What Makes Us Human?
Compiled and designed by Megan Nadkarni
We thought we knew.
But we’re not the only ones who are smart enough to make tools.
We’re not the only ones who are violent ...and yet empathetic.
And we’re not the only ones who nurture our young.
So in 2011, what really makes us human? Scientists across disciplines, from primatologists to neurobiologists to biostatisticans, are starting to piece together a new picture of what makes us unique,
but there are still many missing pieces.
Contents
20 How We’re Related to Apes
Hominin Evolution
34 Why Apes Haven’t Taken Over the World
Cognitive Differences
44 How 1% Can Make a Huge Difference
Comparative Genomics
WE SHARED A COMMON ANCESTOR WITH APES 15 MILLION YEARS AGO.
HUMANS AND APES HAVE SIMILAR SOCIAL CONSTRUCTS AND BEHAVIORAL PATTERNS.
APES ALSO DEVELOP CULTURE THAT THEY PASS ON THROUGH GENERATIONS.
How We’re Related to Apes
SEAN B. CARROLL ON
Hominid Evolution
What makes modern humans different from the great apes and earlier hominids? In what hominids and when in evolution did important physical traits and behaviors appear? Where in our larger brains do human-specific capabilities reside? These have been long-standing questions in palaeoanthropology and comparative anatomy, Since the discovery of Neanderthal skulls and the first studies of great apes in the nineteenth century. Now, the mystery of human origins is expanding beyond the description and history of human traits, towards the genetic mechanisms underlying their formation and evolution. With the characterization of the human genome, and that of our chimpanzee cousin on the way, the quest to discover the genetic basis of the physical and behavioural traits that distinguish us from other apes is rapidly gaining momentum.
Hominids: humans and the African apes Hominins: humans and our evolutionary ancestors back to the separation of humans and apes
Sean B. Carroll “Genetics and the making of Homo sapiens� for Nature, April 24, 2003. Sean B. Carroll is a professor of genetics, medical genetics, and molecular biology at the University of Wisconsin as well as an investigator for the Howard Hughes Medical Institute. He is at the forefront of a field known as evolutionary developmental biology.
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FIGURE 1.1
Common Ancestors A timeline view of hominid evolution, which is constantly subject to revision due to new fossil evidence. HOMININS HOMINIDS (excl. hominins)
Orrorin tugenensis Sahelanthropus tchadensis Ar. r. kadabba Ardipithecus ramidus
Common Ancestor
15 MYA
(MILLION YEARS AGO)
10 MYA
5 MYA
Homo sapiens (Humans)
Kenyanthropus platypos H. ergaster
H. neanderthalensis (Neanderthals)
Australopithecus afaranesis H. erectus
Au. bahrelghazali Au. anamensis
H. heidelbergensis
H. habilis
Au. africanus
H. antecessor
Au. africanus H. rudolfensis P. aethiopicus
P. robustus
Paranthropus biosei
Pan troglodyte (Chimps) Pan paniscus (Bonobos) Gorilla gorilla (Gorillas)
Pongo pygmaeus (Orangutans)
1.8 MYA
0.2 MYA
Present
Many different branches of the hominin lineage were formed, but died out.
The h o m i n i d t r e e To approach the origins of human traits at the genetic level, it is essential to have as a framework a history of our lineage and the characters that distinguish it. It is inadequate and misleading to consider just the comparative anatomy and development (or genomes) of extant humans, chimpanzees and other apes, and then to attempt to infer how existing differences might be encoded and realized. Each of these species has an independent lineage that reaches back as far or further than hominins (‘hominins’ refers to humans and our evolutionary ancestors back to the separation of the human and ape lineages; ‘hominids’ to humans and the African apes). The evolution of ‘modern’ traits was not a linear, additive process, and ideas about the tempo, pattern and magnitude of change can only be tested through fossil evidence, which is always subject to revision by new finds. The fossil record continues to shape views of three crucial issues in hominid evolution. First, what distinguishes hominins from the apes? Second, what distinguishes modern humans (Homo sapiens) from earlier hominins? And third, what was the nature of the last common ancestor of hominins and the Pan lineage?
Inferences about the chronological order and magnitude of the evolution of hominin characters depend on a model of the hominin evolutionary tree. This has always been a contentious issue and remains unsettled, in part because of the pace of exciting new fossil finds over the past two decades. An emerging view portrays hominin evolution as a series of adaptive radiations in which many different branches of the hominin lineage were formed, but died out. One prediction of this model is that various anatomical features would be found in different combinations in hominins through their independent acquisition, modification and loss in different species. For example, the recent, stunning discovery of a 6–7 million year (Myr)-old fossil cranium of Sahelanthropus tchadensis that had a chimpanzee-sized brain but homininlike facial and dental features is the sort of morphology that would be consistent with a radiation of ape-like animals from which the stem of the hominin lineage emerged.
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FIGURE 1.2
All in the Family A comparison of the members of the family Hominidae, meaning Great Ape.
