Current status of the human genome project. Abstract: International project "Human Genome". Comparison of data from general and private projects

Corresponding Member of the Russian Academy of Sciences L. KISELEV, Chairman of the Scientific Council of the Russian National Program "Human Genome" of the Ministry of Science and Technology of Russia.

Achievement of the century: after eight years of work by many research groups, it was possible to accurately determine 97 million nucleotide pairs and their location in the DNA helix that stores the complete hereditary information of the microscopic worm Caenorhabditis elegans.

This is what the heroine of the grand experiment, the nematode C. elegans, looks like under high magnification. Its true size is 1 mm.

Fragments of deciphering the genome structure are viewed.

Employees of the Sanger Center in Cambridge who took part in deciphering the C. elegans genome.

The figure shows the structure of C. elegans: 1 - the so-called ventricle, 2 - small intestine, 3 - ovary, 4 - eggs.

Machines used to sequence the C. elegans genome.

Since ancient times, people have thought about the question of how the characteristics of living organisms are transmitted to their descendants. A variety of theories were developed, sometimes very ingenious and not contradicting many facts, but the truly material basis of heredity began to become clear only 45 years ago, when J. Watson and F. Crick deciphered the structure of DNA. It turned out that this giant molecule twisted into a double rope contains all the characteristics of an organism.

Each strand of a DNA molecule is a chain of four types of units - nucleotides, repeated in different orders. Nucleotides are usually counted in pairs, like boots or gloves, because in a DNA molecule there are two chains and their nucleotides are cross-linked in pairs. Four types of nucleotides, four “letters” make it possible to write down a genetic “text” that is read by the mechanism of protein synthesis in a living cell. A group of three consecutive nucleotides, acting through a rather complex transmission mechanism, forces the ribosome - an intracellular particle involved in protein synthesis - to pick up a certain amino acid from the cytoplasm, the next three nucleotides, through intermediaries, “dictate” to the ribosome which amino acid to put in the next place in the protein chain , and so a protein molecule is gradually formed. And proteins are not only the main building material of a living organism: many of them - enzymes - control processes in the cell. So the information recorded in DNA in triplets of nucleotide pairs is enough to build a new organism with all its features.

Long before the discovery of all these (and many other) molecular subtleties, while studying the transmission of hereditary traits during crossing, biologists realized that each trait is determined by a separate particle, which was called the genome. It was possible to understand that genes lie in the nucleus of the cell, in the chromosomes. And after the discovery of the role of DNA and the mechanism of protein synthesis, it became clear that a gene is a section of a DNA chain on which the structure of a certain protein molecule is recorded. Some genes have only 800 base pairs, others have about a million. A person has about 80-90 thousand genes. The set of genes inherent in an organism is called its genome.

In recent years, a new branch of genetics has emerged - genomics, which studies not individual genes, but entire genomes. Advances in molecular biology and genetic engineering have given humans the ability to read genetic texts - first of viruses, bacteria, and yeast. And now, for the first time, it has been possible to completely read the genome of a multicellular animal - a microscopic worm about a millimeter long that lives in the soil. The decoding of the human genome is in full swing in laboratories around the world. This international program was launched in 1989, at the same time, thanks to the initiative and energy of the outstanding biologist, the late academician A. A. Baev, Russia also joined the program. In February of this year, the “Human Genome-99” conference was held in Chernogolovka near Moscow, dedicated to the tenth anniversary of the beginning of this work and the memory of its initiator, who led the Russian part of the program for the first five years. Now in different countries of the world, in laboratories that have divided the “front of work” among themselves (in total, about three billion nucleotide pairs need to be read), more than a million nucleotide pairs are deciphered every day, and the pace of work is accelerating.

The published article talks about the successes and prospects of genomics.

How it was

Biology, by general recognition, took a dominant position among the natural sciences in the second half of the outgoing century. At the end of 1998, this point of view received new powerful confirmation: eight years of work was completed to decipher the structure of the genome (the set of genes and intergenic regions) of a multicellular animal, a roundworm, a nematode, which has the Latin name Caenorhabditis elegans.

Although this is a very small worm, more like a worm, it is, without any exaggeration, the beginning of a new era in biology. The genome of this nematode consists of 97 million DNA nucleotide pairs, rounded to 0.1 billion pairs. The human genome, according to most estimates, is 3 billion nucleotide pairs. The difference is 30 times. However, it was this work in question that finally convinced even the most inveterate skeptics that deciphering the structure of the entire human genome is not only possible, but also achievable in the coming years.

Decoding, or, as biologists call it, sequencing, of the C. elegans genome was carried out as a joint project by two research groups: from the Center for Genome Sequencing at the University of Washington (USA) and the Sanger Center (Cambridge, England). The journal Science, dated December 11, 1998, published a series of articles detailing this truly monumental work. The number of authors of this work is so large that the journal did not publish a list, referring readers to the Internet, and simply called the authors “The C. elegans Sequencer Consortium.” This is probably the first time in the history of science that a discovery, from the very beginning and with the consent of the authors, seems to become anonymous. This work can rightfully be considered iconic, symbolizing “industrial” science. A visible symbol of modern science, where huge financial investments, robotization, automation, management, discipline, coordination played a decisive role, pushing aside at this stage the role of intelligence and creative ingenuity of individual project participants.

It would be fair to recall who first drew attention to C. elegans as an object of study. In the mid-1960s, Sydney Brenner, an outstanding molecular geneticist who made enormous contributions to the study of the genetic code, worked in the famous laboratory of molecular biology in Cambridge in England (it included Nobel laureates F. Crick, J. Kendrew, M. Perutz, A. . Klug and other famous researchers). After working on the code, S. Brenner decided to devote himself to studying the nervous system and the ways of its origin and formation. He noticed a tiny worm (C. elegans), consisting of only 959 cells, of which 302 were neurons, nerve cells. A remarkable property of the nematode was its transparency: you can monitor the behavior and fate of each individual cell! Sydney Brenner attracted talented young researchers to his “nematode” laboratory, who made many important discoveries. Many of them became the “engine” of the sequencing project, which was implemented at the Sanger Center.

