Decoding the human genome is an event as important in the history of mankind as the discovery of electricity, the invention of radio or the creation of computers.
A little history. IN 1988 The US National Institutes of Health started a project "Human Genome", headed by a Nobel laureate James Watson. The main goal of the project is to find out the sequence of nucleotide bases in all human DNA molecules and establish localization, i.e. completely map all human genes.
It was planned that work would be carried out to determine the nucleotide sequence of human DNA ( DNA sequencing) must end in 2005. However, after the first year of work, it became clear that the speed of DNA sequencing is very low and it would be impossible to complete the work at such a pace it will take about 100 years.
It became obvious that it was necessary search for new technologies sequencing, creation of new computer technology and original computer programs. It was impossible within a single state, and other countries joined the program.
Large-scale coordinated research began to be carried out under the auspices of an international organization ^ Human Genome Organization (HUGO). Since 1989, Russia has also joined the project. All human chromosomes were divided between the participating countries, and Russia received them for research Chromosomes 3, 13 and 19. Were involved in the project several thousand scientists from 20 countries.
In 1996, worldwide human DNA databanks were created. Any newly determined nucleotide sequence larger than 1 thousand bases had to be made public via the Internet within 24 hours after it was deciphered, otherwise articles with this data were not accepted into scientific journals. Any specialist in the world could use this information.
By early 1998, only about ^3% of the genome. At this time, a private American company from Maryland unexpectedly got involved in the work. Celera Genomics under the direction of Craig Venter, which announced that it would complete its work 4 years ahead of the international consortium.
A race unprecedented in science has begun. The two teams worked independently, sparing no effort to reach the finish line first. During the implementation of the Human Genome Project, many new research methods were developed, most of which significantly speed up and reduce the cost of DNA decoding. These analysis methods are now used in medicine, forensics, etc.
In June 2000 year, two competing teams combined their data, officially announcing the completion of their work. And in February 2001 scientific publications of a draft version of the structure of the human genome appeared. The quality of sequencing is quite high and assumes only 1 error per 50 kb.
The Human Genome has gone down in history as one of the most labor-intensive and expensive projects. A total of more than ^ 6 billion dollars.
A natural question arises: what kind of person’s genome was determined as a result of these titanic efforts, who is this particular person? According to available data, Celera focused mainly on the genome of one person, about whom it is known only that he was a white, middle-aged man. Most likely, it was the head of the corporation, Craig Venter himself. The international consortium used material from at least seven different people in its work.
The human genome consists of 24 chromosomes And 3.2 billion bp Human chromosomes were numbered according to size: the largest is on chromosome 1, the smallest is on chromosome 22. Over time, it turned out that chromosome 22 contains more DNA than chromosome 21, but the numbering order was not changed so as not to cause confusion. There are two separate sex chromosomes: X and Y (they can conventionally be called volumes No. 23 and No. 24 of the Encyclopedia of the Human Genome).
^ In the female genome contained only 23 chromosomes out of 24, and all of them are represented in somatic cells in two copies. In men, cells contain the complete Human Encyclopedia, all 24 chromosomes, but two of them (chromosomes X and Y) exist in single copies.
Different chromosomes are very different from each other by the number and properties of genes(the first, largest, chromosome contains 263 million bp, constituting 2237 genes, and chromosome 21 contains 50 million bp and 82 genes). www. ensemble. org
Chromosomes also differ in the importance of the information recorded in them. Number of genes associated with various diseases most on the X chromosome – 208; at 1 hms – 157; and in 11 hms - 135. The fewest such genes are in Y hms - only 3. However, only the totality of all chromosomes provides cells with complete information that allows a person to develop and live normally. In the absence of any pair of chromosomes, the life of a particular individual becomes impossible.
If lost for any reason only one of the pair chromosome state of a person is very different from the norm. For example, partial monosomy 5th chromosome leads to cry-the-cat syndrome. Children with this anomaly have an unusual cry, which is caused by changes in the larynx, as well as the skull and face.
In human cells DNA is also available, located not in chromosomes, but in mitochondria. This is also part of the human genome, called M chromosome. Unlike the nuclear genome, mitochondrial genes are arranged compactly, as in the bacterial genome, and have their own genetic code (a kind of “genetic jargon”). MitDNA is responsible for the synthesis of only a few proteins in the cell. But these proteins are very important for the cell because they are involved in providing the cell with energy.
It is believed that mitochondria appeared in eukaryotic cells as a result of the symbiosis of higher organisms with aerobic bacteria.
MitDNA is passed on from generation to generation only through the female line. During fertilization, a sperm with a set of paternal chromosomes, but without paternal mitochondria, enters the egg. Only the egg provides its mitDNA to the embryo. Therefore, mitDNA is convenient to use to determine the degree of relationship both within species and between different taxa.
One of the goals of researching the human genome was to construct an accurate and detailed map of all chromosomes. Genetic map is a diagram that describes the order in which genes and other genetic elements are located on a chromosome. ( snips-repeat-genes).
IN coding no more proteins are involved 1,5 % human chromosomal DNA ( those. The genetic instructions for the formation of a human individual occupy only 3 cm of a two-meter human DNA molecule).
Analysis of the human genome revealed that he has about ^ 40 thousand. genes (for today). The shortest genes contain only 20 bp (endorphin genes, causing a feeling of pleasure). The longest gene encoding one of the muscle proteins(myodystrophin), contains about 2.5 million bp
^ Density genes on chromosomes vary greatly. Average density is approx. 10 genes per 1 million bp. However, in the chromosome 19 density is 20 genes, and in the Y chromosome - total 1.5 genes per million If we compare the density of genes with the population density of people, the Y chromosome resembles our Siberia, and chromosome 19 resembles the European part of Russia. Gene density decreases with the evolutionary complexity of organisms. For comparison, the bacterial genome contains over 1000 genes per 1.0 million i. n., in yeast about 450 genes by 1.0 million bp, and in the worm C. elegans - about 200 .
Just as people have families, genes are united into families by their similarity. There are about 1.5 thousand such families in the human genome. And only about hundreds of them specific for humans and vertebrates. The bulk of gene families are found in both humans and earthworms.
Different genes of the same family arose during evolution from one precursor gene as a consequence of mutations. “Related” genes most often perform a similar function. For example, the human genome has about 1,000 olfactory receptor genes.