ORANGUTAN Pongo pygmaeus
GORILLA
CHIMPANZEE
BONOBO
HUMAN
Gorilla gorilla
Pan troglodyte
Pan paniscus
Homo sapien
100,000
200,000
20,000-50,000
6.5 billion+
35 years
40 years
40 years
65 years**
Groups up to 20
Groups up to 150
Groups of up to 250
Varies
Peaceful
Peaceful
Peaceful
Peaceful
Leaves, shoots, fruits, vines, insects, sometimes rotting wood
Fruits, leaves, flowers, small animals
Fruits, leaves, truffles, honey, small animals
Omnivorous
POPULATION*
55,000 LIFE EXPECTANCY
35 years DOMINANCE
SOCIAL BEHAVIOR
Live alone SEXUAL BEHAVIOR
TEMPERAMENT
Loners; Territorial DIET
Fruit, leaves, bark, insects, small animals
GEOGRAPHIC DISTRIBUTION
*POPULATION AS OF 2006 **WORLDWIDE AVERAGE
Evolutionary trends Ideally, if every possible fossil human and ape species were identified and many fairly complete specimens were available, one could reconstruct the emergence of human and chimpanzee features through time. But that is not the case for most lineages; in fact, there are no identified archaic chimpanzee fossils. We must make do with a partial and often confusing picture of human trait evolution. From a rather extensive list of qualitative and quantitative features that distinguish humans from other apes, our large brain, bipedalism, small canine teeth, language and advanced tool-making capabilities have been the focus of palaeoanthropology. The major physical traits are generally not singular elements, but entail concomitant changes in skeletal features involved in locomotion (for example, in the vertebral column, pelvis and feet, and in limb proportions), grasping (hand morphology and an opposable, elongated thumb) and chewing of food (the
mandible and dentition), as well as lifehistory traits such as lifespan. It is fortunate that most of the skeletal features lend themselves to detailed quantitative studies of the fossil record. Some trends in the evolution of body size, brain size and dentition are evident within the hominins. More recent species are characterized by larger body mass, relatively larger brains, longer legs relative to the trunk and small teeth, whereas earlier species had, in general, smaller brains and bodies, shorter legs relative to the trunk and large teeth. I highlight these traits to focus attention on the magnitude and timescale of character evolution, and on the (increasing) number of generally recognized hominin taxa. Whatever the branching pattern in the hominin tree, substantial relative changes occurred over an extended time span and a significant number of speciation events. There was a marked increase in absolute brain size by the Early Pleistocene and
again in the Middle Pleistocene, with a long interval of perhaps 1 Myr during which brain size did not change significantly. With regard to modern H. sapiens, it is interesting to note that body and brain size were even greater in H. neanderthalensis; there is no obvious physical explanation for the success of H. sapiens and the demise of H. neanderthalensis.
FIGURE 1.3
Is Bigger Better? Brain size generally grew has hominins evolved with the exception of modern humans. Our brain size is actually smaller than that of our Neanderthal predecessors.
0 MYA
1
2
Homo sapiens H. neanderthalensis H. heidelbergensis H. erectus H. ergaster H. rudolfensis H. habilis Paranthropus boisei
3
4
5
6
Australopithecus africanus
Sahelanthropus tchadensis
7
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FIGURE 1.4
Great Minds Think Alike Although the over skull sizes are roughly comparable, the human cranial capacity and brain are much larger. Communication areas are assymetrical in both chimps and humans, suggesting they had a common ancestor with a communication center that developed on one side of the brain. However, unlike chimpanzees, humans possess two areas of communication. Human Chimpanzee
Broca’s Area ability to speak
Wernicke’s Area understanding written and spoken language
Planum Temporale language and music ability
Brodmann’s Area 44
Planum Temporale
A beautiful mind The relative increase in brain size, although marked, is only a crude index of a potential increase in cognitive abilities. Because it has long been appreciated that there are discrete areas of the brain that process various cognitive, motor and sensory functions, comparative neuroanatomists have sought to identify areas that might be central to the evolution of human capacities. There is a long-standing notion that the frontal cortex (involved in planning, organization, personality, behaviour and other ‘higher’ cognitive functions) is disproportionately larger in humans, but this now seems not to be the case (it is larger, but not disproportionately so). As gross anatomical differences do not account for cognitive capabilities, relative differences in the size, cellular composition, detailed cytoarchitecture and/or connectivity of human and great ape brain areas have been sought to explain the emergence of human capabilities. 30
Of paramount interest is the production and understanding of speech. Two areas in particular have commanded the greatest attention. One is Broca’s area in the frontal lobe of the neocortex. This region is larger in the left hemisphere of the brain than in the right, an asymmetry that has been correlated with language ability. From magnetic resonance images of chimpanzees, bonobos and gorillas, a similar left–right asymmetry has been found in these great apes. This indicates that the neuroanatomical substrate of left-hemisphere dominance in speech production preceded the origin of hominins. The left hemisphere also usually controls right-handedness, so it is interesting to note that in captive apes, manual gestures are right-hand biased, and this bias is increased when vocalization is combined with gesturing, indicating a left-hemispherecontrolled communication process.
