017–1024 (2010).
Costanzo, M. et al. The genetic landscape of a cell. Science 327, 425–431 (2010). This work constructs a genome-scale genetic interaction map covering 75% of all genes of S. cerevisiae and provides experimental evidence that describes how gene redundancy and alternative pathways account for genetic robustness.
Cañestro, C., Catchen, J. M., Rodríguez-Marí, A., Yokoi, H. & Postlethwait, J. H. Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes. PLoS Genet. 5, e1000496 (2009).
McClintock, J. M., Carlson, R., Mann, D. M. & Prince, V. E. Consequences of Hox gene duplication in the vertebrates: an investigation of the zebrafish Hox paralogue group 1 genes. Development 128, 2471–2484 (2001).
Gitelman, I. Evolution of the vertebrate twist family and synfunctionalization: a mechanism for differential gene loss through merging of expression domains. Mol. Biol. Evol. 24, 1912–1925 (2007).
Danchin, E. G., Gouret, P. & Pontarotti, P. Eleven ancestral gene families lost in mammals and vertebrates while otherwise universally conserved in animals. BMC Evol. Biol. 6, 5 (2006).
Payne, J. L. & Wagner, A. Mechanisms of mutational robustness in transcriptional regulation. Front. Genet. 6, 322 (2015).
Hillenmeyer, M. E. et al. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320, 362–365 (2008). This work provides experimental evidence that most of the seemingly dispensable genes of the gene knockout paradox are in fact required for optimal growth in at least one condition.
Musso, G. et al. The extensive and condition-dependent nature of epistasis among whole-genome duplicates in yeast. Genome Res. 18, 1092–1099 (2008).
Makino, T., Hokamp, K. & McLysaght, A. The complex relationship of gene duplication and essentiality. Trends Genet. 25, 152–155 (2009).
Liao, B. Y. & Zhang, J. Mouse duplicate genes are as essential as singletons. Trends Genet. 23, 378–381 (2007).
Aravind, L., Watanabe, H., Lipman, D. J. & Koonin, E. V. Lineage-specific loss and divergence of functionally linked genes in eukaryotes. Proc. Natl Acad. Sci. USA 97, 11319–11324 (2000).
Blanc, G. & Wolfe, K. H. Functional divergence of duplicated genes formed by polyploidy during Arabidopsis evolution. Plant Cell 16, 1679–1691 (2004).
Maere, S. et al. Modeling gene and genome duplications in eukaryotes. Proc. Natl Acad. Sci. USA 102, 5454–5459 (2005).
Seoighe, C. & Gehring, C. Genome duplication led to highly selective expansion of the Arabidopsis thaliana proteome. Trends Genet. 20, 461–464 (2004).
Chen, E. C. et al. The dynamics of functional classes of plant genes in rediploidized ancient polyploids. BMC Bioinformatics 14 (Suppl. 15), S19 (2013).
Blomme, T. et al. The gain and loss of genes during 600 million years of vertebrate evolution. Genome Biol. 7, R43 (2006).
Demuth, J. P., De Bie, T., Stajich, J. E., Cristianini, N. & Hahn, M. W. The evolution of mammalian gene families. PLoS ONE 1, e85 (2006).
Meslin, C. et al. Evolution of genes involved in gamete interaction: evidence for positive selection, duplications and losses in vertebrates. PLoS ONE 7, e44548 (2012).
Koonin, E. V. et al. A comprehensive evolutionary classification of proteins encoded in complete eukaryotic genomes. Genome Biol. 5, R7 (2004).
Castro, L. F. et al. Recurrent gene loss correlates with the evolution of stomach phenotypes in gnathostome history. Proc. Biol. Sci. 281, 20132669 (2014).
Ordonez, G. R. et al. Loss of genes implicated in gastric function during platypus evolution. Genome Biol. 9, R81 (2008).
Sire, J. Y., Delgado, S. C. & Girondot, M. Hen's teeth with enamel cap: from dream to impossibility. BMC Evol. Biol. 8, 246 (2008).