Sometimes found in gene families pseudogenes. These are genes that have lost their ability to be expressed. They are preceded by the Greek letter . It is not entirely clear why the genome needs such genes, why it preserved them in evolution and did not get rid of them. The human genome contains about 20,000 such pseudogenes. In particular, in the huge family of olfactory genes, about 60% are pseudogenes. It is believed that massive loss of functional genes has occurred over the past 10 million years due to the decline in the role of smell in humans compared to other mammals.
About 20% of human genes function in all types of human cells. The remaining genes work only in certain tissues and organs. For example, globin genes are expressed only in blood cells, since their main function is to transport oxygen.
An example of the highest specialization of genes is olfactory genes. In each cell of the human olfactory organ - the olfactory bulb - only 1 gene out of 1000 possible works. Scientists were greatly perplexed by the fact that some of these genes, in addition to the olfactory bulb, are activated in another type of cell - spermatozoa. How this relates to the perception of smell is not yet entirely clear.
Chromosome mapping has also made it possible to identify the localization of regions responsible for some human diseases.
For example, in the first chromosome genes associated with breast ductal cancer. In second - with obesity. IN third- with schizophrenia. IN fourth A gene has been discovered on the chromosome, mutations of which lead to the development of alcoholism. Mutations in the terminal region X-chromosomes cause predisposition to homosexuality.
The attention of specialists was also drawn to genes associated with some features of human behavior. These genes encode proteins involved in transmitting signals between nerve cells (for example, the protein serotonin). Scientists have dubbed the gene encoding the serotonin receptor the “suicide gene.” Mutations in this gene cause people to have a tendency toward negative emotions and suicidal tendencies.
Another signal transmitter in the nervous system is dopamine- a substance that plays a key role in the functioning of the pleasure centers of the brain. Excess dopamine causes exploratory hyperactivity in animals. It was discovered that one of the genes encoding dopamine receptor proteins can exist in different allelic forms (long and short). People with the long allele are more inclined to seek new experiences, which is why the discovered gene was named “novelty-seeking genome.” In Americans, the long allele of the dopamine receptor gene is 25 times more common than in, say, South and East Asians. From history we know how America was settled by Europeans. First of all, they were energetic people, prone to adventurism, curious and impulsive. So they introduced the long allele of the “novelty-seeking gene” into the modern American population.
Recently, two genes were discovered that are responsible for maternal instincts (these genes were named "maternal instinct" genes). At the same time, to everyone’s surprise, it turned out that daughters receive both genes from their fathers. Animals that lacked the “maternal instinct” genes did not care for newborns.
It must be emphasized that, unlike genes responsible for physical parameters, the presence of “sick” genes that shape the psyche and behavior does not mean that a person is completely doomed to certain negative manifestations. Firstly, as a rule, not one, but a set of genes is responsible for mental characteristics. There is a very complex and sometimes very ambiguous interaction between them, the effect of which depends on many different factors. Secondly, according to most scientists, the human psyche and behavior are only one percent 50 are determined by genes.
One of the methods for studying the influence of the environment on the manifestation of a genotype is the observation of identical twins. This approach in genetics is called "twin method"».
Identical twins are formed by the division of the same zygote and contain identical genomes. Although the appearance of twins is a rather rare occurrence (it is believed that a person has one twin every 80-85 births), nevertheless, the available cases are sufficient to conduct appropriate research.
One of the clearest ways to identify a person is fingerprints. Characteristic “patterns” are formed in the embryo already in the third month of development and remain unchanged throughout life. When comparing the skin “patterns” of twins, it was revealed that they are very similar, but, surprisingly, not always completely identical.
When studying a number of other characteristics, slight variations in twins were also observed: eye and hair color, ear shape.
A large-scale comparison of identical twins with each other showed that the occurrence of such infectious diseases, like measles, whooping cough, chickenpox, almost completely depends on the causative agent of the disease, but polio and tuberculosis are also determined by the hereditary properties of a person. In particular, the incidence of tuberculosis in both identical twins is more than 3 times higher than in two fraternal twins.
A study of twins conducted at the Karolinska Institute in Stockholm has convincingly shown the significant impact of environmental factors (smoking, pollution, diet, lifestyle) on the development of some forms of malignant diseases. At the same time, the influence of genetic factors has been noted on the occurrence of cancer prostate, colorectal and breast cancer.
When analyzing twins, it was found that mental development may also be explained genetically. If one of a pair of identical twins is weak-minded, the other almost always turns out to be the same.
Russian scientists conducted a study of twin children aged 7 to 12 months to determine the extent to which genetics and environment influence aggressiveness, irritability, activity and sociability. It turned out that the first three traits of temperament are under strict genetic control: the aggressiveness of an infant's behavior: 94 percent is determined by its genotype, activity - 89 percent, irritability - 85 percent. And sociability is almost 90% formed under the influence of the environment created by parents.
Thanks to the twin analysis method, the widely discussed homosexuality problem. There is already reliable evidence that about 57% of identical twins and brothers of homosexual men are also homosexuals. For lesbian women the figure is approximately 50%.
Awareness of homosexuality as a hereditary disease may help decide how the problem of homophobia(it’s bad to hate sick people), and the problem of aggressive homosexuality(these people demand to be recognized as healthy and full-fledged, sometimes they are even proud of their peculiarity). However, if we consider homosexuality as a disease, as a pathology, the situation changes radically. It’s hard to imagine a person standing proudly with a sign: “I suffer from schizophrenia, so I demand respect for myself as a full-fledged member of society!”
According to modern estimates, life expectancy human, is also associated with genetic factors, the role of which is estimated at 65-70%.
Numerous and varied data suggest that the genome determines much of us, but the environment also significantly interferes with our essence. Scientists sometimes compare the relationship between genes and environment to a loaded gun and trigger. The gun will not fire until the trigger is pulled. The situation is the same in a cell, where a gene serves as a loaded pistol, and all sorts of environmental factors perform the trigger function. There is another comparison - with a card game: a good player can win with bad cards.
To understand the numerous relationships that exist between the manifestation of individual gene variants and the influence of various environmental factors in this process, a special international project was created - The Environmental Genome Project. Among the many objectives of this project, the main one is, of course, the study of the influence of the environment on life expectancy, as well as on the occurrence and development of various human diseases. Ultimately, this project may prove no less important and complex than the famous and very expensive project to sequence the human genome. And there is no doubt that it will last much longer than the genome project.
