The "speech gene" FOXP2 turned out to be a high-level regulator. Language gene Gene responsible for speech

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Article for the competition "bio / mol / text": Speech is considered a unique trait peculiar only to humans, but other species also have their own forms of communication, which are based on mechanisms similar to human ones. The similarity is largely determined by the closeness of their genetic basis. The hero of this story is a gene FOXP2- called the "speech genome", but it was from people that it acquired such properties that allowed us to become who we are.

"Bio / mol / text" -2015

The Science for Life Extension Foundation is the sponsor of the Best Article on the Mechanisms of Aging and Longevity nomination. The People's Choice Award was sponsored by Helicon.

The sponsors of the competition are the 3D Bioprinting Solutions laboratory for biotechnological research and the Visual Science studio of scientific graphics, animation and modeling.

In the late 1980s, in a school in West London, teachers noticed that seven children who had speech problems were growing up in the same family. This family (in the scientific literature it appears under the name "KE family") was of Pakistani origin, and a closer examination of its members revealed that in three generations of this family there are people who have problems with speech (Fig. 1). They had difficulties with the pronunciation of words, and sometimes the words were replaced by similar ones in sound. If they spoke Russian, then, for example, instead of the word "oven" they would pronounce "flow". The family was found to have mild, low severity, disorders and more severe forms of speech disorders, seriously impairing communication.

Picture 1. Genealogical tree of the KE family. In three generations of the family, people were found to have speech problems of varying severity. (blacked-out shapes)... They were representatives of both sexes: men (squares) and women (circles).

Given that speech problems have been passed down from generation to generation, doctors who have studied the KE family have suggested that some genetic disorder is at the root of these disorders. Difficulties with speech occurred in both sexes, which means that the “guilty” gene was not on the sex chromosomes (X or Y), but on autosomes. As a result, a team of geneticists from Oxford was able to determine that the desired gene is located on the 7th chromosome. Also, the KE family was studied by linguists - for example, Myrna Gopnik ( Myrna gopnik) from Canada. They suggested that speech disorders in the family are caused by a mutation in the "grammatical gene", which is responsible for syntactically and grammatically correct construction of phrases. Later it was found that the representatives of the studied family had problems not only with syntax and articulation, but in general experienced difficulties in controlling the language and lips. This disorder was later named verbal dyspraxia... The brain of the representatives of the KE family did not know how to accurately control the lips and tongue, as a result of which the words were not pronounced correctly ( cm. box).

How speech occurs in the brain

For the formation of normal speech, the coordinated work of two parts of the cerebral cortex is important - Broca's zones in the frontal cortex and Wernicke zones in the temporal lobe. Broca's zone is responsible for the pronunciation of words, for the motor component of speech. If this part of the brain is damaged, for example, with a stroke, the patient develops motor aphasia- inability to pronounce words or a pronounced limitation in the number of spoken words. If the pathological process affects Wernicke's zone, then this leads to sensory aphasia (aphasia Wernicke) - impaired understanding of speech. A patient with severe sensory aphasia does not understand what other people are saying to him: instead of words, he hears an unclear set of sounds. Representatives of the KE family developed problems with the functioning of the frontal cortex, that is, their speech disorders were a variant of motor aphasia.

The gene that Oxford scientists localized on chromosome 7 was later named FOXP2 (Forkhead box protein P2). It is active in the brain as well as in the lungs and intestines. FOXP2 is one of the many regulatory genes belonging to the family FOX-genes. On the basis of the gene, a transcription factor is synthesized, which is not directly involved in biochemical processes, but can interact with tens and hundreds of promoter regions of other genes and regulate their activity. Changing this gene leads to the fact that all genes "obeying" it will not do their job correctly.

What does FOXP2 gene say?

