Human-specific loss of regulatory DNA and the evolution of human-specific traits
Open accessAbstract
Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence.
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Changes in conservation of conserved noncoding or nonexonic elements in a subset of lineages are often associated with altered regulatory activity and ultimately phenotypic divergence.
“Changes in conservation of elements, such as conserved noncoding or nonexonic elements, in a subset of lineages are often associated with altered regulatory activity and ultimately phenotypic divergence”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as McLean et al. 2011
The Abstract reports two human-lineage deletions of conserved noncoding enhancers associated with anatomical differences, supporting the proposed link between regulatory change and phenotypic divergence. It does not establish that such changes are often associated with divergence across lineages, and it cautions that the enhancer losses might have followed other genetic changes rather than caused the anatomical differences. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVariants of the apo(a) gene highlight the intersection between gene duplication and cardiovascular risk.
“Others, like variants of the apo(a) gene, highlight the intersection between gene duplication and cardiovascular risk, serving as a striking example of the clinical potential impact of evolutionary research [110].”
From Origin and Evolution of Genes in Eukaryotes: Mechanisms, Dynamics, and Functional Implications (2025) · cites this paper as [110]
The supplied passages and searches for apo(a), lipoprotein(a), gene duplication, and cardiovascular risk found no discussion of the claimed connection. The paper instead discusses human-specific losses of regulatory DNA, including enhancers near AR and GADD45g (Abstract; page unavailable). (LLM, conf=0.76)
Experimental — accuracy not yet measuredExisting relaxed clock methods are not easily scalable to genome-wide data such as is typically encountered when testing for rate changes in conserved elements across a clade for which whole-genomes have been sequenced.
“Moreover, although highly accurate and useful for validating various clock models, these methods are not easily scalable to genome-wide data such as is typically encountered when testing for rate changes in conserved elements across a clade for which whole-genomes have been sequenced”
From Bayesian Detection of Convergent Rate Changes of Conserved Noncoding Elements on Phylogenetic Trees (2019) · cites this paper as McLean et al. 2011
The Methods Summary describes a genome-wide search for conserved sequences and human-specific deletions, but does not assess relaxed-clock methods or their scalability. Searches for relaxed-clock scalability and rate-change testing across a clade found no passage addressing that claim. The indexed passages provide no page numbers. (LLM, conf=0.76)
Experimental — accuracy not yet measuredA systematic search identified 510 human-specific deletions compared with other primate genomes, almost exclusively in noncoding regions.
“Conversely, a systematic search for human-specific deletions compared with other primate genomes identified 510 such deletions in humans that fall almost exclusively in noncoding regions (McLean et al., 2011).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as McLean et al., 2011
One human-specific deletion removes a forebrain germinal zone enhancer near GADD45G, suggesting a possible role in the expansion of specific brain regions in humans.
“One such deletion removes a forebrain germinal zone enhancer near the tumor suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), suggesting a possible role in the expansion of specific brain regions in humans.”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as McLean et al., 2011
An AMH-specific hCONDEL exists in a region upstream of DCC, although it is shared with Neanderthals.
“an AMH-specific hCONDEL exists in a region upstream of DCC, although it is shared with Neanderthals [110]”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [110]
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Self-citationEvolving New Skeletal Traits by cis -Regulatory Changes in Bone Morphogenetic Proteins
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Self-citation3D Genome of macaque fetal brain reveals evolutionary innovations during primate corticogenesis.
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Phylogenetics is the New Genetics (for Most of Biodiversity)
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Genetic Changes Shaping the Human Brain
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Exploring the role of copy number variants in human adaptation
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PERVASIVE GENETIC INTEGRATION DIRECTS THE EVOLUTION OF HUMAN SKULL SHAPE
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Deciphering the transcriptional cis-regulatory code
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Brain evolution and development: adaptation, allometry and constraint
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Human-Specific Histone Methylation Signatures at Transcription Start Sites in Prefrontal Neurons
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Human brain evolution writ large and small
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The significance and scope of evolutionary developmental biology: a vision for the 21st century
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Conserved non-coding elements: developmental gene regulation meets genome organization
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From trans to cis: transcriptional regulatory networks in neocortical development
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A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
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Comprehensive identification and analysis of human accelerated regulatory DNAPreprint
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Self-citationCorrelated Evolution of Two Copulatory Organs via a Single Cis-Regulatory Nucleotide ChangePreprint
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Neurobiological functions of transcriptional enhancers
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Analytical tools and current challenges in the modern era of neuroepigenomics
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Human-specific genomic signatures of neocortical expansion
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Relating enhancer genetic variation across mammals to complex phenotypes using machine learning
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Shaping the brain: The emergence of cortical structure and folding
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Human evolution: the non-coding revolution
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Human–chimpanzee fused cells reveal cis-regulatory divergence underlying skeletal evolution
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Unraveling the Tangled Skein: The Evolution of Transcriptional Regulatory Networks in Development
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A neurochemical hypothesis for the origin of hominids
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Genome structural variation in human evolution
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The mystery of extreme non-coding conservation
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Evolution of transcriptional enhancers and animal diversity
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Cellular and Molecular Mechanisms Linking Human Cortical Development and Evolution
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A Connectomic Hypothesis for the Hominization of the Brain
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The functional and evolutionary impacts of human-specific deletions in conserved elements
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Enhancer Function and Evolutionary Roles of Human Accelerated Regions
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Molecular features driving cellular complexity of human brain evolution
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Enhancers: From Developmental Genetics to the Genetics of Common Human Disease
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Gadd45g Is Essential for Primary Sex Determination, Male Fertility and Testis Development
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Dynamic evolution of regulatory element ensembles in primate CD4+ T cells
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Evolution of Gene Regulation in Humans
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Self-citation
- Authors
- McLean, C. Y., Reno, P. L., Pollen, A. A., Bassan, A. I., Capellini, T. D., Guenther, C., Indjeian, V. B., Lim, X., Menke, D. B., Schaar, B. T., Wenger, A. M., Bejerano, G., & Kingsley, D. M.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Stanford Medicine (US)
- Corresponding author
- Bejerano, Gill
- Kingsley, David M.
- ORCID
- Venue
- Nature
- Published
- 2011-03
- Volume
- 471
- Issue
- 7337
- Pages
- 216-219
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3071156
- OpenAlex
- W2103914320
- Cited by
- 535
- References
- 29
- Citations by year
- 2026: 23 · 2025: 32 · 2024: 31 · 2023: 37 · 2022: 20 · 2021: 31 · 2020: 48 · 2019: 26 · 2018: 35 · 2017: 35 · 2016: 46 · 2015: 44 · 2014: 42 · 2013: 33 · 2012: 36
- FWCI
- 48.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons - PCOM (Philadelphia College of Osteopathic Medicine) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1f32hd062137-01)
- National Human Genome Research Institute (P50HG002568, R01HG005058)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD059862, 1 F32 HD062137-01, F32 HD062137)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Keywords
- human evolution, non-coding DNA, enhancers, androgen receptor, penile spines, GADD45G, brain size evolution, neural development, steroid hormone signaling, chimpanzee comparison, human-specific traits, regulatory mutations, penile anatomy, brain expansion
- MeSH terms
- Animals, Brain, Pan troglodytes, DNA, Enhancer Elements, Genetic, Biological Evolution, Humans, Male, Organ Specificity, Penis, Regulatory Sequences, Nucleic Acid, Species Specificity, Genome, Human, Genes, Tumor Suppressor, Conserved Sequence, Sequence Deletion, Transgenes, Evolution, Molecular, DNA, Intergenic, Chromosomes, Mammalian, Human Characteristics, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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