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Introduction to genomics. Human genome, main features of organization. Methods for studying the human genome
The importance of the human genome study program for practical medicine.
The 21st century is the era of genomics - a time when the DNA sequence in the human genome is almost completely determined, a time when the role of thousands of human genes in health and disease is analyzed. The time of personalized medicine is coming - when the study of small variations in many genes will lead to the identification of a person’s individual predisposition to a particular pathology.
The most important events in genetics of the 20th century, initiating the study of the genome:
Discovery of the DNA double helix (J. Watson, Fr. Crick, 1953)
Development of DNA sequencing method - 1997
Isolation of human embryonic stem cells (1998)
A decisive achievement in molecular biology was the development of DNA sequencing methods in 1977.
The international Human Genome Project officially started in 1990. Scientists from 6 countries - the USA, Great Britain, France, Germany, Japan and China - made a huge contribution. By 2001, 90% had been sequenced with 99.99% accuracy. By 2003, 99% of the human genome had been sequenced. About 400 gaps remain.
During the Human Genome Project, the DNA sequence of all chromosomes and mitochondrial DNA was determined.
Twenty-two autosomal chromosomes, two sex chromosomes X and Y, and human mitochondrial DNA together contain approximately 3.1 billion base pairs.
Full sequencing revealed that the human genome contains 20-25 thousand active genes, which is significantly less than expected at the beginning of the project (about 100 thousand) - that is, only 1.5% of all genetic material encodes proteins. The remainder (97%) is non-coding DNA, often called junk DNA. The human genome is the totality of hereditary material contained in a human cell.
In general, the word "genome" refers to the total DNA content of a given species, including not only genes, but all other DNA. In humans, for example, protein-coding sequences account for only 1.25% of the entire genome. What is the human genome?
The share of introns accounts for up to 20-25%. But a significant part of the intergenic DNA is occupied by regulatory sequences.
Gene classifications:
Active and repressed genes
The bulk of genes that actively function in most cells of the body throughout ontogenesis are genes that provide the synthesis of general-purpose proteins (ribosomal proteins, histones, tubulins, etc.), tRNA and rRNA. Such genes are called constitutive. The work of another group of genes that control the synthesis of specific proteins depends on various regulatory factors. They are called regulated genes. Changing conditions can lead to activation of “silent” genes and repression of active ones. Differential genome expression in mammals determines the development of a huge variety of tissue types.
Coding proteins and RNA
Protein coding sequences (the many sequences that make up exons) make up less than 1.5% of the genome.
In addition to protein-coding genes, the human genome contains thousands of RNA genes, including transfer RNA (tRNA), ribosomal RNA, microRNA (microRNA), and other non-protein-coding RNA sequences.
Structural genes characterized by unique nucleotide sequences encoding their protein products that can be identified by mutations that disrupt protein function.
Housekeeping genes and luxury genes.
All genes are divided into “household” genes and “luxury” genes.
Housekeeping genes encode what any cell always needs, regardless of tissue. Housekeeping genes are genes necessary for maintaining the most important vital functions of the body, which are expressed in almost all tissues and cells at a relatively constant level. Housekeeping genes function everywhere, at all stages of an organism's life cycle.
According to various estimates, humans have 10-20 thousand such genes. These are histone genes, tRNA genes, rRNA genes, etc.
“Luxury” genes, of which there are obviously 2-3 times more, are genes that are expressed in the cells of certain tissues and at a certain time. For example, all genes for protein hormones are “luxury” genes.
Regulatory sequences are nucleotide sequences that do not encode specific proteins, but regulate the action of a gene (inhibition, increase in activity, etc.
The human genome contains many different sequences responsible for gene regulation. Regulation refers to the control of gene expression (the process of constructing messenger RNA along a section of a DNA molecule). These are usually short sequences found either near a gene or within a gene. Sometimes they are located at a considerable distance from the gene (enhancers).
Silencer is a DNA sequence to which repressor proteins (transcription factors) bind. The binding of repressor proteins to silencers leads to a decrease or complete suppression of RNA synthesis.
Insulators
The human genome consists of 23 pairs of chromosomes located in the nucleus, as well as mitochondrial DNA in the form of 2-6 circular molecules. Human chromosomes. Chromosome size varies from 45 million to 280 million bp.
The chromosome is not homogeneous. It alternates between areas of euchromatin (non-dense areas) and heterochromatin (more dense). With differential staining along the length of the chromosome, a number of colored (heterochromatin) and unstained (euchromatin) bands are revealed. The nature of the transverse striation obtained in this way makes it possible to identify each chromosome in the set, since the alternation of stripes and their sizes are strictly individual and constant for each pair.
EUCHROMATIN, a chromosome substance that maintains a despiralized (diffuse) state in the resting nucleus and spirals during cell division. Contains most of the structural genes of the body. Heterochromatin is extended areas of repeating and highly condensed sequences that do not code for any proteins.
Classification of heterochromatin:
Facultative (Depending on the stages of the cell cycle and the type of cell, the same chromosome region can be in the state of both hetero- and euchromatin. Such chromosome regions are called facultative heterochromatin.
Constitutive (pericentromeric, telomeric) Areas that are always condensed. These regions of chromosomes contain tandemly repeated DNA (located one behind the other “head to tail”).
Pericentromeric heterochromatin consists of short tandem repeats up to 20 bp long, organized into long blocks (100-200 tandems). The blocks form rows ranging in length from 250 thousand to 5 million bp. This type of DNA is called satellite, alphoid (alpha satellite). Make up 3% of the genome. At the locations of satellite DNA, maximum compaction is possible; all four levels of DNA packaging are present even in interphase. Using satellite DNA, crossing over occurs between homologous chromosomes.
Telomeres (from the ancient Greek fElpt - end and mespt - part) - minisatellites - the terminal sections of chromosomes. In most eukaryotes, telomeres consist of short tandem repeats and contain thousands of 6-nucleotide repeats: in humans - TTAGGG, (for comparison, in all insects - TTAGG, in plants - TTTAGGG). They are repeated from 250 to 1500 times.
Several proteins are associated with telomeres, forming a protective “cap” - the telomeric complex, which protects telomeres from the action of nucleases and adhesion and, apparently, it is this that preserves the integrity of the chromosome and protects the entire chromosome from destruction. Telomeric regions of chromosomes are characterized by a lack of ability to connect with other chromosomes or their fragments and perform a protective function.
