Genes are to blame for everything

How Genetic Tests work

Alexander Reznik, Post-science

The achievements of modern genetics are actively used in medicine – oncology, gene therapy, family planning, treatment of hereditary diseases and risk management of complex diseases. But today's fashionable genetic tests are most often done to determine the appropriate type of nutrition, choose a sport or even cosmetics. Geneticist Alexander Reznik told post-science how genetics developed and what can actually be found out with the help of genetic tests.

How did you learn about genes and start researching them?

It seems that everyone has at least once heard about the experiments with peas by the humble monk Gregor Mendel, during which in the middle of the XIX century he formulated three fundamental laws describing exactly how certain signs – the color or shape of peas – are inherited. The monk biologist tried to reproduce the results of his experiments on other, more "complex" species, in particular bees, but could not. He decided that he had not made important discoveries, became the abbot of the Starobren monastery and did not return to biology.

Mendel's Three Laws

1. The law of uniformity: when crossing forms that differ by one trait (for example, purple or white flowers), the first-generation hybrids show a stronger (dominant) trait of one of the parents, which suppresses the alternative (recessive) trait. For example, if one parent has blood type A and the other has blood type B, then their children's blood contains antigens characteristic of both blood groups.
2. The law of splitting: when crossing heterozygous hybrids of the first generation, the ratio of the number of descendants with a dominant trait to the number of individuals with a recessive trait turns out to be close to 3:1.
3. The law of independent inheritance: when crossing two individuals that differ from each other in two or more pairs of alternative traits, these traits are inherited independently of each other and combined in all possible combinations. As a result, individuals with new combinations of traits appear among the descendants of the second generation.

The works of Gregor Mendel were recognized at the beginning of the XX century, when scientists from Germany, the Netherlands and Austria Carl Correns, Hugo De Vries and Erich Cermak-Zeisenegg independently "rediscovered" the laws derived by him. The progress made in the twentieth century in the study of the nature of genetic information can be divided into four stages. At the first stage, scientists discovered the cellular basis of heredity – chromosomes. The 1933 Nobel laureate Thomas Morgan identified their role in the transmission of hereditary information and, together with his students, discovered that chromosomes consist of genes that are always arranged in a certain sequence. In this case, the genes in one chromosome are always inherited together. These patterns were called the law of linked inheritance and the chromosomal theory of heredity.

At the second stage, studies were conducted on the molecular basis of heredity – the double helix of the DNA molecule (deoxyribonucleic acid). Despite the fact that it was discovered in the second half of the XIX century, it was only in the 1940s that scientists began to suspect that it was the main one of all living things.

For the discovery of the molecular structure of DNA, the Nobel Prize in Physiology or Medicine was awarded in 1962: the laureates were James Watson, Francis Crick and Maurice Wilkins. Their colleague Rosalind Franklin managed to obtain high-definition X-rays of DNA, and it was they who made it possible to draw conclusions about the structure of the molecule: it looked like a double helix. However, the researcher herself did not live to receive the award.

Watson, Crick and Wilkins established that the main elements of the DNA molecule are nucleotide bases (adenine, thymine, guanine and cytosine) – they not only connect to each other in a certain way and create a natural framework for a double helix, but also form an ideal means of copying genetic information. 

James Watson, Francis Crick and Maurice Wilkins carefully mention their discovery in their 1953 article in the journal Nature. This phrase is considered one of the most famous understatements in the scientific literature: "The observation that the specific compound [of nucleotides] that we postulated immediately suggests a possible mechanism for copying genetic material did not escape our attention."

In the structure of DNA, nucleotides are connected according to the principle of complementarity: thymine always corresponds to the adenine molecule, and cytosine corresponds to guanine, and there can be no other way. Knowing the sequence of nucleotides on one strand of DNA, it is possible to accurately predict their sequence on another. During cell division, the double helix is temporarily divided into two separate strands, and special protein machines complete the nucleotides for each chain. As a result, two identical copies of the DNA molecule are obtained. The technology of genotyping, which is the basis of today's popular genetic tests, is also based on the principle of complementarity.

Drawings: Julia Kuzmina

At the third stage of genetic research of the XX century, scientists focused on the principles of transmission of hereditary information. In 1958, Francis Crick formulated the central dogma of molecular biology, according to which genetic information is transmitted in a cell from DNA to RNA, and then to protein. This discovery made possible laboratory experiments in the field of genetics.

Finally, in the last quarter of the twentieth century, scientists began to seek to decipher what information genes carry, and then whole genomes (initially viral). So a new field of science appeared – genomics, a section of molecular genetics dedicated to the study of genes and the genome of living organisms.

When was the human genome decoded?

The task of obtaining information about the entire sequence of nucleotides in the human genome was first set at scientific conferences in 1984-1986 within the walls of the US Department of Energy. This idea was supported by a specially created commission of the National Academy of Sciences of the USA in 1988, and already in 1990 The Human Genome Project (HGP) was launched. Part of the project, which was planned to be carried out on the basis of the National Institutes of Health, was headed by James Watson. A year later, his unit was named the National Human Genome Research Institute (NHGRI). Genome studies conducted by the US Department of Energy, apparently, were of a closed nature.

