Genomic selection. DNA is the material basis of heredity

Methodology "Cognitive orientation (locus of control)" Author - J. Rotter. The technique allows to identify the orientation of the personality to external (externals) or internal (internals) stimuli. Externals are convinced that their failures are the result of bad luck, accidents,

2. Cognetics and the locus of attention

2. Cognetics and the locus of attention He cried and got irritated, but it was all in vain. Dominic Mancini, not talking about a "frozen" computer, but about Edward V, King of England. "Occupatione Regni Anglie per Riccardum Tercium (1483)". Quoted in Alison Weir's Princes in the Tower (1992)

2.3. Locus of attention

2.3. Locus of Attention You can control the transformation of unconscious thoughts into conscious thoughts to some extent, as you have seen by moving knowledge of the last letter of your name into the conscious realm. However, you cannot intentionally translate your conscious thoughts into

Chromosomes contain two types of molecules - protein molecules and deoxyribonucleic acid (DNA) molecules. At first it was assumed that the main genetic substance is protein. The twenty different amino acids found in protein molecules can give rise to an infinite variety of combinations that can underlie the diversity of genes. And only in the early 50's. DNA has been proven to be the carrier of genetic information. It turned out that DNA by itself, regardless of protein, is capable of transferring hereditary information from one cell to another, while protein without DNA cannot do this. DNA has a molecular structure that provides the ability to duplicate and to form many different forms. The nucleic acid molecule is in the form of a strand, which is a chain nucleotides(Fig. 3.13). Each nucleotide consists of three parts: a nitrogenous base, a carbohydrate component, and phosphoric acid. Individual nucleotides in nucleic acids are connected to each other through phosphoric acid by a strong chemical bond. The carbohydrate component in DNA is represented by sugar - deoxyribose. The sugar and phosphorus components of all nucleotides are the same, as for the bases, there are four types of bases: adenine, cytosine, guanine And thymine. For simplicity, they are often denoted by the letters A, C, G and T. DNA is formed by two strands. Gene- - this is a small section of the chromosome that has a certain biochemical function and has a specific effect on the properties of the individual. Locus- The location on the chromosome where the gene is located. In the same locus, individuals of a certain species may have the same genes, but in many cases the locus does not differ in such constancy and one or another variant of this gene is located in it. Usually, these variants of the same gene are similar, although not identical. These different states of the locus are called allele . Often only two alleles are known for a particular locus, that is, two alternative forms of one gene, but it is not uncommon for a given locus to occur in a number of different states, and then we are dealing co multiple alleles .Despite the greater accuracy of replication DNA during processes mitosis And meiosis, errors inevitably occur from time to time, which lead to a change in the sequence nucleotides in the DNA strand, or gene mutations. A mutation can be a change from one base pair to another, the loss of one or more nucleotides, or, conversely, the addition of additional nucleotides. In this case, the worst option would be the loss or addition of one or two nucleotides. In these cases, the triplet reading frame will inevitably shift one or two bases to the right or left, and all subsequent triplets will be read incorrectly. If three bases fell out or were added at once, then the changes will affect only one amino acid, and the rest of the chain will remain true.
Gene mutations, arising in gametes, have a variety of effects on the body. Many of them are lethal because they cause too severe developmental disorders. It is known, for example, that about 20% of human pregnancies end in natural miscarriage within 12 weeks, and in half of these cases anomalies of the hereditary apparatus are found, which are caused, however, not only by gene mutations.
A gene mutation can cause this locus will match several alleles. This increases genetic diversity and increases the number heterozygous individuals. It is assumed that all genetic polymorphisms arose due to the replacement, loss or addition of nucleotides in the course of evolution.
Most gene mutations recessive relative to the "normal" allele. Such mutant alleles may circulate in a population for many generations until they manage to meet and emerge. From time to time, dominant mutant alleles can also occur, which immediately give an effect.
Mutations that occur in somatic cells are inherited only by those cells that are formed from a mutant cell by mitosis. They can affect only the organism in which they originated, but with death, individuals disappear from the gene pool of the population. For some somatic mutations cells with an increased growth rate are formed, which leads to the appearance of tumors.