With each division cycle, the cell's telomeres shorten due to the inability of DNA polymerase to synthesize a copy of DNA from the very end. DNA polymerase can only begin chain synthesis from an RNA primer. After DNA synthesis is complete, the RNA primers on the lagging strand are removed and the gaps are filled in by DNA polymerase. However, such a gap cannot be filled at the end of the chain. Therefore, 3" sections of DNA remain single-stranded, and 5" sections are under-replicated. Consequently, EACH ROUND OF REPLICATION WILL LEAD TO A REDUCTION OF THE ENDS OF THE CHROMOSOME. This phenomenon is called terminal underreplication and is one of the most important factors of biological aging. Thus, in a newborn, the length of telomeres varies about 15 thousand bp; in chronic diseases it decreases to 5 kb. Scientists from Cardiff University have found that the critical length of the human telomere, at which chromosomes begin to connect with each other, is 12-13 telomeric repeats.
With such critical shortening of telomeres, the structure of chromosomes is disrupted, adjacent genes can be damaged and chromosomal aberrations begin to form, which often lead to malignancy. To prevent this from happening, special molecular mechanisms block cell division, and the cell enters a state of rest - an irreversible stop of the cell cycle. As a result, the cell may die or stop dividing. This occurs in most normal somatic cells, which have a limited ability to reproduce. Many stimuli can bring a cell into such a state of rest - telomere dysfunction, DNA damage, which can be caused by mutagenic environmental influences, endogenous processes, strong mitogenic signals (overexpression of oncogenes Ras, Raf, Mek, Mos, E2F-1, etc.) , chromatin disorders, stress, etc.
However, in germ, germ and stem cells there is a special enzyme - telomerase, which is capable of restoring telomeric sequences that are shortened with each act of replication.
Protective mechanisms of terminal underreplication.
There is a special enzyme - telomerase (RNA + protein), which, using its own RNA template, completes telomeric repeats and lengthens telomeres. Telomerase is blocked in most differentiated cells, but is active in stem and germ cells.
Telomerase reactivation is believed to be an important step in malignant processes because it allows cancer cells to defy the proliferation limit. Telomere dysfunction promotes chromosomal fusions and aberrations, which most often lead to malignant neoplasms. Active telomerase is found in 90% of cancer tumors, which ensures the uncontrollable proliferation of cancer cells. Therefore, currently among the drugs that are used to treat cancer, there is also a telomerase inhibitor.
For the discovery of the protective mechanisms of chromosomes against terminal underreplication using telomeres and telomerase in 2009, the Nobel Prize in Physiology or Medicine was awarded to Australian Elizabeth Blackburn working in the United States, American Carol Greider and her compatriot Jack Shostak. Szostack).
In addition, telomeric DNA has come under intense scrutiny in recent years due to the discovery of a link between telomere shortening and aging.
Other classes of tandem repeats are genes for RNA, such as ribosomal RNA. These genes are localized in the NORs of 5 pairs of acrocentric chromosomes.
Another group of repeats are dispersed repeat sequences, which are scattered throughout the genome individually rather than in tandem. They are mobile (mobile) genetic elements - retrotransposons. 15% of the genome is occupied by long dispersed elements - LINE, 12% - short SINE. These sequences produce enzymes - endonucleases that can make cuts in DNA and insert their sequences there. The integration of MGE into DNA can disrupt gene function. In humans, about 30 retrotranspositions are known to cause disease. Why doesn’t the genome get rid of such dangerous areas? Repeat sequences and MGEs are an important source of genome remodeling.
Systematization of these sequences, understanding of the mechanisms of operation, as well as issues of mutual regulation of a group of genes by a group of corresponding enzymes are currently only at the initial stage of study. The mutual regulation of groups of genes is described using gene regulatory networks. The study of these issues is at the intersection of several disciplines: applied mathematics, high-performance computing and molecular biology. Knowledge comes from comparisons of the genomes of different organisms and from advances in artificial gene transcription in the laboratory.
All genes are divided into structural and functional according to their functions.
Structural genes carry information about the structure of proteins and RNA.
Among the functional genes are:
modulator genes that enhance or weaken the functioning of structural genes (suppressors (inhibitors), activators, modifiers);
genes that regulate the functioning of structural genes (regulators and operators).
genome underreplication protein
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As a science, genetics arose at the turn of the 19th and 20th centuries. Many consider the official date of her birth to be 1900, when Correns, Cermak and de Vries independently discovered certain patterns in the transmission of hereditary characteristics. The discovery of the laws of heredity took place, essentially, for the second time - back in 1865, the Czech natural scientist Gregor Mendel obtained the same results while experimenting with garden peas. After 1900, discoveries in the field of genetics followed one after another, research on the structure of the cell, the functions of proteins, the structure of nucleic acids discovered by Miescher in 1869, step by step brought man closer to unraveling the secrets of nature, new scientific directions were created, and new methods were improved. And finally, at the end of the 20th century, genetics came close to solving one of the fundamental questions of biological science - the question of completely deciphering hereditary information about a person.
220 scientists from different countries, including five Soviet biologists, took part in the implementation of a grandiose project to decipher the genetic code of DNA, called HUGO (Human Genome Organization). Our country created its own “Human Genome” program, headed by Academician Alexander Aleksandrovich Baev.
The idea of organizing such a program was first put forward in 1986. Then the idea seemed unacceptable: the human genome, that is, the totality of all its genes, contains about three billion nucleotides, and in the late 80s the cost of determining one nucleotide was about 5 US dollars. In addition, the technologies of the 80s allowed one person to determine no more than 100,000 nucleotides per year. However, already in 1988, the US Congress approved the creation of an American research project in this area; the program manager, J. Watson, defined its prospects as follows: “I see an exceptional opportunity for the improvement of humanity in the near future.” The Russian program began in 1989.
