by Frank Ryan
Within a few years of the extraction of the Denisovan nuclear genome, an international group of geneticists confirmed the advantage of hybrid genomic novelty in terms of survival when the going got tough. One of the most celebrated examples of such an adaptation in humans is the ability of Tibetans to survive extreme high altitude in their Himalayan homeland. Geneticists had already discovered that Tibetans possessed a unique “hypoxia pathway gene,” known as EPAS1, that lowered their hemoglobin levels in conditions of low oxygenation—the very opposite of what happens when a non-Tibetan is exposed to such a low-oxygen atmosphere. The normal thickening of blood under such conditions would put people at risk of life-threatening blood clots. Tibetans only shared the gene EPAS1 with one other group of people—the Denisovans. In the researchers’ opinion: “Our findings illustrate that admixture with other hominin species has provided genetic information that helped humans to adapt to new environments.”
The surprises just kept on coming.
The Atapuerca Mountains, in the northeast Spanish province of Burgos, are honeycombed with caves containing hominin fossils and artifacts. One of these caves, known as the Sima de los Huesos—the “pit of bones”—has yielded one of the greatest assemblage of hominin bones ever found, including the remains of at least 28 individuals that have been dated to more than 300,000 years old. The skeletons have some features that resemble those of the Neanderthals, but many of their features are more typical of the more archaic Homo heidelbergensis, thought by some to be the ancestor of Neanderthals, and by others to be the ancestor of both modern humans and Neanderthals. The promise of this archeological treasure trove was heightened by the fact that these bones were remarkably well preserved, suggesting they might be a good source of archaic DNA. Spanish paleontologists supplied Pääbo with a complete femur in remarkably good condition, and this was duly drilled to supply 1.95 grams of powdered bone. As earlier, the geneticists began by sequencing the mitochondrial DNA, to produce yet another round of astonishment when they revealed the results in a Nature article, published online in December 2013 and in printed form the following January.
The experts had anticipated a mitochondrial genome closely related to, and very likely ancestral to, the Neanderthal sequences. But what they found was a genome that was closer to that of the Denisovans than to either the Neanderthals or to modern humans. They had provoked yet another mystery that appeared to shake up our prior ideas about our human origins.
In a covering article in Nature, the authors confessed that they were now scratching their heads to explain the surprising discovery. Everyone seemed to have their own different ideas as to the explanation. As Clive Finlayson, an archeologist at the Gibraltar Museum, commented, the findings were actually somewhat “sobering and refreshing.” Too many ideas about human evolution had been derived from limited samples and overblown notions. From now on the real truth would be revealed by the genetics, which, in Finlayson's words, “doesn't lie.” In Pääbo's admission, he was as bemused as everybody else. “My hope is that eventually we will bring not turmoil but clarity to the situation.”
What a refreshing light paleogenetics is shining on the real history of our distant ancestors!
While we cannot rule out skirmishes, even limited violence, between the different species and populations, it would appear that the different evolving species of humans were not intent on exterminating their evolutionary rivals. They surely came across one another from time to time—they may even have lived cheek by jowl in some geographic areas—when, to judge from recognizable human behavior, they would probably have been intensely curious about one another. They must have recognized their common humanity, held conversations with one another, looked at each other's traditions. They may have learned from one another, too, picking up ideas about hunting or foraging, or information on the manufacture of tools, how they operated as groups, or the traditions of family life, the rules of sexual partnership, how they took care of and educated children, how they decorated their bodies, manufactured their clothing and homes, how they worshipped, or grieved for and dealt with their dead.
This is what Pääbo and his colleagues want to know more about. It is also what you and I want to know more about—the real human history, the story that is forever retained within and being constantly added to anew in that mysterious world of our common human genome.
The preservation of favorable variations and the rejection of injurious variations, I call Natural Selection. Variations neither useful nor injurious would not be affected by natural selection, and would be left a fluctuating element…
CHARLES DARWIN
In the celebrationary issue of The Daily Telegraph, on Monday, February 12, 2001, Roger Highfield, the newspaper's science editor, forecast that cracking the mysterious code of the human genome made every human being special. He was absolutely right. Just how special is, of course, still in the process of being unraveled.
It will have long been apparent on this journey that we all share the genomic legacy of a fascinating and extraordinary evolutionary history. It is a history that straddles the very beginnings of life on Earth and what is turning out to be an epochal age, in which our species is beginning to explore the universe beyond our ocean-girdled planet. We caught a snapshot of this history when, in 2001, the first draft of our human genome revealed that we share thousands of genes with many other forms of life, and not just the great apes or even the mammals, but with reptiles, fish, the fruit fly, and the nematode worm. And it goes even deeper than this. My late friend and distinguished scientist Lynn Margulis showed us how we have inherited so much of our distant prehistory, and much of our fundamental internal chemistry, from the bacterial stage of life—in the jargon, the Proterozoic stage—that pioneered many of the genes and metabolic pathways that life depends on today. And, chapter by chapter, we have discovered how all four of the mechanisms that give rise to hereditary change, those same mechanisms I grouped together under the umbrella concept of “genomic creativity,” have provided the “variation” necessary for Darwin's pioneering idea of evolution to mold our wonderful human genome.