LECTURE 1. Classical and molecular genetics. Basic concepts: trait, phenotype, genotype, gene, locus, allele, homozygote, heterozygote, hemizygote.

ICG SB RAS and FEN NSU, Novosibirsk, 2012

1.1. Classical and molecular genetics

Today's lecture is introductory, we will move on to the specifics later. As in the case of almost any science, it is rather difficult to delineate the boundaries of genetics, and a very general definition " genetics - the science of heredity' is not particularly fruitful. Zhimulev, for example, once said that now genetics is present everywhere - in medicine, forensics, the theory of evolution, archeology, and in genetics itself, even nucleic acids are almost invisible - entirely protein interactions. Thus, he actually put an equal sign between genetics and all modern biology. On the other hand, for about the first two thirds of the 20th century, genetics was perhaps the most isolated and clearly defined area of ​​biology, distinguished primarily by its synthetic methodology, in contrast to the analytical methodology of other branches of biology. In order to find out about the structure of her object, she did not divide it into parts, but judged the parts indirectly, by observing the whole (namely, by observing the behavior of traits in crossings) and relying on mathematics, and was convinced of the correctness of her conclusions, receiving live organisms with predicted properties. Thus, genetics from its very beginning had the ability to create something new, and not just describe the observed. At the same time, in the second half of the 20th century, molecular biology was developing rapidly - at first a purely analytical science, splitting into parts. However, its progress was carried out largely by genetic methods - to remember at least that genetic code was established in the experiments of Benzer and Crick using mutations in bacteriophages. However, in this case, the genetics of microorganisms was used, and the progress of "classical" genetics has always been associated with the genetics of eukaryotes.

As a result, molecular biology has received almost exhaustive knowledge of what and how a living organism is arranged. The subjects of molecular biology and genetics overlapped in many respects: both of them studied the transmission and implementation of hereditary information (and a living organism is the realization of hereditary information), however, they moved towards understanding this subject from opposite sides - genetics "from the outside", molecular biology "from the inside ".

In the last third of the twentieth century, molecular biology and genetics, so to speak, met, including in the study of eukaryotes. The speculative objects of genetics have turned into completely specific physical and chemical objects of a known structure, and molecular biology has become a synthetic science, capable of influencing at its own discretion even higher multicellular organisms - for example, genetic modification. Here the boundaries of genetics as a science were erased to indistinguishability - it became impossible to say where molecular biology ends and genetics begins. Moreover, the term “molecular genetics” appeared to designate the resulting synthetic science, as a result of which it became unclear what exactly remained in genetics outside the latter. The genetics of the premolecular period, with all its approaches based on crosses and probability theory, has been given the honorary title of "classical genetics". On the other hand, with this title, she was, as it were, sent into an honorable retirement. One may recall how Watson and Crick refused to discuss their model of DNA structure in their Nature paper because the implications were too large and obvious. At some point, it might seem that all genetics follows from this model.