International Aphid Genomics Consortium. Genome sequence of the pea aphid Acyrthosiphon pisum. PLoS Biol. 8, e1000313 (2010).
Paterson, A. H. et al. Many gene and domain families have convergent fates following independent whole-genome duplication events in Arabidopsis, Oryza, Saccharomyces and Tetraodon. Trends Genet. 22, 597–602 (2006).
Freeling, M. Bias in plant gene content following different sorts of duplication: tandem, whole-genome, segmental, or by transposition. Annu. Rev. Plant Biol. 60, 433–453 (2009).
Qian, W. & Zhang, J. Gene dosage and gene duplicability. Genetics 179, 2319–2324 (2008).
Conant, G. C., Birchler, J. A. & Pires, J. C. Dosage, duplication, and diploidization: clarifying the interplay of multiple models for duplicate gene evolution over time. Curr. Opin. Plant Biol. 19, 91–98 (2014).
McLysaght, A. et al. Ohnologs are overrepresented in pathogenic copy number mutations. Proc. Natl Acad. Sci. USA 111, 361–366 (2014).
Cañestro, C., Albalat, R., Irimia, M. & Garcia-Fernandez, J. Impact of gene gains, losses and duplication modes on the origin and diversification of vertebrates. Semin. Cell Dev. Biol. 24, 83–94 (2013).
Davis, J. C. & Petrov, D. A. Do disparate mechanisms of duplication add similar genes to the genome? Trends Genet. 21, 548–551 (2005).
Scannell, D. R. et al. Independent sorting-out of thousands of duplicated gene pairs in two yeast species descended from a whole-genome duplication. Proc. Natl Acad. Sci. USA 104, 8397–8402 (2007).
Langham, R. J. et al. Genomic duplication, fractionation and the origin of regulatory novelty. Genetics 166, 935–945 (2004).
Thomas, B. C., Pedersen, B. & Freeling, M. Following tetraploidy in an Arabidopsis ancestor, genes were removed preferentially from one homeolog leaving clusters enriched in dose-sensitive genes. Genome Res. 16, 934–946 (2006).
Makino, T. & McLysaght, A. Positionally biased gene loss after whole genome duplication: evidence from human, yeast, and plant. Genome Res. 22, 2427–2435 (2012).
Braasch, I. & Postlethwait, J. in Polyploidy and Genome Evolution (eds Soltis, P. S. & Soltis, D. E.) 341–383 (Springer, 2012).
Liu, S. et al. The Brassica oleracea genome reveals the asymmetrical evolution of polyploid genomes. Nat. Commun. 5, 3930 (2014).
Schnable, J. C., Springer, N. M. & Freeling, M. Differentiation of the maize subgenomes by genome dominance and both ancient and ongoing gene loss. Proc. Natl Acad. Sci. USA 108, 4069–4074 (2011).
Sémon, M. & Wolfe, K. H. Reciprocal gene loss between Tetraodon and zebrafish after whole genome duplication in their ancestor. Trends Genet. 23, 108–112 (2007).
Scannell, D. R., Byrne, K. P., Gordon, J. L., Wong, S. & Wolfe, K. H. Multiple rounds of speciation associated with reciprocal gene loss in polyploid yeasts. Nature 440, 341–345 (2006).
Mizuta, Y., Harushima, Y. & Kurata, N. Rice pollen hybrid incompatibility caused by reciprocal gene loss of duplicated genes. Proc. Natl Acad. Sci. USA 107, 20417–20422 (2010).
McGrath, C. L. & Lynch, M. in Polyploidy and Genome Evolution (eds Soltis, S. P. & Soltis, E. D.) 1–20 (Springer, 2012).
Kassahn, K. S., Dang, V. T., Wilkins, S. J., Perkins, A. C. & Ragan, M. A. Evolution of gene function and regulatory control after whole-genome duplication: comparative analyses in vertebrates. Genome Res. 19, 1404–1418 (2009).
Bergero, R., Qiu, S. & Charlesworth, D. Gene loss from a plant sex chromosome system. Curr. Biol. 25, 1234–1240 (2015).
