The Mysterious World of the Human Genome

by Frank Ryan

  During the search for Neanderthal fossils that grew up around Pääbo's genomic exploration, Russian archeologists had been digging in the floor of a gigantic cavern high up in the Altai Mountains of southern Siberia. The climate on the northern slopes where the cave is situated is arid and cold, with a mean year-round temperature of about zero degrees Celsius. In 2010, the archeologists discovered a toe bone from a Neanderthal female from a layer dated to approximately 50,000 years ago. This bone proved to be incredibly rich in archaic DNA, enabling Pääbo's group to extract the best-quality Neanderthal nuclear genomic sequences to date. In January 2014, scientists from many different centers and laboratories combined forces with Pääbo's group to analyze and report the complete Neanderthal nuclear genome of this individual, comparing and contrasting it with the human genome and with what was already known from the previous examination of Neanderthals from widely different geographic localities, including three Neanderthal individuals from the Vindija Cave in Croatia and a Neanderthal infant from the Mezmaiskaya Cave in the Caucasus.

  Were we to return to our magical train, would we recognize the sections of track that we owe to the Neanderthal part of our heritage?

  In March 2014, three different Harvard-based groups of evolutionary geneticists, including David Reich and colleagues based at the Department of Genetics at the Harvard Medical School, and groups at the Broad Institute and Howard Hughes Medical Institute, combined forces with Pääbo's group at the Max Planck Institute in Germany to publish an overview on the genomic contribution of Neanderthals to present-day humans. In the opinion of these authors, the answer to my question is a definite yes. Although a lot of time has gone by since the hybridization event, the Neanderthal chunks of track are readily distinguishable because of their haplotypes. Where at the time of hybridization fully half the genome of the first offspring would have been Neanderthal, the dilutional effects of time and a succession of within-species matings has reduced the Neanderthal sections to sequences of DNA less than 100,000 sleepers long—small perhaps against the overall size of the genome at 6.4 billion sleepers, but enough to offer a series of lengthy journeys to our magical steam train. In the words of the authors: “Neanderthal haplotypes are distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci.” What then did they actually discover when they visited the genomes of some 1,004 present-day humans, examining the track in minute detail and taking a long hard look at these regions that are identifiably Neanderthal?

  The Reich group concluded that regions of our modern genome that are particularly rich in Neanderthal genes included those coding for the proteins that make keratin filaments. Keratin is the structural material that makes up the outer layer of our skin and in modified form is the main structural component of our hair and nails. One of the specific genes they may have bequeathed us is BNC2, which is involved in skin pigmentation. Researchers based in the University of Arizona also discovered that a proportion of Eurasians, and especially Melanesians, had inherited the genetic region known as STAT2 from Neanderthal ancestors. STAT2 is part of the system that determines the identity of self and our ability to fight infections.

  This same genetic analysis confirmed that the Neanderthal skin color was light, but probably as variable as we see in modern Europeans. Their eye color ranged from brown to blue, or blue-green or possibly hazel. Those of us who have inherited the lighter skins of Western Europe may have inherited part of our appearance from our Neanderthal distant grandparents. We may also have inherited our inclination to red hair and freckled skin, with the tendency to sunburn that goes with it. Moreover, as a report in the Sunday Times newspaper explained, part of our Neanderthal legacy may include a particular variant of the Major Histocompatibility Complex—the part of our genome that defines self and deals with foreign invaders—that increases the genetic risk of specific diseases such as type 2 diabetes, lupus, and Crohn's disease.

  On a lighter note, when Professor Stringer tested British comedian Bill Bailey and BBC science presenter Alice Roberts for the levels of their Neanderthal ancestry, he found that Bailey had inherited about 1.5 percent of his genome from the Neanderthals, and Roberts had inherited 2.7 percent. Stringer's own legacy lay in between, at 1.8 percent. In his book, Pääbo would relate some comical extrapolations of the hybridization going public, with men and women wondering if their Neanderthal inheritance explained the oddities they had observed in their own appearance or behavior, or the oddities they attributed to their spouses.