Naturally, it is impossible to decipher a genome of such gigantic dimensions as that of the named nematode (let me remind you: 97 million pairs of DNA nucleotides) without a huge amount of preparatory work. It was mostly completed by 1989. First, a physical map of the entire nematode genome was constructed. The physical map represents small sections of DNA of a known structure (markers), located at certain distances from one another.

And in 1990, sequencing itself began. Its rate in 1992 was 1 million base pairs per year. If this rate were maintained, it would take almost 100 years to decipher the entire genome! It was possible to speed up the work in the simplest way - the number of researchers in each center increased to approximately 100. People and machines worked around the clock, the productivity of each machine was increased due to a larger number of tracks on which DNA fragments were sequenced.

As the nucleotide sequence of C. elegans DNA was revealed, two misconceptions had to be dispelled. Firstly, it turned out that she has not 15 thousand genes, as originally thought, but 19099. Secondly, the hope that the genes are concentrated in the middle of the chromosomes, and become very thin towards the ends, was only partly justified; the genes are distributed along the chromosomes relatively evenly, although there are still more of them in the central part.

If in yeast the function of half the genes in the genome is unknown (the so-called silent genes), then in the worm this share is even greater: out of 19 thousand genes, 12 thousand remain mysterious.

Two research centers that solved a task of enormous complexity gained unique experience - both in the process of obtaining the results themselves and in the course of their comprehension, storage and processing. It's no surprise, then, that both groups recently said they were ready to solve the structure of half the human genome, a job 15 times larger than what was done on the worm genome. And it's real. Let me give you these numbers. Currently, more than 1 million nucleotide pairs are deciphered worldwide per day—as many as in all of 1992. The speed has increased 365 times!

The significance of sequencing the nematode genome, of course, goes far beyond what can be called a testing ground for deciphering the human genome. C. elegans is the first multicellular organism whose genome has been revealed almost completely. It may be recalled that two years ago the first genome of a eukaryotic organism was deciphered - yeast, that is, an organism whose cells contain formed nuclei. (Eukaryotes include all higher animals and plants, as well as unicellular and multicellular algae, fungi and protozoa. Yeast, according to biological taxonomy, belongs to unicellular fungi.) In other words, in two years the path from the genome of a unicellular to the genome of a multicellular organism was passed. Biologists know that this is a gigantic distance on the ladder of evolution and, therefore, on the path of complication of genomes. It's amazing how incredibly quickly this path has been covered!

By now comparing the genomes of bacteria (more than 20 genomes are already known) with the genomes of yeast and nematodes, evolutionary biologists have a unique opportunity to compare not individual genes or even gene ensembles, but entire genomes - such an opportunity in biology simply did not exist ten years ago, but this was just a dream. In the coming months, when the enormous volumes of information received begin to be assimilated and comprehended, we should expect the emergence of fundamentally new concepts in the theory of biological evolution.

New data and perspectives in biology

What are the immediate prospects now opening up in biology? Here are the most obvious ones. Humans have only five times more genes than nematodes. Therefore, at least about 20% of the human genome must have relatives among the now known C. elegans genes. This greatly facilitates the search for new human genes. The functions of yet unknown nematode genes are much easier to study than similar genes in humans. The genes of the worm can be easily changed (mutated), while simultaneously monitoring changes in the structure of the gene and the properties of the organism. In this way, it is possible to identify the biological role of gene products (that is, proteins) in the worm, and then extrapolate these data to other organisms, primarily to humans. Or you can suppress the activity of genes (for example, using special molecules of specific RNA) and monitor how the behavior of the organism changes. This path also reveals the functions of unknown genes and, of course, will greatly influence the study of the human genome and other higher organisms.

Biologists are always intrigued by the question: how is the work of genes regulated? Although we know a lot about this, our knowledge is obtained mainly from individual genes, and therefore does not provide a complete picture of the regulation of the functioning of the entire genome as a whole. Nowadays the technology of so-called biochips (by analogy with microchips in cybernetics) is rapidly developing. These are small plates on which, using precision instruments, microscopic amounts of DNA fragments are applied at thousands of points, at strictly fixed distances from one another.

Such a microarray could, for example, contain all 19,000 genes of a nematode - one gene at each point - and could be used to determine which genes are working in a given worm cell and which are silent. Of course, it is possible to use cells at any stage of development and from any part of the worm's body. As a result, the researcher will receive information about the functional state of all genes of any cell at any stage of worm development. The experiments have already begun, and there is every reason to have no doubt that we will learn about the first results this year. This will be a truly revolutionary breakthrough for developmental biology. In addition to perfect microtechnology, these experiments also require perfect computer programs so that the actual data obtained can be comprehended and interpreted.

The biochip technique opens up a new strategy for solving one of the most difficult problems in biology - the problem of interconnection of signaling regulatory pathways. The main difficulty is that the interaction of the protein products of many genes occurs simultaneously, and the combinations of proteins change not only in time, but also in cellular space. As a result, studying individual genes and their products (which has been mostly done until now) has often been ineffective.

What is the ratio of regions in the C. elegans genome that code for protein synthesis (exons) and those that do not (introns)? Computer analysis shows that exons and introns occupy approximately equal shares in the nematode genome (27 and 26%), the rest (47%) are repeats, intergenic regions, etc., that is, DNA with functions unknown to science.

If we compare the yeast genome and the human genome using these data, it becomes obvious that during evolution the proportion of coding regions per genome decreases sharply: in yeast it is very high, and in humans it is very small. This has been known for a relatively long time, but now these relationships have acquired not only a quantitative measure, but also a structural basis. We come, at first glance, to a rather paradoxical conclusion. Evolution in eukaryotes from lower to higher forms is associated with a “dilution” of the genome - per unit length of DNA there is less and less information about the structure of proteins and RNA and more and more information “about nothing,” that is, incomprehensible and unreadable for us.

This is one of the great mysteries of biological evolution. There are a variety of assumptions about “extra” DNA, often directly opposite in meaning. Many years ago, F. Crick, one of the fathers of the DNA double helix, called this “extra” DNA “selfish” or “junk.” He considered it a cost of evolution that accumulates in the genome as a result of incomplete perfection of genetic processes, “ballast,” a payment for the perfection of the rest of the genome. It is possible that some small "egoistic" fraction in the DNA of humans and other higher organisms is indeed of this type. However, it has now become clear that the bulk of "selfish" DNA is preserved in evolution and even increases because it gives its owners evolutionary advantages.

A classic example of “selfish” DNA is the so-called short repeats of DNA sections (Alu elements, alpha satellite DNA, and others). As it turned out in recent years, their structure is absolutely conservative, that is, mutations that violate the “rules” established by nature for these elements are not preserved, they are “rejected” by selection. Structural consistency is a powerful argument in favor of the idea that such regions are not "selfish" at all, but are a very important part of DNA for the life of a species. Another thing is that we do not yet know what exactly its biological role is.

Human genomics and the future of humanity

Today, almost every day the general press of the United States and Western European countries reports on more and more new human genes and their functions or connections with certain diseases. In 1998, the US government spent $300 million on a project to study the human genome, and private companies, primarily biotechnology, even more than this amount. At least 20 of the most developed countries in the world have their own national programs for studying the human genome.

Now the genomic program has already proven its outstanding importance for the development of our knowledge about life in general. It is interesting to remember how these ideas were received when they were initially discussed and the program was created. The scientific community was then divided into two parts: one greeted the idea of ​​a genomic program with enthusiasm, while the other - with skepticism, mistrust and suspicion. Among this second group were prominent scientists, such as Nobel Prize winner David Baltimore, one of the fathers of reverse transcription. The main objection of opponents: the creation of a genomic program is aimed at attracting large financial resources (and thereby taking them away from other areas of biology), and not at obtaining new knowledge.

The past 10 years have shown that the new level of understanding of biological problems that has emerged as a result of the results of genomic research has already more than justified all organizational efforts and financial investments. Moreover, it became clear that the information obtained could not be obtained simply by the support of hundreds of individual research groups, even highly qualified and well-equipped ones. But at the same time, we now understand that 10 years ago it was difficult to assess the depth and breadth of the influence of human genomics (the field of biology that studies genomes) on biology as a whole.

One of the strong arguments against the genomic program was also that the “industrialization” of biology would lead to the loss of its creative potential, the disappearance of “small” biology - small research groups led by talented, original-minded researchers who would not want to go to work in “sequencing factories.” DNA." Among the scientists who held such views was, for example, Bruce Alberts, the current president of the US National Academy.

It is certainly true that one of the main links in the genomic program is sequencing, which on such a gigantic scale is achievable only by industrial methods. However, the very achievement of this phase required great intellectual effort, new instrumentation, new methods, and new research tools. This required the creative effort of individual scientists. And this creativity as a necessary component of industrialization was underestimated by skeptics.

The ideas and methods developed in human genomics have universal significance and are applicable to solving a huge range of biological problems that are far removed from the human genome itself. Let us recall only some of them.

For genome mapping (a mandatory stage of research preceding sequencing), highly effective techniques have been developed, such as radiation hybrids (collections of cells in which different small fragments of each chromosome have been removed), or artificial yeast chromosomes containing huge fragments of human chromosomes, bacterial and phage vectors , allowing the propagation (cloning) of human DNA fragments... New technologies together made it possible to construct a detailed map of the human genome, which by the end of 1998 contained more than 30 thousand markers that created a detailed map of the genome.

Sequencing technology has progressed rapidly (for example, multichannel capillary electrophoresis has dramatically accelerated and reduced the cost of deciphering the primary structure of DNA), and computer programs have been created that make it possible to find genes in deciphered DNA sections.

It is important to emphasize that all this instrumentation and methodology can be fully applied to any genomes, from bacteria to farm animals and plants.

Perhaps, microbiology has currently benefited most from the development of human genomics, since more than 20 complete genomes have already been deciphered, including the causative agents of many dangerous diseases (tuberculosis, typhus, stomach ulcers and others). It is safe to say that without the genomic project, these data would have been obtained much later and, probably, in a much smaller volume. Knowledge of the genomic structure of pathogenic bacteria is very important for the creation of vaccines (and rationally designed ones), for diagnostics and other medical purposes. Genomics also has a great influence on medical genetics, which deals with the gene diagnosis of hereditary diseases and the genetic basis of predisposition to many common diseases.

Private companies that financed the project received thousands of patents for new genes, DNA fragments, new techniques and
etc. This has a kind of double effect. On the one hand, genomics is receiving a powerful additional impetus for development, and on the other, the commercialization of genomics leads to the fact that many of the information received are classified by companies, especially on the genomics of microorganisms, forcing some scientists to do the same.

Genomic methods of personal identification, developed and practically implemented in human genomics, have far-reaching consequences for society. Indeed, criminology has at its disposal an absolutely reliable method of proving a person’s guilt or innocence. For such a genomic analysis (often called genomic fingerprinting), one drop of blood, one hair, a piece of nail, traces of sweat, semen, saliva, dandruff, etc. are enough. Today in the world, thousands of people are convicted or acquitted only on the basis of genomic analysis. Identification of people's family ties now solves the problems of paternity and maternity, the problems of inheriting rights and property between relatives and non-relatives, if these issues arise.

The invasion of genomics into human history, ethnography, linguistics and other areas of human knowledge is of great interest. Biological sciences such as anthropology and paleontology, and the theory of evolution are already involved in this orbit. Many controversial issues in the history of civilizations in ancient times will most likely be resolved not by historians, but by genome scientists. For example, it is already clear (although this work began quite recently) that the origin and migration of many peoples in the world (and, of course, including in Russia) will most easily be traced using genomic markers that provide quantitative and unambiguous information.

The Human Genome Program, as already mentioned, is a universal human program. Each laboratory, no matter what country it is located in, makes its contribution to it. And as soon as someone manages to discover the structure of a new gene, this information immediately enters the International Data Bank, accessible to every researcher. Without exaggeration, it must be said that the development of computer science plays a truly enormous role in the success of the global genomic program.

In Russia, about 100 research groups are working under this program. There are original works that have received international recognition (last year alone, program participants published more than 70 articles in international journals). For the first five years, the main thing in the program was mapping, in other words, the placement of “identification marks,” an attempt to understand where, in what part of the chromosome, scientists are located - just as geographers of the past compiled the first maps of the Earth.

Now the focus has shifted, and researchers are trying to determine the functions of individual genes. This is a transition from “industrial science,” which requires primarily equipment, to intellectual science. And at this stage we hope to succeed. “Mass production” was inaccessible to us primarily due to lack of funding, and besides, Russian scientists never liked mechanical work.

Looking back 10 years later, the importance of genomics has been underestimated, and its impact has been much broader and deeper than expected. It is also clear that the creation of the genome project was a huge achievement for biologists around the world, since for the first time it placed biology among those sciences that are capable of implementing global projects with a huge not only general scientific, but also practical output. Comparing the genomic project with the space exploration project (the program of flights to the Moon and Mars, the program of near-Earth stations), it is clear that the biological program, being many times cheaper, is not only not inferior in its impact on people’s lives, but ultimately, will certainly surpass the achievements of space programs, since it will influence almost every inhabitant of the Earth in the 21st century.

The 1000 Genomes Project is a large-scale project launched in January 2008, the initial goal of which was to completely sequence (decipher) the genomes of thousands of people - representatives of different races and nationalities. Teams of researchers from the USA, Great Britain, Italy, Peru, Kenya, Nigeria, China and Japan took part in the work. Deciphering the complete human genome is not an easy task, since

it contains 20-25 thousand active genes. However, this makes up a very small part of all genes - the rest belong to the so-called “junk DNA”, that is, they do not encode any proteins. But taking into account “junk DNA”, the volume of the human genome reaches about 3 billion nucleotide pairs.

The large-scale work done by scientists is directly related to all people living on the planet. During the work, scientists were able to decipher the genomes of 2,504 people representing 26 different populations. Researchers have been able to determine exactly what variations each human gene has - and this may help to understand what genetic disease it is responsible for. Scientists have already managed to understand

which genetic variations are responsible for the occurrence of diseases of the heart muscle (myocardium), chronic inflammation of the gastrointestinal tract, sickle cell anemia (disorders of hemoglobin structure) or Gaucher disease - a hereditary disease that leads to the accumulation of complex fats in many tissues, including the spleen, liver, kidneys, lungs, brain and bone marrow.

The data obtained as a result of the work available on the project website. On the night from Tuesday to Wednesday in the journal Nature came out two articles, presenting the latest overview data that was obtained during the work. A correspondent for the science department of Gazeta.Ru managed to communicate with three scientists who were directly involved in deciphering the human genome: Paul Flicek (one of the leading researchers of the 1000 Genomes Project and leading researcher at the European Molecular Physics Laboratory), Gonzalo Abecasis (professor at the University of Michigan ) and Adam Oton (Albert Einstein Medical College of New York) and talk with them about future plans and the possibility of practical application of the results of seven years of work.

— In 2008, when the project was just beginning, scientists were given a goal: to decipher the complete genome of a thousand people. In October 2012, the journal Nature announced that 1,092 genomes had been deciphered. To date, by the end of the project, you have managed to sequence 2,504 genomes. Tell me, how did you manage to exceed the plan so significantly?

Paul Flickek: We were able to sequence so many samples because the technologies that enable genome sequencing have advanced significantly in recent years. That is why we were able to obtain approximately 25 times more data than was originally stated.

Gonzalo Abecasis: We should not forget about the cost of such an analysis. If in 2008 a complete decoding of the human genome cost about $100 thousand, now this amount is less than $2 thousand.

— On September 30, it was announced that the final stage of the project was completed. Can we talk about complete completion of the work or are you going to move on and set new goals for yourself?

Paul Flickek: We face many new goals regarding both DNA sequencing and the search for relationships between variations in different genes, the occurrence of genetic diseases and other human characteristics. The completion of the 1000 Genomes Project is truly the culmination of efforts we began 15 years ago to create an open source resource for human gene information.

In the future, we plan to expand the base of our research and involve people representing a larger number of populations from different countries of the world - there are populations in Africa, Asia and the Middle East that are not included in the study. Now this work will be carried out within the framework of the project.

Gonzalo Abecasis: In addition, in the future we plan to focus on how variations in each gene affect the course of a specific disease. To do this, it is necessary to study as many cases of the course and treatment of such diseases as possible.

Adam Oton: We're also going to test how genetic variations affect a person's phenotype.

— Is it possible to apply the information you received in practice now? Or does it still require additional time to process the data?

Gonzalo Abecasis: The information we have collected is useful for researchers now - it helps scientists understand how many variations each gene has, and which of these variations are responsible for the occurrence of different diseases. True, some time will still pass before this knowledge leads to the development of new drugs.

Adam Oton: The information is actively used, and not only by doctors, but by everyone in general. If a researcher - from any field - wants to know what functions a gene performs, how distributed it is among the world's population, or what some part of the genome looks like, he can easily obtain this information.

Paul Flickek: I think the main practical benefit of our data is that it helps map the distribution of a gene on the planet.

Let’s say a person originally from Asia is diagnosed with a rare genetic disease. But the data from our project says that a variation of a certain gene (that causes this disease) is only in the DNA of Africans. This will mean that the roots of the disease must be sought in changes in another gene. We also have a better understanding of how different human populations migrated around the world.

— If you were asked to describe the results of seven years of work in one or two sentences, what would you say?

Paul Flickek: The most important result of the 1000 Genomes Project is the compilation of a catalog of variations in human genes and the analysis of methods and tools that can be used for further sequencing of the human genome. This catalog is completely free and open access.

Gonzalo Abecasis: We now have a catalog of different versions of every DNA sequence, and therefore every gene, and from which we can determine which regions of the planet each version is found in. We can use this information to reduce the time and cost required to sequence other people's genomes.

Adam Oton: The 1000 Genomes Project has greatly improved our understanding of how human gene variation is distributed around the world.

— And the last question: how do you feel now that the seven-year project in which you were directly involved has been completed?

Gonzalo Abecasis: I feel it's time to take on the next challenge: put what we've learned into practice and start developing treatments for genetic diseases.

Adam Otton: The project became the basis for further work: everyone wants to know what gene variations can tell us about various diseases. The next few years promise to be very busy.

Paul Flickek: I'm a little sad. Our project was a clear demonstration of what modern technology is capable of. The project has constantly grown and developed along with the development of technology, and its completion truly marks the end of an era. Although, of course, the use of data obtained by deciphering DNA is just beginning, and it seems to me that the 1000 Genomes Project can be compared to a child who still has time to grow.

“Human Genome” thirty years after the launch of the international scientific program

In 1988, the state scientific and technical program “Human Genome” was officially launched in the USSR by Resolution of the Council of Ministers of the USSR “On measures to accelerate work in the field of the human genome” No. 1060. Academician A.A. Baev took the initiative to sequence the human genome. - scientist in the field of genetic engineering.
We were not the only ones who were puzzled by the problems of genetics during this period. The Human Genome program has become international and at the same time the largest and most ambitious in the entire centuries-old history of science!

How it all began
In 1988, in the United States, two geneticists William Gilbert and James Watson came up with the idea of ​​​​conducting the Human Genome scientific program. The main goal of the program was to decipher the human genome, as well as other species: bacteria, yeast, mice. It was planned that the discovery of the human genome would be the key to understanding many processes of evolution, would make it possible to study many genetic diseases, and also to develop effective medications. Unexpectedly, the idea was supported by the US Department of Energy and the US National Institutes of Health, which agreed to sponsor the program. Its cost was initially planned at 3 billion US dollars.
It was largely possible to receive such high support thanks to the status of James Watson, who in 1962 received the Nobel Prize for the discovery of the double helix of DNA, after which he built one of the best biological laboratories in the world, Cold Spring Harbor, which still exists today.
In subsequent years, other countries joined the program: Great Britain, France, Germany, Italy and other countries (23 states in total; the human genome consists of 23 pairs of chromosomes). It is worth noting that the USSR did not skimp on financing the development of genetics. Already in the first year, 20 million US dollars were allocated to the Human Genome Program for the reconstruction of laboratories, the development of new equipment and the creation of an internal information base. Each country was allocated its own chromosome for research, and the work was in full swing.

First results
It should be noted that the difficult political and economic situation in Russia in the 90s also had a negative impact on the development of science. Less and less funding began to be allocated to the Human Genome program, so Russia’s participation in the international program was almost reduced to nothing. At the same time, scientists from the Institute of Cytology and Genetics SB RAS (Novosibirsk, Akademgorodok) made a great contribution to the development of genetics. Under the guidance of Professor N.A. Kolchanov. Several computer programs have been created to search for regulatory regions of the genome.
At the same time, government funding in the United States during this period was also reduced, and scientific work slowed down. In fact, the program was saved by the private laboratory “Celera Genomics”, headed by biologist J. Venter. For comparison: a program funded by governments around the world could decipher a million nucleotide pairs per year, Celera Genomics deciphered at least 10 million nucleotide pairs per day. This allowed significant progress to be made in a short time.
And another important discovery of Celera Genomics was a new method of deciphering the genome, later called the method of random sequencing by fragmentation. With its help, it was possible to simulate a complete genome in a computer program, having only its fragments physically available. Using this method, it was possible for the first time to identify the genome of the bacterium Haemophilus in-fluenzae Rd. Then, in 1996, the genome of a yeast cell was revealed using the same method, and already in 1998 it was possible to decipher the genome of a multicellular organism - the earthworm Caenorhabolits elegans.

Discovery of the human genome
The human genome is a set of genetic material, complete with a haploid set of chromosomes (23 pairs) in an organism cell.
In 2000, the US President and British Prime Minister made an ambitious announcement to decipher the human genome and end the genetic race. As it turned out later, the statement was premature, since at that time the genome was only 90% studied. Perhaps the unreliable punishment of government officials was due to the fact that states no longer had the opportunity to invest huge amounts of money in the Human Genome program or simply sought to appropriate the laurels of a long-term international program to raise their political ratings.
In fact, the final version of the human genome was deciphered in 2003, that is, only 15 years ago! At the same time, some gaps in knowledge of the human genetic code remain even today. Scientists continue to work on the secrets of the Homo sapiens genome.

What did this discovery give us?

Medicine . Deciphering human DNA first of all opened up new frontiers of medicine. After this discovery, it was possible to scientifically confirm that a huge number of diseases are hereditary and are transmitted from ancestors to descendants. In addition, understanding the dynamics and signs of the disease from the point of view of molecular biology has made it possible to create progressive medical methods and tools. This process continues today, thanks to which more and more effective methods of treating pathologies such as oncology, diabetes, Alzheimer's disease and many others are emerging.
Knowledge of the secrets of the DNA molecule gives the green light to the development of “personalized medicine,” which has been discussed for many years. The term means applying individual treatment methods to each patient. The era of standard treatment methods is becoming a thing of the past. This is due to the fact that we now know that every person is genetically unique; in nature, there are no people with the same set of genes! This means that there are no universal medical remedies.
Biologists have been able to identify the role and significance of many genes in the human body. Today, extensive medical practice includes DNA tests that analyze the genes of a specific person. A genetic test allows us to identify a person’s predisposition to common pathologies, the risks and characteristics of his body. With such in-depth data, doctors have the opportunity to select an individual treatment and prevention program for the patient.

It turned out that genes play a huge role in many aspects of human life. Genetic tests are also used in such areas of medicine as nutrition, cosmetology, and trichology. For example, the tendency to be overweight, the characteristics of metabolism and assimilation of food are also genetically determined. Now scientists are actively studying the influence of genes on a person’s character and talents.

Forensics. Knowledge of the uniqueness of each person marked the beginning of a new milestone in the development of criminology. Now even one left hair, a drop of blood, a fragment of skin, saliva and any biomaterial of a criminal can serve to identify his DNA. Moreover, under proper storage conditions, DNA can be stored for a very long time. For example, modern scientists study the DNA of the remains of soldiers who died during the Great Patriotic War and compare them with DNA fragments from letters from the front. Moreover, research is even being conducted on the mummies of Egyptian pharaohs, who have lain in the ground for more than three thousand years.

Story. Until the deciphering of the human genome, we received most of the data about past civilizations from archaeological excavations. Since the discovery of the genome, historians have been able to understand many historical events more deeply. For example, it was possible to analyze the process of settling Europe: it turned out that at first it was populated by people from the Middle East who had dark hair and eyes, gradually the genes mutated, as a result of which, in the Middle Ages, people with blond hair and blue eyes already lived in Europe. This is largely due to the climatic conditions under which the body progressively mutates.
An interesting find was a mutation in the lactase gene (this is an enzyme that breaks down milk sugar - lactose). Initially, people did not have the ability to break down lactose throughout their lives, but could only do this in infancy (that is, they could only consume milk during the infant's lactation period). A gradual mutation of the gene led to the fact that people began to drink milk throughout their lives. The mutation first spread in the population about 4 thousand years ago, which means that people became able to consume milk not immediately after they domesticated animals. Probably, people did not immediately understand that they could eat animal milk. As a result, this habit has taken root so thoroughly that today 70% of the planet’s population has the genetic ability to consume animal milk throughout their lives. At the same time, for example, residents of China practically do not consume milk and do not have the ability to break down lactose. Hysterically, it turned out that in this territory, due to the monsoon climate, cattle breeding was poorly developed. Thus, the lactase gene mutation did not develop in these peoples.

Summing up, we can conclude that the scientific program “Human Genome” had significant results and made a serious contribution to the development of genetics and other sciences. According to unofficial data, 3 billion US dollars of budget funds were spent on its implementation and the same amount was financed by private companies. In total, the program cost about $6 billion. Thanks to the contributions of private corporations, the program was completed even earlier than planned and fully met the expectations of its creators. But we cannot stop there, so the era of scientific discoveries in genetics continues...

Introduction……………………………………………………………..3

"Human Genome". Project milestones…………………..….…...…..4 Chromosome maps. Approaches to their compilation………………..6 Development of new technologies………………………….……...9

4. Results. Challenges for the future…………………………….10

Conclusion………………………………………………………15

References……………………………………………………………..16

Introduction.

The international Human Genome Project was launched in 1988 under the leadership of James Watson under the auspices of the US National Health Organization. This is one of the most time-consuming and expensive projects in the history of science. If in 1990 about $60 million was spent on it in total, then in 1998 the US government alone spent $253 million, and private companies - even more. The project involves several thousand scientists from more than 20 countries. Since 1989, Russia has also participated in it, where about 100 groups are working on the project. All human chromosomes are divided between the participating countries, and Russia received the 3rd, 13th and 19th chromosomes for research.

The goal of the project is to determine the sequence of bases in all DNA molecules in human cells. At the same time, the localization of all genes must be established, which would help to clarify the causes of hereditary diseases and thereby open the way to their treatment. Several thousand scientists specializing in biology, chemistry, mathematics, physics and technology are involved in the project.

A working draft of the genome structure was released in 2000, the complete genome was released in 2003, however, even today additional analysis of some sections has not yet been completed. Beyond its obvious fundamental importance, determining the structure of human genes is an important step for the development of new medicines and other aspects of healthcare.

While the goal of the Human Genome Project is to understand the genome of the human species, the project has also focused on several other organisms, including bacteria such as Escherichia coli, insects such as the fruit fly, and mammals such as the mouse.

"Human Genome". Project milestones.

There are 23 pairs of chromosomes in any human somatic cell. Each of them contains one DNA molecule. The length of all 46 molecules is almost 2 m.

An adult human has approximately 5 x 1013 cells, so the total length of DNA molecules in the body is 1011 km (almost a thousand times the distance from the Earth to the Sun). There are 3.2 billion pairs of nucleotides in the DNA molecules of one human cell. Each nucleotide consists of a carbohydrate, a phosphate, and a nitrogenous base. Carbohydrates and phosphates are the same in all nucleotides, and there are four nitrogenous bases. Thus, the language of genetic records is four-letter, and if the base is its “letter,” then the “words” are the order of amino acids in the proteins encoded by the genes. In addition to the composition of proteins in the genome (the totality of genes in a single set of chromosomes), other interesting information is recorded. We can say that Nature (as a result of evolution or God's providence) encoded in DNA instructions on how cells survive, respond to external influences, prevent “breakdowns”, in other words, how the body develops and ages.

Any violation of these instructions leads to mutations, and if they occur in germ cells (sperm or eggs), the mutations are passed on to subsequent generations, threatening the existence of that species.

How to visualize 3 billion bases? To reproduce the information contained in the DNA of a single cell, even in the smallest print (as in telephone directories), would require a thousand 1000-page books!

How many genes, that is, sequences of nucleotides encoding proteins, are there in human DNA? Back in 1996, it was believed that a person has about 100 thousand genes; now bioinformatics experts suggest that there are no more than 40 thousand genes in the human genome, and they account for only 3% of the total length of cell DNA, and the functional role of the rest 97% not yet installed.

The goal of the project is to find out the sequences of nitrogenous bases and gene positions (mapping) in every DNA molecule of every human cell, which would reveal the causes of hereditary diseases and ways to treat them. The project employs thousands of specialists from all over the world: biologists, chemists, mathematicians, physicists and technicians.

The project consists of five main stages:

Drawing up a map on which genes are marked that are separated from each other by no more than 2 million bases, in the language of specialists, with a resolution of 2 MB (Megabase - from the English word “base” - base); completion of physical maps of each chromosome at 0.1 Mb resolution; obtaining a map of the entire genome in the form of a set of individually described clones (0.005 Mb); by 2004, complete DNA sequencing (1 base resolution); mapping at 1-base resolution all human genes (by 2005). Once these steps are completed, the researchers will determine the full functions of the genes, as well as the biological and medical applications of the results.

2. Chromosome maps. Approaches to their compilation.

During the project, three types of chromosome maps are created: genetic, physical and sequence (from the English sequence - sequence). Identifying all the genes present in the genome and establishing the distances between them means localizing each gene on the chromosomes. Such genetic maps, in addition to inventorying genes and indicating their positions, will answer the extremely important question of how genes determine certain characteristics of an organism. After all, many traits depend on several genes, often located on different chromosomes, and knowledge of the position of each of them will make it possible to understand how the differentiation (specialization) of cells, organs and tissues occurs, as well as to more successfully treat genetic diseases. In the 20s and 30s, when the chromosomal theory of heredity was being created, elucidation of the position of each gene led to the fact that on the genetic maps of first Drosophila, and then corn and a number of other species, it was possible to mark special points, as they said then, “genetic markers” » chromosomes. Analysis of their position in chromosomes helped provide new information to the genetic maps of human chromosomes. The first data on the position of individual genes appeared back in the 60s. Since then, they have multiplied like an avalanche, and the position of tens of thousands of genes is now known. Three years ago, the resolution of the genetic map was 10 Mb (for some areas - even 5 Mb).

Another area of ​​research is the compilation of physical maps of chromosomes. Back in the 60s, cytogeneticists began to stain chromosomes to identify special transverse bands on them. After staining, the stripes were visible under a microscope. It was possible to establish a correspondence between the bands and genes, which made it possible to study chromosomes in a new way. Later, they learned to “tag” DNA molecules (with radioactive or fluorescent labels) and monitor the attachment of these tags to chromosomes, which significantly increased the resolution of their structure: up to 2 Mb, and then up to 0.1 Mb (during cell division). In the 70s, they learned to “cut” DNA into sections with special (restriction) enzymes that recognize short stretches of DNA in which information is written in the form of palindromes - combinations that are read the same from beginning to end and from end to beginning. This is how restriction maps of chromosomes arose. The use of modern physical and chemical methods and means has improved the resolution of physical maps hundreds of times.

Finally, the development of sequencing methods (the study of the exact sequences of nucleotides in DNA) opened the way to the creation of sequence maps with a record resolution to date (these maps will indicate the position of all nucleotides in DNA).

The number of chromosomes and their length vary among different species. Bacterial cells have only one chromosome. Thus, the genome size of the bacterium Mycoplasma genitalium is 0.58 Mb (it contains 470 genes), the bacterium Escherichia coli has 4200 genes (4.2 Mb) in its genome, and the plant Arabidopsis thaliana has 25 thousand genes. (100 Mb), the fruit fly Drosophila melanogaster has 10 thousand genes (120 Mb). The DNA of mice and humans contains 50-60 thousand genes (3000 MB). Of course, the same methods are not applicable to compiling maps of such different objects, so two approaches that differ in methodology are used:

The first involves dividing the DNA into small pieces and, studying them individually, reconstructing the entire structure. This approach has been successful in drawing up relatively simple maps; For more complex genomes, the second approach is more effective. In these cases, it is unwise to divide the DNA molecule into short pieces convenient for detailed study. There would be so many of them that the confusion in the sequences would be insoluble. Therefore, when starting to decipher, the molecule is divided, on the contrary, into the longest pieces possible and they are compared in the hope of finding common terminal sections. If this succeeds, the pieces are combined, after which the procedure is repeated. With the improvement of computers and mathematical methods of information processing, the pieces combined according to this principle become larger and larger, gradually approaching the whole molecule. This approach, in particular, made it possible to compile a genetic map of the 3rd chromosome of Drosophila. Development of new technologies.

An important aspect of the Human Genome Project is the development of new research methods. Even before the start of the project, a number of very effective methods of cytogenetic research were developed (now they are called first-generation methods). Among them: the creation and use of the mentioned restriction enzymes; obtaining hybrid molecules, cloning them and transferring DNA sections using vectors into donor cells (most often E. coli or yeast); DNA synthesis on messenger RNA templates; gene sequencing; copying genes using special devices; methods of analysis and classification of DNA molecules by density, mass, structure.

In the last 4-5 years, thanks to the Human Genome Project, new methods have been developed (second generation methods), in which almost all processes are fully automated. Why did this direction become central? The smallest chromosome of human cells contains DNA 50 Mb long, the largest (chromosome 1) - 250 Mb. Until 1996, the largest section of DNA isolated from chromosomes using reagents had a length of 0.35 Mb, and with the best equipment their structure was deciphered at a speed of 0.05-0.1 Mb per year at a cost of 1-2 dollars per base . In other words, this work alone would require approximately 30 thousand days (almost a century) and 3 billion dollars.

Improvements in technology by 1998 increased productivity to 0.1 MB per day (36.5 MB per year) and lowered the cost to $0.5 per base. The use of new electromechanical devices, which also consume less reagents, made it possible already in 1999 to speed up work another 5 times (by 2003, the decryption speed was up to 500 MB per year) and reduce the cost to $0.25 per base ( even cheaper for human DNA).

4. Results. Tasks for the future.

Over the past six years, international data banks on nucleotide sequences in the DNA of different organisms (GenBank / EMBL / pBJ) and on amino acid sequences in proteins (PIR / SwissPot) have been created. Any specialist can use the information collected there for research purposes. The decision to make information freely available was not an easy one. Scientists, lawyers, and legislators have worked hard to prevent the intentions of commercial firms to patent all the results of the project and turn this field of science into a business.

Deciphered genomes.

1995 - bacterium Hemophilus influenza;.

1996 - yeast cell (6 thousand genes, 12.5 Mb);

1998 - roundworm Caenorhabditis elegans (19 thousand genes, 97 MB).

The main results of the completed stages of the project are presented in the journal Science (1998. Vol. 282, No. 5396, R. 2012-2042).

Studied human genes. During 1995, the length of human DNA sections with an established base sequence increased almost 10 times. But although progress was evident, the result for the year was less than 0.001% of what was to be done. But by July 1998, almost 9% of the genome had been deciphered, and then new significant results appeared every month. By studying a large number of gene copies in the form of cDNA and comparing their sequences with sections of chromosomal DNA, by November 1998, 30,261 genes (about half the genome) had been deciphered.

Functions of genes. The results of the completed part of the project make it possible to judge the role of two-thirds of genes in the formation and functioning of organs and tissues of the human body. It turned out that the most genes are needed to form the brain and maintain its activity, and the least to create red blood cells - only 8.

The data obtained made it possible for the first time to realistically assess the functions of genes in the human body.

