DNA ‘lives’ to tell the tale

Abstract

The July 11th, 1997 issue of the journal Cell had an unusual illustration on its cover: the original Neanderthal skull-cap recovered in 1856 from a cave that opened onto the south wall of the valley of the river Düssel, not far from Düsseldorf, in what is now Germany. The cover referred to a landmark paper in that issue of the journal by Svante Pääbo and colleagues in which they showed that the short fragments of the hypervariable region I (HVRI) of the mitochondrial DNA (mtDNA) control region, recovered from a large chunk of the shaft of the right upper arm bone of the Neanderthal 1 type specimen, were almost certainly remnants of the ancient DNA of that individual. When the researchers compared the sequence of the 360 bp segment of the control region to the same region in modern humans, they found that the average number of sequence differences between modern humans and the Neanderthal 1 sequence was three times greater than the average sequence difference between any two randomly selected modern humans. Two implications stood out. First, the Neanderthal 1 sequence was no closer to the sequences of modern Europeans than it was to the sequences of contemporary humans from other regions of the world. Second, the new data suggested that the mtDNA sequence recovered from Neanderthal 1 diverged from the modern human lineage c.690–550 thousand years ago. This was considerably older than the estimated age of the most recent common ancestor of all modern humans (c.150–120 thousand years old) that had been generated using the differences among the mtDNA of regional populations of modern humans. In the two decades since its quantitatively modest beginning, ancient DNA research has made huge strides. In 2006, Noonan and colleagues used new methods of high-throughput sequencing and analysis to generate the first Neanderthal genomic library (approximately 65 kb of genomic sequence data) and provide an estimate of Neanderthal and modern human genome similarity (99.5%). Four years later, Green and colleagues reported a draft sequence of the Neanderthal nuclear genome, and, when they compared their draft with the draft nuclear genome of the chimpanzee and the nuclear genomes of five modern humans, they found that a small portion (around 1–4%) of the draft Neanderthal genome was more similar to non-African modern human samples than to those taken from the only African modern human who had been sampled. The researchers interpreted this as an indication of a modest amount of admixture between Neanderthals and modern humans. In 2008, the bone at the end of the little finger of a human hand was recovered from deposits dating back c.48–30 thousand years in the Denisova Cave, located in the Altai Mountains in Russia. The morphology of the finger bone was not sufficiently distinctive to assign it to a particular taxon, but the circumstances of its fossilization and post-depositional history were such that its DNA was particularly well preserved. The expectation was that it belonged to one of the Neanderthals known to be preserved at Denisova, but, rather than deducing that its mtDNA was within the Neanderthal range, Krause and his colleagues concluded in 2010 that the finger bone sampled a hominin that was distinct from both modern humans and Neanderthals. Based on the differences from the mtDNA of a chimpanzee and a bonobo, Krause et al. suggested that the hominin to whom the pinky bone belonged most likely shared a common ancestor with modern humans and Neanderthals c.1.0 million years ago. The discovery of the Denisovans — as they were called — was the first example of genetic evidence being used to search for a distinctive phenotype. In 2014, Meyer and colleagues recovered most of the mtDNA from a single individual from the c.450,000-year-old collection of hominins from Sima de los Huesos, a cave deep in the Sierra de Atapuerca near Burgos in Spain. Although its mitochondrial genome was unlike that of any other hominin, it grouped most closely with the mtDNA of the Denisovans. Two years later, Meyer’s research group extracted nuclear DNA from the same individual, and, in contrast to the evidence from the mtDNA, they found that its nuclear DNA was closer to Neanderthals than to the Denisovans. The Sima de los Huesos research is an example of the strand of hominin ancient DNA studies that is trying to extend the recovery of ancient DNA into ever deeper time. In a recent book, David Reich, a major figure in ancient DNA research, expands on the advances that I have summarized. However, the main focus of Reich’s book is not the technical tours de force developed by the Meyer group and others but a relatively new subfield of ancient DNA research that uses the DNA recovered from recent modern human fossils to reconstruct how modern humans populated the major regions of the world. The first section of Reich’s book, taking up just over 70 of its 286 pages of text, sets the scene and does an excellent job of explaining what DNA is and does and how ancient DNA can be exploited to help recover the last million years or so of human evolutionary history. Reich explains why the researchers who worked on the Denisovan genome decided not to give the new taxon a formal species name, a decision that was as sensible as it was wise, but he suggests that fossils from three Chinese sites — Dali, Jinnuishan and Maba — may be the phenotypic expression of the Denisovan genome. In the second section, which at 148 pages is the longest, Reich discusses the most recent evidence for the peopling of Europe, Western Asia, the New World, Eastern Asia and Africa. Before ancient DNA research was recruited to help investigate the relatively recent evolutionary history of modern humans, the conventional wisdom was that the modern humans in each of the major regions of the world were descended from founder populations, each of which was derived from the most recent wave of modern human migrants from Africa. Thus, when that