Now the determination of one nucleotide costs only one dollar, machines have been created that can sequence (from the Latin sequi - follow) up to 35 million nucleotide sequences per year. One of the important achievements was the discovery of the so-called polymerase chain reaction, which makes it possible to obtain a volume of DNA sufficient for genetic analysis from microscopic amounts of DNA in a few hours. According to experts, it is possible to complete the project in 15 years, and the program is already bringing useful results. The essence of the work is as follows: first, genome mapping is carried out (determining the position of a gene on a chromosome), localization of some genes, and after that sequencing (determining the exact sequence of nucleotides in a DNA molecule). The first gene to be localized was the color blindness gene, mapped to the sex chromosome in 1911. By 1990, the number of identified genes reached 5000, of which 1825 were mapped, 460 were sequenced. It was possible to localize genes associated with severe hereditary diseases, such as Huntington's chorea, Alzheimer's disease, Duchenne muscular dystrophy, cystic fibrosis, etc.
Thus, the human genome research project is of enormous importance for studying the molecular basis of hereditary diseases, their diagnosis, prevention and treatment. It should be noted that over the past decades in industrialized countries the share of hereditary diseases in the total volume of diseases has increased significantly. Heredity determines predisposition to cancer and cardiovascular diseases. This is largely due to the environmental situation, environmental pollution, since many industrial and agricultural wastes are mutagens, that is, they change the human gene pool. Considering the current level of development of genetics, it can be assumed that future scientific discoveries will make it possible to adapt a person to unfavorable environmental conditions by changing the genome. As for the fight against hereditary diseases, their treatment by replacing diseased genes with healthy ones seems feasible now. All this means that a person will have the opportunity not only to change living organisms, but also to construct new forms of life. This raises a number of serious questions.
In my opinion, one of the most important issues is the use of genetic information for commercial purposes. Despite the fact that both participants in the HUGO project and representatives of international organizations, in particular UNESCO, are unanimous that any results of research on genome mapping and sequencing should be available to all countries and cannot serve as a source of profit, private capital is beginning to play an increasingly important role role in genetic research. When the HUGO program appeared, so-called genomic companies emerged and began deciphering the genome on their own. An example is an American organization called the Institute of Genomic Research (TIGR) or the company Human Genome Sciences Inc. (HGS). There is a fierce battle for patents between large firms. So in October 1994, Crack Venter, the head of the aforementioned TIGR company, said that his corporation had at its disposal a library of 35,000 DNA fragments synthesized using RNA on genes obtained in the laboratory. These fragments were compared with 32 known genes for hereditary diseases. It turned out that 8 of them are completely identical, and 19 are homologous. TIGR was in possession of valuable scientific information, but its leaders said that the chemical structure of all sequences from this library is classified and will be made public only if the company is recognized as the owner of all 35,000 fragments. This is not the only case, and meanwhile, the development of genetics is much faster than the development of the corresponding legislative framework. Although steps are being taken in this direction (in Russia, for example, at the end of 1996 the law “On State Regulation in the Field of Genetic Engineering Activities” was adopted, in 1995 a law on bioethics was adopted in France, in the USA the Civil Rights Act prohibits discrimination in hiring to work on the basis of race, gender, religion and nationality, while the gene for sickle cell anemia, in particular in blacks, can be considered a racial characteristic, another law prohibits discrimination in the hiring of persons with reduced ability to work, and persons with a family history may also be considered as such , the so-called Tarasova principle is of great importance, obliging doctors to violate the confidentiality of medical information in order to prevent possible harm to society), international acts regulating all aspects of activities related to genetics do not yet exist.
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There is a point of view, shared by a considerable number of specialists, that all human diseases with the exception of injuries are associated with genetic defects. Obviously, this is an extreme view, but it nonetheless reflects the importance of genetic factors in determining people's health. Genetic defects come in varying degrees of severity and condition.
Although diabetes and muscular dystrophy are commonly thought of as diseases, and cleft palate or color blindness as hereditary defects, they are all the result of mutations in the genetic material. It has also been shown that predisposition to the disease also depends on the genetic constitution.
Genetic defects or mutations in the DNA sequence are expressed in the replacement of one nucleotide with another, the loss of an entire fragment or its transfer to another position in the genome, etc. Such changes can lead to changes in the structure (and function) of the protein that is encoded by this DNA fragment or to changes in regulatory gene regions that are fatal to cells. When we talk about hereditary diseases, we mean mutations that appear in germ cells and are passed on to offspring.
Mutations also accumulate in somatic cells throughout life, which can cause disease, but they are not inherited. Previously, it was believed that all mutations were harmful. This is due to the fact that it was with such mutations that cause diseases that the study of human genetic characteristics began. But now, when almost the entire human nucleotide text has been read, it has become clear that most of the mutations are neutral. Harmful mutations that lead to gross disruption of the development of the organism are eliminated by selection - their carriers do not survive or do not produce offspring.
Enormous advances in understanding how inherited genes influence a person's physical and psychological characteristics have occurred in recent decades thanks to discoveries made in the study of the human genome. A number of genetic diseases, as well as predisposition to them, have been identified and diagnosed, and at the very early stages of embryo development. Great hopes for expanding the capabilities of modern medicine are associated with the implementation of the Human Genome Project.
Implementation of the scientific project “Human Genome”
The Human Genome Scientific Project is an international program whose ultimate goal was to determine the nucleotide sequence (sequencing) of the entire human genomic DNA, as well as the identification of genes and their localization in the genome (mapping). In 1988, the US Department of Energy and the US National Institutes of Health introduced an extensive project that included sequencing the genomes of humans, as well as bacteria, yeast, nematodes, fruit flies and mice - organisms that have been widely used as model systems in the study of human genetics .Congress allocated $3 billion for the implementation of this project. (one dollar for each nucleotide of the human genome). Nobel Prize winner James Watson was appointed project director. Other countries have joined the project - England, France, Japan, etc.
In 1989, on the initiative of Academician A.A. Baev, a scientific council was organized in our country for the “Human Genome” program. In 1990, the International Human Genome Organization (HUGO) was created, whose vice-president for several years was academician A.D. Mirza-beyov. Regardless of the contribution and national affiliation of individual program participants, from the very beginning, all information they received during the work was open and accessible to all its participants.
Twenty-three human chromosomes were divided among the participating countries. Russian scientists had to study the structures of the 3rd and 19th chromosomes. However, soon funding for this project was greatly reduced, and our country did not take any real part in sequencing. Nevertheless, work on the genomic project in our country did not stop: the program was revised and focused on the development of bioinformatics - mathematical methods, computer technology, software, improving methods for describing and storing genomic information that would help understand and comprehend the deciphered information.