We have seen how the symbiotic union of the genomes of former parasitic microbes with the genomes of our ancestors has contributed to this inexorable evolution, from the capture of the energy of sunlight by cyanobacteria and the production of high-energy oxygen as a by-product, to the respiration of the oxygen by the bacterial forerunners of the mitochondria that now add a second genome to our living cells, as well as the invasion of the endogenous retroviruses that are still changing the way our genome works. We have seen how, as the genome became more and more complex, powerful systems of epigenetic regulation have become intricately involved with the bureaucratic systems of governance of genes and many other aspects of the genome. Some scientists would now regard the genes as hardware and the regulatory systems as software, with the implications that where the hardware is for ordinary purposes fixed, the software is capable of changing in relation to signals from the environment in every individual human being. And we have seen how sexual crosses between cousin species have added major injections of genetic diversity to our evolving ancestral genome.
All of this may appear a confusion of competing forces—and so it would be if evolution was random, but thanks to Darwin we realize that it is not random. There is an additional powerful editorial force—Darwin's brilliant concept of natural selection—which selects for those changes in heredity that enhance survival and selects against those that threaten survival. Survival, and through it reproduction, governs every mechanism that contributes to what might appear a confusion of competing forces. And yes, built into this history of our constantly evolving genome is the inevitability that every one of us is genomically unique.
We are unique, to begin with, because each of us, other than genetic twins, inherits a randomized mixture of the genomes of two different individuals—our parents. The mixing is inherent in the way the germ cells are created within the ovaries and testes of our mo
thers and fathers. It is brought about during the process known as “meiosis,” when the chromosomes line up in parallel to one another and then the similar chromosomes break up into fragments and swap these matching fragments with one another. This process of sexual homologous recombination explains why brother is not identical to brother and sister to sister, even though they share the same parents. Only identical, or so-called “monozygotic,” twins share identical genes, because they develop from the same fertilized egg. But now, following our exploration of epigenetics, we know that even identical twins are already developing differences in their epigenetic systems of regulatory control by the time they are born. And if we looked really closely at their genomes throughout life, we would discover that they become increasingly different, because their epigenetic systems have been responding to different environmental stimuli.
A key region in making every human being unique is a portion we have repeatedly visited on our journey, the major histocompatibility complex, or MHC. Located on chromosome 6, this contains more than a hundred protein-coding genes, and it determines our immune defenses as well as our antigenic identity, for example, when it comes to blood transfusions and organ transplants. No part of our genome so tellingly defines us as “self.” This personal genetic identity begins within the developing embryo in the mother's womb and it continues to update itself, through interaction with invading microbes, throughout all of our lifetime. It is through some damage or aberration of this complex recognition of self that autoimmune diseases such as rheumatoid arthritis, lupus, and juvenile onset diabetes arise.
We have seen how tiny errors are made every time the DNA of our genome is copied to give rise to the ovum and sperm—these mutations in parts of our DNA that are of no consequence to natural selection give rise to the Snips, haplotypes, and haplogroups that enable genetic historians to trace origins and movements of historic populations.
Thus at conception we share roughly half our genes, including those vast numbers of single nucleotide polymorphisms, or Snips, with each parent. We also share roughly half of our genes and Snips with our siblings. If we have identical twins, we begin our embryological development by sharing all of our genes and Snips with our twins. In similar fashion, we share a quarter of the same with our grandparents, an eighth with our great-grandparents, and so on back in time. But there is already potential for change even in this seemingly well-ordered system. So vast is the genome that there is a measurable potential for small mistakes during its copying. And those mistakes guarantee that tiny parts of us will be different even from the genetic sequences we would have expected to inherit from the genomes of our parents.
Whole genome sequencing has now established the mutation frequency for whole genomes. From one generation to the next—in other words from parents to child—there are, on average, about 70 new mutations. The vast majority of these are not located in the 1.5 percent protein-coding fraction of the genome, where the average is a single mutation for every three parent-to-child generations. Instead, the majority are to be found in the viral and epigenetic regulatory regions. We shall return to this shortly, but I would like to continue to focus on mutational change. As an integral part of this predictable mutational change, you and I can expect to have Snips unique to our genomes. Something closely related to this has contributed to the uniqueness of individual genomes that is essential to what we know as DNA fingerprinting.
We are familiar with DNA fingerprinting as a means of determining family relationships, for example in paternity testing or identifying the perpetrator of a crime. Up until the 1980s, accurate forensic identification had largely relied on fingerprinting, but in many crimes there was no fingerprint evidence. DNA profiling offered the same accuracy of individual identification, whether from saliva, or a spot of blood or semen, or a sample of tissue of any kind, including bone. But first there was a workaday methodological problem that needed to be overcome; a busy forensic service could not be expected to screen an entire human genome, with all of its 6.4 billion nucleotides, in the search for the elusive evidence of individual peculiarities. What was needed was a simple and reliable system of automated screening capable of spotting differences between individuals to the same high fidelity as fingerprinting. In 1985, a Leicester-based British geneticist called Alec Jeffreys provided this.