Cortez, D. et al. Origins and functional evolution of Y chromosomes across mammals. Nature 508, 488–493 (2014).
Bellott, D. W. et al. Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. Nature 508, 494–499 (2014).
Hughes, J. F. et al. Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes. Nature 483, 82–86 (2012).
Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999). The author proposes the view of gene loss as a major force of molecular evolution and formulates the less-is-more hypothesis.
Olson, M. V. & Varki, A. Sequencing the chimpanzee genome: insights into human evolution and disease. Nat. Rev. Genet. 4, 20–28 (2003).
Hottes, A. K. et al. Bacterial adaptation through loss of function. PLoS Genet. 9, e1003617 (2013). This work carries out selection experiments on mutagenized bacteria that show how substantial adaptation can be achieved solely through gene loss.
Sokurenko, E. V., Hasty, D. L. & Dykhuizen, D. E. Pathoadaptive mutations: gene loss and variation in bacterial pathogens. Trends Microbiol. 7, 191–195 (1999).
Jain, N. et al. Loss of allergen 1 confers a hypervirulent phenotype that resembles mucoid switch variants of Cryptococcus neoformans. Infect. Immun. 77, 128–140 (2009).
Maurelli, A. T., Fernandez, R. E., Bloch, C. A. & Rode, C. K. & Fasano, A. “Black holes” and bacterial pathogenicity: a large genomic deletion that enhances the virulence of Shigella spp. and enteroinvasive Escherichia coli. Proc. Natl Acad. Sci. USA 95, 3943–3948 (1998).
Moore, R. A. et al. Contribution of gene loss to the pathogenic evolution of Burkholderia pseudomallei and Burkholderia mallei. Infect. Immun. 72, 4172–4187 (2004).
Yu, H., Hanes, M., Chrisp, C. E., Boucher, J. C. & Deretic, V. Microbial pathogenesis in cystic fibrosis: pulmonary clearance of mucoid Pseudomonas aeruginosa and inflammation in a mouse model of repeated respiratory challenge. Infect. Immun. 66, 280–288 (1998).
Domergue, R. et al. Nicotinic acid limitation regulates silencing of Candida adhesins during UTI. Science 308, 866–870 (2005).
Will, J. L. et al. Incipient balancing selection through adaptive loss of aquaporins in natural Saccharomyces cerevisiae populations. PLoS Genet. 6, e1000893 (2010).
Lu, X., Wu, Q., Zhang, Y. & Xu, Y. Genomic and transcriptomic analyses of the Chinese Maotai-flavored liquor yeast MT1 revealed its unique multi-carbon co-utilization. BMC Genomics 16, 1064 (2015).
Hoballah, M. E. et al. Single gene-mediated shift in pollinator attraction in Petunia. Plant Cell 19, 779–790 (2007).
Zufall, R. A. & Rausher, M. D. Genetic changes associated with floral adaptation restrict future evolutionary potential. Nature 428, 847–850 (2004).
Shimizu, K. K., Shimizu-Inatsugi, R., Tsuchimatsu, T. & Purugganan, M. D. Independent origins of self-compatibility in Arabidopsis thaliana. Mol. Ecol. 17, 704–714 (2008).
Greenberg, A. J., Moran, J. R., Coyne, J. A. & Wu, C. I. Ecological adaptation during incipient speciation revealed by precise gene replacement. Science 302, 1754–1757 (2003).
McBride, C. S., Arguello, J. R. & O'Meara, B. C. Five Drosophila genomes reveal nonneutral evolution and the signature of host specialization in the chemoreceptor superfamily. Genetics 177, 1395–1416 (2007).
Clark, A. G. et al. Evolution of genes and genomes on the Drosophila phylogeny. Nature 450, 203–218 (2007).
Goldman-Huertas, B. et al. Evolution of herbivory in Drosophilidae linked to loss of behaviors, antennal responses, odorant receptors, and ancestral diet. Proc. Natl Acad. Sci. USA 112, 3026–3031 (2015).
Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Science 273, 1856–1862 (1996).
Tournamille, C., Colin, Y., Cartron, J. P. & Le Van Kim, C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat. Genet. 10, 224–228 (1995).
