Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Evolution and implications of de novo genes in humans

Nature Ecology & Evolution volume 7, pages 804–815 (2023)Cite this article

Subjects

Abstract

Genes and translated open reading frames (ORFs) that emerged de novo from previously non-coding sequences provide species with opportunities for adaptation. When aberrantly activated, some human-specific de novo genes and ORFs have disease-promoting properties—for instance, driving tumour growth. Thousands of putative de novo coding sequences have been described in humans, but we still do not know what fraction of those ORFs has readily acquired a function. Here, we discuss the challenges and controversies surrounding the detection, mechanisms of origin, annotation, validation and characterization of de novo genes and ORFs. Through manual curation of literature and databases, we provide a thorough table with most de novo genes reported for humans to date. We re-evaluate each locus by tracing the enabling mutations and list proposed disease associations, protein characteristics and supporting evidence for translation and protein detection. This work will support future explorations of de novo genes and ORFs in humans.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms that drive gene birth in humans.
Fig. 2: Characteristics of a newly compiled list of human de novo genes.
Fig. 3: De novo genes expressed in the testis could be positively selected for, despite their tumour-promoting role.
Fig. 4: Evolutionary trajectories and expression characteristics of five human de novo genes associated with disease.
Fig. 5: Open questions for de novo genes in humans.

Similar content being viewed by others

References

  1. Casari, G., De Daruvar, A., Sander, C. & Schneider, R. Bioinformatics and the discovery of gene function. Trends Genet. 12, 244–245 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Boguski, M. S., Tolstoshev, C. M. & Bassett, D. E. Gene discovery in dbEST. Science 265, 1993–1994 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Harrow, J. et al. GENCODE: the reference human genome annotation for the ENCODE project. Genome Res. 22, 1760–1774 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kong, S., Tao, M., Shen, X. & Ju, S. Translatable circRNAs and lncRNAs: driving mechanisms and functions of their translation products. Cancer Lett. 483, 59–65 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Lu, S. et al. A hidden human proteome encoded by ‘non-coding’ genes. Nucleic Acids Res. 47, 8111–8125 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ruiz-Orera, J., Villanueva-Cañas, J. L. & Albà, M. M. Evolution of new proteins from translated sORFs in long non-coding RNAs. Exp. Cell. Res. 391, 111940 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Mudge, J. M. et al. Standardized annotation of translated open reading frames. Nat. Biotechnol. 40, 994–999 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Frankish, A. et al. GENCODE 2021. Nucleic Acids Res. 49, D916–D923 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Kozak, M. Structural features in eukaryotic mRNAs that modulate the initiation of translation. J. Biol. Chem. 266, 19867–19870 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Kaessmann, H. Origins, evolution, and phenotypic impact of new genes. Genome Res. 20, 1313–1326 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jacob, F. Evolution and tinkering. Science 196, 1161–1166 (1977).

    Article  CAS  PubMed  Google Scholar 

  12. Carvunis, A.-R. et al. Proto-genes and de novo gene birth. Nature 487, 370–374 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ruiz-Orera, J., Verdaguer-Grau, P., Villanueva-Cañas, J. L., Messeguer, X. & Albà, M. M. Translation of neutrally evolving peptides provides a basis for de novo gene evolution. Nat. Ecol. Evol. 2, 890–896 (2018).

    Article  PubMed  Google Scholar 

  14. Baalsrud, H. T. et al. De novo gene evolution of antifreeze glycoproteins in codfishes revealed by whole genome sequence data. Mol. Biol. Evol. 35, 593–606 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Schmitz, J. F., Ullrich, K. K. & Bornberg-Bauer, E. Incipient de novo genes can evolve from frozen accidents that escaped rapid transcript turnover. Nat. Ecol. Evol. 2, 1626–1632 (2018).

    Article  PubMed  Google Scholar 

  16. Zhao, L., Saelao, P., Jones, C. D. & Begun, D. J. Origin and spread of de novo genes in Drosophila melanogaster populations. Science 343, 769–772 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, L. et al. Rapid evolution of protein diversity by de novo origination in Oryza. Nat. Ecol. Evol. 3, 679–690 (2019).