wave reached a major region of the world, it provided the ancestors of the modern humans living in that region today. This scenario suggests that regions closer to Africa would have experienced longer periods of local continuity than regions further from Africa. Another expectation was that there would be more evidence of admixture between modern humans and Neanderthals closer to the likeliest locations for that admixture — the Near East, for example — than in locations further afield. This conventional wisdom was familiar to Reich because he is an academic grandchild of Luca Cavalli-Sforza, whose book The History and Geography of Human Genes was the most influential vehicle for promoting this scenario. But Cavalli-Sforza did not have access to the creative ways that ancient DNA evidence and complex mathematics are now being combined to generate hypotheses about the peopling of the major regions of the world. Reich suggests that the reality is much more complex than the conventional wisdom that I have outlined. The picture he paints is one where regional continuity is the exception, and not the rule. For example, ancient DNA sequences from individuals only tens of thousands of years old suggest that modern humans in Europe are the result of a series of episodes through time during which contemporary populations underwent a process that recalls the churning needed to make butter. There are many instances where sequences from sub-recent modern human fossils from a region are more than subtly different from the sequences of the modern humans living in that region today. Reich describes how he, together with a close colleague, Nick Patterson, who is a mathematician, developed a series of tests based on inter-individual sequence variation: currently the test is capable of comparing the sequence data from four populations at a time. When these tests were applied to the European data, they suggested to Reich and his colleagues that the peopling of Europe involved hypothetical ancient ‘ghost’ populations for which, for the most part, we only have the equivalent of circumstantial evidence. The Ancient North Eurasians are an example of an inferred ‘ghost’ population, who it is suggested made a significant contribution to the genome of the modern humans living in that region today. In 2013, Willerslev and colleagues published the genome of a 24,000-year-old boy from a site called Mal’ta in south-central Siberia, and its sequence matched the one predicted by Reich and his colleagues for the hypothetical Ancient North Eurasians. Reich and his colleagues have predicted the existence of comparable, influential populations in other regions of the world, such as the Basal Eurasians, two groups in North America, and the East African Foragers, but the fossil equivalents of these and other hypothesized ‘ghost’ populations have, thus far at least, proved to be elusive. This section of the book includes many references to examples where scenarios based on archeological evidence and linguistics have been challenged by the ancient DNA data. I am not qualified to judge whether much of this discussion is authoritative, but the few examples I know well enough suggest that it is. One minor gripe is that there is little consideration of equifinality. Presumably there is more than one explanation for the observed sequences, and some sense of how much more likely the preferred scenario is to the next most likely one would have been helpful. The third, and shortest, section of the book is an excellent and thoughtful reflection on the implications of these ancient DNA data for pressing social issues, such as inequality and racism. Reich is especially critical of the views of Nicholas Wade and James Watson. He takes them to the woodshed, so to speak, and his justifiably harsh and blunt criticism is refreshing. He also pours cold water on the recent rash of sites that claim to provide reliable information about an individual’s ancestry. As excellent as this book is, there is one glitch that is revealing for more reasons than one. On page 56, when Reich is discussing the Denisovans, he suggests that the large size of the teeth subsequently recovered from Denisova is comparable to the tooth size of earlier hominins he refers to as “primarily plant-eating australopithecenes”. First, I am having difficulty typing this section because my word-processing program automatically corrects the last word of the quote to ‘australopithecine’. This is because there is no such word as ‘australopithecene’, italicized or otherwise. The ending ‘-cene’ was introduced for use in geology and reflects its root from the Greek ‘kainos’, meaning ‘new’ — hence Miocene, Pleistocene, and so on. Also, many paleoanthropologists have abandoned ‘australopithecine’ for the even more informal term ‘australopith’. But even if you did want to use australopithecine, or australopith, there is no reason to italicize it. Italics are reserved for Latin binomial species names, such as Homo neanderthalensis. So writing australopithecenes would be like me referring to nucliar DNA in my review. I am belaboring this ‘nit’ because I think it reflects a C.P. Snow-like ‘two cultures’ problem. If molecular evidence is to play the important role that Reich’s book suggests it will, then folk like me need to get our heads round DNA research methods and terminology, and ancient DNA researchers need to learn a little more about the fossil record and its terminology. Overall, the book provides copious evidence of the care Reich has taken to provide his readers with all they need to understand the implications of applying ancient DNA research methods to more recent human evolutionary history. The consistent style of the deceptively simple figures complements the clear text, and the heading on each page of the notes that tells you the text pages to which it refers is a helpful convention that other authors should adopt. I learned a good deal from this book, and I encourage others to do the same.