Howes, R. E. et al. The global distribution of the Duffy blood group. Nat. Commun. 2, 266 (2011).
Hodgson, J. A. et al. Natural selection for the Duffy-null allele in the recently admixed people of Madagascar. Proc. Biol. Sci. 281, 20140930 (2014). The authors propose that null mutations of DUFFY have been positively selected, supporting the hypothesis that malaria resistance drove fixation of the DUFFY -null allele in mainland sub-Saharan Africa.
Novembre, J., Galvani, A. P. & Slatkin, M. The geographic spread of the CCR5 Δ32 HIV-resistance allele. PLoS Biol. 3, e339 (2005). The authors propose that null mutations of the CCR5 gene have been positively selected and show how long-range dispersal and selection gradients have been important processes for the spread of the advantageous null allele.
Galvani, A. P. & Novembre, J. The evolutionary history of the CCR5-Δ32 HIV-resistance mutation. Microbes Infect. 7, 302–309 (2005).
Saxena, S. K. Controversial role of smallpox on historical positive selection at the CCR5 chemokine gene (CCR5-Δ32). J. Infect. Dev. Ctries 3, 324–326 (2009).
Hedrick, P. W. Population genetics of malaria resistance in humans. Heredity 107, 283–304 (2011).
Stedman, H. H. et al. Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428, 415–418 (2004). This work reveals that the loss of MYH16 in the human lineage after the separation from chimpanzees could have facilitated an increase in the size of the brain and the human origin.
Chou, H. H. et al. Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution. Proc. Natl Acad. Sci. USA 99, 11736–11741 (2002).
Wang, X., Grus, W. E. & Zhang, J. Gene losses during human origins. PLoS Biol. 4, e52 (2006).
Kvitek, D. J. & Sherlock, G. Whole genome, whole population sequencing reveals that loss of signaling networks is the major adaptive strategy in a constant environment. PLoS Genet. 9, e1003972 (2013). This work carries out whole-genome, whole-population sequencing on replicate evolution experiments that provide experimental evidence supporting gene loss as an important adaptive evolutionary force responding to environmental perturbations.
Herron, M. D. & Doebeli, M. Parallel evolutionary dynamics of adaptive diversification in Escherichia coli. PLoS Biol. 11, e1001490 (2013).
Cooper, V. S., Schneider, D., Blot, M. & Lenski, R. E. Mechanisms causing rapid and parallel losses of ribose catabolism in evolving populations of Escherichia coli B. J. Bacteriol. 183, 2834–2841 (2001).
Moreau, R. & Dabrowski, K. Body pool and synthesis of ascorbic acid in adult sea lamprey (Petromyzon marinus): an agnathan fish with gulonolactone oxidase activity. Proc. Natl Acad. Sci. USA 95, 10279–10282 (1998). This work shows a paradigmatic case of recurrent gene loss in which genes are studied that are involved in the synthesis of vitamin C. These genes have been lost in several cases during vertebrate evolution, which is associated with changes in environmental conditions (specifically, diet).
Drouin, G., Godin, J. R. & Page, B. The genetics of vitamin C loss in vertebrates. Curr. Genom. 12, 371–378 (2011).
Darwin, C. On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life (John Murray, 1872).
Protas, M. E. et al. Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism. Nat. Genet. 38, 107–111 (2006). In this work, the authors illuminate one of the puzzling enigmas that has existed since the time of Darwin: regressive evolution of dispensable traits in perpetual dark environments. The authors identify independent loss-of-function mutations in Oca2 , which lead to the loss of pigmentation and vision in different cavefish populations.
Leys, R., Cooper, S. J., Strecker, U. & Wilkens, H. Regressive evolution of an eye pigment gene in independently evolved eyeless subterranean diving beetles. Biol. Lett. 1, 496–499 (2005).
Protas, M. E., Trontelj, P. & Patel, N. H. Genetic basis of eye and pigment loss in the cave crustacean, Asellus aquaticus. Proc. Natl Acad. Sci. USA 108, 5702–5707 (2011).