  The deeper exploration of our hybrid origins and evolution is only just beginning. In particular, scientists have only begun to examine the potential Neanderthal contribution to more subtle aspects of our physiology; our immunological identity of self; our ability to counteract disease, including infections; and the differences, if any, between modern humans and Neanderthals in terms of intrinsic brain development, with its applications to cognition, creativity, and the many social and cultural aspects of societal makeup.

  A surprising discovery in the genome of the Altai female was a peculiarly low level of genetic diversity. She appeared to be the offspring of inbreeding parents who were related at the level of half-siblings. Occasional inbreeding is a feature of hunter-gatherer societies, including early modern humans. But this finding in the Altai genome raised an important question: Were the Neanderthals, who appeared from the archeological record to live in relatively small groups, with little evidence of wider mobility when compared to contemporaneous modern humans, more at risk of inbreeding than early modern humans? This will need to be explored further with high-quality sequencing of a wider range of Neanderthal genomes, but if inbreeding was significantly commoner in Neanderthal groups it might explain the impoverishment in genetic diversity seen in the Altai genome. This in turn would have increased the risk of inborn errors of metabolism. An individual inheriting a single recessive gene from one of her parents would be protected from the disease if she inherited a normal variant of the gene from the other parent. If both parents were closely related, as in the Altai female's case, there would be a significantly greater risk that she would inherit the defective gene from both parents.

  Another important revelation of the Altai genome was its suggestion of a surprisingly low population of Neanderthals at this late stage in their occupation of the Eurasian landmass. It raises a vitally important question: What were the relative population sizes of Neanderthals and modern humans at the time when the two populations met in Eurasia?

  Of potential relevance is the climatic catastrophe known as the Last Glacial Maximum, which afflicted the ecology of the Neanderthals roughly 48,000 years ago, a freeze so severe that vast areas of the land were buried under glaciers miles deep and vast tracts of the northern Atlantic Ocean were similarly frozen over. There is evidence that this decimated the population of animals and people surviving throughout Eurasia. Could this explain the reduced numbers, and tendency to inbreeding, of the surviving Neanderthals at the time—a catastrophe that still afflicted their numbers some five thousand years later when our modern human ancestors arrived?

  We are now in a position to take a more measured look at what might really have happened to the Neanderthals, who were more similar to ourselves than we had previously thought. Their populations may have been reduced to relatively small and infrequent hunter-gatherer bands by the time our ancestors met them. This makes all the more relevant Mellars's and French's suggestion that at the time of early cohabitation of Europe by the two peoples, our ancestors may have outnumbered the Neanderthals population by roughly ten to one. While we cannot rule out skirmishes, or even the extermination of some population groups, we might question how purposeful hostilities or massacres might have been in such circumstances. We know that the two populations interbred, perhaps with less inhibition and on a larger scale than some would like to imagine. Such interbreeding between a small and a much larger population is likely to result in the bulk of the smaller population being assimilated into th
e larger.

  Could this then be the explanation for the mysterious fate of the Neanderthals?

  It would certainly explain why we find none of the pathognomonic skeletal features in the Eurasian population within 10,000 to 15,000 years of modern human arrival—this is plenty of time for the Neanderthal cranial and skeletal features to be melded into and swallowed up within the rapidly expanding, and still evolving, larger population of early Homo sapiens. If this is what happened, the Neanderthals did not become extinct—or at least not in the way we previously imagined. They disappeared as a separate, distinguishable population but live on as an integral part of our own hereditary pedigree.

  In April 2014, Paolo Villa from the University of Colorado, and Wil Roebroeks from Leiden University in the Netherlands teamed up to write an overview of what they termed “the Modern Human Superiority Complex,” by which they meant the overweening assumption by many scientists and public alike as to our superiority over the Neanderthal cave men and women. They concluded: “This systematic review of the archeological records of Neanderthals and their modern human contemporaries finds no support for such interpretations, as the Neanderthal archeological record is not different enough to explain the demise in terms of inferiority in archeologically visible domains.” Instead they proposed that complex processes of interbreeding and assimilation was indeed the more likely explanation for the disappearance of the Neanderthal skeletal and physical features from the fossil record.

