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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 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
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In the citing paper
“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]
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“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
Experimental — accuracy not yet measuredIn the citing paper
“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
In the citing paper
“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
In the citing paper
“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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“Long-term evolutionary conserved sequences are typically subject to purifying selection and tend to retain conserved functions.27”
From A genomic compendium of hundreds of teleost fishes reveals their evolutionary landscape (2026) · cites this paper as [27]
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Metadata
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › 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
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