Hominid features
The morphological differences between modern humans, earlier hominins and the great apes are, of course, the product of changes during development. Comparative studies of human and chimpanzee skull development, remarkably detailed examinations of Neanderthal craniofacial ontogeny, and early hominin dentition formation have yielded crucial insights into a variety of developmental shifts that underlie modern human cranial size and morphology. One of the long-appreciated, fundamental differences in chimpanzee and human development is the relative rate of skull growth and maturation. Human neonates have less mature skulls in terms of shape in comparison to young chimpanzees, but much larger skulls (and brains). These are classically described as heterochronic changes, which produce neotenic features in which maturation is retarded, size increases and shape resembles juvenile forms of ancestors. Chimpanzee and human skulls eventually grow to the same size, reflecting further relative shifts in juvenile and adolescent growth periods, and marked differences in face size and cerebral volume. Importantly, all of the skeletal changes associated with bipedalism are structural innovations independent of neoteny. These observations suggest that the human brain is not a product of simple shifts in growth relationships, but of multiple, independent and superimposed modifications. With respect to more recent hominin species, modern human craniofacial form appears to have been shaped by changes
in elements that influence the spatial position of the face, neurocranium and cranial base. Modern humans are marked by greater roundedness of the cranial vault and facial retraction (the anteroposterior position of the face relative to the cranial base and neurocranium). Comparisons with Neanderthal skull development inferred from fossils of different aged individuals suggest that the characteristic cranial differences between Neanderthal and modern human features arise early in ontogeny. Our prolonged childhood, delayed sexual maturation and long lifespan are lifehistory traits that shape important aspects of human society. Insights into the evolution of these development shifts in evolution are offered by detailed comparative analysis of dental development, which is correlated with stages of primate growth and development. Rates of enamel formation in fossil hominins suggest that tooth-formation times were shorter in australopiths and early members of the genus Homo than they are in modern humans. This indicates that the modern pattern of dental formation and correlated developmental traits appeared late in human evolution. When considered in the context of other traits, such as brain size and body proportions, a mosaic pattern of evolution emerges with different traits appearing at different times and perhaps in different combinations in hominin history.
31
Were we special? The magnitude, rate and pattern of change during hominin evolution, inferred from the fossil record, comparative neuroanatomy and embryology, provide the essential foundation for approaching the genetics of human evolution. From the studies discussed above, five key points emerge that have a bearing on attempts to reconstruct the genetic events that underlie the origin
Five key points emerge that have a bearing on attempts to reconstruct the genetic events that underlie the origin and modification of human traits. and modification of human traits. First, trait evolution was nonlinear. The 1,000-cm increase in brain size over 5–7 Myr did not occur at the same relative rate in hominin phylogeny: it was static at times, faster in some intervals, and reversed slightly more recently. Second, most trait evolution can be characterized as simple quantitative changes (that is, traits are continuous). Third, evolutionary rates were not at all exceptional with respect to mammalian evolution. For example, fossil horse lineages in the late Pliocene– Pleistocene show similar rates of body-size and other character changes as do those of hominids. Fourth, much evolutionary change preceded the origin of the Homo genus and of H. sapiens: the history of our species represents just the last 3% of the time span of hominin evolution. And fifth, many characters are present not only in humans, but also in apes. This suggests that modification of existing structures and developmental pathways, rather than the invention of new features, underlies much of human evolution. These observations indicate that morphoÂlogical evolution in hominins was not special, but the product of genetic and developmental changes typical of other mammals and animals.
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Evolution in hominins was not special.
Why Apes Haven’t Taken Over the World
IMPULSE CONTROL SEEMS TO BE A POWERFUL EVOLUTIONARY ADAPTATION FOR HUMANS.
BONOBOS ARE CAPABLE OF BEING COOPERATIVE BUT TEAMWORK IS VERY DIFFICULT FOR CHIMPANZEES.
THERE IS NO EVIDENCE THAT APES HAVE SHARED COMMITMENTS TOWARDS SHARED GOALS.
TEACHING, NOT IMITATION, IS THE SKILL THAT ALLOWS FOR THE RATCHETING UP OF PROGRESS
36
JOHN RUBIN ON
Cognitive Differences Congratulations: You are an ape. A “great ape,” technically. Alongside us in this brainy family of animals are four other living species: chimpanzees, gorillas, orangutans, and bonobos (formerly called “pygmy chimpanzees”). The biological gap between us and our great ape cousins is small. At last count, only 1.23 percent of our genes differ from those of chimpanzees. But mentally, the gap between us and them is a Grand Canyon. On an average day in the life of the human species, we file thousands of patents, post tens of thousands of Internet videos, and think countless thoughts that have never been thought before. On a good day, chimpanzees are lucky to exploit rudimentary tried-and-true techniques, such as using stone tools to crack nuts. Not only do we innovate more than the other great apes, we are vastly better at sharing ideas with one another. The majority of recent behavioral studies focus on information-transmission rather than invention. All of the great apes can learn new tricks by imitating a human or another ape. But only humans go one step further and routinely teach each other. Teaching may be the signature skill of our species, and researchers are now zeroing in on three particular mental talents that make it possible.
Many skills are not unique to humans. It is the combination of all of them and our particularly high proficiency at them that really differentiates us from other animals.
John Rubin “What Makes Us Human?” for PBS Online, January 1, 2008. John Rubin holds a Ph. D. in cognitive science from the Massachussetts Institute of Technology. He also wrote, produced, and directed the documentary “Ape Genius” for NOVA.
