As more details emerge from the genomes of humans1,2, our closest living relatives the apes3,4 and our closest extinct relative the Neandertal, it will become possible to say what defines us as a species from a genetic point of view. Detailed studies of genes that carry human-specific evolutionary traits should reveal which ones have been especially important during human evolution. Ultimately, these efforts could uncover the biology beneath human cognition, language and culture, and might improve our understanding of conditions such as autism, schizophrenia and language impairments.
The common chimpanzee and the bonobo or pygmy chimpanzee are our closest living relatives, with whom we share a common ancestor that lived 5–7 million years ago. Humans and chimpanzees share a common ancestor with gorillas — the other major species of African apes — that lived 6–8 million years ago, whereas the common ancestor shared with the Asian orangutans lived 12–16 million years ago (Fig. 1).
Many species that were more closely-related to humans have lived and become extinct since the time of the chimpanzee- human ancestor. They are collectively called hominins. One hominin is the Neandertal, whose lineage diverged from ours 300,000–500,000 years ago. Neandertals lived in western Eurasia, sometimes alongside our ancestors, until they became extinct around 30,000 years ago.
Our technical ability to sequence genomes is improving rapidly and the cost is continually dropping. Soon it will be possible to sequence mammalian genomes accurately and cheaply in a matter of days. At the same time, technologies that allow high-speed surveys of proteomes and metabolomes — that is, all the proteins and metabolic molecules present in a tissue or cell — are also being developed.
Today, the most complete primate genome available is that of the human; the genomes of the chimpanzee, gorilla, orangutan and rhesus macaque are of lower and variable quality.
This year, a group of researchers published the first draft of the complete Neandertal genome5. Studying these genomes will help researchers identify the millions of nucleotide changes, and tens of thousands of insertions, deletions and duplications of short stretches of DNA, that have occurred since the divergence of modern humans from chimpanzees and, more recently, from the Neandertals.
Accurate comparative studies of the human genome with those of other primates will require genomic data of similar, high quality for the living apes and extinct hominins. However, the available ape genomes are currently of low quality. Over the next few years, researchers aim to sequence the genomes of most monkey species and raise ape genomes to human-level reliability.
Also of great importance is variation within species, as patterns of differences in DNA sequence among individuals allow identification of positive selection. Several large projects (for example, HapMap, ENCODE and 1000 Genomes) are providing insight into genomic variation among humans, but there are no equivalent projects for ape or primate genomes.
A simple first step towards this type of undertaking would be to collect blood and tissue samples from captive apes. These represent only a limited sample of the total ape genetic variation; wild ape genetic samples are urgently needed, as these populations are endangered and might disappear in coming decades. Non-invasive samples, such as faeces or hair, from all great apes across their entire current ranges should be collected and preserved for the future. Establishing ape cell lines and sequence libraries from such samples will extend their useful life.
More accurate Neandertal genome sequencing is also in progress, and should be extended to several Neandertal individuals and other extinct hominins. Researchers should develop standards and protocols for working with ancient DNA, particularly ancient hominid DNA, to ensure that results are reliable and not the product of, for example, contamination of modern human DNA.
However, it is not enough to compare only DNA sequences within and between species; gene activity is also of crucial importance. Transcription patterns, splicing variants and levels of gene expression in different tissues need to be studied6. Current efforts to study gene activity in non-human primate genomes rely on the assumption that gene structure, splicing and regulatory RNA are largely similar to those in humans.
Improved sequencing techniques will allow RNA from each species to be studied directly and will also help reveal the activity of less well-studied portions of the genome, such as those that do not encode proteins. Together with mass spectroscopy-based methods to study the proteome, this will help scientists understand how the genome relates to protein production — in each cell and organ, and during the course of an individual’s life.
Ultimately, analyses of extant and extinct primate genomes coupled with the study of gene activity in extant primates will identify those DNA sequences that make humans unique. To test the effects of these sequences, it will be necessary to develop novel in vitro experimental systems. One such system could include tissue cultures that mimic human tissues formed, for example, by the use of induced pluripotent stem cells. Another approach could be ‘humanizing’ genes or whole pathways in animal models such as the laboratory mouse7. Genetic manipulations of such systems will then provide an avenue for testing aspects of traits specific to humans.
Understanding the biological basis for human-specific characteristics such as cognition, language and culture will be of interest to society. It might also be of medical utility in the case of conditions such as speech disorders, autism and schizophrenia that affect human-specific traits. Better understanding of the genetic roots of these abilities might help improve treatments.
A first draft version of the Neandertal genome has recently been produced at the Max Planck Institute for Evolutionary Anthropology. It allows us to identify genomic features by which all present-day humans differ from our closest evolutionary relatives, as well as genomic regions that were subject to positive selection during the evolution of fully modern humans (Green, R. E. et al. Science, in the press).