It took 15 years to decipher the human genome. However, the constant development of sequencing technology allowed the project to be completed 2 years earlier. The private American company Celera, headed by J. Venter (formerly a biologist at the US National Institutes of Health), played a significant role in intensifying the work. While in the early years of the project several million nucleotide pairs were sequenced around the world per year, by the end of 1999 Celera was deciphering at least 10 million nucleotide pairs per day. To achieve this, work was carried out around the clock in automatic mode by 250 robotic installations; the information was immediately transferred to data banks, where it was systematized, annotated and posted on the Internet.
Working in 1995, Venter and his co-authors developed and published an entirely new approach to genome sequencing called random whole genome sequencing (better known as random fractional sequencing), which allowed the assembly of a complete genome from partially sequenced DNA fragments using a computer model .
This method was the first to completely sequence the genome of a self-replicating free-living organism - the bacterium Haemophilus in-fluenzae Rd. Copies of bacterial DNA were cut into pieces of arbitrary length from 200 to 1,600 bp. These fragments were sequenced several hundred from each end. In addition, longer fragments of 15-20 kb were sequenced. The resulting sequences were entered into a computer, which compared them, distributed them into groups and according to similarity.
Non-repetitive sequences were identified first, followed by repeated fragment sequences. Long fragments helped establish the order of frequently repeated, almost identical sequences. The gaps between the resulting major pieces of DNA were then filled. Sequencing the genome of Haemophilus influenzae took one year and the sequence of 1,830,137 bp was determined. and 1,749 genes located on 24,304 fragments.
It was an undoubted success and proved that the new technology could be applied to quickly and accurately sequence entire genomes. In 1996, the genome of the first eukaryotic cell, yeast, was mapped, and in 1998, the genome of a multicellular organism, the round earthworm Caenorhabolits elegans, was sequenced for the first time.
In February 2001, a working version of the human genome (90% completed) was simultaneously published in the journals “Nature” - the results of HUGO and “Science” - the results of Celera research. Analysis of the resulting variant of the human genome revealed about 25 thousand genes. Previously it was assumed that this number should reach 140 thousand (based on the postulate “one gene encodes one protein”). Currently, it seems possible that one gene can encode 5-6 proteins. The diversity of proteins encoded by the same gene is ensured by several mechanisms: through alternative splicing, post-translational transformations of proteins - phosphorylation, acetylation, methylation, glycosylation and many others.
In 2003, the final complete sequence of the human genome was published. All this information is available and can be found on the Internet on several sites. However, some elements of the genome are still not amenable to sequencing with modern technologies, and our knowledge of the genome remains incomplete. It turned out that only 30% of the genome encodes proteins and is involved in the regulation of gene action.
What are the functions of the remaining regions of the genome and whether they exist at all remains completely unclear. About 10% of the genome consists of so-called Alu elements, about 300 bp long. They appeared from nowhere in the course of evolution only among primates. Once they reached humans, they multiplied to half a million copies and were distributed along the chromosomes in the most bizarre way.
As for the coding regions of DNA, in a purely molecular computer analysis they were called genes according to purely formal criteria: the presence of punctuation marks necessary for reading the information and synthesizing a specific gene product. However, the timing and action of most potential genes is still unclear, and it may take at least a hundred years to determine their functions.
ON THE. Voinov, T.G. Volova
On April 25, now distant 1953, the journal Nature published a small letter from the young and unknown F. Crick and J. Watson to the editor of the journal, which began with the words: “We would like to offer our thoughts on the structure of the DNA salt. This structure has new properties that are of great biological interest." The article contained about 900 words, but - and this is not an exaggeration - each of them was worth its weight in gold.
The “rumpy youth” dared to speak out against Nobel laureate Linus Pauling, the author of the famous alpha helix of proteins. Just the day before, Pauling published an article according to which DNA was a three-stranded helical structure, like a girl's braid. No one knew then that Pauling simply had insufficiently purified material. But Pauling turned out to be partly right - now the three-stranded nature of some parts of our genes is well known. At one time they even tried to use this property of DNA in the fight against cancer, turning off certain cancer genes (oncogenes) using oligonucleotides.
Nucleic acid biology has been unlucky for a long time. Suffice it to say that the first Nobel Prize for the discovery of the structure of nucleotides was received by the German A. Kossel back in 1910. And the famous Feulgen reaction for staining DNA was proposed on the eve of the First World War and improved in the 1920s. Then a new era of biology could begin, however...
However, biologists were confident that “monotonic” DNA, with its only four different bases, simply could not carry the genetic information for millions of diverse proteins. And although Morse code with three coding elements had already been used, the mentality of researchers had not yet reached the level of the information era with its binary recording system (“0” and “1”) for any information.
Only by the beginning of the 1950s. Some scientists began to pay attention to DNA, the role of which in the transmission of hereditary characteristics in microorganisms was established in 1943 by Oswald Avery. Avery’s results were believed by Salvador Luria, who, together with Max Delbruck, organized a laboratory near New York at a biological station in the town of Cold Spring Harbor.
Let us note in parentheses that the physicist M. Delbrück was a student of N.V. Timofeev-Resovsky in biology and co-author of their famous article with K. Zimmer on determining the size of a gene. Luria and Delbrück studied the life cycle of bacteriophages - viruses of microorganisms, as a result of which they came to assumptions about the biological role of DNA. Luria sent his graduate student James Watson to the Cavendish Laboratory in Cambridge, where Maurice Wilkins and Rosalind Franklin studied the structure of DNA using X-rays (the British were leaders in X-ray diffraction analysis of biomolecules).
A fairly young physicist, Francis Crick, also worked in Wilkins’ laboratory, known in narrow laboratory circles for his scientific skepticism: for him there were simply no authorities, which is how he earned himself a reputation as a brawler. Pauling's article was brought to the laboratory by his son, who, by the way, helped Watson and Crick understand the role of pairwise complementary compounds of nitrogenous bases. The article was the last straw before the insight, or understanding... that took shape in the discovery of young scientists.
The scientific community, however, did not immediately recognize their discovery. Suffice it to say that the Nobel Prize for work in the field of DNA was first awarded by the “judges” from Stockholm in 1959 to the famous American biochemists Severo Ochoa and Arthur Kornberg. Ochoa was the first (1955) to synthesize ribonucleic acid (RNA). Kornberg received the prize for DNA synthesis in vitro (1956).