Everything FOX-genes regulate the normal development of the embryo, and FOXP2- not an exception. The expression of this gene is increased in the progenitor cells of the brain neurons, and when turned off FOXP2 their occurrence is suppressed. One of the ways that FOXP2 regulates cell maturation, is its control over gene activity SRPX2 (sushi repeat-containing protein X-linked 2), which encodes the structure of the protein peroxiredoxin. Through this gene FOXP2 controls the formation of synapses (synaptogenesis), and decreased activity SRPX2 leads to disruption of synaptogenesis and sound communication in mice.

During the evolutionary process, DNA can change randomly, that is, mutations occur in the molecule. Substitutions in the nucleotide sequence in which the structure of the protein does not change are called synonymous... If a substitution in DNA leads to the appearance of a new amino acid in a protein, then such a substitution is considered nonsynonymous and, as a rule, leads to a change in the function of the protein. When studying molecular evolution FOXP2 interesting circumstances were revealed. This gene is one of the most conservative in human DNA, and the largest changes in FOXP2 within the group of primates occurred after the divergence of the evolutionary lines of humans and chimpanzees - our closest relatives. In rhesus monkeys, gorillas, and chimpanzees, only synonymous substitutions in DNA occurred, and only orangutans had one nonsynonymous substitution (Fig. 2). The high conservatism of the gene structure is associated with the many functions that it regulates and their importance for the developing organism. If mutation FOXP2 such forms of the protein encoded by it arose that did not perform the necessary functions completely, this led to the abnormal development of the embryo and its death. Such mutations could not be passed on to the next generation. Two nonsynonymous substitutions that occurred in a person in a gene FOXP2, apparently, gave our ancestors a serious advantage and entrenched themselves in the genome Homo sapiens.

Figure 2. Evolution of a gene FOXP2. The numbers indicated with a line represent the number of substitutions (mutations) in the DNA sequence: the number of nonsynonymous substitutions is given to the line, and the number of synonymous substitutions after the line. In humans, for example, in comparison with chimpanzees, only two changes occurred, but both were nonsynonymous, that is, they led to a qualitative change in the gene. At the same time, 131 synonymous substitutions and only one nonsynonymous substitution occurred in mice.

Bird trills

If a person has a gene FOXP2 is associated with speech, then in other animals it must regulate similar functions. The first thing that comes to mind is birdsong. You may think that birds always sing the same way, but they are not. Singing is one of the tools to attract the attention of representatives of your species. Singing in the presence of females is called directed, and when males sing "for the soul" or for the purpose of training, then such singing is considered undirected... Behind the light and airy trills of songbirds is the clear and well-coordinated work of their nervous system and the machinery of genes that control its functioning.

The zebra finch ( Taeniopygia guttata) (Fig. 3), and the most studied (in terms of singing) part of the bird's brain is area X (area X), located in the striatum - striatum. The birds, whose song changes with the season, show changes in area X throughout the year. It increases during the breeding season, when the bird needs to conquer the female, and becomes smaller when this period ends. The increase in the X region in birds is directly related to the formation of new synapses for mastering new singing techniques.

Figure 4. Expression FoxP2. When directed (directed) singing, the level of gene expression is higher than with undirected (undirected)... This connection may indicate that harmonious activity of the nervous system is required for more harmonious singing, which is provided by FoxP2.

The zebra finch is not a bird whose song changes with the seasons; it is more characterized by a combination of directional and non-directional singing throughout the year. To study activity FoxP2 not during the development of the brain, but with different types of its activity, scientists conducted the following experiment. Several males of zebra finches sang "for the soul", in the absence of females and males of their own species, while other males sang to females, which were constantly changed by the experimenters. There was also a control group of birds that did not sing. During the experiment, audio recording of bird songs was carried out. It turned out that with undirected singing, the level of expression FoxP2 decreases, and with directional remains high (Fig. 4). However, with undirected singing, there was a greater variety of melodies than with directional singing. This difference can be explained by the level of expression FoxP2: The more intense the expression, the more orderly and stable the bird's songs become. It is worth noting that the scientists who conducted the study did not indicate the reason why the finches that did not sing had an expression level FoxP2 remained high.