    Article  PubMed  Google Scholar 

  18. Wu, D.-D., Irwin, D. M. & Zhang, Y.-P. De novo origin of human protein-coding genes. PLoS Genet. 7, e1002379 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ruiz-Orera, J. et al. Origins of de novo genes in human and chimpanzee. PLoS Genet. 11, e1005721 (2015).

  20. Zhu, S. et al. An oncopeptide regulates m6A recognition by the m6A reader IGF2BP1 and tumorigenesis. Nat. Commun. 11, 1685 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guo, Z.-W. et al. Translated long non-coding ribonucleic acid ZFAS1 promotes cancer cell migration by elevating reactive oxygen species production in hepatocellular carcinoma. Front. Genet. 10, 1111 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shao, Y. et al. GenTree, an integrated resource for analyzing the evolution and function of primate-specific coding genes. Genome Res. 29, 682–696 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guerzoni, D. & McLysaght, A. De novo genes arise at a slow but steady rate along the primate lineage and have been subject to incomplete lineage sorting. Genome Biol. Evol. 8, 1222–1232 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen, J.-Y. et al. Emergence, retention and selection: a trilogy of origination for functional de novo proteins from ancestral lncRNAs in primates. PLoS Genet. 11, e1005391 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Samusik, N., Krukovskaya, L., Meln, I., Shilov, E. & Kozlov, A. P. PBOV1 is a human de novo gene with tumor-specific expression that is associated with a positive clinical outcome of cancer. PLoS ONE 8, e56162 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, C.-Y. et al. A human-specific de novo protein-coding gene associated with human brain functions. PLoS Comput. Biol. 6, e1000734 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Suenaga, Y. et al. NCYM, a cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas. PLoS Genet. 10, e1003996 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Knowles, D. G. & McLysaght, A. Recent de novo origin of human protein-coding genes. Genome Res. 19, 1752–1759 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xie, C. et al. Hominoid-specific de novo protein-coding genes originating from long non-coding RNAs. PLoS Genet. 8, e1002942 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Van Oss, S. B. & Carvunis, A.-R. De novo gene birth. PLoS Genet. 15, e1008160 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Schlötterer, C. Genes from scratch – the evolutionary fate of de novo genes. Trends Genet. 31, 215–219 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. McLysaght, A. & Hurst, L. D. Open questions in the study of de novo genes: what, how and why. Nat. Rev. Genet. 17, 567–578 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Weisman, C. M. The origins and functions of de novo genes: against all odds? J. Mol. Evol. 90, 244–257 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tautz, D. & Domazet-Lošo, T. The evolutionary origin of orphan genes. Nat. Rev. Genet. 12, 692–702 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Dujon, B. The yeast genome project: what did we learn? Trends Genet. 12, 263–270 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Khalturin, K., Hemmrich, G., Fraune, S., Augustin, R. & Bosch, T. C. G. More than just orphans: are taxonomically-restricted genes important in evolution? Trends Genet. 25, 404–413 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Weisman, C. M., Murray, A. W. & Eddy, S. R. Many, but not all, lineage-specific genes can be explained by homology detection failure. PLoS Biol. 18, e3000862 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Levy, A. How evolution builds genes from scratch. Nature 574, 314–316 (2019).

    Article  CAS  PubMed  Google Scholar 

  39. Toll-Riera, M. et al. Origin of primate orphan genes: a comparative genomics approach. Mol. Biol. Evol. 26, 603–612 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Suntsova, M. V. & Buzdin, A. A. Differences between human and chimpanzee genomes and their implications in gene expression, protein functions and biochemical properties of the two species. BMC Genom. 21, 535 (2020).

    Article  CAS  Google Scholar 

  41. Zhuang, X., Yang, C., Murphy, K. R., Christina Cheng, C. H. & Cheng, C.-H. C. Molecular mechanism and history of non-sense to sense evolution of antifreeze glycoprotein gene in northern gadids. Proc. Natl Acad. Sci. USA 116, 4400–4405 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grandchamp, A., Berk, K., Dohmen, E. & Bornberg‐bauer, E. New genomic signals underlying the emergence of human proto‐genes. Genes 13, 284 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vakirlis, N., Vance, Z., Duggan, K. M. & McLysaght, A. De novo birth of functional microproteins in the human lineage. Cell Rep. 41, 111808 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clark, M. B. et al. The reality of pervasive transcription. PLoS Biol. 9, 5–10 (2011).