In the world, every hundredth child is born with some kind of hereditary defect. To date, about 10 thousand different human diseases are known, more than 3 thousand of which are hereditary. Mutations have already been identified that are responsible for diseases such as hypertension, diabetes, some types of blindness and deafness, and malignant tumors. Genes responsible for one of the forms of epilepsy, gigantism, etc. have been discovered. Here are some diseases that arise as a result of damage to genes, the structure of which has been completely deciphered:

Chronic granulomatosis; Cystic fibrosis; Wilson's disease; Early breast/ovarian cancer; Emery-Dreyfus muscular dystrophy; Atrophy of the spinal muscles; Albinism of the eye; Alzheimer's disease; Hereditary paralysis; Dystonia.

Other organisms. When the research program for the project was being drawn up, we decided to first test the methods on simpler models. Therefore, at the first stage of the project, 8 different representatives of the world of microorganisms were studied, and by the end of 1998 - already 18 organisms with genome sizes from 1 to 20 Mb. These include representatives of many genera of bacteria: archaebacteria, spirochetes, chlamydobacteria, E. coli, pathogens of pneumonia, syphilis, hemophilia, methane-forming bacteria, mycoplasma, rickettsia, cyanobacteria. As already mentioned, genetic analysis of a single-celled eukaryote, the yeast Saccharomyces cerevisae, and the first multicellular animal, the worm C. elegans, has been completed.

Gene damage and hereditary diseases. Of the 10 thousand known human diseases, about 3 thousand are hereditary diseases. They are not necessarily inherited (passed on to descendants). They are simply caused by disorders of the hereditary apparatus, that is, genes (including in somatic cells, and not just in reproductive cells). Identifying the molecular causes of gene “breakdown” is the most important result of the project. The number of studied disease-causing genes is growing rapidly, and in 3-4 years we will know all 3 thousand genes responsible for certain pathologies. This will help to understand the genetic programs for the development and functioning of the human body, in particular, to understand the causes of cancer and aging. Knowledge of the molecular basis of diseases will help their early diagnosis, and therefore more successful treatment. Targeted supply of drugs to affected cells, replacement of diseased genes with healthy ones, control of metabolism and many other dreams of science fiction writers are turning into real methods of modern medicine before our eyes.

Molecular mechanisms of evolution. Knowing the structure of genomes, scientists will get closer to unraveling the mechanisms of evolution. In particular, such a stage as the division of living beings into prokaryotes and eukaryotes. Until recently, prokaryotes included archaebacteria, which differ in many ways from other representatives of this group of microorganisms, but also consist of only one cell without a separate nucleus, but with a DNA molecule in the form of a double helix. When the genome of archaebacteria was deciphered a year ago, it became clear that this is a separate branch on the evolutionary tree.

Significant progress has been made in the practical field of creating new products for the medical industry and the treatment of human diseases. Currently, the pharmaceutical industry has gained a leading position in the world, which is reflected not only in the volume of industrial production, but also in the financial resources invested in this industry (according to economists, it entered the leading group in terms of the volume of purchase and sale of shares in the securities markets papers). An important novelty was that pharmaceutical companies included in their sphere the development of new varieties of agricultural plants and animals and spend tens of billions of dollars a year on this; they also monopolized the production of household chemicals, additives for construction industry products, etc. Not tens of thousands, but perhaps several hundred thousand highly qualified specialists are employed in the research and industrial sectors of the pharmaceutical industry, and it is in these areas that interest in genomic and genetic engineering research is extremely high.

Taking into account the constant increase in the pace of work, the project managers announced at the end of 1998 that the project would be completed much earlier than planned, and formulated tasks for the near future:

2001 - preliminary analysis of the human genome;

2002 - deciphering the genome of the fruit fly Drosophila melanogaster;

2003 - creation of complete maps of the human genome;

2005 - deciphering the mouse genome using cDNA methods and yeast artificial chromosomes.

In addition to these goals, which are officially included in the international project supported by the United States and several other countries at the government level, some research centers have announced tasks that will be achieved primarily through grants and donations. Thus, scientists from the University of California (Berkeley), the University of Oregon and the F. Hutchinson Center for Cancer Research began deciphering the dog genome.

The main strategic task for the future is to study DNA variations (at the level of individual nucleotides) in different organs and cells of individual individuals and to identify these differences. Typically, single mutations in human DNA occur on average per thousand unchanged bases. Analysis of such variations will make it possible not only to create individual gene portraits and, thereby, treat any diseases, but also to determine differences between populations and high-risk regions, draw conclusions about the need for priority cleanup of territories from certain contaminants, and identify industries that are dangerous for the genomes of personnel . However, along with the rosy expectations of the common good, this grandiose goal also causes quite conscious anxiety among lawyers and human rights activists. In particular, there are objections to the dissemination of genetic information without the permission of those concerned. After all, it’s no secret that today insurance companies are striving to obtain such information by hook or by crook, intending to use this data against those they insure. Companies are unwilling to insure clients with potentially disease-causing genes or charge exorbitant sums for their insurance. Therefore, the US Congress has already passed a number of laws aimed at strictly prohibiting the dissemination of individual genetic information.

What forecasts will come true: optimistic or pessimistic - the near future will show...

Conclusion.

Almost all the goals that the project set for itself were achieved faster than expected. The project to decipher the human genome was completed two years earlier than planned. The project set a reasonable, achievable goal of sequencing 95% of DNA. The researchers not only achieved it, but also exceeded their own predictions and were able to sequence 99.99% of human DNA. The project not only exceeded all goals and previously developed standards, but also continues to improve the results already achieved.

Bibliography

Carson R., Butcher J., Mineka S. Abnormal psychology. – 11th ed. – St. Petersburg: Peter, 2004. – 1167 pp.: ill. – (Series “Masters of Psychology”). Knorre D.G. Biochemistry of nucleic acids // Soros educational journal. 1996 No. 3 pp. 10-11, 1998 No. 8 pp. 30-35. Sekach M.F. Health psychology: a textbook for higher education. – 2nd ed. – M.: Academic project: Gaudeamus, 2005. – 192 p. – (“Gaudeamus”).