Another study on zebra finches clarified the role of FoxP2 in the formation of singing abilities. It was determined that there are two populations of neurons in the X region. The first population consists of neurons with high activity FoxP2, the second - with low. As the bird grows up, the number of neurons from the first population decreases (Fig. 5), and with it the variety of bird songs decreases. However, the expression level FoxP2 still increases with directional singing, which indicates a biphasic effect of this gene. During growing up, neurons in which are actively expressed FoxP2, are responsible for the final formation of the X region. After reaching functional maturity, the increase in gene activity occurs during directional singing, which requires coherence and clarity. If you break the expression FoxP2 in area X, then when learning to sing, birds reproduce melodies with errors and not in full. Disruption of the “speech gene” also disrupts the normal variability of singing motives in young and adult birds. This is due to the disruption of dopaminergic modulation of the activity of the X region. FoxP2 participates in the formation of dopamine receptors on the dendrites of neurons in the X region and the signal transmission system from them into the cell, which means that a change in its expression leads to problems in this circuit. In more detail the similarity of the genetic mechanisms of the formation of bird songs and human speech is described in the article by Elena Naimark on "Elements".

Figure 5. Age differences in the number of neurons belonging to different populations in zebra finches. The population of neurons actively expressing FoxP2, gradually decreases with increasing age. The size of the population of "low-activity" neurons is not related to the age of the bird.

Big-headed Mickey Mouse

Modern methods of molecular biology make it possible to “transplant” genes from one organism to another. It is possible to introduce a human FOXP2 into the gene of another animal in order to understand what advantages this variant of the gene gives in the work of the brain.

The very first work in this direction was carried out in 2009. The research object of scientists was mice, in the genome of which the "mouse" variant Foxp2 replaced by "humanized". It is necessary to clarify that it was not the whole gene that changed, but only two nucleotides that determine the difference in the amino acid sequences of the FOXP2 protein from humans and chimpanzees (the mouse protein differs in one more amino acid). All mice with a "human" gene ( hum) survived and were able to leave offspring. The study compared another type of mice ( wt / ko), in which one of the alleles of the gene Foxp2 belonged to an ordinary mouse ( wild type, wt), and the other was a gene variant found in people with speech impairments ( ko). Also studied "normal" mice, and their results were taken as a conditional norm, but were not taken into account in the discussion.

Figure 6. Dopamine levels in the brains of two groups of mice. Hum mice produce less dopamine in different brain structures compared to wt / ko mice.

Humanized mice showed less exploratory activity than wt / ko mice, but at the same time they participated in group contacts more often. In hum mice, in comparison with the wt / ko group, the level of dopamine, the main “motivating” neurotransmitter, was lower in the brain (Fig. 6). There may be a direct link between dopamine levels and exploratory behavior. The reduced dopamine level in hum mice does not form a motivation for the action of such a force and in such an amount as in wt / ko mice. However, it cannot be said that this is bad. In a sense, hum mice can be said to be less fussy and more collected than their wt / ko cousins. In the striatum (a region rich in dopamine neurons) of hum mice, neurons with longer dendrites - processes that transmit information to other cells - were found. Apart from this, the normal human variant Foxp2 increased neuroplasticity in the brain of hum mice. In general, it seems that the “humanization” of the gene streamlined the functioning of the nervous system of hum mice due to more fine tuning of dopaminergic signal transmission.

Another study by a group of European scientists analyzed different types of learning in mice with a human version. Foxp2... There are two fundamentally different types of training - declarative and procedural... Declarative learning requires conscious control over each action, awareness of its meaning. Procedural learning is accomplished through automatic repetition of actions. In the experiment, ordinary mice and mice with a human variant Foxp2 had to go through the maze, using different types of training. Procedural learning occurred when the rodents were required to always turn right to find a treat. In another variant of the task, which involved declarative learning, the treat was always placed in the same part of the maze, but since the mice were launched into it from different sides, they had to take this circumstance into account and remember the location of the reward, relying on additional external signals.