37
Our unique talents Mind-reading. Humans are exceptionally skilled at thinking about what’s on other people’s minds. A teacher, for example, needs to understand what a student knows and doesn’t know. Researchers used to
All of the great apes can learn new tricks by imitating a human or another ape. But only humans go one step further and routinely teach each other. believe that chimpanzees lacked this talent entirely. Although recent experiments at the Max Planck Institute for Evolutionary Anthropology in Germany are showing that chimps share at least a bit of this skill, humans are clearly head and shoulders above the great apes in mind-reading savvy. The Triangle. Watch a human parent building a block tower with a child and you’ll see a special skill at work. Let’s call it the Triangle; its three points are the adult, the youngster, and the tower. Both adult and child are not only focused on the same
38
object, they know the other is focused on it too. The Triangle is the foundation for teaching—a mentor and pupil must jointly pay attention to the lesson at hand. Amazingly, humans seem to be the only great apes that possess this mental skill. Impulse control. Whereas mindreading and the Triangle are cognitive skills, the third mental talent that sets us apart from our kin is emotional. We seem to have much greater control over our emotions, and being less reactive and impulsive is a good way to get to the head of the class. Researchers discovered all three of these distinguishing human talents by observing human and ape behavior, sometimes with solid, carefully controlled experiments. But what’s going on under the biological hood? What brain mechanisms are responsible for the mental and behavioral differences between them and us? Biologically inclined researchers are starting to answer these questions, and the clues they are finding, while still patchy and nascent, are tantalizing.
FIGURE 2.1
Monkey See, Monkey Do While all apes are capable of imitation, which is itself a complex cognitive skill, only humans routinely teach each other. This partly thanks to a skill called the Triangle skill. The Triangle skill involves a mentor and a pupil jointly paying attention to something as well as the awareness that the other is focused on the same thing too.
AWARENESS OF EACH OTHER
AWARENESS OF THE BOOK
This new PET scan technique holds huge promise.
FIGURE 2.2
Resting Brain Activity PET scan images of humans and chimps indicate that both have similarly high levels
of resting-state brain activity. While the results are consistent with the existence of theory of mind in chimpanzees, they do not require that conclusion, because homologous brain regions can evolve to take on different functions in different species. The scans also indicate the possibility that the resting state of chimpanzees involves emotionally laden episodic memory retrieval and some level of mental self-projection, albeit in the absence of language and conceptual processing.
activity
activity
A place for mind-reading The mind-reading skill, it turns out, appears to have its own particular region of the human brain. In 2003, Rebecca Saxe of mit ran studies using functional magnetic resonance imaging, or fMRI, a non-invasive technology that creates a kind of movie of brain activity. The studies revealed an area perhaps half the volume of a sugar cube above and behind the right ear. This brain region appears to have a remarkably specific function. When I am thinking about who a friend believes will be the next American president, this area in my brain is highly active. But when I am thinking about whether my friend is thirsty, another internal state, but not a belief, this
brain region is quiet. Saxe’s discovery, one of the most surprising in cognitive science in the last decade, begs a question: Do the other great apes have their own version of this brain area, and if so, what is it doing? With fMRI, a conscious person lies still inside a scanner. Why not use the same technique with apes? Apes, not surprisingly, are strong, impulsive animals with little inclination to hold still inside a big, noisy cylinder. So the prospect of scanning apes to see what’s on their minds seemed dim, until primatologist Lisa Parr and colleagues at the Yerkes National Primate Center at Emory University solved the problem in 2007.
Using a different kind of scanning, positron emission tomography, or pet, Parr’s team showed chimps pictures after injecting them with a fast-decaying radioactive agent. When the chimps were anesthetized for a pet scan, the brain areas selectively activated by looking at the pictures remained “lit up.” Parr is currently investigating the area of chimp brains responsible for recognizing faces. Functional brain imaging of apes is just beginning, but this new technique holds huge promise.
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Where Other Talents Lie Another important concept that has previously long been thought to be uniquely human is the theory of mind, or the idea that only humans have awareness of the mind. Recent behavioral experiments show evidence that this may not be uniquely human. However, this concept as a whole is highly debated among scientists because of the varying definitions of mind and the lack of a reliable method of proving or disproving its presence in animals.
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The Triangle skill has also been suggestively linked to a particular region of the human brain. In a study conducted by Andrew Whiten and colleagues at the University of St. Andrews in Scotland, a person’s brain is scanned using fMRI. When the human subject and an animated character on a TV screen are both looking at the same moving object, a small area in the human’s brain—located an inch behind the middle of forehead—is highly active. But when the person and cartoon character are looking in separate directions, this brain region is much less active. In a separate study by other researchers, this same brain region is more active when a person is watching two cartoon characters collaborating on a joint project compared to when the characters are working independently. Yet another region of the brain—the frontal lobes, the part of the brain behind your forehead—is linked, by many lines of evidence, to impulse control. Anthropologist Katerina Semendeferi of the University of California, San Diego compared the size of this brain area across the great apes. To her surprise, she discovered that humans do not possess proportionately bigger frontal lobes. Semendeferi is now investigating more subtle differences in the wiring of this region: Humans have far more neural connections in their frontal lobes than do other apes.
Other researchers are exploring different compelling avenues. Neuroscientist John Allman at Caltech and colleagues are investigating a particular kind of brain cell, for example. “Spindle neurons” are found in humans, orangutans, gorillas, bonobos, and chimpanzees—but not in any of the roughly 350 other primate species. In a rare evolutionary event, spindle cells seem to have arisen abruptly 15 to 20 million years ago with the emergence of the great apes. The function and significance of these intriguing cells, like so much else in this field, remain to be worked out. Clearly, for anyone interested in the gap between us and our nearest living relatives, these are exciting times. Comparative studies of our own minds and brains and those of the other great apes are finally getting traction on one of biggest questions in science: What makes us human?