Jeffreys made his discovery by accident when exploring differences in DNA sequences between individual family members of one of his laboratory technicians. He had been examining odd-looking DNA sequences from the “repeat” sections of the genome—those huge chunks of virus-related sequences that were scattered widely throughout the chromosomes. Here and there he observed regions of DNA containing repeats of the same handful of nucleotide letters. These so-called repeats were hardly uncommon in the human genome, but in certain locations within the chromosomes the actual number of them seemed to vary from one individual to another.
If we were to pay one such region a visit on our magical steam train, we would find ourselves hopping down to walk along a highlighted section of track, noting that the sequence began with, say, four sleepers, that read perhaps T, C, A, and G. As we continue to perambulate the track, we find the same sequence, TCAG, repeating itself, possibly three times. Since these repeats occur in tandem along the track, they are called “tandem repeats.” As far as Jeffreys could see, they served no purpose in the sense of the DNA translating to protein—or, in these more enlightened times, to genomic regulation, genetic or epigenetic. These were typical of the sort of sequence that would be ignored by natural selection because they would make no difference to individual survival or reproductive capability. So if we were to examine many different individuals within a population, through chance alone the numbers of tandem repeats at these sites would be very variable. They might show closer than average similarity among siblings, other than identical twins, but even siblings would show some differences as a result of sexual homologous recombination. In the jargon, these sites were locations of “variable number of tandem repeats,” or VNTR.
What Jeffreys did next was to develop a simple methodology based on the numbers of repeats at ten different VNTR locations scattered throughout the chromosomes. Why ten? We might indulge in the same simple mathematics we used earlier to determine how many nucleotides we needed in an overlap between fragments of chromosomes for it to be significant beyond reasonable doubt. Ten loci, say with variation from 1 to 4 repeats, proved to be more than enough to identify an individual beyond phenomenal levels of reasonable doubt. Jeffreys then added a simple genetic test that would determine whether the forensic evidence came from a male or a female. As we might have expected, the effectiveness of the actual genetic screening is greatly improved by using PCR, which needs only trace amounts of an individual's DNA to find a match. Thus forensic scientists were given an incredibly accurate new tool of individual identification, based on the very fact that every human being really is genomically unique; and that evidence could be gleaned from a trace of blood or body fluids, from a single hair, or from the cells shed from skin—indeed from a very wide variety of personal identification left behind at a great many different crime scenes. It just remained to be demonstrated that the new genetic methodology would prove to be every bit as helpful as traditional fingerprinting.
One of the earliest applications of genetic fingerprinting was in the search in the county of Leicestershire for a rapist killer of two teenage girls. Not only did this process discover the real murderer, it also exonerated an innocent man who until then had been considered the prime suspect. Since then Jeffreys's methodology has been taken up by forensic laboratories around the world, helping to solve a vast array of family pedigree genetic enquiries as well as criminal cases. But we should not confuse DNA fingerprinting with the complete DNA sequencing of an individual human genome. This remains a formidable undertaking, although it is much easier to conduct these days, with high-throughput computer-assisted sequencing machines. Whole genome sequencing is becoming increasingly comm
on, for various purposes, and this has highlighted how unique each and every individual human being really is at levels that go far beyond variable tandem repeats.
A single endogenous retrovirus insert, or locus, is roughly 10,000 nucleotides long. People hailing from Africa or the Near East are much more likely to contain the loci of HERV-113 and HERV-115 in their genomes than people originating in Western Europe or Asia. Meanwhile, those same Western Europeans are far more likely to contain tracts of DNA of Neanderthal origins than people hailing from sub-Saharan Africa. Asians and Polynesians are also likely to contain some Neanderthal DNA and to contain even more Denisovan DNA, amounting to as much as one-sixteenth of all their genome. How much information will the more detailed exploration of these differences provide of our human history of origins and migrations that was previously thought lost to the dust and fossils of prehistory? We are only beginning to explore the implications of these two major hybridization events. Yet such differences do not feed into the slanted viewpoints of racists. Rather, they confirm and extend what the earliest geneticists, such as Luigi Luca Cavalli-Sforza, were at pains to emphasize and celebrate: our oneness not only as a species but as a human family.
Whole genomic sequencing must, by definition, include both the mitochondrial and the nuclear genome. This has led to surprising differences when we screen populations. We have already seen significant differences between males and females when we conduct haplogroup screening of European populations, with females showing a much greater homogeneity throughout all populations when compared to males. Sexual differences in haplogroup movements are also seen in much more recent population screenings, for example in the peopling of the various nations among the British Isles. Whole genomic sequencing may help to clarify what this might mean. As we saw with the Neanderthals, screening of the mitochondrial genome, or perhaps the similarly limited screening of Y-chromosome sequences, may actually be giving us subtly different information from the screening of the entire nuclear genome. How interesting if this translates to real differences in the prehistoric movements of the two sexes within ancient societies!