The Role of Neoteny in Human Evolution: From Genes to the Phenotype

Part of the Primatology Monographs book series (PrimMono)


Humans are separated from their closest living relatives, the chimpanzees, by 6–7 million years of evolution. This is a short period in evolutionary terms: genetically, the two species are as much as 99% identical. Within this short time, however, human ancestors evolved a unique set of cognitive abilities distinguishing humans from other species. This raises the question: how, mechanistically, could human cognitive abilities evolve in such a short time interval? More than 30 years ago M.C. King and A. Wilson had already proposed that identifying differences in the timing of gene expression during brain development between humans and apes would be crucial for understanding human evolution. Indeed, change in timing and rate of ontogenetic changes, or heterochrony, has long been known as a potent mechanism of creating evolutionary novelties. If true, this mechanism offers a solution to the conundrum of human evolution, by allowing novel human cognitive abilities to develop on the basis of preexisting cognitive machinery. Comparison of human and chimpanzee ontogenetic changes on the molecular level, however, has visibly lagged behind those in model organisms. Here, we describe recent advances in this field, which imply a molecular link between the evolution of two seemingly independent human-specific features: cognitive abilities and longevity.


Gene Expression Change Human Phenotype Human Longevity Human Lifespan Extrinsic Mortality 





Messenger RNA


Reactive oxygen species



M.S. was supported by Chinese Academy of Sciences young scientist fellowship (no. 2009Y2BS12) and a Natural Science Foundation of China research grant (no. 31010022).