Chipman, A. D. et al. The first myriapod genome sequence reveals conservative arthropod gene content and genome organisation in the centipede Strigamia maritima. PLoS Biol. 12, e1002005 (2014).
Zhao, H. et al. The evolution of color vision in nocturnal mammals. Proc. Natl Acad. Sci. USA 106, 8980–8985 (2009).
Kim, E. B. et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011).
Emerling, C. A. & Springer, M. S. Eyes underground: regression of visual protein networks in subterranean mammals. Mol. Phylogenet Evol. 78, 260–270 (2014).
Cavalier-Smith, T. Economy, speed and size matter: evolutionary forces driving nuclear genome miniaturization and expansion. Ann. Bot. 95, 147–175 (2005).
Kuo, C. H., Moran, N. A. & Ochman, H. The consequences of genetic drift for bacterial genome complexity. Genome Res. 19, 1450–1454 (2009).
Rocha, E. P. Inference and analysis of the relative stability of bacterial chromosomes. Mol. Biol. Evol. 23, 513–522 (2006).
Karcagi, I. et al. Indispensability of horizontally transferred genes and its impact on bacterial genome streamlining. Mol. Biol. Evol. http:dx.doi.org/10.1093/molbev/msw009, (2016).
Lang, G. I., Murray, A. W. & Botstein, D. The cost of gene expression underlies a fitness trade-off in yeast. Proc. Natl Acad. Sci. USA 106, 5755–5760 (2009).
Wilkens, H. Genes, modules and the evolution of cave fish. Heredity 105, 413–422 (2010).
Yoshizawa, M., O'Quin, K. E. & Jeffery, W. R. Evolution of an adaptive behavior and its sensory receptors promotes eye regression in blind cavefish: response to Borowsky (2013). BMC Biol. 11, 82 (2013).
Gunter, H. & Meyer, A. Trade-offs in cavefish sensory capacity. BMC Biol. 11, 5 (2013).
McGaugh, S. E. et al. The cavefish genome reveals candidate genes for eye loss. Nat. Commun. 5, 5307 (2014).
Nei, M., Suzuki, Y. & Nozawa, M. The neutral theory of molecular evolution in the genomic era. Annu. Rev. Genom. Hum. Genet. 11, 265–289 (2010).
Wagner, A. Neutralism and selectionism: a network-based reconciliation. Nat. Rev. Genet. 9, 965–974 (2008).
Moran, N. A. Microbial minimalism: genome reduction in bacterial pathogens. Cell 108, 583–586 (2002).
Giovannoni, S. J. et al. Genome streamlining in a cosmopolitan oceanic bacterium. Science 309, 1242–1245 (2005).
Mira, A., Ochman, H. & Moran, N. A. Deletional bias and the evolution of bacterial genomes. Trends Genet. 17, 589–596 (2001).
Lynch, M. & Conery, J. S. The origins of genome complexity. Science 302, 1401–1404 (2003).
Wyder, S., Kriventseva, E. V., Schroder, R., Kadowaki, T. & Zdobnov, E. M. Quantification of ortholog losses in insects and vertebrates. Genome Biol. 8, R242 (2007).
Ptitsyn, A. & Moroz, L. L. Computational workflow for analysis of gain and loss of genes in distantly related genomes. BMC Bioinformatics 13 (Suppl. 15), S5 (2012).
Dainat, J., Paganini, J., Pontarotti, P. & Gouret, P. GLADX: an automated approach to analyze the lineage-specific loss and pseudogenization of genes. PLoS ONE 7, e38792 (2012).
Novozhilov, A. S., Karev, G. P. & Koonin, E. V. Biological applications of the theory of birth-and-death processes. Brief Bioinform. 7, 70–85 (2006).
Baurain, D., Brinkmann, H. & Philippe, H. Lack of resolution in the animal phylogeny: closely spaced cladogeneses or undetected systematic errors? Mol. Biol. Evol. 24, 6–9 (2007).
Postlethwait, J. H. The zebrafish genome in context: ohnologs gone missing. J. Exp. Zool. B Mol. Dev. Evol. 308, 563–577 (2007).
