After millennia of speculation, we can approach the question of what makes us human in a scientific manner, considering all the dimensions represented by many relevant disciplines. Studies of human genetic and genomic differences from our closest evolutionary relatives have much to offer. The evolutionary relatedness of humans and the African ‘great apes’ (now reclassified and grouped with humans and orangutans as hominids) was predicted by Huxley and Darwin1,2
, and given molecular credence a century later by investigators such as Sarich, Wilson and Goodman3,4
. Since the late 1800s, there has been an increasing interest in comparing humans with non-human hominids (NHHs), particularly chimpanzees, our closest living evolutionary relatives5
. Initial studies involved anatomical and skeletal analyses of dead chimpanzees. Then came behavioural studies in captivity, particularly by Kohts, Köhler and Yerkes — and the field observations of Goodall, Imanishi, Nishida and others5
. Much additional data concerning the behaviour, cognition, physiology and pathology of chimpanzees and other NHHs has since accumulated, showing how remarkably similar we are, and yet how different.
Early molecular comparisons by King and Wilson6
showed that the problem was going to be difficult, as all of the protein sequences they studied were practically identical. Ironically, this classic paper might have diminished enthusiasm for further molecular comparisons, because of the fear that significant differences would be difficult to determine. This attitude changed in the 1990s with the discovery of specific genetic differences between humans and other hominids7-9
, and there were calls for the sequencing of the NHH genomes10-12
, including a biomedical rationale13
. Subsequent sequencing of the chimpanzee genome14
spawned many molecular comparisons between humans and other hominids, some aspects of which are cited throughout this Review. The possibility of obtaining genomic information from our closest extinct evolutionary cousins, the Neanderthals15,16
, has further raised hope of elucidating the genetic components of what makes us human.
Of course, studies of genotypic variation need to be related to phenotypic differences12,17
); however, the gap between phenomic and genomic studies remains large. It is time to set aside divisive and unproductive ‘genes versus environment’ arguments18
, and explicate the human phenotype as the outcome of complex and ongoing interactions among genomes and the environment — and the effects of behaviour and cultural activities. Two approaches are taken here. The first is a genome-wide one, in which we consider the genomic and other molecular mechanisms that could be involved in uniquely human features, surveying roles of protein-coding changes, gene expression differences and genomic structural variation. The second approach considers potential contributions of genomic changes to organ-system differences. In both instances, we have selected examples largely from our own work as representative of the spread of topics and results in this field. Investigations in this area also have potential implications for understanding uniquely human aspects of disease processes13,19,20
Box 1 Human uniqueness — what do we need to explain?
Ultimately, it is necessary to understand uniquely human aspects of phenotype in the context of genotypic differences from the non-human hominids (NHHs). Many lists of such differences have been published and it is becoming increasingly clear that several of these differences are relative rather than absolute. Some commonly discussed features are relative brain size, hairless sweaty skin, striding bipedal posture, long-distance running, ability to learn to swim, innate ability to learn languages in childhood, prolonged helplessness of the young, ability to imitate and learn, inter-generational transfer of complex cultures, awareness of self and of the past and future, theory of mind, increased longevity, provisioning by post-menopausal females, difficult childbirth, cerebral cortical asymmetry and so on (see ref. 20
for a more extended listing).
The type of approach proposed in this Review is necessary in order to eventually correlate the genotype with these and many other phenotypic differences. In this regard it is striking that although we know a lot about the human phenotype (that is, the human phenome), remarkably little detail is known about the phenome of the NHHs. Thus, a decade ago we proposed a ‘great ape phenome project’17
that would attempt to identify all of these differences, with the goal of understanding which are indeed uniquely human characteristics.
Although this concept has gained interest, the opportunity to study the phenome of the NHHs is now greatly reduced, owing to recent decisions by the National Institutes of Health and other research agencies around the world that will markedly restrict or ban research on chimpanzees, and also stop all further breeding in captivity175
. It is ironic that this ban is occurring just when the greatest opportunity exists in terms of emerging genomic information. Although there are clearly special ethical issues to be considered when exploring the phenotype of NHHs, it seems reasonable to suggest that studies that can be ethically done in humans can also be done in other hominids, of course with appropriate mechanisms for protection of individual rights and dignity175
. Without such an approach, we will be left with piecing together limited information on the NHHs, and arbitrarily trying to relate them to our extensive knowledge of the human phenome174
As it is unlikely that we will fully answer questions about human uniqueness soon, we will be somewhat speculative and bold in the last part of this Review, closing by presenting a somewhat contrarian view of human genome dynamics. These final sections are meant to provoke discussion and debate. We will suggest that some of the common ‘rules’ of Darwinian genomic evolution through natural selection do not fully apply in humans, and that primate genomes (and the human genome in particular) have partially escaped such mechanisms because of buffering by culturally transmitted learned behaviours.