  1. Aiello L, Dean C (1990) An introduction to human evolutionary anatomy. Academic, LondonGoogle Scholar
  2. Aiello LC, Wheeler P (1995) The expensive-tissue hypothesis: the brain and the digestive system in human and primate evolution. Curr Anthropol 36:199–221CrossRefGoogle Scholar
  3. Alberch P, Gould SJ, Oster GF et al (1979) Size and shape in ontogeny and phylogeny. Paleobiology 5:296–317Google Scholar
  4. Ambros V, Horvitz HR (1984) Heterochronic mutants of the nematode Caenorhabditis elegans. Science 226:409–416PubMedCrossRefGoogle Scholar
  5. Atsalis S, Videan E (2009) Reproductive aging in captive and wild common chimpanzees: factors influencing the rate of follicular depletion. Am J Primatol 71:271–282PubMedCrossRefGoogle Scholar
  6. Baek D, Villén J, Shin C et al (2008) The impact of microRNAs on protein output. Nature (Lond) 455:64–71CrossRefGoogle Scholar
  7. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  8. Beckman K, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581PubMedGoogle Scholar
  9. Bell JF, Sharpless NE (2007) Telomeres, p21 and the cancer-aging hypothesis. Nat Genet 39:11–12PubMedCrossRefGoogle Scholar
  10. Bersaglieri T, Sabeti P, Patterson N et al (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74:1111–1120PubMedCrossRefGoogle Scholar
  11. Blalock E, Chen K, Sharrow K et al (2003) Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 23:3807–3819PubMedGoogle Scholar
  12. Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310:1954–1957PubMedCrossRefGoogle Scholar
  13. Bogin B (1997) Evolutionary hypotheses for human childhood. Yearb Phys Anthropol Am J Phys Anthropol 104:63–89CrossRefGoogle Scholar
  14. Brown DD (1997) The role of thyroid hormone in zebrafish and axolotl development. Proc Natl Acad Sci USA 94:13011–13016PubMedCrossRefGoogle Scholar
  15. Budovskaya YV, Wu K, Southworth LK et al (2008) An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134:291–303PubMedCrossRefGoogle Scholar
  16. Caceres M, Lachuer J, Zapala MA et al (2003) Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci USA 100:13030–13035PubMedCrossRefGoogle Scholar
  17. Carroll SB (2003) Genetics and the making of Homo sapiens. Nature (Lond) 422:849–857CrossRefGoogle Scholar
  18. Cavalli A (2007) Casper or “the cabinet of horrors”. J Anal Psychol 52:607–623PubMedCrossRefGoogle Scholar
  19. Caygill EE, Johnston LA (2008) Temporal regulation of metamorphic processes in Drosophila by the let-7 and mir-125 heterochronic microRNAs. Curr Biol 18:943–950PubMedCrossRefGoogle Scholar
  20. Charnov EL (1993) Life history invariants. Oxford University Press, New YorkGoogle Scholar
  21. Cohen E, Dillin A (2008) The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci 9:759–767PubMedCrossRefGoogle Scholar
  22. Comfort A (1979) The biology of senescence. Churchill Livingstone, EdinburghGoogle Scholar
  23. Consortium CSaA (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature (Lond) 437:69–87CrossRefGoogle Scholar
  24. Coqueugniot H, Hublin JJ, Veillon F et al (2004) Early brain growth in Homo erectus and implications for cognitive ability. Nature (Lond) 431:299–302CrossRefGoogle Scholar
  25. de Graaf-Peters VB, Hadders-Algra M (2006) Ontogeny of the human central nervous system: what is happening when? Early Hum Dev 82:257–266PubMedCrossRefGoogle Scholar
  26. de Magalhães JP (2006) Anage database, build 9.
  27. de Magalhaes JP, Church GM (2005) Genomes optimize reproduction: aging as a consequence of the developmental program. Physiology 20:252–259PubMedCrossRefGoogle Scholar
  28. DeSilva J, Lesnik J (2006) Chimpanzee neonatal brain size: implications for brain growth in Homo erectus. J Hum Evol 51:207–212PubMedCrossRefGoogle Scholar
  29. Enard W, Khaitovich P, Klose J et al (2002) Intra- and interspecific variation in primate gene expression patterns. Science 296:340–343PubMedCrossRefGoogle Scholar
  30. Enard W, Gehre S, Hammerschmidt K et al (2009) A humanized version of FoxP2 affects cortico-basal ganglia circuits in mice. Cell 137:961–971PubMedCrossRefGoogle Scholar
  31. Erraji-Benchekroun L, Underwood MD, Arango V et al (2005) Molecular aging in human pre-frontal cortex is selective and continuous throughout adult life. Biol Psychiatry 57:549PubMedCrossRefGoogle Scholar
  32. Gems D, Doonan R (2009) Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8:1681–1688PubMedCrossRefGoogle Scholar
  33. Gould SJ (1977) Ontogeny and phylogeny. Harvard University Press, Cambridge, MAGoogle Scholar
  34. Gurven M, Kaplan H, Gutierrez M (2006) How long does it take to become a proficient hunter? Implications for the evolution of extended development and long life span. J Hum Evol 51:454–470PubMedCrossRefGoogle Scholar
  35. Han Y, Gu S, Oota H et al (2007) Evidence of positive selection on a class I ADH locus. Am J Hum Genet 80:441–456PubMedCrossRefGoogle Scholar