The Human Genome project involved 20 research teams from the USA, Great Britain, Japan, France, Germany and China. Work on it lasted for 13 years and cost about $ 2.7 billion. For comparison: today it will take only a few months and about 1.5 thousand dollars to decipher the human genome.

In 2001, the journal Nature published an article about the first version of the complete human genome. Her authorship was shared by 2,800 scientists. Two years later, the Human Genome project ended with the publication of the final version of the article, where researchers finally estimated how many genes the human genome has. There were not 50 or 100 thousand of them, as some scientists previously believed. According to modern estimates, there are 21,306 genes in the human genome, but researchers still have not come to a consensus on this issue. During the project, they also received information about the entire nucleotide sequence of the DNA molecule and compiled genetic and physical maps of the genome. The completion of the Human Genome project marked the beginning of the so-called post-genomic era of genetics, which continues to this day.

Is there a "happiness gene"?

An important consequence of the Human Genome project was the obvious inconsistency of the concept of "one gene – one trait". Throughout the XX century, it was fashionable to investigate the so-called genes of war, happiness, depression, propensity to study, committing crimes, and so on. However, after decoding the human genome, it became clear that most of our traits are polygenic in nature. For example, several genes are responsible for human growth at once.

Any parameter of our body in the language of genetics is called a sign. Growth, peculiarities of smell perception, whether a person will be right–handed or left-handed, what kind of structure of the iris of the eye he will have, and so on - all these are signs. A set of polygenic traits is commonly called a phenotype, that is, a set of observed traits (eye or hair color, blood type, presence or absence of manifestations of any disease). The genetic basis of a phenotype is called a genotype.

What is a gene? The term "genetics" was coined in 1907 by the English biologist William Batson, and the concepts of "gene", "phenotype" and "genotype" were proposed two years later by the Danish biologist Wilhelm Johansen. He formulated the concept of a gene in this way: a gene is a discrete unit of heredity. With the accumulation of knowledge, this definition has changed, and now a gene is understood as a structural and functional unit of heredity that contains instructions for protein assembly. Since everything that happens in our body is the result of the interaction of protein molecules, individual characteristics of the body and predisposition to diseases will depend on changes in the DNA molecule.

In the post–genomic era, the contribution of genetics to our phenotype is studied within the framework of large-scale genetic research - Genome-Wide Association Studies (GWAS). The medical community has long assumed that most multifactorial or complex diseases that develop during life under the influence of environmental factors and due to an incorrect lifestyle have a genetic basis. But only at the beginning of the XXI century, technological progress made it possible to test these guesses on large groups of people – for example, in 2018, more than a million people took part in GWAS.

The first such study was conducted in 2005. It studied the genetic predisposition to the development of age-related macular degeneration (AMD) – chronic progressive disease, the main cause of poor vision and blindness in people over 50 years of age in developed countries. By 2010, the genetic basis for 250 multifactorial diseases had been determined. In 2020, we have already conducted 4,500 studies and understood the genetic nature of 5,000 different diseases and signs.

All studies on genome-wide association search have a similar design. A control group consisting of healthy people is formed, and a study group consists of participants with an established diagnosis. First, changes in the DNA molecules of the two groups are studied using genotyping technology. And then they make a conclusion about which changes are associated with the disease, and which correspond to the state of almost complete health. If a currently healthy person has genetic variants associated with the disease, then he falls into the risk group and should carefully monitor his health.

Genotyping is carried out on DNA microchips - complex devices the size of a microscope slide, on which fragments of a single–stranded DNA molecule with a pre-known sequence are applied in a certain order. These fragments act as probes, with which DNA fragments from the test sample, usually labeled with a special fluorescent dye, are bound according to the principle of complementarity. When the DNA under study interacts with the microchip, an optical signal is generated, which is read by the scanner and interpreted by the program, the operator and the geneticist. In one study, data is obtained on more than half a million points in a sample of a DNA molecule that have a proven connection with the studied trait, whether it is a disease or a feature of the body – for example, the perception of the fragrance of flowers or a tendency to develop insomnia.

The information that the development of the disease depends on a set of changes in various parts of the DNA molecule allows us to assess the risks of complex diseases in a new way. Within the framework of the polygenic risk calculation concept, they are calculated based on the cumulative effect of multiple genetic variants.

When did the era of "consumer genetics" begin?

Once the risk can be assessed, then it can be managed. This simple thesis was guided by the founders of companies engaged in so-called consumer genetic testing (because of the negative connotations of the word "consumer" in Russian, they can be called genetic "tests for healthy people"). For the first time such tests became available in 1996. With their help, it was possible to assess the risk of hereditary forms of breast and ovarian cancer. Another pioneer in the field of genetic testing is the company 23andMe, created by American entrepreneur Ann Wojicki. In 2006, she began selling her first genetic tests over the Internet, with the help of which it was possible to learn about the carrier of hereditary diseases, determine the risks of developing a number of diseases and signs not directly related to health.

The "era of consumer genetics 1.0" has begun. Players in the market of tests for healthy people sought to give customers the fullness of genetic information. Because of this, a number of issues have arisen, including of an ethical nature. For example, the data that companies received during the study of samples did not initially undergo proper quality control, and doctors did not participate in the interpretation of the results and did not discuss them with customers. In addition, there were no restrictions on the content of genetic tests, they often cited results that were not confirmed by science, and the Food and Drug Administration (FDA) initially did not control the work of such "genetic" companies.

But their activities still soon attracted the attention of the FDA. The Department conducted an investigation: genetic tests were acquired through front persons, and then requests were sent with a request to explain the results and disclose the basics of the companies' policies. The requests were not satisfied, so in 2013 the sale of genetic tests for healthy people in the United States was banned. As a result, 23andMe was forced to conduct a number of evidence-based studies. Two years later, the company received FDA approval for the sale of tests aimed at assessing the risk of hereditary diseases, and two years later, in 2017, multifactorial.

Thus came the "era of consumer genetics 2.0". Its distinctive features are the regulation of the activities of companies providing tests, multi–stage analytical verification of the data obtained (by programmers, laboratory assistants and geneticists), a clear division into important health information and cognitive and entertainment genetics, as well as restrictions on the content of genetic tests. Thus, they cannot include ambiguous information that has not been verified in the course of high–quality genome-wide (GWAS) studies - for example, it is forbidden to determine psychiatric diseases and various inclinations, including the development of addictions, using genetic tests. But the main feature of the new state of affairs in "consumer" genetics is that doctors must interpret the results, and company representatives must make sure that their clients have correctly understood the recommendations.

The favor of the FDA has become one of the reasons for the real boom of genetic tests. Even before that, they were steadily gaining popularity, as they offered everyone to find out about their origin. According to the MIT analytical report, by the beginning of 2019, more than 26 million genetic tests were sold in the United States alone – more than in all previous years of the existence of genetic tests combined. More than 250 companies offered various test options on the market. At the beginning of 2020, some experts noted a decrease in buyer interest. But perhaps this is only a temporary phenomenon, because with the further development of medical genomics, the relevance of such tests will only increase. After all, we live in a time when the concept of personalized medicine is being implemented – and genetics is at its center.

What can you learn by undergoing genetic testing?

Reputable organizations like the American College of Medical Genetics and Genomics constantly monitor what is happening in modern genetics and voice their position on new or controversial practices. So, today genetic tests are in great demand for the selection of diets, preparation of training programs, selection of specific sports and cosmetics. The Association of Molecular Pathology opposes such tests. And the consensus of geneticists and sports doctors, published in the British Journal of Sports Medicine, prohibits genetic tests for children to select a suitable sport (with a note that adults can spend their money the way they want). Unfortunately, the scientific community today does not have the results of high-quality, that is, large-scale, genetic research in these areas.

Modern genetic tests make it possible to clarify the risks of developing several dozen multifactorial diseases (high blood pressure, coronary heart disease, obesity, type II diabetes, etc.). Also, with the help of such tests, you can get important information for pregnancy planning: check for hereditary diseases that you should know about before conception. The genetic test does not exclude that in the future it will be necessary to undergo additional consultations and examinations, but it allows you to find out about the problem in time and take active actions – to make an appointment with a geneticist. Special tests allow you to objectively assess the hereditary risks of cancer, but this is primarily a service for people who have had or are suffering from cancer relatives. Publicly available genetic tests, as a rule, contain information only about the most frequent mutations associated with a hereditary form of breast and ovarian cancer.

Based on the results of the genetic test, it is still impossible to choose the optimal diet: alas, there is no proven scientific data on this topic. But it is possible to assess the predisposition to food intolerances (not allergies – their genetic basis is still poorly investigated), to identify the peculiarities of nutrient metabolism and taste perception. A separate interest is traditionally caused by cognitive and entertaining genetics of origin. Some companies, for example ancestry.com and 23andMe even offer services to search for living genetic relatives. Finally, there are genetic tests that are not directly related to health. With their help, you can find out, for example, the type of earwax, the severity of the smell of sweat, the perception of the fragrance of flowers, the structure of the iris, and so on.

Is our behavior conditioned by genes? Yes and no. What shapes a person's personality – his habits, inclinations, character, external traits, mental characteristics (altruism, empathy, tendency to risky behavior or addictions), ability to learn – of course, depends on genetics. However, her contribution to us is still less than the influence of the environment and society, upbringing and important events taking place in our lives. We still do not have high-quality scientific information that would allow us to fully interpret the test results and select treatment based on them or change prevention tactics. However, scientists are constantly conducting large-scale genetic research, and they are the future of medicine. 

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