A paradoxical situation is emerging. All courses in genetics begin with the history of this science. It understands how Mendel worked with peas, what he got and how he interpreted it based on his knowledge, then how Morgan and his school worked with Drosophila, what they got and how they interpreted. It is impossible to omit both of these topics - Mendel is an example of a person who developed from scratch and brilliantly applied a genetic methodology based on mathematics, and during the first three decades of the 20th century, the Morgan school developed the chromosome theory of heredity and, in fact, all classical genetics. Further, courses in genetics can be divided into two broad classes. Some work out in detail the entire history and internal logic of the development of this science, demonstrating both the power of its methodology and the capabilities of the human mind in speculative penetration into the depths of things. Other courses, having quickly skipped this historical period, proceed to molecular genetics and there they consider what is known at the moment about the structure and work of genes. In fact, both types of courses place classical genetics in the past and differ only in the detail of retrospection. It turns out that classical genetics has, as it were, only historical significance. However, its powerful methodology has not gone away and is necessary for a very wide range of studies. If we look at papers with quite molecular biological titles and published in the best journals, we will see that they are all based on extensive material concerning hundreds of individual mutations and their combinations, taking into account the relationship between the nature of mutations and the phenotype that they cause. This is true both for Drosophila or mice, for which huge genetic collections have been collected and special laboratory lines have been created (some about a hundred years ago, others recently), and for humans, where a huge amount of medical and genetic, in fact, population-based, has been accumulated. genetic - data associated with hereditary diseases. And the richer this arsenal of knowledge and model organisms, the more elegant the work. All these more than serious studies are impossible without the simultaneous mastery of the methodology of classical and molecular genetics. Therefore, it is best to study these “two genetics” in parallel, no matter how difficult it is to organize.

IN modern science one can also observe examples of how the neglect of "outdated" classical genetics leads to curiosities. For example, a group of European scientists needed to get a heterozygote for a translocation in a pea. (I am now speaking on the basis that you have some idea of ​​what is at stake. If you do not have it, it does not matter, we will consider all this in almost too much detail; for now, we are talking about the need for genetic knowledge). They got it through the fusion of the protoplasts of the parental lines. Regeneration from cell culture in peas is extremely difficult, it is an extremely laborious path. Why did they do it? Apparently, they thought that translocation carriers did not cross with ordinary peas! In fact, problems with reproduction when crossing parents that differ in translocation do arise, but only in the next generation and consist in the loss of only half of the fertility.

But these scientists at least needed a heterozygote. Meanwhile, the general fascination with molecular biology and neglect of classical genetics leads to the fact that the existence of heterozygotes - that is, that in eukaryotes each gene is represented in two copies, which may differ, or may be identical - is often completely forgotten. For example, an article by German authors came to my review, in which they directly read some non-coding DNA sequence from 38 dragonfly specimens caught in different regions (Western Europe, Western Siberia, Japan and North America) and found 20 variants of it. It was written as if only one variant was found in each individual. However, if the variability is indeed as high as they claim, then the probability that there is at least one individual in their sample for which both copies of this sequence are the same is not very different from zero. And it wasn't even discussed. After the review, they wrote that in five cases there was a suspicion of heterozygosity. If there really are only five, then they had in their hands the amazing phenomenon of the transformation of heterozygotes into homozygotes through mechanisms that are still unknown, but they did not even seem to understand this.

Phylogeny reconstructions based on certain DNA sequences are now widespread. So, very often attempts are made to judge, based on the time of divergence between populations, whether these populations belong to the same species or to different ones. (Note that it is the divergence time that is estimated, since the studied genes, whose variability is more or less constant over time, are obviously not those genes whose change could be associated with speciation). Meanwhile, the time of divergence generally has little to do with this problem - the moments of acquisition of reproductive isolation by a certain local population, that is, the moments of speciation, occur under certain conditions and usually do not take much time from a paleontological point of view (tens to hundreds of thousands of years), then how populations can diverge for a long time without speciation. The question is precisely to find out whether there is reproductive isolation (at least potential) between populations. To do this, you should see if there is an exchange of genes between them (if it is physically possible) or not. Here it is just very important to find out whether heterozygotes are present at the junction of populations according to the alleles characteristic of each of them, and what is their frequency. But almost no one does this, and whether populations belong to the same or to different species is judged by the level of differences between them, comparing them with differences in those cases that are assumed to be undoubted.

In general, if a single organism (for example, as a representative of its species) can be studied using molecular genetics methods, then as soon as it comes to a multitude of organisms, that is, a population genetic problem arises - and such a problem arises quite often, for example, in population biology and breeding - one cannot do without the approaches of classical genetics. Classical genetics is indispensable in everything that concerns individual differences and the characteristics of many individuals of the same species. This is precisely its element, and it is precisely in it that those current scientists who have replaced classical genetic education with molecular biological education often find themselves helpless.