FIGURE 2.3
There’s No ‘I’ in Team Scientists have a hypothesis of how characteristic traits of “deep social mind” work synergistically to reinforce each other as an adaptive complex in humans, which chimps and other apes lack.
R D I N AT I O N COO L A I TA R I A N I S M EG
IDEOLOGIES GENERALIZED SHARING OF INFORMATION & INNOVATION
CULTURE
LEARNED TECHNIQUES
AC HI D NG PL ERS AN TA S & ND IN ING TE OT NT H PS COM IO ER YC M NS S ’ HO ON LO GY
TE
IM
ITA TIO
N
COOPERATION
UN
AL CY NT EN ME PAR S AN
TR
MINDREADING
RATS ARE MORE DIFFERENT FROM MICE THAN WE ARE FROM CHIMPANZEES.
WE SHARE 99 PERCENT OF OUR GENETIC CODE WITH CHIMPANZEES.
GENETIC STUDIES INDICATE THAT BEING HUMAN IS NOT ALL ABOUT THE BRAIN.
How
1% Can Make a Huge Difference
46
KATHERINE S. POLLARD ON
Comparative Genomics
Six years ago I jumped at an opportunity to join the international team that was identifying the sequence of dna bases, or “letters,” in the genome of the common chimpanzee (Pan troglodytes). As a biostatistician with a long-standing interest in human origins, I was eager to line up the human dna sequence next to that of our closest living relative and take stock. A humbling truth emerged: our dna blueprints are nearly 99 percent identical to theirs. That is, of the three billion letters that make up the human genome, only 15 million of them—less than 1 percent—have changed in the six million years or so since the human and chimp lineages diverged. Evolutionary theory holds that the vast majority of these changes had little or no effect on our biology. But somewhere among those roughly 15 million bases lay the differences that made us human. I was determined to find them. Since then, I and others have made tantalizing progress in identifying a number of dna sequences that set us apart from chimps.
It’s important to remember that there is no such thing as ‘a gene for’ any particular characteristic. What must be sought is the variation in the sequences of those genes, or the versions of the genes, that determine, or contribute to determining the partcular characteristic differences we see between humans and their nearest relatives.
Katherine S. Pollard “What Makes Us Human?” for Scientific American, April 20, 2009. Katherine S. Pollard is a biostatisticians at the University of California, San Francisco. She holds a Ph. D from the University of California, Santa Cruz where she also participated in the sequencing of the chimpanzee genome.
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FIGURE 3.1
Building Blocks A genome is the entirety of an organism’s genetic information (DNA). DNA can be divided into two categories, coding and non-coding.
GENOME
PROTEIN CODING DNA
NON-CODING DNA
REGULATORY FUNCTION (turning genes on and off) 6 TYPES OF RNA CODING mRNA tRNA intron UNKNOWN FUNCTION
DNA has several functions, many of which scientists still don’t fully understand. Only 1.5% of our DNA actually codes for proteins.
98.5%
of our DNA is NONCODING, also known as ‘JUNK’ DNA
WE SHARE 99 PERCENT OF OUR GENETIC CODE WITH CHIMPANZEES.
ONLY 1%
of our DNA has changed in the past 6 million years. This is roughly equivalent to 15 MILLION base changes out of 3 BILLION bases.
30% of our proteins are IDENTICAL to chimpanzees. Our proteins differ by just 2 amino acids on average.
There are 15 genes where the human ‘disease’ variant is the only variant in chimpanzees. This suggests we may be evolving even further from the ancestral version of these genes.
An early surprise When comparing genomes between species, scientists often refer to the human genome. However it is important to remember that there is no ‘one’ human genome. Everyone has a genome that differs slightly. Humans are 99.9% similar to each other. HARs are areas of DNA that have evolved drastically in humans, but have remained relatively the same in birds and mammals.
Despite accounting for just a small percentage of the human genome, millions of bases are still a vast territory to search. To facilitate the hunt, I wrote a computer program that would scan the human genome for the pieces of dna that have changed the most since humans and chimps split from a common ancestor. Because most random genetic mutations neither benefit nor harm an organism, they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common forebear (this rate of change is often spoken of as the “ticking of the molecular clock”). Acceleration in that rate of change in some part of the genome, in contrast, is a hallmark of positive selection, in which mutations that help an organism survive and reproduce are more likely to be passed on to future generations. In other words, those parts of the code that have undergone the most modification since the chimp-human split are the sequences that most likely shaped humankind.