When learning types were examined separately, there was no difference between the two groups of mice: both groups performed about the same task. Hum mice gained a clear advantage over ordinary mice if they first learned in a “declarative” maze, and then moved on to a “procedural” one. Apparently, the transition from declarative to procedural learning improves in humanized mice. According to the experimenters, such a feature of the functioning of the nervous system of mice can demonstrate changes in the human brain that have adapted it to speech. Scientists, in particular, believe that in hum mice, the balance of declarative and procedural learning is biased towards procedural, while in ordinary mice it is vice versa. The phenomenon of rapid switching from declarative to procedural learning with an increase in the success of the latter is called by researchers proceduralization.

This effect of amino acid substitutions in Foxp2 is possible because this protein regulates a large number of genes and ultimately controls the development of the striatum, the brain region required for learning. Human version Foxp2 in striatal neurons, it lengthens dendrites, and also increases long-term depression ( long-term depression- V.L.) conduction of a signal in neurons and neuroplasticity, which also has a beneficial effect on the activity of the brain. Apparently, stronger connections are formed in the brain, which perform their function more stable. The result of these changes is a better integration of learning processes into the pattern of behavior. Proceduralization does not speed up the "automation" of the skill, otherwise hum-mice would have a big advantage over conventional ones already at the stage of isolated testing of different types of training. It allows you to learn a skill and subsequently learn similar actions at an accelerated pace, at an automatic level, that is, it “treads a path” for other information. In principle, this is very similar to teaching speech, when a child, having mastered the basics, begins to learn on his own, literally on the go, including constructing words on his own.

Perhaps the most notable contribution FOXP2 in the evolutionary history of our species is proceduralization of our training that simplified not only speech. It could have led to more efficient creation of tools, the development of methods of cooking and the emergence of other important components of our culture. If you give free rein to your imagination, then you can imagine that modern civilization arose thanks to two amino acid substitutions in the FOXP2 protein, and this is a rather exciting idea.

Literature

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American scientists used transgenic tissue cultures to study the work of the FOXP2 speech gene. They evaluated the expression of all genes in cell cultures with human and simian variants of FOXP2. It was possible to identify a whole complex of genes, the work of which is somehow associated with FOXP2. Eight of them are direct targets of this gene, and more than a hundred other genes are indirectly regulated. This entire genetic cascade is responsible for the normal development of the brain, especially those parts on which the coordination of movements and, including the articulation of speech, depend. Scientists have suggested that the rapid evolution of the FOXP2 gene was associated with the evolution of other genes from this cascade.

Among the genes that distinguish humans from other primates, a special role is assigned to the FOXP2 gene (see the review article Will the genetic basis of the mind be deciphered ?, "Elements", 09.10.2006). This famous gene, according to classical ideas, is responsible for human speech. That is, for that special trait that is inherent exclusively in humans. In mammals, this gene is very conserved, for example, the mouse FOXP2 gene differs from the monkey analog by only one amino acid substitution. And the human version of the FOXP2 gene differs from that of the chimpanzee by two amino acid substitutions. This implies the rapid evolution of the FOXP2 gene in the human line. It is assumed that driving selection acted in the direction of improving the function of this particular gene, and as a result, a person acquired the ability to articulate speech. Therefore, it is easy to understand how much attention scientists pay to the study of this gene.

Previous work has identified a number of diseases that are caused by mutations in the FOXP2 gene; these diseases are manifested in speech defects and the structure of the craniofacial region, in mental disability. Hence, we can conclude that the FOXP2 gene is associated with speech. A notable study of the functions of FOXP2 was carried out by Wolfgang Enard and colleagues at the Max Planck Institute in Leipzig, Germany. German scientists bred transgenic mice carrying human FOXP2. The transgenic mice grew up quite healthy, although in some traits they differed from normal mice. Among the main differences, the authors of the study named the elongation of dendrites and an increase in synaptic plasticity in the basal nuclei, or ganglia of the brain, a decrease in dopamine levels, a decrease in exploratory activity and a decrease in the timbre of the voice.