  It is an extraordinary story, brought about by extraordinary scientific breakthroughs in genetic research, but still there were more surprises to come during the fruitful period in which Pääbo's breakthrough was being applied to hitherto refractory fossil bones.

  In July 2008, a Russian archeologist, Alexander Tsybankov, was digging in the floor of the same cathedral-like cavern high up in the Altai Mountains of southern Siberia. Working through deposits dating back 30,000 to 50,000 years, Tsybankov discovered a fragment of a single finger bone, an unprepossessing chip from the tip of the little finger. When he showed his find to his boss, Anatoly Derevianko, the latter thought that the bone was probably modern human. This would explain how it came to be in the same deposit as some sophisticated artifacts, including a bracelet of polished green stone. But Neanderthal remains had previously been found in the same cave, so Derevianko chopped the fragment of bone into two parts, putting the smaller of the two into an envelope and arranging for it to be hand delivered to Pääbo in Germany for genetic analysis. The tiny sliver of bone arrived just as Pääbo's team were about to complete the first draft sequence of the Neanderthal nuclear genome, and the team were already very busy, with a backlog of fossils waiting to be examined. The Russian bone went to the back of the queue.

  It wasn't until late 2009 that Pääbo's colleague Johannes Krause, assisted by Chinese graduate student Qiaomei Fu, found the time to perform a preliminary screen of the Altai bone's mitochondrial DNA. Minuscule as the fossil was, it proved to be incongruously rich in DNA, and it was also relatively uncontaminated. And what they found was so startling that they were obliged to repeat the analysis. The strange findings were unchanged. An excited Krause picked up the phone and called Pääbo, who was attending a meeting at Cold Spring Harbor Laboratory in New York. Krause began by asking him: “Are you sitting down?”

  He wasn't sitting down.

  “Maybe you had better find a chair?”

  Pääbo would subsequently confess that he had indeed found himself a chair because he feared that something terrible had happened. The mitochondrial genome extracted by Fu was not that of a Neanderthal. It was so surprising that Krause had counter-checked it because he couldn't believe Fu's findings. He had then insisted on comparing it to all six versions of the Neanderthal mitochondrial genomes now filed in their records. Without question, it was not Neanderthal. No more was it the mitochondrial genome of any of the modern humans that had been sequenced from all around the world. Whereas the Neanderthal mitochondrial genome had differed from that of modern humans in 202 nucleotides, or Snips, this differed in 385. The staggering truth was that it wasn't like any mitochondrial genome they, or anybody else, had ever sequenced before.

  The implications flashed through Pääbo's mind. Could it be that they had turned up a hitherto unknown species of human? Working on the basis of the Snips, if the Neanderthals had split from modern humans around 500,000 years ago, then this species must have split from a common ancestor maybe 800,000 years ago. Yet a member of this same species must have been alive in Siberia some 50,000 to 30,000 years ago? In Pääbo's recollection: “My head was spinning.”

  When he got back to the Max Planck Institute, some three days later, he talked over the findings with Krause. The sliver of finger bone was, it seemed, almost miraculously rich in DNA. For example, the very best source of Neanderthal DNA in the fossil bones they had tested had yielded 4 percent, but the new bone yielded 70 percent. Not only had it come from an amazing human source, it had experienced an equally amazing level of preservation. Nevertheless, Pääbo insisted that Krause and Fu repeat the analysis on what little was left of the tiny bone. The results were exactly the same. He emailed Anatoly Derevianko and they arranged to meet at the Institute of Archaeology and Ethnography in Akademgorodok, a Russian city that had been purpose-built for science by the Soviet regime in the 1950s. Pääbo arrived in deep winter, with an ambient temperature of 35 degrees below zero. He knew that the sliver of bone had been part of a slightly larger whole, and he asked for the remainder to work on the nuclear genome. But the Russians told him they had sent it to a colleague in America, who appeared to have lost it.