  36. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300PubMedGoogle Scholar
  37. Hawkes K, O’Connell JF, Jones NG et al (1998) Grandmothering, menopause, and the evolution of human life histories. Proc Natl Acad Sci USA 95:1336–1339PubMedCrossRefGoogle Scholar
  38. Herndon JG, Lacreuse A (2009) Commentary: “Reproductive aging in captive and wild common chimpanzees: factors influencing the rate of follicular depletion”. Am J Primatol 71:891–892PubMedCrossRefGoogle Scholar
  39. Herrmann E, Call J, Hernandez-Lloreda MV et al (2007) Humans have evolved specialized skills of social cognition: the cultural intelligence hypothesis. Science 317:1360–1366PubMedCrossRefGoogle Scholar
  40. Hill K, Boesch C, Goodall J et al (2001) Mortality rates among wild chimpanzees. J Hum Evol 40:437–450PubMedCrossRefGoogle Scholar
  41. Hill K, Hurtado AM, Walker RS (2007) High adult mortality among Hiwi hunter-gatherers: implications for human evolution. J Hum Evol 52:443–454PubMedCrossRefGoogle Scholar
  42. Horder T (2006) Heterochrony. In: Encyclopedia of Life Sciences.
  43. Johnson MH (2001) Functional brain development in humans. Nat Rev Neurosci 2:475–483PubMedCrossRefGoogle Scholar
  44. Kaplan HS, Robson AJ (2002) The emergence of humans: the coevolution of intelligence and longevity with intergenerational transfers. Proc Natl Acad Sci USA 99:10221–10226PubMedCrossRefGoogle Scholar
  45. Kavanagh KD, Evans AR, Jernvall J (2007) Predicting evolutionary patterns of mammalian teeth from development. Nature (Lond) 449:427–432CrossRefGoogle Scholar
  46. Khaitovich P, Hellmann I, Enard W et al (2005) Parallel patterns of evolution in the genomes and transcriptomes of humans and chimpanzees. Science 309:1850–1854PubMedCrossRefGoogle Scholar
  47. Khaitovich P, Enard W, Lachmann M et al (2006a) Evolution of primate gene expression. Nat Rev Genet 7:693–702PubMedCrossRefGoogle Scholar
  48. Khaitovich P, Tang K, Franz H et al (2006b) Positive selection on gene expression in the human brain. Curr Biol 16:R356–R358PubMedCrossRefGoogle Scholar
  49. Kim J, Kerr JQ, Min G (2000) Molecular heterochrony in the early development of Drosophila. Proc Natl Acad Sci USA 97:212–216PubMedCrossRefGoogle Scholar
  50. Kimura M (1968) Evolutionary rate at the molecular level. Nature (Lond) 217:624–626CrossRefGoogle Scholar
  51. King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188:107–116PubMedCrossRefGoogle Scholar
  52. Kirkwood TBL (2005) Understanding the odd science of aging. Cell 120:437–447PubMedCrossRefGoogle Scholar
  53. Klingenberg CP (1998) Heterochrony and allometry: the analysis of evolutionary change in ontogeny. Biol Rev 73:79–123PubMedCrossRefGoogle Scholar
  54. Lahdenpera M, Lummaa V, Helle S et al (2004) Fitness benefits of prolonged post-reproductive lifespan in women. Nature (Lond) 428:178–181CrossRefGoogle Scholar
  55. Laland KN, Odling-Smee J, Feldman MW (2001) Cultural niche construction and human evolution. J Evol Biol 14:22–33CrossRefGoogle Scholar
  56. Laurie G (1999) What is heterochrony? Evol Anthropol 7:186–188CrossRefGoogle Scholar
  57. Lee C, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294PubMedCrossRefGoogle Scholar
  58. Leigh S (2004) Brain growth, life history, and cognition in primate and human evolution. Am J Primatol 62:139–164PubMedCrossRefGoogle Scholar
  59. Lieberman DE (1998) Sphenoid shortening and the evolution of modern human cranial shape. Nature (Lond) 393:158–162CrossRefGoogle Scholar
  60. Loerch PM, Lu T, Dakin KA et al (2008) Evolution of the aging brain transcriptome and synaptic regulation. PLoS One 3:e3329PubMedCrossRefGoogle Scholar
  61. Lu T, Pan Y, Kao S et al (2004) Gene regulation and DNA damage in the ageing human brain. Nature (Lond) 429:883CrossRefGoogle Scholar
  62. Marsh R, Gerber AJ, Peterson BS (2008) Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders. J Am Acad Child Adolesc Psychiatry 47:1233–1251PubMedCrossRefGoogle Scholar
  63. McKinney ML, McNamara KJ (1991) Heterochrony: the evolution of ontogeny. Plenum Press, New YorkGoogle Scholar
  64. McNamara KJ (1997) Shapes of time: the evolution of growth and development. Johns Hopkins University Press, BaltimoreGoogle Scholar
  65. Mitteroecker P, Gunz P, Bernhard M et al (2004) Comparison of cranial ontogenetic trajectories among great apes and humans. J Hum Evol 46:679–698PubMedCrossRefGoogle Scholar
  66. Montagu MFA (1955) Time, morphology, and neoteny in the evolution of man. Am Anthropol 57:13–27CrossRefGoogle Scholar
  67. Muller MN, Thompson ME, Wrangham RW (2006) Male chimpanzees prefer mating with old females. Curr Biol 16:2234–2238PubMedCrossRefGoogle Scholar
  68. Naef A (1926) Über die urformen der anthropomorphen und die stammesgeschichte des men-schenschädels. Naturwissenschaften 14:472–477CrossRefGoogle Scholar