Those parts of the code that have undergone the most modification since the human-chimp split are the sequences that most likely shaped human kind. In November 2004, after months of debugging and optimizing my program to run on a massive computer cluster at the University of California, Santa Cruz, I finally ended up with a file that contained a ranked list of these rapidly evolving sequences. With my mentor David Haussler leaning over my shoulder, I looked at the top hit, a stretch of 118 bases that together became known as human accelerated region 1 (har1). Using the U.C. Santa Cruz genome
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browser, a visualization tool that annotates the human genome with information from public databases, I zoomed in on har1. The browser showed the har1 sequences of a human, chimp, mouse, rat and chicken—all of the vertebrate species whose genomes had been decoded by then. It also revealed that previous large scale screening experiments had detected har1 activity in two samples of human brain cells, although no scientist had named or studied the sequence yet. We yelled, “Awesome!” in unison when we saw that har1 might be part of a gene new to science that is active in the brain. We had hit the jackpot. The human brain is well known to differ considerably from the chimpanzee brain in terms of size, organization and complexity, among other traits. Yet the developmental and evolutionary mechanisms underlying the characteristics that set the human brain apart are poorly understood. har1 had the potential to illuminate this most mysterious aspect of human biology. We spent the next year finding out all we could about the evolutionary history of har1 by comparing this region of the genome in various species, including 12 more vertebrates that were sequenced during that time. It turns out that until humans came along, har1 evolved extremely slowly. In chickens and chimps—whose lineages diverged some 300 million years ago— only two of the 118 bases differ, compared with 18 differences between humans and chimps, whose lineages diverged far more recently. The fact that har1 was essentially frozen in time through hundreds of millions of years indicates that it does something very important; that it then underwent abrupt revision in humans suggests that this function was significantly modified in our lineage.
FIGURE 3.2
Change is the Only Constant HARs are areas of DNA that have evolved drastically in humans, but have remained relatively
the same in birds and mammals. For example in HAR1, a sequence 118 bases long, only 2 bases differ between chickens and chimpanzees whose lineages diverged 300 million years ago. However there are 18 base changes in the evolution between chimpanzees and humans who diverged only about 6 million years ago.
2 CHANGES
Chicken Âť Chimpanzee
300 MIL YEARS
T A G A T G
G G A G C A
A C T C A T
A A G G A T
A A G G A T
Chimpanzee Âť Human
T A G A T G
G G A G C A
A C T C A T
A A G G A T
C C G C A T
G G C G T C
G T G G G C
A G T A A T
G T A A A C
G C G A A A
A A A T G A
G G C G T G
A C G G G T
C T C T T T
G G A T T T
T A C T T C
18 CHANGES
A A G G A T
C C G C A T
G G C G T C
G T G G G C
T A G C A A
A A T T G
C T C A A
6 MIL YEARS
A G T A A T
G T A A A C
G C G A A A
A A A T G A
G G C G T G
A C G G G T
C T C T T T
G G A T T T
T A C T T C
T A G C A A
A A T T G
C T C A A
FIGURE 3.3
Lighting the Way DNA sequences are given a fluorescent molecular tag that lights up when the sequence is activated in a cell (i.e. when DNA is copied to RNA).
1 DNA Sequence is Marked with a Fluorescent Molecular tag
2 Cell Copies DNA into mRNA
3 mRNA serves as a template for making proteins
4 Cells producing protein with this molecular tag light up
A critical clue to the function of har1 in the brain emerged in 2005, after my collaborator Pierre Vanderhaeghen of the Free University of Brussels obtained a vial of har1 copies from our laboratory during a visit to Santa Cruz. He used these dna sequences to design a fluorescent molecular tag that would light up when har1 was activated in living cells—that is, copied from dna into rna. When typical genes are switched on in a cell, the cell first makes a mobile messenger rna copy and then uses the rna as a template for synthesizing some needed protein. The labeling revealed that har1 is active in a type of neuron that plays a key role in the pattern and layout of the developing cerebral cortex, the wrinkled outermost brain layer. When things go wrong in these neurons, the result may be a severe, often deadly, congenital disorder known as lissencephaly (“smooth brain”), in which the cortex lacks its characteristic folds and exhibits a markedly reduced surface area. Malfunctions in these same neurons are also linked to the onset of schizophrenia in adulthood. Har1 is thus active at the right time and place to be instrumental in the formation of a healthy cortex. (Other evidence suggests that it may additionally play a role in sperm production.) But exactly how this piece of the genetic code affects cortex development is a mystery my colleagues and I are still trying to solve. We are eager to do so: har1’s recent burst of substitutions may have altered our brains significantly. Beyond having a remarkable evolu tionary history, har1 is special because it does not encode a protein. For decades,
molecular biology research focused almost exclusively on genes that specify proteins, the basic building blocks of cells. But thanks to the Human Genome Project, which sequenced our own genome, scientists now know that protein-coding genes make up just 1.5 percent of our dna. The other 98.5 percent—sometimes referred to as junk dna— contains regulatory sequences that tell other genes when to turn on and off and genes encoding rna that does not get translated into a protein, as well as a lot of dna having purposes scientists are only beginning to understand. Based on patterns in the har1 sequence, we predicted that har1 encodes rna—a hunch that Sofie Salama, Haller Igel and Manuel Ares, all at U.C. Santa Cruz, subsequently confirmed in 2006 through lab experiments. In fact, it turns out that human har1 resides in two overlapping genes. The shared har1 sequence gives rise to an entirely new type of rna structure, adding to the six known classes of rna genes. These six major groups encompass more than 1,000 different families of rna genes, each one distinguished by the structure and function of the encoded rna in the cell. har1 is also the first documented example of an rna-encoding sequence that appears to have undergone positive selection. It might seem surprising that no one paid attention to these amazing 118 bases of the human genome earlier. But in the absence of technology for readily comparing whole genomes, researchers had no way of knowing that har1 was more than just another piece of junk dna.
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You do not need to change very much of the genome to make a new species.