In 1962 it was the turn of Crick, Watson and Wilkins. R. Franklin had already died of cancer at the age of 37, otherwise this would have been the only time in the history of the Nobel Prizes when the award would have been awarded to four, although this is not allowed by the charter. Franklin's contribution to the development of X-ray diffraction analysis of DNA was simply invaluable.
After the discovery of Watson and Crick, the most important problem was to identify the correspondence between the primary structures of DNA and proteins. Since proteins contain 20 amino acids, and there are only 4 nucleic bases, at least three bases are needed to record information about the sequence of amino acids in polynucleotides. Based on such general reasoning, variants of “three-letter” genetic codes were proposed by physicist G. Gamov and biologist A. Neyfakh. However, their hypotheses were purely speculative and did not cause much response among scientists.
The three-letter genetic code was deciphered by F. Crick by 1964. It is unlikely that he then imagined that in the foreseeable future it would become possible to decipher the human genome. This task seemed insurmountable for a long time. However, two discoveries made it possible to move the problem forward.
In 1970, unknown to the general scientific community, G. Temin and D. Baltimore published articles in Nature on reverse transcriptase (RT), an enzyme of RNA-containing viruses, including cancer ones, that synthesize DNA on an RNA template, i.e. . carry out a reaction opposite to that previously observed in cells.
The discovery of reverse transcriptase made it possible to isolate the first genes. But this process was extremely labor-intensive and extremely expensive. And 15 years later, a certain chemist from California proposed to his colleagues a unique polymerase chain reaction (PCR), which immediately became famous. In this reaction, the enzyme, polymerase, “walks like a shuttle” along a DNA fragment, so PCR allows you to produce any quantities of this fragment necessary for analysis*.
PCR, as well as the advent of the latest electronic technology and computers, have made the task of deciphering the entire human genome quite realistic. The long debate ended at the end of September 1988, when J. Watson was appointed head of the HUGO project - the Human Genome Organization.
Time magazine called Watson a “gene hunter” in this regard. The scientist himself said the following: “This is an exciting prospect. Thirty years ago we could not even dream of knowing the genome structure of even the smallest virus. And today we have already deciphered the genome of the AIDS virus and almost completely read the genome of Escherichia coli with a volume of 4.5 million letters of the gene code. Knowing exactly the detailed structure of the human genome is amazing!”
And now the genome has been read
The completion of work on deciphering the human genome by a consortium of scientists was planned for 2003, the 50th anniversary of the discovery of the structure of DNA. However, competition has had its say in this area as well.
Craig Venter founded a private company called Selera, which sells gene sequences for big money. By joining the race to decipher the genome, she did in one year what took an international consortium of scientists from different countries ten years to achieve. This became possible thanks to a new method for reading genetic sequences and the use of automation of the reading process.
So, the genome has been read. It would seem that we should rejoice, but scientists were perplexed: very few genes turned out to be in humans - about three times less than expected. They used to think that we had about 100 thousand genes, but in fact there were about 35 thousand of them. But this is not even the most important thing.
The bewilderment of scientists is understandable: Drosophila has 13,601 genes, round soil worms have 19 thousand, mustard has 25 thousand genes. Such a small number of genes in humans does not allow us to distinguish him from the animal kingdom and consider him the “crown” of creation.
But where genes are located, the activity of DNA and enzymes that synthesize its copies in the form of messenger RNA molecules increases 200–800 times! These are the “hot spots” of the genome.
In the human genome, scientists have counted 223 genes that are similar to the genes of E. coli. E. coli arose approximately 3 billion years ago. Why do we need such “ancient” genes? Apparently, modern organisms have inherited from their ancestors some fundamental structural properties of cells and biochemical reactions that require appropriate proteins.
It is therefore not surprising that half of mammalian proteins have similar amino acid sequences to Drosophila fly proteins. After all, we breathe the same air and consume animal and plant proteins, consisting of the same amino acids.
It’s amazing that we share 90% of our genes with mice, and 99% with chimpanzees!
Our genome contains many sequences that we inherited from retroviruses. These viruses, which include cancer and AIDS viruses, contain RNA instead of DNA as hereditary material. A feature of retroviruses is, as already mentioned, the presence of reverse transcriptase. After DNA synthesis from the RNA of the virus, the viral genome is integrated into the DNA of the cell chromosomes.
We have many such retroviral sequences. From time to time they “break out” into the wild, resulting in cancer (but cancer, in full accordance with Mendel’s law, appears only in recessive homozygotes, i.e. in no more than 25% of cases). More recently, a discovery was made that allows us to understand not only the mechanism of viral insertion, but also the purpose of non-coding DNA sequences. It turned out that a specific sequence of 14 letters of genetic code is required to integrate the virus. Thus, one can hope that soon scientists will learn not only to block aggressive retroviruses, but also to purposefully “introduce” the necessary genes, and gene therapy will turn from a dream into a reality.
In the mammalian body, retroviruses play another important role. In relation to mammals, in which the fetus develops inside the mother’s body, the question is legitimate: why does the mother’s immune system allow the development of an organism that is half genetically foreign to her, since half of the fetus’s genome is paternal?
It's all about retroviruses that block the activity of immune T-lymphocytes responsible for the rejection of organs and tissues containing foreign proteins, for example, after organ transplantation. These retroviruses are activated in the genome of the cells of the placenta, which is formed by fetal tissue.
Recently, a virus was discovered that blocks the development (expression) of a retrovirus. If a pregnant mouse is infected with this blocking virus, the pups are born normal and on time. But if it is introduced into the cells of the placenta, a miscarriage of the fetus occurs, as the mother’s T-lymphocytes are activated.
Do not forget that retroviral sequences also appear directly at the ends of chromosomes - telomeres. As you know, telomeres consist of single-stranded DNA, which is synthesized by the enzyme telomerase using an RNA template. Telomeres are thought to be our molecular clock as they shorten with each cell division. Previously, it was believed that there were no genes in telomeres, but deciphering the genome showed that there are quite a lot of genes there and they are active in childhood and young adulthood, gradually “fading away” as the body ages.
Tandem repeats are not so inactive either. Normally, they have a certain number of repeating threes, fives and even sevens of letters. But in some cases, as a result of mutations, the number of repeats begins to increase, which leads to genome instability. It even goes so far as to “break” the ends of chromosomes. Fragmentation of the terminal sections of a chromosome can lead to movements (translocation) of DNA sections to another chromosome, as well as the synthesis of such forms of protein that cause the death of nerve cells, as is observed in hereditary Huntington's chorea.
