The Mysterious World of the Human Genome
Page 25
JOÃO ZILHÃO AND ERIK TRINKAUS
There are, as we have seen, two quite different genomes within each human cell: the mitochondrial and the nuclear. Since there are hundreds of mitochondria in every cell, each with its own bacterium-derived genome, by far the most copious DNA in a fossil bone is going to be mitochondrial. The mitochondrial genome is also much smaller than the nuclear genome. So the logical place to begin the exploration of the Neanderthal genome was with the extraction and decipherment of the mitochondrial DNA.
After some preliminary sequence discoveries over a number of years, in 2008, Pääbo and his team at the Max Planck Institute, working in cooperation with colleagues from America, Croatia, and Finland, published the first complete sequencing of Neanderthal mitochondrial DNA, which they had extracted from a 38,000-year-old fossil bone. The discovery was groundbreaking, not merely in the historic sense but also in the significance of their findings: “It establishes that the Neanderthal mitochondrial DNA falls outside the variation of extant human mitochondrial DNAs.”
This confirmed the long-held view that Neanderthals were a different evolutionary line from modern humans. In applying the customary search for nucleotide polymorphisms, Green and colleagues discovered far more Snip-type differences between Neanderthals and humans than we see across the global modern human divide. Given that mutations occur at roughly predictable intervals, as in the mutational clock, “[It] allows an estimate of the divergence date between the two lineages of 660,000 plus or minus 140,000 years.” This came close to the divergence date previously proposed by paleontologists on the basis of fossils and archeological findings.
This and the Prüfer paper predicted something that might prove helpful in working out the fate of the Neanderthals after the arrival of early modern humans into Europe, the Middle East, and Asia: “There is evidence that…the effective population size of Neanderthals was small.” By effective population size, the scientists were referring to the Neanderthal species gene pool—or, to put it another way, the genetic diversity of the Neanderthal species. We need to be cautious in interpreting something as sweeping as this from a first draft of the relatively small, and entirely female-associated, mitochondrial genome. But if this were to be confirmed from study of the nuclear genome, it would have important implications for the impact of interbreeding between Neanderthals and modern humans. For the moment, let us flag this as something to keep in mind. Meanwhile, we should consider the suggested timeline for the separation of the modern human and Neanderthal lineages.
Both the paleontological and genetic evidence is pointing to a divergence of the modern human and Neanderthal lineages roughly half a million years ago. Based on the study of other mammals, this is a relatively short time for complete separation into two reproductively distinct and separate species, which is generally thought to require something like a million years. So let us flag that as a second consideration to keep in mind. Some readers might have realized the oddity posed by this timing of divergence; if the Neanderthals and modern humans began their separate evolutionary trajectories roughly 500,000 years ago, how do we explain the purported African origins of the modern human evolutionary line at 180,000, perhaps at most 200,000 years ago?
In fact there is no contradiction. There is a common consensus that both species evolved, albeit through different lineages, from a common ancestor, H. erectus. For the first 300,000 years after separation, both lineages would have continued to evolve, presumably without contact with one another, modern humans in Africa and Neanderthals in Eurasia. And thus, by 180,000 years ago they had become sufficiently different to be considered distinct evolutionary lineages, heading toward becoming separate species. In Neanderthal terms, there is a general consensus that the intervening interval between H. erectus and the Neanderthals was filled by the intermediate ancestral lineage of H. heidelbergensis. This also leaves open the question as to whether H. sapiens evolved from H. heidelbergensis—albeit given a different name—in Africa.
Puzzled about this, I wrote to Professor Stringer, the human-origins expert at the Natural History Museum in London, and essentially he confirmed that there were indeed two alternative theories. One theory proposed that both the Neanderthal and the modern human lineages went through the intermediate step of H. heidelbergensis, probably separately in Africa and in Europe. The other theory proposed that only the Neanderthal lineage went through the H. heidelbergensis stage in Europe; meanwhile, H. sapiens evolved directly from H. erectus in Africa. Here then is another situation that we might keep in mind with respect to any future genomic revelations.
All along Pääbo had made clear that it was his ambition to reconstruct the entire Neanderthal nuclear genome. In 2007, a year before the mitochondrial announcement, and the same year he was named one of Time magazine's 100 most influential people of the year, European researchers reported that Neanderthals had a gene mutation that was associated with the fair skin seen in modern Europeans. This same mutation may have given some of them red hair. The following year, another paper reported that Neanderthals had the same O blood group as modern humans and they shared the language-associated gene, FOXP2, with us. In 2009, at the annual meeting of the American Association for the Advancement of Science, it was announced that the Max Planck Institute for Evolutionary Anthropology had completed the first rough draft of the Neanderthal nuclear genome, which included some four billion of the estimated total of 6.4 billion nucleotide “sleepers” of DNA extracted from the fossil bones of three individuals. This was duly published in 2010.
The first and the predictable outcome was that more than 99 percent of the Neanderthal genome was identical to our own. This was hardly surprising since we had evolved from a common ancestor only half a million years earlier. Much of our genome, and in particular the protein-coding portion, has to do with everyday aspects of our inner chemistry, cell structures, cell repair, cell death and removal, and cell regeneration, as well as immunological determination of self and the constant battle against microbial disease. We would expect these portions of the two genomes to be largely identical. A more surprising discovery was that the Neanderthal genome showed more commonality with modern humans who had evolved in Europe and Asia than with modern humans who had evolved in Africa. In scientific parlance, “a parsimonious explanation for these observations is that Neanderthals exchanged genes with the ancestors of non-Africans.” In ordinary English, our modern human ancestors interbred to a significant degree with Neanderthals. To put it more bluntly still, some of our distant grandparents were Neanderthals.
The findings suggested that people of European origins inherited between 1 and 4 percent of their nuclear genomic DNA from Neanderthal ancestors. The preliminary evidence suggested that people of Asian origins may have inherited even higher percentages of their DNA from their distant Neanderthal ancestors. As the paper expressed it, Neanderthals appeared to be as closely related to Chinese and Papua New Guineans as they were to Europeans, despite the fact that Neanderthal fossils have only been found in Europe and western Asia. Perhaps early moderns had already mixed with Neanderthals part way through their migration, taking their Neanderthal ancestry with them in their expansion into Eurasia.
Just how commonplace was the interbreeding between the two populations?
Previous studies of hybridization in evolutionary biology had suggested that when a colonizing new population encountered a resident population, even a small number of breeding events along the wave of interaction can result in substantial introduction of new genes into the colonizing population. It's all a question of population numbers and subsequent population expansion. It seems that the incoming genes—Neanderthal in this situation—can “surf” to high frequency as the colonizing population expands. There is, of course, an alternative, simpler explanation. Perhaps interbreeding between modern humans and Neanderthals was truly commonplace?
The news that Europeans and Asians were part Neanderthal in their genetic origins hit the popular media like a bombshell. W
hat should have been anticipated, really, given human behavior, now provoked astonishment.
From the first discovery of their fossils, Neanderthals had been the subject of fascination as a rival species to our own—but they had also been the subject of enormous prejudice, and this, alas, was true of professionals and lay media alike. Marcellin Boule, the first expert to review their fossil remains, painted a picture of a brutally apish creature in which there could only be “rudimentary intellectual faculties” and in which “all traces of any preoccupations of an esthetic or of a moral kind” were unimaginable. This pejorative pattern dominated the opinion of Neanderthals for the first half of the twentieth century. It was an unfortunate accident of fate that Boule's post-mortem examination featured the partial skeleton of an older male who had been badly maimed in some accident, provoking severe secondary osteoarthritis. This prejudicial interpretation from such a distinguished source influenced opinion far beyond the objective world of archeology and paleontology.
H. G. Wells wrote a story featuring the deserved extermination of what he labeled the “grisly folk.” While more recent writers, such as William Golding and Jared Diamond, presented a more sympathetic view of the Neanderthals, they also assumed their extinction at the hands of our more advanced ancestors, even though there is no hard paleontological evidence to support it.
This bigotry prevailed until relatively recently, with anthropologists arguing that Neanderthals couldn't speak, or if they did so it was in a peculiar voice, this in spite of the fact they had brains slightly larger than our own and the speech area of their brains, known as Broca's area, was little different too. The large brain was downplayed as poor in quality. Their tools, typical of what is called the Mousterian culture, were less sophisticated than those of modern humans. In particular, they appeared to lack throwing spears, compelling them to face up directly to the huge prey they hunted, such as woolly mammoths and rhinoceroses.
There were, of course, very real differences in skeletal morphology between Neanderthals and early modern humans, but researchers chose to focus on the differences while ignoring the similarities. In the last two decades a growing number of paleontologists have reevaluated the evidence for Neanderthal society and culture, concluding that preconceived notions may have led earlier researchers to ignore the actual evidence for Neanderthal inventiveness and culture. Their brains had large frontal lobes—the regions associated with intelligence and culture. Ralph Holloway at Columbia University in New York has studied hundreds of brain casts from Neanderthal skulls to confirm that they had the same level of development of the speech area as we do. Sites in France have confirmed that Neanderthals didn't just occupy caves and rock overhangs, but they erected shelters, leaving traces of the supportive wooden posts. Their tools are now seen as difficult to manufacture, involving planning, vision, and great skill. There is growing evidence that they wore clothes and that they adorned themselves with symbolic artifacts, including perforated and painted shells. They buried their dead, perhaps with ceremony, and may have played music. And although they hunted formidable prey, such as rhinos, mammoths and bison, they also adapted their strategies to suit different environments, trapping and hunting birds and rabbits and gathering seafood.
Penny Spikins, and her colleagues at York University, identified at least three sites—Wansunt Road in Kent, Foxhall Road in Ipswich, and Rhenen in the Netherlands—where miniature Neanderthal hand axes, which were likely to be children's toys, have come to light. In Arcy-sur-Cure in France, and a site in Belgium, other paleoarcheologists have discovered collections of expertly chipped stone tools next to some very inexpert attempts, which suggest Neanderthal adults teaching children how to make them in a Stone Age equivalent of schooling. The role of emotions, such as compassion, is central to the behaviors and intimate relationships that define human society, but paleontologists have been cautious about extrapolating emotional significance to archeological findings. Spikins and her colleagues have attempted to explore scientific constructs that might offer a basis for such studies, looking for the evidence of empathy and compassion in archeological contexts from the earliest archaic humans to modern society. They found such compassion, in caring for sick and injured individuals, in Neanderthal sites from “the Old Man of Shanidar,” who suffered from terrible injuries, to the Sima de los Huesos—the pit of bones—where a child suffering from a hereditary disease affecting the skull was cared for up to its death at the age of eight.
Given this accumulation of evidence, Erik Trinkaus at Washington University in St. Louis, Missouri, has concluded: “If you look at the archeological evidence of Neanderthals and modern humans…they are very similar. Neanderthals were people, and they probably had the same range of mental abilities we do.”
Of course, not everybody agrees. Some distinguished researchers, such as Mellars, think that Neanderthals, while skilled enough to survive in their Eurasian landscape for more than 200,000 years, were less cognitively equipped than contemporaneous modern humans. He argues that by the time modern humans arrived into Europe, they had better technology, better social organization, and, by inference, better brains. Steven Mithen, at the University of Reading, agrees with him. They may be right. However, we need to distinguish social evolution from the hereditary ability for intellectual thought. We also need to be careful to compare like with like—in other words, to compare Neanderthal culture with modern human culture during the same era. One only needs to reflect on the massive cultural differences between different modern human populations a century or two ago—which were more associated with education and the inheritance of ideas than differences in heredity or inherent intellectual ability between populations.
The encouraging momentum that is now sweeping like a tsunami of potential adjudication through such passionate debate is that, thanks to Pääbo and his discoveries, the hard facts of genetics can now be combined with the equally hard facts of archeological dating techniques, and it will be facts and not prejudicial supposition that will ultimately define future belief.
Meanwhile, there are some relevant hard facts that should be taken fully into account in the fast-developing scenario.
Hybridization, or sexual crossing between dissimilar species—or subspecies—is one of the four major mechanisms that give rise to the hereditary genetic change that makes evolution possible. It can, where there are major genetic differences between the hybrid partners, give rise to serious genetic dysfunction, including infertility. Scientists who study hybridization in animals and plants have found that the closer the evolutionary lineages involved, the shorter the time of separation from a common ancestor, and thus the less different the two genomes and therefore the more stable the genetic outcomes. The genetic interbreeding between Neanderthals and our modern human ancestors hardly gave rise to infertility since we are the hybrid descendants. And the Neanderthal component of our Eurasian genomes today is not small. At its upper range of 4 percent, this is the genetic legacy you or I would have inherited from a great-great-great grandparent from just a century ago. At DNA level, this is huge. One need only divide 6.4 billion sleepers by 25 to see how many sleepers our train would have to traverse in the exploration of this genomic contribution—260 million—all making up distinctive genes, viral sections, regulatory sequences, and non-coding RNAs.
Some authors appear to be missing the point in interpreting such a major “hybridization event.” The pooling of two different evolutionary lineages will give rise to an immediate dramatic increase in genetic diversity in the hybrid offspring, an increase that will be inherited by the descendants in all future generations.
We might consider what this implies: that the two genomes contain differing genetic histories, including genetic adaptations, with potential advantages for survival that have been hard won in different ecologies and environments. Studies of the effects of such “hybrid creativity” in nature suggest that the hybrid offspring may be better able to withstand tough environmental conditions, including harsh cl
imates, than the non-hybrid parental lineages. Natural selection will not choose one lineage over another. Since both lineages are now common to a single genome, selection will now work at the level of the hybrid genome, just as it worked at the level of the holobiontic genome in cases of genetic symbiosis. Genetic sequences that impair survival, regardless of their species origins, will be selected against; meanwhile, genetic sequences that enhance survival, regardless of origin, will be favored. The fact that we still retain a huge Neanderthal component to our genomic makeup speaks for itself. It strongly suggests that our ancestors did gain an advantage for survival in the sexual crossing with Neanderthals. Moreover, it isn't hard to see why this might be so.
Our modern human ancestors had evolved in the tropical heat and bright sunshine of Africa. They encountered Neanderthals when moving into a much colder, less sunny environment in which the winters in particular would be long, cloudy, and gloomy. One key effect of this would have been a failure to make enough vitamin D in their darker skins. Given the effects of vitamin D deficiency in softening bones, or in weakening the immune system, this Neanderthal contribution would have given the hybrid offspring a better chance of survival.
But the benefits of cooperation between the two populations may well have extended far beyond increased genetic diversity. How likely was it that there would have been social and cultural advantages of exchange between the two different populations? This was no meeting of Europeans bearing the fruits of Renaissance enlightenment, or the Industrial Revolution, into a Stone Age hunter-gatherer society. Both populations were still at the Stone Age hunter-gatherer stage. The exchange of knowledge of the local geography, of flora and fauna, of seasonal availability of foods, sources of shelter, perhaps evolved techniques of working skins or other items of clothing, herb lore—and, perhaps, more symbolic aspects of culture, such as decoration or music—would have worked both ways.