'Anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews disciplinary barriers and rejects artificial 'genes versus environment' dichotomies.
The genomic and genetic approach towards this goal is made quite difficult by the discovery of much greater molecular variation than originally expected, both within and between species.
As only a few simple molecular differences have been identified that might underlie human uniqueness, both traditional and novel approaches are needed to understand the genetic aspects of human evolution.
It is fruitless to argue over whether differences in gene expression, in protein and RNA sequence variation, or in genomic deletions, duplications and insertions are more important in exploring human uniqueness. Examples of each have been found, and it is likely that final answers will involve many more in each category.
Integrated molecular studies along with parallel organ-systems approaches are required to identify and characterize candidate genes.
Genome interactions with environment, behaviour and culture are likely to be more prominent in humans than in other species.
Aspects of human uniqueness might have arisen because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture, rather than hard-wired instinctual behaviours.
This, in turn, might have relaxed allowable thresholds for large-scale genomic structural variation in primates in general, and humans in particular.
In addition to conventional Darwinian mechanisms, there are potential roles for the Baldwin effect; humans might have escaped the second phase of the Baldwin effect, wherein there is genetic hard-wiring of learned behaviour that is beneficial to a population.
The unusual degree of exaptation of the human mind might require consideration of additional novel mechanisms, as originally suggested by Alfred Russel Wallace.
What makes us human? Specialists in each discipline respond through the lens of their own expertise. In fact, 'anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews such barriers. Here we take a genomic and genetic perspective towards molecular variation, explore systems analysis of gene expression and discuss an organ-systems approach. Rejecting any 'genes versus environment' dichotomy, we then consider genome interactions with environment, behaviour and culture, finally speculating that aspects of human uniqueness arose because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture — perhaps relaxing allowable thresholds for large-scale genomic diversity.
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The authors gratefully acknowledge comments from P. Gagneux, R. Bingham, D. Nelson, P. Churchland, F. Ayala, S. Hrdy, and two anonymous reviewers; M. Oldham for adapting the figure in Box 4; and funding from the Howard Hughes Medical Institute (HHMI), the Mathers Foundation and the Gordon and Virginia MacDonald Foundation (to D.H.G.). The authors have National Institutes of Health grant funding: GM32373 to A.V., H60233 to D.H.G. and GM58815 to E.E.E.
The term that is now often used to refer to the clade that includes both humans and great apes (that is, chimpanzees, bonobos, gorillas and orangutans). The term hominoid is also no longer routinely used for great apes. In recognition of these changes, we have introduced the term non-human hominids in place of great apes in most places. However, we recognize that the nomenclature is still in flux.
- Positive selection
A form of natural selection that increases the frequency of beneficial alleles in a population.
A related but taxonomically distinct species that can be used to infer the ancestral state of a particular characteristic.
- Tissue heterogeneity
The presence of a large and variable number of cell types within a given tissue. Tissue heterogeneity in the brain might blunt the ability to detect the most variable low abundant genes in the brain relative to less complex tissue.
- Neutral theory
The word 'neutral' has two different meanings in population genetics literature. The strictly neutral model assumes that all mutations are neutral, whereas the biologically neutral model assumes that all mutations are either neutral or deleterious.
An increase in brain size relative to body size.
- Array comparative genomic hybridization
(ArrayCGH). A technique used to measure the relative copy number of a test and reference DNA sample based on differential hybridization to DNA molecules fixed on a microarray.
- Copy-number variant
(CNV). A gain or loss of a >1 kb DNA region that contains genes. Most copy-number polymorphisms tend to be small (<10 kb) in size. De novo CNVs are variants that largely arise by new mutation, as opposed to hereditary transmission.
- Gene conversion
A non-reciprocal recombination process that results in an alteration of the sequence of a gene to that of its homologue during meiosis.
A hierarchical organization of concepts. The Gene Ontology framework provides one means for determining whether gene expression differences represent enrichment for specific functional categories.
- Scale-free network
A network in which a few nodes (for example, genes) are central (that is, they act as 'hubs') and therefore serve as control points in the network, whereas most nodes are more peripheral and have few connections.
- Parallel distributed circuits
Interconnected brain regions that work coordinately, to yield cognition and behaviour.
- Frontotemporal dementia
A degenerative disease that frequently involves dilapidation of social cognition.
Changes within the coding region of a gene that prevent transcription of a functional protein product.
When a useful feature arises during evolution for a different reason, but is subsequently co-opted for its current function.
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Varki, A., Geschwind, D. & Eichler, E. Human uniqueness: genome interactions with environment, behaviour and culture. Nat Rev Genet 9, 749–763 (2008). https://doi.org/10.1038/nrg2428
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