    Article  Google Scholar 

  45. Ulitsky, I. & Bartel, D. P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruiz-Orera, J., Messeguer, X., Subirana, J. A. & Alba, M. M. Long non-coding RNAs as a source of new peptides. eLife 3, e03523 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Wilson, B. A. & Masel, J. Putatively noncoding transcripts show extensive association with ribosomes. Genome Biol. Evol. 3, 1245–1252 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aspden, J. L. et al. Extensive translation of small open reading frames revealed by poly-Ribo-seq. eLife 3, e03528 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Van Heesch, S. et al. Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes. Genome Biol. 15, R6 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cabili, M. N. et al. Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution. Genome Biol. 16, 20 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Brar, G. A. et al. High-resolution view of the yeast meiotic program revealed by ribosome profiling. Science 335, 552–557 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Andreev, D. E. et al. Non-AUG translation initiation in mammals. Genome Biol. 23, 111 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kozak, M. Pushing the limits of the scanning mechanism for initiation of translation. Gene 299, 1–34 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ruiz-Orera, J. & Albà, M. M. Conserved regions in long non-coding RNAs contain abundant translation and protein-RNA interaction signatures. NAR Genom. Bioinform. 1, e2 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Xie, C. et al. A de novo evolved gene in the house mouse regulates female pregnancy cycles. eLife 8, e44392 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dowling, D., Schmitz, J. F. & Bornberg-Bauer, E. Stochastic gain and loss of novel transcribed open reading frames in the human lineage. Genome Biol. Evol. 12, 2183–2195 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vakirlis, N. et al. De novo emergence of adaptive membrane proteins from thymine-rich genomic sequences. Nat. Commun. 11, 781 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Neme, R., Amador, C., Yildirim, B., McConnell, E. & Tautz, D. Random sequences are an abundant source of bioactive RNAs or peptides. Nat. Ecol. Evol. 1, 0127 (2017).

    Article  Google Scholar 

  59. Palmieri, N., Kosiol, C. & Schlötterer, C. The life cycle of Drosophila orphan genes. eLife 3, e01311 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wilson, B. A., Foy, S. G., Neme, R. & Masel, J. Young genes are highly disordered as predicted by the preadaptation hypothesis of de novo gene birth. Nat. Ecol. Evol. 1, 0146 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Casola, C. From de novo to “de nono”: the majority of novel protein-coding genes identified with phylostratigraphy are old genes or recent duplicates. Genome Biol. Evol. 10, 2906–2918 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Durand, É. et al. Turnover of ribosome-associated transcripts from de novo ORFs produces gene-like characteristics available for de novo gene emergence in wild yeast populations. Genome Res. 29, 932–943 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Vakirlis, N. et al. A molecular portrait of de novo genes in yeasts. Mol. Biol. Evol. 35, 631–645 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Heames, B. et al. Experimental characterisation of de novo proteins and their unevolved random-sequence counterparts. Preprint at https://doi.org/10.1101/2022.01.14.476368 (2022).

  65. Albà, M. M. & Castresana, J. Inverse relationship between evolutionary rate and age of mammalian genes. Mol. Biol. Evol. 22, 598–606 (2005).

    Article  PubMed  Google Scholar 

  66. Neme, R. & Tautz, D. Phylogenetic patterns of emergence of new genes support a model of frequent de novo evolution. BMC Genom. 14, 117 (2013).

    Article  CAS  Google Scholar 

  67. Janssen, J. W. G. et al. Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32). Blood 95, 2691–2698 (2000).

    CAS  PubMed  Google Scholar 

  68. Lynch, M. & Marinov, G. K. The bioenergetic costs of a gene. Proc. Natl Acad. Sci. USA 112, 15690–15695 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ángyán, A. F., Perczel, A. & Gáspári, Z. Estimating intrinsic structural preferences of de novo emerging random-sequence proteins: is aggregation the main bottleneck? FEBS Lett. 586, 2468–2472 (2012).