Catchen, J. M., Conery, J. S. & Postlethwait, J. H. Automated identification of conserved synteny after whole-genome duplication. Genome Res. 19, 1497–1505 (2009).
Tang, H. et al. SynFind: compiling syntenic regions across any set of genomes on demand. Genome Biol. Evol. 11, 3286–3298 (2015).
Zhu, J. et al. Comparative genomics search for losses of long-established genes on the human lineage. PLoS Comput. Biol. 3, e247 (2007).
Zhang, Z. D., Frankish, A., Hunt, T., Harrow, J. & Gerstein, M. Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates. Genome Biol. 11, R26 (2010).
Zhao, Y. et al. Identification and analysis of unitary loss of long-established protein-coding genes in Poaceae shows evidences for biased gene loss and putatively functional transcription of relics. BMC Evol. Biol. 15, 66 (2015).
Inoue, J., Sato, Y., Sinclair, R., Tsukamoto, K. & Nishida, M. Rapid genome reshaping by multiple-gene loss after whole-genome duplication in teleost fish suggested by mathematical modeling. Proc. Natl Acad. Sci. USA 112, 14918–14923 (2015).
Hiller, M. et al. A “forward genomics” approach links genotype to phenotype using independent phenotypic losses among related species. Cell Rep. 2, 817–823 (2012). The authors introduce a computational 'forward genomics' strategy that is able to associate mutations in specific genomic regions with phenotypic losses.
Hiller, M., Schaar, B. T. & Bejerano, G. Hundreds of conserved non-coding genomic regions are independently lost in mammals. Nucleic Acids Res. 40, 11463–11476 (2012).
MacArthur, D. G. & Tyler-Smith, C. Loss-of-function variants in the genomes of healthy humans. Hum. Mol. Genet. 19, R125–R130 (2010).
MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012). The authors use the whole-genome sequences of 185 humans to show that there are approximately 80 heterozygous and, importantly, approximately 20 homozygous loss-of-function variants in a typical healthy individual, supporting the presence of a substantial number of non-functional variants in natural populations.
Burgess, D. J. Genomics: how pervasive are defective genes? Nat. Rev. Genet. 13, 222 (2012).
Henn, B. M., Botigue, L. R., Bustamante, C. D., Clark, A. G. & Gravel, S. Estimating the mutation load in human genomes. Nat. Rev. Genet. 16, 333–343 (2015).
Rivas, M. A. et al. Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome. Science 348, 666–669 (2015).
Lim, E. T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014). The authors describe how loss-of-function alleles of the LPA gene confer protection from cardiovascular disease, providing proof of concept of the potential of population gene loss analyses for biomedical studies.
Koch, L. Population genomics: a new window into the genetics of complex diseases. Nat. Rev. Genet. 15, 644–645 (2014).
Cañestro, C. in Polyploidy and Genome Evolution (eds Soltis, P. S. & Soltis, D. E.) 309–339 (Springer, 2012).
King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).
Hahn, M. W., Demuth, J. P. & Han, S. G. Accelerated rate of gene gain and loss in primates. Genetics 177, 1941–1949 (2007).
Bouquet, J. M. et al. Culture optimization for the emergent zooplanktonic model organism Oikopleura dioica. J. Plankton Res. 31, 359–370 (2009).
Marti-Solans, J. et al. Oikopleura dioica culturing made easy: a low-cost facility for an emerging animal model in EvoDevo. Genesis 53, 183–193 (2015).
Omotezako, T., Onuma, T. A. & Nishida, H. DNA interference: DNA-induced gene silencing in the appendicularian Oikopleura dioica. Proc Biol Sci 282, 20150435 (2015).
Albalat, R., Marti-Solans, J. & Cañestro, C. DNA methylation in amphioxus: from ancestral functions to new roles in vertebrates. Brief Funct. Genom. 11, 142–155 (2012).
Fu, X., Adamski, M. & Thompson, E. M. Altered miRNA repertoire in the simplified chordate. Oikopleura dioica. Mol. Biol. Evol. 25, 1067–1080 (2008).