Based on the foregoing, I see my task in presenting classical genetics not so much in a historical aspect, following the great scientists of the past, but starting from state of the art science, in particular - without abstracting from the knowledge that you have already received in the courses of molecular biology and cytology. At the same time, some patterns, discovered as purely empirical at the level of organisms, acquire a completely natural interpretation at the molecular level and look almost trivial. At the same time, these regularities themselves should be clearly understood, since they should be used at the level of organisms. In a sense, such a course in genetics is thought of as something like a "demonstration of tricks with revelations" - where both the trick itself and its background are equally "medical facts". Such a course would be designed to teach a very productive methodology: to go down from a trait to genes and, through understanding the mechanism of their action, climb back to the synthesis of new traits.

As you already understood, at the moment the content of genetics is huge and heterogeneous, so the time allotted to us is hardly enough even for a brief introduction. This forces us to leave behind the scenes the history of genetics as independent topic to which the special course should have been devoted.

Unfortunately, none of the existing textbooks corresponds to the ideal of studying genetics at the present stage outlined above - from trait to gene and vice versa, most likely because this science is developing too quickly now. As some compensation for this circumstance, I will try to post my modest lectures on my own website, where they will be available to those to whom I give their address - that is, to you. I would recommend taking as a basis the textbook - Vechtomov "Genetics with the basics of selection." The textbook of Academician Igor Fedorovich Zhimulev "General and Molecular Genetics" is also well known, in which the main emphasis is on molecular genetics, and Leonid Vladimirovich recommends it as a basic textbook. I understand that two basic textbooks is not the most convenient situation for passing the exam. But it does contribute to the understanding of the subject. I can say that I personally am here and generally work at the Institute of Cytology and Genetics solely because I took a course in genetics by Vladimir Aleksandrovich Berdnikov. It was best course, which I heard, and it did not correspond to any textbook at all, because V.A. prepared it based on the materials of the latest reviews in scientific periodicals, which have not yet been included in any textbooks. Igor Fedorovich also turned his original course of lectures into a textbook.

We will touch on the basics of genetics very thoroughly in order to feel them well. We will start from the very beginning, despite the fact that the most elementary foundations of genetics are covered at school, so that, God forbid, we do not miss something simple, but important. On the other hand, I am dealing with undergraduate students who have already taken a course in molecular biology and are currently studying the theory of probability and mathematical statistics, which allows me not to be too distracted by the materials of these courses, which are so necessary for studying genetics. For example, I will assume that you know (or will know at the right time) what is alternative splicing or Poisson distribution.

The standard logic for presenting biology in university courses is to move from the bottom up, from atoms to molecules and macromolecules, then to the structures of the cell, to the life of the cell itself, and then to the multicellular organism. When we know the principles of organizing life to the end, this order of presentation turns out to be organic and natural. These principles also include the mechanism of functioning of nucleic acids as a carrier of information, primarily about a variety of proteins and functional RNAs (which, after the discovery of small RNAs, turned out to be more diverse than previously thought), and not only about their structure, but also about when, where and how many particular RNAs or proteins should be synthesized. The control of these processes is again carried out with the help of certain proteins (and often RNA). There is a cascade principle in the unfolding of genetic control systems - genes encode proteins (RNA) necessary to control genes that encode other proteins (RNA), etc. Since almost everything in the body is “made” by proteins (plus some RNA) , it turns out that, in fact, information about the whole organism is recorded in nucleic acids - however, reading this information is impossible without previously synthesized (again, according to the DNA matrix) proteins that operate on DNA.