    Article  PubMed  Google Scholar 

  70. Kesner, J. S., Chen, Z., Aparicio, A. A. & Wu, X. A unified model for the surveillance of translation in diverse noncoding sequences. Preprint at https://doi.org/10.1101/2022.07.20.500724 (2022).

  71. Castro, J. F. & Tautz, D. The effects of sequence length and composition of random sequence peptides on the growth of E. Coli cells. Genes 12, 1913 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Eicholt, L. A., Aubel, M., Berk, K., Bornberg-Bauer, E. & Lange, A. Heterologous expression of naturally evolved putative de novo proteins with chaperones. Protein Sci. 31, e4371 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Papadopoulos, C. et al. Intergenic ORFs as elementary structural modules of de novo gene birth and protein evolution. Genome Res. 31, 2303–2315 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bornberg-Bauer, E., Hlouchova, K. & Lange, A. Structure and function of naturally evolved de novo proteins. Curr. Opin. Struct. Biol. 68, 175–183 (2021).

    Article  CAS  PubMed  Google Scholar 

  75. Brunet, T. D. P. & Doolittle, W. F. The generality of constructive neutral evolution. Biol. Philos. 33, 2 (2018).

    Article  Google Scholar 

  76. Keeling, D. M. et al. The meanings of ‘function’ in biology and the problematic case of de novo gene emergence. eLife 8, e47014 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Chen, J. et al. Pervasive functional translation of noncanonical human open reading frames. Science 367, 1140–1146 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yu, J. et al. lncRNA MYCNOS facilitates proliferation and invasion in hepatocellular carcinoma by regulating miR-340. Hum. Cell 33, 148–158 (2020).

    Article  CAS  PubMed  Google Scholar 

  79. Lange, A. et al. Structural and functional characterization of a putative de novo gene in Drosophila. Nat. Commun. 12, 1667 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rivard, E. L. et al. A putative de novo evolved gene required for spermatid chromatin condensation in Drosophila melanogaster. PLoS Genet. 17, e1009787 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Jiang, X. et al. Characterization of a novel human testis-specific gene: testis developmental related gene 1 (TDRG1). Tohoku J. Exp. Med. 225, 311–318 (2011).

    Article  CAS  PubMed  Google Scholar 

  82. Florio, M. et al. Evolution and cell-type specificity of human-specific genes preferentially expressed in progenitors of fetal neocortex. eLife 7, e32332 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  83. van Heesch, S. et al. The translational landscape of the human heart. Cell 178, 242–260.e29 (2019).

    Article  PubMed  Google Scholar 

  84. Martinez, T. F. et al. Accurate annotation of human protein-coding small open reading frames. Nat. Chem. Biol. 16, 458–468 (2020).

    Article  CAS  PubMed  Google Scholar 

  85. Raj, A. et al. Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. eLife 5, e13328 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gaertner, B. et al. A human ESC-based screen identifies a role for the translated lncRNA LINC00261 in pancreatic endocrine differentiation. eLife 9, e58659 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Calviello, L. et al. Detecting actively translated open reading frames in ribosome profiling data. Nat. Methods 13, 165–170 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Ji, Z., Song, R., Regev, A. & Struhl, K. Many lncRNAs, 5′UTRs, and pseudogenes are translated and some are likely to express functional proteins. eLife 4, e08890 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47, D442–D450 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Craig, R., Cortens, J. P. & Beavis, R. C. Open source system for analyzing, validating, and storing protein identification data. J. Proteome Res. 3, 1234–1242 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Deutsch, E. W. et al. State of the human proteome in 2014/2015 as viewed through PeptideAtlas: enhancing accuracy and coverage through the AtlasProphet. J. Proteome Res. 14, 3461–3473 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Deutsch, E. W. et al. Human Proteome Project mass spectrometry data interpretation guidelines 3.0. J. Proteome Res. 18, 4108–4116 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Wright, B. W., Molloy, M. P. & Jaschke, P. R. Overlapping genes in natural and engineered genomes. Nat. Rev. Genet. 23, 154–168 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. Zhang, Y. E., Landback, P., Vibranovski, M. D. & Long, M. Accelerated recruitment of new brain development genes into the human genome. PLoS Biol. 9, e1001179 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bekpen, C., Xie, C. & Tautz, D. Dealing with the adaptive immune system during de novo evolution of genes from intergenic sequences. BMC Evol. Biol. 18, 121 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Deng, Y. et al. Spatial profiling of chromatin accessibility in mouse and human tissues. Nature 609, 375–383 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Majic, P. & Payne, J. L. Enhancers facilitate the birth of de novo genes and gene integration into regulatory networks. Mol. Biol. Evol. 37, 1165–1178 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Zhang, S. et al. Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC-based neurodevelopmental model. Stem Cell Res. 29, 88–98 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. An, N. A. et al. De novo genes with an lncRNA origin encode unique human brain developmental functionality. Nat. Ecol. Evol. 7, 264–278 (2023).