Language Clues Whole-genome comparisons in other species have also provided another crucial insight into why humans and chimps can be so different despite being much alike in their genomes. In recent years the genomes of thousands of species (mostly microbes) have been sequenced. It turns out that where dna substitutions occur in the genome—rather than how many changes arise overall—can matter a great deal. In other words, you do not need to change very much of the genome to make a new species. The way to evolve a human from a chimp-human ancestor is not to speed the ticking of the molecular clock as a whole. Rather the secret is to have rapid change occur in sites where those changes make an important difference in an organism’s functioning. Har1 is certainly such a place. So, too, is the foxp2 gene, which contains another of the fast-changing sequences I identified and is known to be involved in speech. Its role in speech was discovered by researchers at the University of Oxford in England, who reported in 2001 that people with mutations in the gene are unable to make certain subtle, high-speed facial movements needed for normal human speech, even though they possess the cognitive ability to process language. The typical human sequence displays several differences from the chimp’s: two base substitutions that altered its protein product and many other substitutions that may have led to shifts affecting how, when and where the protein is used in the human body. A recent finding has shed some light on when the speech-enabling version of foxp2 appeared in hominids: in 2007 scientists at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, sequenced foxp2 extracted from a Neandertal fossil and found that these extinct humans had the modern human version of the gene, perhaps permitting them to enunciate as we do. Current estimates for when the Neandertal and modern human lineages split suggest that the new form of foxp2 must have emerged at least half a million years ago . Most of what
distinguishes human language from vocal communication in other species, however, comes not from physical means but cognitive ability, which is often correlated with brain size. Primates generally have a larger brain than would be expected from their body size. But human brain volume has more than tripled since the chimp-human ancestor—a growth spurt that genetics researchers have only begun to unravel. One of the best-studied examples of a gene linked to brain size in humans and other animals is aspm. Genetic studies of people with a condition known as microcephaly, in which the brain is reduced by up to 70 percent, uncovered the role of aspm and three other genes— mcph1, cdk5rap2 and cenpj—in controlling brain size. More recently, researchers at the University of Chicago and the University of Michigan at Ann Arbor have shown that aspm experienced several bursts of change over the course of primate evolution, a pattern indicative of positive selection. At least one of these bursts occurred in the human lineage since it diverged from that of chimps and thus was potentially instrumental in the evolution of our large brains. Other parts of the genome may have influenced the metamorphosis of the human brain less directly. The computer scan that identified har1 also found 201 other human accelerated regions, most of which do not encode proteins or even rna. (A related study conducted at the Wellcome Trust Sanger Institute in Cambridge, England, detected many of the same hars.) Instead they appear to be regulatory sequences that tell nearby genes when to turn on and off. Amazingly, more than half of the genes located near hars are involved in brain development and function. And, as is true of foxp2, the products of many of these genes go on to regulate other genes. Thus, even though hars make up a minute portion of the genome, changes in these regions could have profoundly altered the human brain by influencing the activity of whole networks of genes.
There are 202 HARs. Since most of them don’t code for proteins or even an RNA structure, only a handful of them have been studied for their function.
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FIGURE 3.4
DNA Sequence Functions HUMAN ACCELERATED REGIONS GENES
HAR1 development of cerebral cortex; possibly sperm production
ASPM, MCPH1, CDK5RAP2, CENPJ controls brain size
FOXP2 fine muscle movement in the mouth, facilitating speech AMY1 digestion of starch
LCT digestion of milk
HAR2 fine muscle movement in the hand, wrist, and thumb; dexterity
HAR152 protein regulation (not shown)
Beyond the brain Although much genetic research has focused on elucidating the evolution of our sophisticated brain, investigators have also been piecing together how other unique aspects of the human body came to be. har2, a gene regulatory region and the second most accelerated site on my list, is a case in point. In 2008 researchers at Lawrence Berkeley National Laboratory showed that specific base differences in the human version of har2 (also known as hacns1), relative to the version in nonhuman primates, allow this dna sequence to drive gene activity in the wrist and thumb during fetal development, whereas the ancestral version in other primates cannot. This finding is particularly provocative because it could underpin morphological changes in the human hand that permitted the dexterity needed to manufacture and use complex tools. Aside from undergoing changes in form, our ancestors also underwent behavioral and physiological shifts that helped them adapt to altered circumstances and migrate into new environments. For example, the conquest of fire more than a million years ago and the agricultural revolution about 10,000 years ago made foods high in starch more accessible. But cultural shifts alone were not sufficient to exploit these calorie-rich comestibles. Our predecessors had to adapt genetically to them. Changes in the gene amy1, which encodes salivary amylase, an enzyme involved in digesting starch, constitute one well-known adaptation of this kind. The mammalian genome contains multiple copies of this gene, with the number of copies varying between species and even between individual humans. But overall, compared with other primates, humans have an especially large number of amy1 copies. In 2007 geneticists at Arizona State University showed that individuals carrying more copies of amy1 have more amylase in their saliva, thereby allowing them to digest
more starch. The evolution of amy1 thus appears to involve both the number of copies of the gene and the specific changes in its dna sequence. Another famous example of dietary adaptation involves the gene for lactase (lct), an enzyme that allows mammals to digest the carbohydrate lactose, also known as milk sugar. In most species, only nursing infants can process lactose. But around 9,000 years ago—very recently, in evolutionary terms—changes in the human genome produced versions of lct that allowed adults to digest lactose. Modified lct evolved independently in European and African populations, enabling carriers to digest milk from domesticated animals. Today adult descendants of these ancient herders are much more likely to tolerate lactose in their diets than are adults from other parts of the world, including Asia and Latin America, many of whom are lactose-intolerant as a result of having the ancestral primate version of the gene. Lct is not the only gene known to be evolving in humans right now. The chimp genome project identified 15 others in the process of shifting away from a version that was perfectly normal in our ape ancestors and that works fine in other mammals but, in that old form, is associated with diseases such as Alzheimer’s and cancer in modern humans. Several of these disorders afflict humans alone or occur at higher rates in humans than in other primates. Scientists are currently researching the functions of the genes involved and are attempting to establish why the ancestral versions of these genes became maladaptive in us. These studies could help medical practitioners identify those patients who have a higher chance of getting one of these life-threatening diseases, in hopes of helping them stave off illness. The studies may also help researchers identify and develop new treatments.