This order of presentation completely coincides with the order in which life itself developed. At first, these were some kind of “simple” (but only in comparison with what later emerged from them) systems of self-reproducing macromolecules, apparently, nucleic acids. Then they happened to surround themselves with a phospholipid membrane, which allowed them to build their own microcosm within it. This is how cells were born. Proteins played an increasingly important role in the functioning of these first living creatures, but nucleic acids retained full control. Cells became more complex and learned to divide more and more correctly. After division, they sometimes did not disperse, forming colonies. These colonies faced increasingly complex problems due to their size and shape - all the cells in the colony had to be supplied with everything necessary for life. The resolution of these problems was achieved through a certain structure of the colonies and the division of labor between their constituent cells. Simple colonies have turned into states of cells, that is, into multicellular organisms. The problems of their self-reproduction as complex structures were also solved, and this was realized in such a way that each organism could develop from one cell by deploying a complex genetic program that regulates cell division and interaction between them.

However, this standard order of presentation of biological knowledge is diverted from how it was obtained. And they were obtained as science developed in the opposite direction - from organisms to organs, cells, macromolecules and atoms. As they dived into each of these levels, scientists could only make guesses about how the deeper level works. Once upon a time, the maximum they could do was open the body, look at the organs and guess how they work. When the cages were opened, they were first thought to be filled with emptiness. Then they discovered protoplasm, but at first they saw it only as a viscous liquid, in which, however, in some mysterious way the essence of life was contained. Discovered the nucleus and organelles of the cell. They found dyes that color them differently, and thus approached their chemical composition. At the end of the nineteenth century. discovered nucleic acids and figured out their approximate chemical composition, but their specific structure has long remained a mystery, the solution of which looked so brilliant. On this dive into the depths of biology, perhaps, stopped. The period of accumulation of particulars at this deep molecular level has come. There were an unusually large number of particulars. Now we are going through a period when this huge number of details are beginning to be combined into a certain coherent picture - a model of the structure of a living organism. Moreover, this model is so complex that it can not be fully understood. human consciousness, so that not only its construction, but also a visual description and use is impossible without modern computers. However, by the end of the twentieth century. all the basic principles of biology were discovered. Classical genetics, by the efforts of a few talented scientists, developed almost in its entirety during the first three decades of the 20th century as a coherent and logical science.

Classical genetics is just a vivid example of the movement of the researcher from the macro level to the micro level. It reconstructs the scheme of the system from its behavior, approaching it as a black box. As if alien mechanisms of an unknown device fell into the hands of scientists without any schemes and instructions for them. Two main features can be noted. First, this is the amazing depth of reconstruction, which she achieved with a lack of direct information about the structure of the object. The power of the classical genetic approach is impressive: dealing only with visible signs, it made it possible to create an idea about intelligible genes, about their placement in some kind of mysterious linear carriers, about changes in genes and these carriers. Based on the pattern of inheritance of traits, with its help, an idea was obtained about the structure of carriers of genetic information, the transfer of this information to descendants and its transformation into living flesh. The second feature is the already mentioned synthetic rather than analytical nature of genetic knowledge, the validity of which, in the very process of obtaining it, was immediately embodied in the creation of some new one - organisms with new features. It is enough to have a well-studied genetics of a few model objects, then the rest of the objects can be judged according to their similarity. The well-known aphorism of Thomas Morgan “what is true of the fly is true of the elephant”, of course, is a rather strong exaggeration, and we will see this. However, such an approach (which also found its expression in the so-called law homologous series) still works.

Crossing is the main method of classical genetics. Geneticists came to most of their conclusions by observing the behavior of the traits of parents and offspring, and the actions of the researcher with each new generation are determined by the results obtained in the previous one. That's why genetic research a bit like a chess game. The conclusions drawn from such studies were extremely detailed and, as the further development of science showed, were correct. Gregor Mendel in his experiments on peas in late XIX V. actually postulated the existence and described the behavior of chromosomes in meiosis, without having the slightest idea about chromosomes. The relationship of genes to chromosomes was established only at the beginning of the 20th century, and almost until its middle it was strongly suspected that proteins were the material carrier of heredity. In other words, if other branches of biology were not very detached from the descriptive approach, then genetics in its models was far ahead of the time when the objects it studied could be described as material entities. In the tragic period of the history of Russian science, which fell under the ideological dictate in the 30-50s of the last century, this gave rise to declaring genetics an idealistic pseudoscience and throwing our country, which was at its forefront, far back, and destroying the best geneticists physically.

Such a cognitive power of classical genetics as a science capable of drawing correct conclusions about the behavior of certain cell microstructures based on the behavior of traits in crosses, even without having an idea of ​​what they consist of, is primarily due to the fact that genetics includes a lot of mathematics from its various industries. And this circumstance owes its existence to the fact that the object of genetics is not a certain biological structure, but information. Information can be studied regardless of the material medium on which it is implemented. So, in his work, a programmer does not need knowledge about how exactly his program will be embodied in the state of crystals in a computer processor, although he is aware that it will be implemented on this very computer. physical basis. Genetics is essentially biological informatics. Computer science used to be called cybernetics. And it was another "pseudo-science" that was persecuted under Stalin and Khrushchev, for all the difference between them. (Fortunately, at that time it was not as developed as a branch of mathematics as genetics as a branch of biology, and as a result, less damage was done by this company).

"classical" genetics(sometimes called Mendelian, although what is meant is much broader than what Mendel discovered, and the notorious ideological stigma “Mendelism-Morganism” would be more suitable here) can be defined as the science of heredity, operating with the abstract elements of the organism's development control system, being distracted from their material carrier and, in fact, not needing it. Respectively, molecular genetics can be defined as the science of the molecular mechanisms underlying heredity. I hope it would be superfluous to call not to give these and similar formal definitions of great importance. In real scientific practice"two geneticists", and even more so, there is no boundary between them, and the above definitions in themselves only indicate the general direction of thought ...

However, it is known that any definition of anything is imperfect, since our thinking is not mathematical logic and concepts - what our thinking operates on - do not come down to words - that with the help of which we fix and communicate with certain losses. thinking results. Concepts can only understand(with varying degrees of distinctness), observing their interactions with previously witnesses concepts on a set of texts, where concepts are denoted by words. A definition is just the most concise and effective text that brings you closer to understanding, but there will always be situations where any definition does not work (despite the fact that concepts do). Where possible, I try to give definitions that seem to me the most successful, not particularly caring about how they correspond to those previously proposed or original, but I do not take them too seriously and am very far from thinking that writing them down from dictation and memorization can make it easier understanding of the subject.

At first, genetics consisted of the lonely feat of the only scientist who was not understood by any contemporary and who, by virtue of personal genius and versatile education, himself proposed a fruitful methodology, and scrupulously carried out lengthy and extensive experiments and made an unobvious speculative assumption. Shortly after the rediscovery of genetics, that is, its emergence as a science of many, it was discovered that the factors of heredity are located in a strictly defined order and at a certain distance from each other in several linear structures, the number, relative size and behavior of which coincided with the number, relative the size and behavior of chromosomes during meiosis. The chromosome theory of heredity was formulated in 1900-1903. American cytologist William Setton and German embryologist Theodore Boveri and further developed by the famous American geneticist Thomas Morgan and his school - Möller, Sturtevant, Brizhdes. (This was the first time since 1906 that they began to conduct research on Drosophila, and at first they planned rabbits, but this plan was not missed by the financial manager of their university. Charles Woodworth was the first to cultivate Drosophila, he also suggested that it could become a convenient object for the study of heredity.) And this important conclusion about finding heredity factors in chromosomes, obtained so early, was rejected by official science in the USSR from the late 1940s to the early 1960s!

Comparison of speculative genetic maps (the relative location of genes in these structures) and various parts of chromosomes made it obvious that the genes are located in them. But this is not so necessary for classical genetics - its models, tested by the results of crossings, put genes in a kind of "virtual chromosomes". So to this day, for most objects, there are two types of chromosome maps: physical maps, showing exactly where on the chromosomes visible under the microscope or on the DNA molecule the genes are located, and genetic, or recombination cards, reconstructing mutual arrangement genes from crosses. The order of the genes in these two types of maps completely coincides, the relative distances between them are far from always, and there are quite exhaustive explanations for this, which will be discussed later.