    PubMed  PubMed Central  Google Scholar 

  100. Qi, J. et al. A human-specific de novo gene promotes cortical expansion and folding. Adv. Sci. 10, e2204140 (2023).

    Article  Google Scholar 

  101. Duffy, E. E. et al. Developmental dynamics of RNA translation in the human brain. Nat. Neurosci. 25, 1353–1365 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Levine, M. T., Jones, C. D., Kern, A. D., Lindfors, H. A. & Begun, D. J. Novel genes derived from noncoding DNA in Drosophila melanogaster are frequently X-linked and exhibit testis-biased expression. Proc. Natl Acad. Sci. USA 103, 9935–9939 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, 0976–0985 (2005).

    Article  CAS  Google Scholar 

  104. Vinckenbosch, N., Dupanloup, I. & Kaessmann, H. Evolutionary fate of retroposed gene copies in the human genome. Proc. Natl Acad. Sci. USA 103, 3220–3225 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rödelsperger, C. et al. Spatial transcriptomics of nematodes identifies sperm cells as a source of genomic novelty and rapid evolution. Mol. Biol. Evol. 38, 229–243 (2021).

    Article  PubMed  Google Scholar 

  106. Witt, E., Benjamin, S., Svetec, N. & Zhao, L. Testis single-cell RNA-seq reveals the dynamics of de novo gene transcription and germline mutational bias in Drosophila. eLife 8, e47138 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kondo, S. et al. New genes often acquire male specific functions but rarely become essential in Drosophila. Genes Dev. 31, 1841–1846 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Gubala, A. M. et al. The goddard and saturn genes are essential for Drosophila male fertility and may have arisen de novo. Mol. Biol. Evol. 34, 1066–1082 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Su, Q., He, H. & Zhou, Q. On the origin and evolution of Drosophila new genes during spermatogenesis. Genes 12, 1796 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kopania, E. E. K., Larson, E. L., Callahan, C., Keeble, S. & Good, J. M. Molecular evolution across mouse spermatogenesis. Mol. Biol. Evol. 39, msac023 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kaneko, Y. et al. Functional interplay between MYCN, NCYM, and OCT4 promotes aggressiveness of human neuroblastomas. Cancer Sci. 106, 840–847 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Suenaga, Y., Nakatani, K. & Nakagawara, A. De novo evolved gene product NCYM in the pathogenesis and clinical outcome of human neuroblastomas and other cancers. Jpn. J. Clin. Oncol. 50, 839–846 (2020).

    Article  PubMed  Google Scholar 

  113. Zhao, X. et al. CTCF cooperates with noncoding RNA MYCNOS to promote neuroblastoma progression through facilitating MYCN expression. Oncogene 35, 3565–3576 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Kanatsu-Shinohara, M. et al. Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal. Genes Dev. 30, 2637–2648 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Zhang, R., Xia, L. Q., Lu, W. W., Zhang, J. & Zhu, J. S. lncRNAs and cancer. Oncol. Lett. 12, 1233–1239 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. de Magalhães, J. P. Every gene can (and possibly will) be associated with cancer. Trends Genet. 38, 216–217 (2022).