Weill, M., Philips, A., Chourrout, D. & Fort, P. The caspase family in urochordates: distinct evolutionary fates in ascidians and larvaceans. Biol. Cell 97, 857–866 (2005).
Yadetie, F. et al. Conservation and divergence of chemical defense system in the tunicate Oikopleura dioica revealed by genome wide response to two xenobiotics. BMC Genomics 13, 55 (2012).
Seo, H. C. et al. Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica. Nature 431, 67–71 (2004).
Cañestro, C., Postlethwait, J. H., Gonzàlez-Duarte, R. & Albalat, R. Is retinoic acid genetic machinery a chordate innovation? Evol. Dev. 8, 394–406 (2006).
Duester, G. Retinoic acid synthesis and signaling during early organogenesis. Cell 134, 921–931 (2008).
Cañestro, C. & Postlethwait, J. H. Development of a chordate anterior-posterior axis without classical retinoic acid signaling. Dev. Biol. 305, 522–538 (2007).
Blanpain, C. et al. Multiple nonfunctional alleles of CCR5 are frequent in various human populations. Blood 96, 1638–1645 (2000).
Honeybee Genome Sequencing Consortium. Insights into social insects from the genome of the honeybee Apis mellifera. Nature 443, 931–949 (2006).
Wang, Y. et al. Functional CpG methylation system in a social insect. Science 314, 645–647 (2006).
Albalat, R. Evolution of DNA-methylation machinery: DNA methyltransferases and methyl-DNA binding proteins in the amphioxus Branchiostoma floridae. Dev. Genes Evol. 218, 691–701 (2008).
Tribolium Genome Sequencing Consortium. The genome of the model beetle and pest Tribolium castaneum. Nature 452, 949–955 (2008).
Colbourne, J. K. et al. The ecoresponsive genome of Daphnia pulex. Science 331, 555–561 (2011).
Moroz, L. L. et al. The ctenophore genome and the evolutionary origins of neural systems. Nature 510, 109–114 (2014).
Pisani, D. et al. Genomic data do not support comb jellies as the sister group to all other animals. Proc. Natl Acad. Sci. USA 112, 15402–15407 (2015).
Borenstein, E., Shlomi, T., Ruppin, E. & Sharan, R. Gene loss rate: a probabilistic measure for the conservation of eukaryotic genes. Nucleic Acids Res. 35, e7 (2007).
Krylov, D. M., Wolf, Y. I., Rogozin, I. B. & Koonin, E. V. Gene loss, protein sequence divergence, gene dispensability, expression level, and interactivity are correlated in eukaryotic evolution. Genome Res. 13, 2229–2235 (2003).
Wolf, Y. I., Carmel, L. & Koonin, E. V. Unifying measures of gene function and evolution. Proc. Biol. Sci. 273, 1507–1515 (2006).
Albertson, R. C., Cresko, W., Detrich, H. W. 3rd & Postlethwait, J. H. Evolutionary mutant models for human disease. Trends Genet. 25, 74–81 (2009).
Postlethwait, J. H. “Wrecks of ancient life”: genetic variants vetted by natural selection. Genetics 200, 675–678 (2015).
The authors thank the interesting and helpful comments of the three anonymous thoughtful referees. The authors apologize to the researchers whose work has not been directly cited owing to space restrictions. Support is acknowledged from past grant BFU2010-14875 from Ministerio de Economía y Competitividad (Spain) and SGR2014-290 from Generalitat de Catalunya. The authors also thank the team members of the Cañestro and Albalat laboratories for fruitful discussions on Oikopleura's passion for gene loss.
The authors declare no competing financial interests.
Examples of gene losses associated to parasitic/endosymbiontic life styles (PDF 142 kb)
Examples of gene losses in animals concomitant with the evolution of new biological features (PDF 158 kb)
Supplementary information (PDF 118 kb)
An evolutionary phenomenon whereby a gene loses its function, accumulates mutations and becomes a pseudogene.
Clade that classically includes all animals (metazoan) except sponges and Placozoa, although recent analyses of ctenophores have challenged the monophyly of this group.
Genes that share sequence similarity because they have evolved from a common ancestral gene.
An animal clade that includes protostomes and deuterostomes. Members of this clade are characterized by a stage during their life cycle in which they have right–left symmetry (unlike the radial symmetry present in most cnidarians and sponges).
A superphylum that includes animals in which the first opening, the blastopore, becomes the anus. This superphylum includes Ambulacraria (hemichordates and echinoderms) and Chordates (cephalochordates, urochordates and vertebrates).
A superphylum that includes animals in which the first opening, the blastopore, becomes the mouth. This superphylum includes two groups: Ecdysozoa (for example, arthropods and nematodes) and Lophotocozoa (for example, molluscs, annelids and platyhelminthes).
- Propensity for gene loss
Proclivity of a gene to be lost during evolution of a clade, as estimated from the fraction of lineages in which a given gene has been lost and corrected by the time during which the gene was lost or preserved.
- 'Patchy' orthologues
Orthologues belonging to gene families that have suffered extensive gene loss during the evolution of a given clade, such that their presence is unevenly distributed and restricted to a few species in the clade.
A hypothetical subkingdom that includes all animals apart from poriferans and ctenophores based on the absence of homeobox (Hox)–ParaHox genes from the first sequenced species of the later groups.
A term coined in honour of Susumo Ohno that refers to paralogues that originated from genome duplication (in contrast to paralogues that originated from small-scale duplications).
Acquisition of additional genetic content due to whole-genome duplication.
- Reductive evolution
Refers to the loss of genetic material that is usually observed during the evolution of parasitic or symbiotic species.
The ability of a particular genotype (or phenotype) to survive and reproduce in a specific environment, which is usually expressed in relation to other possible genotypes.
- Developmental genetic toolkits
Sets of genes that are required for development and that are widely shared among species.
- Mutational robustness
Property of a biological system to maintain unaltered phenotypes in the face of mutations.
- Synthetic genetic array
(SGA). Methodology designed to map genetic interactions on a genome-wide scale that combines arrays of mutant strains with robotic manipulations for high-throughput double-mutant construction.
- Synthetic lethality
This occurs when a combination of mutations in two or more genes leads to death, but when no effects on the viability of the organism are apparent when the genes are mutated individually.
- Cryptic variation
Genetic diversity within a population that does not normally generate phenotypic diversity but that does occur on environmental or genetic perturbation.
- Flux balance analyses
(FBAs). Mathematical approaches for calculating the flow of metabolites through a metabolic network, which can be applied to reconstruct genome-scale metabolic networks and to predict the growth rate of an organism.
- Gene Ontology
(GO). A system for classification of genes in terms of their associated biological processes, cellular components and molecular functions in a species-independent manner.
- Conserved synteny
Conservation of similar blocks of genes between orthologous or paralogous chromosomal regions, which can be useful in detecting gene losses after speciation or large-scale genomic duplications, respectively.
- Reciprocal gene loss
Divergent resolution of gene duplicates, such that one species has lost one copy, whereas the second species has lost the other copy.
- Baker's rule
This rule states that self-compatible organisms are better colonizers after long-distance dispersal than self-incompatible ones.
- Genetic drift
Stochastic changes in allele frequencies in a population due to random sampling effects through successive generations, which is therefore highly affected by the population size.
- Gene loss rate
(GLR). The maximum likelihood estimate of the measure of gene loses that maximizes the probability of the phyletic pattern of presence and absence of a given gene considering estimated branch lengths of all possible ancestral phylogenetic trees for the species under study.
- Antagonistic pleiotropy
This occurs when a gene controls several traits, in which at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to the organism's fitness.
- Hitchhiking effect
This occurs when a neutral mutation is in linkage disequilibrium with a second locus that is undergoing a selective sweep.
- Long-branch attraction
The phenomenon of inferring an incorrect phylogenetic tree owing to the presence of sequences that evolve rapidly and generate long branches that are mispositioned — usually attracted to the base — and thus distort the tree.
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