  69. Penin X, Berge C, Baylac M (2002) Ontogenetic study of the skull in modern humans and the common chimpanzees: neotenic hypothesis reconsidered with a tridimensional Procrustes analysis. Am J Phys Anthropol 118:50–62PubMedCrossRefGoogle Scholar
  70. Powell A, Shennan S, Thomas MG (2009) Late Pleistocene demography and the appearance of modern human behavior. Science 324:1298–1301PubMedCrossRefGoogle Scholar
  71. Rice SH (2002) The role of heterochrony in primate brain evolution. In: Minugh-Purvis N, McNamara KJ (eds) Human evolution through developmental change. Johns Hopkins University Press, BaltimoreGoogle Scholar
  72. Rose MR, Mueller LD (1998) Evolution of human lifespan: past, future, and present. Am J Hum Biol 10:409–420CrossRefGoogle Scholar
  73. Rosenberg K, Trevathan W (2002) Birth, obstetrics and human evolution. Br J Obset Gynaecol 109:1199–1206CrossRefGoogle Scholar
  74. Sabeti PC, Schaffner SF, Fry B et al (2006) Positive natural selection in the human lineage. Science 312:1614–1620PubMedCrossRefGoogle Scholar
  75. Schriner SE, Linford NJ, Martin GM et al (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911PubMedCrossRefGoogle Scholar
  76. Selbach M, Schwanhäusser B, Thierfelder N et al (2008) Widespread changes in protein synthesis induced by microRNAs. Nature (Lond) 455:58–63CrossRefGoogle Scholar
  77. Sgro CM, Partridge L (1999) A delayed wave of death from reproduction in Drosophila. Science 286:2521–2524PubMedCrossRefGoogle Scholar
  78. Shaw P, Eckstrand K, Sharp W et al (2007) Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA 104(49):19649–19654PubMedCrossRefGoogle Scholar
  79. Shea BT (1989) Heterochrony in human evolution: the case for neoteny reconsidered. Am J Phys Anthropol 32:69–101CrossRefGoogle Scholar
  80. Smith JM, Szathmary E (1998) The major transitions in evolution. Oxford University Press, OxfordGoogle Scholar
  81. Smith TM, Toussaint M, Reid DJ et al (2007) Rapid dental development in a Middle Paleolithic Belgian Neanderthal. Proc Natl Acad Sci USA 104:20220–20225PubMedCrossRefGoogle Scholar
  82. Somel M, Franz H, Yan Z et al (2009) Transcriptional neoteny in the human brain. Proc Natl Acad Sci USA 106:5743–5748PubMedCrossRefGoogle Scholar
  83. Somel M, Guo S, Fu N et al (2010) MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res 20:1207–1218PubMedCrossRefGoogle Scholar
  84. Sowell ER, Thompson PM, Toga AW (2004) Mapping changes in the human cortex throughout the span of life. Neuroscientist 10:372–392PubMedCrossRefGoogle Scholar
  85. Stedman HH, Kozyak BW, Nelson A et al (2004) Myosin gene mutation correlates with anatomical changes in the human lineage. Nature (Lond) 428:415–418CrossRefGoogle Scholar
  86. Taglialatela JP, Russell JL, Schaeffer JA et al (2008) Communicative signaling activates Broca’s homolog in chimpanzees. Curr Biol 18:343–348PubMedCrossRefGoogle Scholar
  87. Tomasello M (2008) Origins of human communication. MIT Press, CambridgeGoogle Scholar
  88. Vallender EJ, Lahn BT (2004) Positive selection on the human genome. Hum Mol Genet 13:R245–R254PubMedCrossRefGoogle Scholar
  89. Veenema AH (2009) Early life stress, the development of aggression and neuroendocrine and neurobiological correlates: what can we learn from animal models? Front Neuroendocrinol 30:497–518PubMedCrossRefGoogle Scholar
  90. Vermulst M, Bielas JH, Kujoth GC et al (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39:540–543PubMedCrossRefGoogle Scholar
  91. Viegas J (2008) Africa’s oldest chimp, a conservation icon, dies.
  92. Vinicius L (2005) Human encephalization and developmental timing. J Hum Evol 49:762–776PubMedCrossRefGoogle Scholar
  93. Vrba ES (1998) Multiphasic growth models and the evolution of prolonged growth exemplified by human brain evolution. J Theor Biol 190:227–239PubMedCrossRefGoogle Scholar
  94. Walker R, Burger O, Wagner J et al (2006) Evolution of brain size and juvenile periods in primates. J Hum Evol 51:480–489PubMedCrossRefGoogle Scholar
  95. Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411CrossRefGoogle Scholar
  96. Yuan Y, Yi-Ping PC, Shengyu N et al (2011) Development and application of a modified dynamic time warping algorithm (DTW-S) to analyses of primate brain expression time series. BMC Bioinformatics 12:347CrossRefGoogle Scholar
  97. Zahn JM, Poosala S, Owen AB et al (2007) AGEMAP: a gene expression database for aging in mice. PLoS Genet 3:e201PubMedCrossRefGoogle Scholar
  98. Zakany J, Gerard M, Favier B et al (1997) Deletion of a HoxD enhancer induces transcriptional heterochrony leading to transposition of the sacrum. EMBO J 16:4393–4402PubMedCrossRefGoogle Scholar
  99. Zhang C, Cuervo AM (2008) Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14:959–965PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Partner Institute for Computational Biology, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  2. 2.Max Planck Institute for Evolutionary AnthropologyLeipzigGermany

Personalised recommendations