  Chagrined, the German team returned to Leipzig, though they had succeeded in bringing back a most unusual tooth that the Russian archeologists had recovered from the same cavern in the Altai. The tooth was unusually large in size and primitive in appearance when compared to that of a modern human or a Neanderthal.

  On April 10, 2010, Pääbo's team and their Russian colleagues published their findings of the extraordinary mitochondrial genome in the Letters section of the journal Nature. It was a unique paper, the first time an extinct human species had been discovered by genomic analysis of a fossil bone. In the scientists’ opinion, the most likely explanation of the Altai finger bone is that it represents “a hitherto unknown type of hominin”—one that, a very long time ago, shared a common ancestor with modern humans and Neanderthals. There were some “exceptionally archaic features” to the mitochondrial DNA that tallied with the archaic nature of the two teeth. The differences between this new hominin and the other two were so marked that they considered formally announcing it as the discovery of a new species, but then—prudently, as it turned out—they changed their minds.

  The cave where the sliver of bone was discovered had been inhabited by a hermit named Denis back in the eighteenth century. So they decided that they would label the newly discovered people the “Denisovans.”

  And still the litany of surprises was growing…

  The tiny chip of bone was so rich in DNA that they managed to extract a high-quality nuclear genome from it. In December of the same year, Pääbo's team combined forces with David Reich of Harvard Medical School and colleagues from a large number of other institutes in America, Germany, Spain, China, Canada, and Russia to publish the Denisovan nuclear genome. They could now confirm that at the time when our modern human ancestors emerged in Africa, around 180,000 years ago, a number of cousin species shared the world with them. First they dealt with the modern human and Neanderthal split. They gauged, from the two different genomes, that the human lineage and Neanderthal lineages had split into separate lines a little later than they had earlier surmised, between 270,000 and 440,000 years ago. This confirmed that the split was probably too recent for complete species separation, thus allowing interbreeding between the two emerging species with fertile hybrid offspring. Examination of the Denisovan genome and comparison with that of Neanderthals suggested that the Denisovans had also shar
ed a common ancestor with the Neanderthals, but the split between these lineages had been much earlier than that of Neanderthals and modern humans, at roughly 640,000 years ago. The last shared ancestor of the Denisovan and human ancestral lineages was put even further back, at roughly 800,000 years ago.

  The comparative genetics showed that the Denisovans were more closely related to the Neanderthals than they were to us, but not so close that they extensively mated with them. It also confirmed that they were not merely a subgroup of Neanderthals but a separate species very likely inhabiting a wide geographic area of Asia and with an evolutionary history distinct from that of modern humans and Neanderthals. Some of the genetic sequences in the Denisovan genome looked so primitive that it made them wonder if the Denisovans had acquired these sequences through hybrid crossing with a more archaic species still. The latter was described as an as-yet-unidentified species, but the most likely candidate is fascinating: it could signify our first glimpse into the genome of the common ancestor of all three species—modern humans, Neanderthals, and Denisovans—the amazing global traveler and pioneer of early humanity, Homo erectus.

  Like the Neanderthals, the Denisovans had interbred with early modern humans, but where the Neanderthals had contributed to most European lineages, the Denisovans had only contributed to Asian lineages, and in particular to native peoples of Polynesia, Melanesia, and Australia. The geneticists found that the Denisovans had contributed some 4 to 6 percent of the genome to Melanesians who currently inhabit areas of southeast Asia, suggesting that the Denisovans inhabited a large geographic area in Asia long ago. The paper ended with an emerging picture of a distant period of human evolution, known as the Upper Pleistocene, in which “gene flow among different hominin groups was common.” Not species genocide then, but mutual sharing of culture and genetic inheritance.