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With the good comes the bad Battling disease so we can pass our genes along to future generations has been a constant refrain in the evolution of humans, as in all species. Nowhere is this struggle more evident than in the immune system. When researchers examine the human genome for evidence of positive selection, the top candidates are frequently involved in immunity. It is not surprising that evolution tinkers so much with these genes: in the absence of antibiotics and vaccines, the most likely obstacle to individuals passing along their genes would probably be a life-threatening infection that strikes before the end of their childbearing years. Further accelerating the evolution of the immune system is the constant adaptation of pathogens to our defenses, leading to an evolutionary arms race between microbes and hosts. Records of these struggles are left in our dna. This is particularly true for retroviruses, such as hiv, that survive and propagate by inserting their genetic material into our genomes. Human dna is littered with copies of these short retroviral genomes, many from viruses that caused diseases millions of years ago and that may no longer circulate. Over time the retroviral sequences accumulate random mutations just as any other sequence does,
The story of what made us human is probably not going to focus on changes in our protein building blocks but rather on how evolution assembled these blocks in new ways by changing when and where in the body different genes turn on and off. so that the different copies are similar but not identical. By examining the amount of divergence among these copies, researchers can use molecular clock techniques to date the original retroviral infection. The scars of these ancient infections are also visible in the host immune system genes that constantly adapt to fight the ever evolving retroviruses. pterv1 is one such relic virus. In modern humans, a protein called trim5αα works to prevent pterv1 and related retroviruses from replicating. Genetic evidence suggests that a pterv1 epidemic plagued ancient chimpanzees, gorillas and humans living in Africa about four million 58
years ago. To figure out how different primates re-sponded to pterv1, in 2007 researchers at the Fred Hutchinson Cancer Research Center in Seattle used the many randomly mutated copies of pterv1 in the chimpanzee genome to reconstruct the original pterv1 sequence and re-create this ancient retrovirus. They then performed experiments to see how well the human and great ape versions of the trim5α gene could restrict the activity of the resurrected pterv1 virus. Their results indicate that a single change in human trim5α most likely enabled our ancestors to fight pterv1 infection more effectively than our primate cousins could. (Additional changes in human trim5α may have evolved in response to a related retrovirus.) Other primates have their own sets of changes win trim5α, probably reflecting retroviral battles that their predecessors won. Defeating one type of retrovirus does not necessarily guarantee continued success against others, however. Although changes in human trim5α may have helped us survive pterv1, these same shifts make it much harder for up to fight hiv. This finding is helping researchers to understand why hiv infection leads to aids in humans but not in nonhuman primates. Clearly, evolution can take one step forward and two steps back. Sometimes scientific research feels the same way. We have identified many exciting candidates for explaining the genetic basis of distinctive human traits. In most cases, though, we know only the basics about the function of these genome sequences. The gaps in our knowledge are especially large for regions such as har1 and har2 that do not encode proteins. These rapidly evolving, uniquely human sequences do point to a way forward. The story of what made us human is probably not going to focus on changes in our protein building blocks but rather on how evolution assembled these blocks in new ways by changing when and where in the body different genes turn on and off. Experimental and computational studies now under way in thousands of labs around the world promise to elucidate what is going on in the 98.5 percent of our genome that does not code for proteins. It is looking less and less like junk every day.
Despite our best efforts, we will still have to make do with a partial and often confusing picture of human evolution. It’s impossible for us to ever determine exactly how we evolved. But with the information from these different fields, we may be able to determine how the mind functions, how human culture flourished, and how language developed in addition to better understanding human-specific diseases.
References Articles: Carroll, Sean B. “Genetics and the Making of Homo sapiens.” Nature 422 (2003): 849-857. Pollard, Katherine S. “What Makes Us Human?” Scientific American 20 Apr. 2009: 44-49. Rubin, John. “What Makes Us Human?” PBS Online, PBS, 1 Jan. 2008. Web. 8 Jan. 2011. Photos: thundafunda.com brittanica.com pardon.pl Tech. Sgt. Mike R. Smith, National Guard Bureau Ken McCagh, Daily News Fernando Turmo, Global Giving The Walt Disney Company Nancy Mohrbacher Michael Neugebauer Still from The Chimp (1932) calxibe.com Charles Wiles animalpicturesforkids.info baraza.wildlifedirect.org Will Foster Cover of Adventures on the Planet of the Apes Still from The Ape Man Michael Neugebauer
This book was designed by Megan Nadkarni at Sam Fox School of Design & Visual Arts at Washington University in St. Louis. Typefaces used include Acropolis, Din, and Mercury. Printed on an IKON CPP 500.