A new study by American specialists from the University of California, Los Angeles, Yerkes National Primatology Research Center and the Department of Pathology and Medicine of Emory University (Atlanta) shows how diverse the connections and functions of the FOXP2 gene really are. They are clearly not limited to the formation of articulate speech, but, rather, are aimed at coordinating a whole cascade of genes and proteins necessary for the development and normal functioning of the brain.

This work is based on a variety of different biochemical and genetic techniques, which together are designed to reveal differences in the composition of genes and proteins associated with the expression of FOXP2 in humans and chimpanzees. First, cultures of neural progenitors were transgenically derived, in which a chimpanzee analogue with corresponding two amino acid substitutions worked instead of human FOXP2. Then the expression of all (!) Genes in normal and transgenic cells was compared. It is clear that the difference in gene expression in two cultures in this case should be attributed only to differences in the work of the FOXP2 gene (naturally, the researchers had at their disposal several transgenic repeats for statistics).

In general, chimpanzee FOXP2 is produced more actively, that is, there is more of it in cells than in humans. It was also found that in cultures with chimpanzee and human FOXP2, the expression of 116 genes differs: in the human variant, 61 genes show increased expression, and 55 genes - decreased expression. Some of these genes are direct target genes for FOXP2, that is, FOXP2 binds directly to the promoters of these genes. For others, FOXP2 is an indirect regulator, acting indirectly through other regulators. Indeed, the promoters of some selected genes from this array bind differently to the human and chimpanzee FOXP2 (this part of the experiment was done using immunological tests with luminous proteins).

As a result of the analysis of the structure of individual genes and their mutual influence on each other, scientists obtained a diagram of a whole block of genetic relationships (see below the diagram from the article under discussion). This scheme includes those genes that somehow change their work depending on the modification of FOXP2. Another cascade of genes was obtained, also linked to FOXP2, but working in the same way with both modifications of this gene.

Previously, it was shown that genes DLX5 and SYT4 - and they are important nodes in this circuit - regulate the development and normal functioning of the brain. It is now clear that these genes represent only part of the entire regulatory network. This regulatory cascade includes some genes, mutations in which cause severe hereditary diseases. These include, for example, the PPP2R2B gene (see below right in the diagram, above the EBF3 gene), defects in which lead to a special form of cerebellar ataxia. The symptom of this disease is speech disorder.

Also in this scheme there are genes for which, as for FOXP2, the action of driving selection in the human line has been proven. These genes include the AMT gene. The differences in the nucleotide sequences of this gene from monkey analogs are very significant. It can be assumed that there was a coupled accelerated evolution of the selective part of this cascade, which led to important "human" changes in the functioning of the brain.

All of these results were obtained in cultures of germline precursors of nerve cells, but not formed cells of adult individuals. It is clear that completely different proteins can be expressed in "adult" cells, which actually work in a person speaking, under the guidance of a different regulatory cascade. Scientists, anticipating this obvious objection, conducted additional research. They evaluated the expression of genes in tissues of various parts of the brain in adults and chimpanzees and compared with the results obtained for the corresponding cell cultures (cell cultures with the chimpanzee gene were compared with the brain of an adult chimpanzee, and cultures with a human gene were compared with human brain). It turned out that the pattern of gene expression in cell cultures is extremely similar to that in the tissues of the "adult" brain. The similarity was found to be high for both human cells and cells with the chimpanzee gene.

The work carried out once again confirmed that the differences between humans and monkeys cannot be explained only by differences in protein-coding sequences. The most important "human" traits, including those associated with brain function, are formed due to changes in regulation and quantitative differences in gene expression. The most important regulatory factor that alters the expression of a whole complex of genes is the FOXP2 gene. Among the many functions of this regulator gene is the control of the work of the muscles involved in the formation of speech. But, despite its established reputation as the leader of speech, the FOXP2 gene performs other equally important tasks in brain cells.