    Article  PubMed  Google Scholar 

  117. Li, J. & Liu, C. Coding or noncoding, the converging concepts of RNAs. Front. Genet. 10, 496 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Nam, J.-W., Choi, S.-W. & You, B.-H. Incredible RNA: dual functions of coding and noncoding. Mol. Cells 39, 367–374 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dinger, M. E., Gascoigne, D. K. & Mattick, J. S. The evolution of RNAs with multiple functions. Biochimie 93, 2013–2018 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Brunet, M. A. et al. OpenProt: a more comprehensive guide to explore eukaryotic coding potential and proteomes. Nucleic Acids Res. 47, D403–D410 (2019).

    CAS  PubMed  Google Scholar 

  121. Neville, M. D. C. et al. A platform for curated products from novel open reading frames prompts reinterpretation of disease variants. Genome Res. 31, 327–336 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Olexiouk, V., Van Criekinge, W. & Menschaert, G. An update on sORFs.org: a repository of small ORFs identified by ribosome profiling. Nucleic Acids Res. 46, D497–D502 (2017).

    Article  PubMed Central  Google Scholar 

  123. Graur, D. et al. On the immortality of television sets: ‘function’ in the human genome according to the evolution-free gospel of encode. Genome Biol. Evol. 5, 578–590 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Ruiz-Orera, J., Albà, M. M. & Alba, M. M. Translation of small open reading frames: roles in regulation and evolutionary innovation. Trends Genet. 35, 186–198 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Prensner, J. R. et al. Noncanonical open reading frames encode functional proteins essential for cancer cell survival. Nat. Biotechnol. 39, 697–704 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Xing, L. et al. Expression of human‐specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility. EMBO J. 40, e107093 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Schmidt, E. R. E., Kupferman, J. V., Stackmann, M. & Polleux, F. The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development. Sci. Rep. 9, 18692 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Suzuki, I. K. et al. Human-specific NOTCH2NL genes expand cortical neurogenesis through Delta/Notch regulation. Cell 173, 1370–1384.e16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Pollen, A. A. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 176, 743–756.e17 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Sidhaye, J. et al. Integrated transcriptome and proteome analysis in human brain organoids reveals translational regulation of ribosomal proteins. Preprint at https://doi.org/10.1101/2022.10.07.511280 (2022)

  132. Fischer, J. et al. Human‐specific ARHGAP11B ensures human‐like basal progenitor levels in hominid cerebral organoids. EMBO Rep. 23, e54728 (2022).

  133. Heide, M., Huttner, W. B. & Mora-Bermúdez, F. Brain organoids as models to study human neocortex development and evolution. Curr. Opin. Cell Biol. 55, 8–16 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Fiddes, I. T. et al. Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis. Cell 173, 1356–1369.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cardoso-Moreira, M. et al. Gene expression across mammalian organ development. Nature 571, 505–509 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Luuk A. Broeils & Sebastiaan van Heesch

  2. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

    Jorge Ruiz-Orera & Norbert Hubner

  3. Theoretical Biology and Bioinformatics, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    Berend Snel

  4. Charité-Universitätsmedizin, Berlin, Germany

    Norbert Hubner

  5. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany

    Norbert Hubner

Authors
  1. Luuk A. Broeils
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge Ruiz-Orera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Berend Snel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norbert Hubner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sebastiaan van Heesch
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.A.B. and S.v.H. carried out conceptualization, methodology, visualization and writing of the original draft. L.A.B. was responsible for data curation, investigation and software. L.A.B. and J.R.-O. carried out formal analysis. Supervision was carried out by S.v.H. L.A.B., S.v.H., J.R.-O., B.S. and N.H. reviewed and edited the manuscript.

Corresponding author

Correspondence to Sebastiaan van Heesch.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Ecology & Evolution thanks Chuan-Yun Li, Lars Eicholt and Nikolaos Vakirlis for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Information, Discussion and References for Supplementary Tables.

Supplementary Tables

Supplementay Tables 1 and 2.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Broeils, L.A., Ruiz-Orera, J., Snel, B. et al. Evolution and implications of de novo genes in humans. Nat Ecol Evol 7, 804–815 (2023). https://doi.org/10.1038/s41559-023-02014-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41559-023-02014-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing