How losing important sections of DNA made us modern man

The other: It is quite clear that these creatures are not us. The uprightness of our walk, our big and wise minds and a long list of other qualities distinguish us sharply from them. What were the key events in evolution that set us apart as humans? Why did they happen and how? Anthropologists and evolutionary biologists have been grappling with these questions for decades. Recently, they often use modern genetic methods to try to crack the mystery. We found that some of the most important characteristics of humans, markers that distinguish us from those closest to us, did not appear as a result of the addition of genes as one might have expected, but rather from a loss: the disappearance of key segments of DNA.

Several research laboratories, including my own, have located some DNA segments that were lost over time when they compared the genomes of humans with those of other mammals and even of ancient human species: Neanderthals and lesser-known relatives known as Denisovans. We learned that during the eight million years that have passed since our lineage split from the chimpanzees, several DNA "switches" that activate important genes during development were removed from the genome of our ancestors. The Neanderthals share the lack with us, so it's clear that the extinction event happened early in our evolution.

In fact, the loss of these DNA sequences is related to the traits that most characterize humans: large brains, upright walking and special mating habits. (The last part of the project led me, as part of my experiments, to acquire a surprising amount of knowledge about the structure of the monkey's penis.)

Losers

I first developed a special interest in human evolution during my years as a doctoral student in the well-known anthropologist's laboratory S. Owen Lovejoy from Kent State University. So I learned about the difference between male and female skeletons of our extinct ancestors. I wanted to continue this type of work to learn what changed in our genes and developmental processes as humans progressed along the evolutionary path. Fortunately for me, I was accepted for a postdoctoral position in the laboratory of David Kingsleyat Stanford University which also focused on exactly the type of questions that fascinated me.

Among other work, Kingsley's lab identified DNA changes involved in the evolution of stingray fish. Among other things, the researchers found that a missing segment of DNA in freshwater stingray fish is responsible for the disappearance of the rear spiny fins in these species. The lost piece of DNA contained a "switch" that was necessary for the activation of a gene associated with the development of the posterior part of the spine at the right time and in the right place.

If this kind of process happened in stingrays, why doesn't it happen in humans as well? It is therefore reasonable to assume that minute changes in the time and place where genes are activated during embryonic development can serve as one of the ways in which our genome has evolved to create our unique anatomy.

Inspired by the fish example, we decided to see if we could find important switches that have disappeared in humans in the course of evolution. Today, thanks to the availability of the complete sequences of the human genome and the genome of great apes and the computerized tools that make it possible to analyze the data, such studies are possible. Our group in Kingsley's lab is a companyGil Bejarnofrom Stanford University specializing in computational science [who received his doctorate from the Hebrew University of Jerusalem - the editors] and a Ph.D. Corey McLean to design the experiments.

Due to the enormous size of the genome, finding missing switches is not an easy task. Our genome contains 3.2 billion bases (the letters that make up the DNA sequence), and about 100 million of them are different from those of the chimpanzees. How can such an experiment be carried out? To understand our approach a little background is needed.

We know that DNA segments that play important roles in the genome of any creature are preserved with great precision throughout evolution. It is also known that the closer two species are to each other, the greater the similarity in their genetic sequence. In chimpanzees and humans, for example, only a tiny part of the genome, less than 99 percent, contains the instructions for making proteins. This important part is 96% the same in both sexes. whereas the extensive regions that do not contain protein-coding genes are XNUMX% identical.

Search the junk pile

We were specifically interested in the extensive area, segments that we previously considered "junk" DNA, but now we know that they are full of switches that turn genes on and off. The operation of these switches is essential. Although almost all body cells in humans contain the same 20,000 genes, they are not activated everywhere and at all times. Only certain genes are needed to build a brain, for example, and other genes are needed to build bones or hair. Despite the differences between chimpanzees and humans, the basic structure of their bodies is similar. It is therefore no wonder that the wide area containing switches is very similar.

And the differences are the important ones for us. In particular, we wanted to find sequences that have been conserved during evolution in many species (which suggests that these sequences are important), but are not found in humans. For this purpose, our partners from the field of genomic computing first of all compared the genomes of chimpanzees, roach monkeys and mice. They located hundreds of pieces of DNA that remained almost unchanged in the three species. The next step was to scan this list for bits that are not in the human genome and therefore disappeared at some point after our lineage split from the chimpanzees. We found more than 500 such pieces.

Which one to explore? Because we wanted to find switches that could alter mammalian development, we focused on deficiencies located near known genes that we know are involved in development. One of my colleagues dealt with a missing segment located near a gene that regulates the generation of nerve cells; Another worked on a missing segment near a gene involved in skeleton formation.

And as for me, due to my interest in the differences between male and female body shapes, I was enthusiastic about a missing section located near the garden of Androgen receptor. Androgens, such as Testosterone, are hormones necessary for the development of characteristics unique to men. They are formed in the testicles and travel in the bloodstream. In response, cells that produce androgen receptors will be responsible for the development of a male pattern: for example, the formation of a penis instead of a clitoris or (later in life) the growth of a beard and an enlarged throat cavity for a deep voice.

First of all, we had to check if those pieces of DNA indeed contain activating switches. For this purpose, we extracted them from the DNA of chimpanzees and mice and connected them to a gene that turns cells blue, but only on the condition that the gene is activated. We injected the attached piece of DNA into fertilized mouse egg cells to see if any parts of the embryos would stain blue, a sign of a functioning switch in the piece of DNA, and if so, where.

Zachary Junction

The results I got were exciting: they did show that I was working on a real activator switch for the androgen receptor, which is missing in humans. in mouse embryos, Genital lumps (which develop into a penis or a clitoris) were colored blue, and also Sebaceous glands and points found on the surface of the mouse in places where sensory bristles ("whiskers") are formed. It is known that in all these tissues the androgen receptors respond to testosterone. With a more discerning eye, I saw that the color in the developing genitalia was located in the places where spikes made of hard protein later form on the mouse's penis as eyes.

Humans of course do not have sensory bristles in their whiskers nor spiny fins, but they are found in many mammals such as mice, monkeys and chimpanzees. It is also known that a lack of testosterone causes short sensory bristles in male rodents and the absence of stings in the penis of rodents and monkeys. Penile stings and sensory bristles can also be absent as a result of the loss of an essential DNA switch responsible for the production of androgen receptors in these tissues.

We believe that the loss of penile stings is one of the most far-reaching changes on our evolutionary path.

While I was working on my experiments, others were working on the missing pieces they chose to investigate, and the results they got were just as interesting. The doctoral student Alex Pollan He found that his piece of DNA activates the neural gene located near it, exactly at the points where the brain develops. The gene is involved in a key process: it helps kill the excess nerve cells that are created during embryonic development. This discovery raises an intriguing idea: since the human brain is much larger than the chimpanzee brain (1,400 cc vs. 400 cc), is it possible that the loss of this switch contributed to the evolutionary acceleration by releasing the brakes on brain growth?

and Ahan B. Indjian, who was then a postdoctoral student in the lab, found that his switch activates the gene involved in skeletal growth: in the development of the hind limbs, especially the toes. The toes, from the second to the fifth, are shorter in humans compared to apes and mice, a change that improves the adaptation of the foot structure to upright walking.

It is not difficult to understand how brain and bone switches fit the pattern of human evolution: big brain and walking on two feet. The loss of sensory bristles is easy to explain by the fact that we no longer grope in the dark with our noses in search of food or capture prey, but use our hands in the daylight to find food. But although their importance may be less, it is not clear why it is better for us to exist without them.

Sensitive relationships

The story of penile stings is harder to explain intuitively, but it may have the most impact, and it fits wonderfully with the story of our species' adaptation to its environment. We believe that the loss of the stingers is one of a series of changes that collectively had a far-reaching effect on our evolutionary path. These genetic changes have reshaped the way we mate, the physical appearance of males and females, the kinship between partners and the way we care for our offspring.

The stings are made ofKeratin, the material from which the nails are made. They are found in many mammals, including monkeys, rodents, cats, bats and opossums. They appear in a variety of forms, from simple microscopic cones to stings and multi-pointed spurs. They can be used in a variety of roles, depending on the biological sex: intensifying stimulation, inducing ovulation, removing sperm left by other males, or damaging the female's vaginal wall to prevent her interest in mating with other males.

The mating time of proboscis monkeys is remarkably short: usually less than ten seconds in chimpanzees. Experiments done in the distant past in monkeys showed that removing the stingers could extend the mating time by two thirds. From such observations we can assume that the loss of penile stings was one of the changes in humans that extended the duration of sexual intercourse and thus deepened the intimacy between the couple compared to our ancestors with stings. It sounds nice, but it can also serve our species evolutionarily.

Our reproductive strategy is not similar to that of the great apes. In the monkeys, the intense competition between the males is at the center. In chimpanzees and bonobos, males compete with each other for the right to mate with as many fertile females as possible. They produce an enormous amount of sperm cells (chimpanzee testicles are three times larger than humans), have penile stings, and like all great apes and apes have deadly fangs to deter competitors. They leave the rearing of the offspring exclusively to the females. So for them, successful mating is a full commitment: pregnancy, breastfeeding and growing the womb until independence. Females do not conceive again until offspring are weaned.

different people. They form a fairly loyal couple bond. The males usually help raise the offspring, which allows for earlier weaning and a faster rate of reproduction. The competition between the men is not fierce. We believe that simultaneously with the loss of the stings in the penis, other characteristics related to power competition (such as dangerous fangs) were also lost and other characteristics were added that promoted attachment and cooperation between the couple.

Walking on two legs, as Lujoy suggested, could be one of these characteristics. Most likely the male's help in the early stages of rearing the offspring was initially based on obtaining foods rich in fat and proteins, such as larvae, insects and small vertebrates, an action that required vigorous searching and carrying of the food. To do this, the males had to go far with free hands for carrying, and this probably provided the initial selective advantage for walking on two legs.

Loss of genes and gain of traits

and moreover. Cooperation and the fulfillment of needs allowed parents to raise offspring that depend on them for a longer period of time and thus to extend the period of childhood even after weaning. This allowed a longer time for learning and therefore accelerated the benefit of a large and agile brain. These changes may therefore have set the stage for brain evolution.

If we continue in this line of thought, then the stories about the three missing DNA segments, which seem seemingly unrelated to each other, are intertwined in one and the same story.

When I arrived at Kingsley's laboratory I did not expect this turn in my work. Little did I imagine that I would be delving into soggy 40s texts on the structure of the genitalia in mammals. In my laboratory we continue to research in this direction. But we are looking at other genetic and developmental changes that had far-reaching consequences: the evolutionary design of the shape of the delicate bones in the human wrist, which qualified them for making tools.

We will probably never know many details about that distant history, no matter how eager we may be to discover them. But even if we cannot be sure about the question of why certain evolutionary changes happened, with the help of the tools of modern molecular biology we can now face the question of how they happened - a fateful and exciting question in itself.