K. Venter said that understanding the genome will take hundreds of years. After all, we still do not know the functions and roles of more than 25 thousand genes. And we don’t even know how to approach solving this problem, since most genes are simply “silent” in the genome, not manifesting themselves in any way.
It should be taken into account that the genome has accumulated many pseudogenes and “changeover” genes, which are also inactive. It seems that non-coding sequences act as an insulator for active genes. At the same time, although we don’t have too many genes, they provide the synthesis of up to 1 million (!) of a wide variety of proteins. How is this achieved with such a limited set of genes?
As it turned out, there is a special mechanism in our genome - alternative splicing. It consists in the following. On the template of the same DNA, the synthesis of different alternative mRNAs occurs. Splicing means “splitting” when different RNA molecules are formed, which, as it were, “split” the gene into different variants. This results in an unimaginable diversity of proteins with a limited set of genes.
The functioning of the human genome, like that of all mammals, is regulated by various transcription factors - special proteins. These proteins bind to the regulatory part of the gene (promoter) and thus regulate its activity. The same factors can manifest themselves differently in different tissues. A person has his own, unique to him, transcription factors. Scientists have yet to identify these purely human features of the genome.
SNP
There is another mechanism of genetic diversity, which was revealed only in the process of reading the genome. This is a singular nucleotide polymorphism, or the so-called SNP factors.
In genetics, polymorphism is a situation where genes for the same trait exist in different variants. An example of polymorphism, or, in other words, multiple alleles, are blood groups, when one chromosomal locus (region) may contain variants of the A, B or O genes.
Singularity in Latin means loneliness, something unique. A SNP is a change in the “letter” of the genetic code without “health consequences.” It is believed that in humans SNP occurs with a frequency of 0.1%, i.e. Each person differs from others by one nucleotide for every thousand nucleotides. In chimpanzees, which are an older species and also much more heterogeneous, the number of SNPs when comparing two different individuals reaches 0.4%.
But if differences in SNP do not affect the health of individuals, then why are they interesting and important? Firstly, the study of SNP is of great theoretical importance. They allow us to compare the ages of populations and determine their migration routes. For example, 22 SNP factors were identified in the male sex chromosome (Y), the analysis of which in 1007 Europeans made it possible to determine that 80% of European men have a similar “SNP pattern”, i.e. "drawing". This suggests that thousands of generations ago, 4/5 of European men had a common ancestor!
But the practical significance of SNP is also great. Perhaps not everyone knows that today the most common medications are effective for no more than a quarter of the population. Minimal genetic differences caused by SNP determine the effectiveness of drugs and their tolerability in each specific case. Thus, 16 specific SNPs were identified in diabetic patients. In total, when analyzing the 22nd chromosome, the location of 2730 SNPs was determined. In one of the genes encoding the synthesis of the adrenaline receptor, 13 SNPs were identified, which can be combined with each other, giving 8192 different variants (haplotypes).
It is not yet entirely clear how quickly and fully the information received will begin to be used. For now, let's give one more concrete example.
Among asthmatics, the drug albuterol is quite popular, which interacts with this adrenaline receptor and suppresses an attack of suffocation. However, due to the diversity of people's haplotypes, the medicine does not work on everyone, and for some patients it is generally contraindicated. This is due to SNP: people with the sequence of letters in one of the genes TCTC (T-thymine, C-cytosine) do not respond to albuterol, but if the terminal cytosine is replaced by guanine (TCTCG), then there is a reaction, but partial. For people with thymine instead of the terminal cytosine in this region - TCTCT - the medicine is toxic!
Proteomics
This entirely new branch of biology, which studies the structure and function of proteins and the relationships between them, is named after genomics, which dealt with the human genome. The very birth of proteomics already explains why the Human Genome program was needed. Let us explain with an example the prospects for a new direction.
Back in 1962, John Candrew and Max Perutz were invited to Stockholm from Cambridge along with Watson and Crick. They were awarded the Nobel Prize in Chemistry for the first deciphering of the three-dimensional structure of the proteins myoglobin and hemoglobin, responsible for the transport of oxygen in muscles and red blood cells, respectively.
Let us remember that even in the early 1990s. deciphering the structure of each new protein presented significant difficulties. Each analysis took up to ten years. And although nuclear magnetic resonance (NMR) is now used instead of X-rays, it takes a lot of time and money to determine the spatial structure of each protein.
Proteomics makes this work faster and cheaper. K. Venter noted that he spent 10 years isolating and sequencing the human adrenaline receptor gene, but now his laboratory spends 15 seconds on it. Back in the mid-90s. Finding the “address” of a gene in chromosomes took 5 years, in the late 90s – six months, and in 2001 – one week! By the way, information about SNPs, of which there are already millions today, helps to speed up the determination of the gene position.
Let's return to proteomics. Knowledge of amino acid sequences and the three-dimensional structure of certain proteins made it possible to develop programs for comparing genetic sequences with amino acids, and then programs for their putative location in the three-dimensional structure of polypeptides. Knowledge of the three-dimensional structure allows you to quickly find chemical variants of molecules in which, for example, the active center is blocked, or determine the position of the active center in a mutant enzyme.
It is known that an increase in blood pressure is caused by the enzyme ACE, the abbreviated name of which is translated from English as angiotensin-converting enzyme. Angiotensin, formed under the action of the enzyme, acts on the walls of the artery, which leads to hypertension. Relatively long ago, ACE enzyme blockers were discovered and began to be sold as medications for high blood pressure. However, these drugs turned out to be ineffective.
Genome analysis made it possible to isolate the ACE-2 gene, which encodes a more common and efficient version of the enzyme. Then the virtual structure of the protein product was determined, after which chemical substances that actively bind to the ACE-2 protein were selected. This is how a new drug against blood pressure was found, in half the time and for only 200 instead of 500 million dollars!
We admit that this was an example of the “pre-genomic” period. Now, after reading the genome, proteomics comes to the fore, the goal of which is to quickly understand the million proteins that could potentially exist in our cells. Proteomics will make it possible to more thoroughly diagnose genetic abnormalities and block the adverse effects of mutant proteins on the cell.
And over time, it will be possible to plan “correction” of genes.