As a science of information and control, classical genetics even has a structure similar to mathematics. It rests entirely on a system of speculative a priori concepts with which observed phenomena are correlated (in contrast, for example, to cytology, whose conceptual apparatus is introduced on the basis of empirical facts visible to the eye). Unfortunately, in the terminology corresponding to these concepts (and concepts and terms are not the same thing), a certain inconsistency has accumulated during the existence of genetics, which I will specifically focus on so that you are not misled by various word usage in the genetic literature. Of course, genetic concepts are introduced on the basis of observed facts. But the main ones are introduced rather as speculative mathematical concepts. There are many concepts and corresponding terms in genetics. But they are really needed, and, once introduced, they practically exhaust the subject. In many cases, it is enough to compare the observed phenomenon with a suitable concept, and everything becomes clear. Perhaps a good explanatory dictionary of genetic terms could serve as a textbook on genetics. Pedagogically, it would be more correct to introduce the conceptual apparatus and terminology as they become necessary. But there is no harm in introducing and discussing the basic concepts from the very beginning, and then noting the places where they are needed. We will proceed from the fact that you are already familiar with some concepts at least from the school course and sometimes use them even before discussing them in detail.

1.2. signs of organisms. Phenotype and genotype.

Perhaps the most important genetic concept is sign. Genetics as a science began precisely at the moment when Gregor Mendel began to analyze individual traits, and not all heredity as a whole. Can you tell me what is a sign? And how many can there be? A sign is anything associated with an individual, as long as there is a way to somehow register it. Height, weight, color, call height, half length of tail added to the square root of a third of nose length, number of hairs in beard, shape of burrow or anthill, number of males chasing one female, length of time during which you can not breathe underwater , the number of lovers the mother or daughter of the studied subject has. I'm not kidding - among the signs of carriers of a certain variant of one of the dopamine receptors, there is a high frequency of the sign "grew up without a father" (it is clear that here it was more about the sign of one of the parents, and not the subject under discussion, who, however, could inherit the predisposition ).

The choice is huge, but the more successful, wiser or wittier you choose a sign, the more information you will learn from experience. It is clear that you should not add the square root of the length of the nose to the length of the tail, since both lengths have the same dimension, and as a result you will get mathematical abracadabra. But if we add the cube root of the body mass to the length of the tail, then this makes more sense, because the mass depends on the cube of linear dimensions and, having extracted the cube root, we get a value commensurate with the length of the tail, and adding the two mentioned quantities, we get a certain measure linear dimensions.

It is easy to understand that not all signs from their infinite variety are equally informative. Some are equally informative, but add nothing to each other. For example, if we take two such signs: the length of the right leg and the length of the left leg, then it is even intuitively clear that although the two legs may differ slightly in length, the second will add little to the first. Take the following signs: the length of the left leg and height. What can we say about them? The greater the height, the greater the length of the legs - this is quite obvious. The height and length of the legs are correlated - no more, but no less. Indeed, if we take a sample of people, measure the height and length of the legs and calculate the correlation coefficient, then it will be quite close to unity and highly reliable. But we know that people are generally short-legged and long-legged. And if we take height and the ratio of leg length to height, we get two completely independent traits - linear dimensions and long legs, which can be inherited independently.

We have a ratio of two measured values. As a rule, working with many features immediately requires correct statistical processing. For such processing it is not very convenient to deal with relations. But there is a set of mathematical methods called multivariate statistics(in particular, principal component method for quantitative traits), which allows us to obtain N new traits from N of any traits that we have measured, which are linear combinations of the original ones (their sums with different coefficients) that will not correlate with each other. This means that each of them will carry independent information. And if we look at how N of these new features are composed, we will see that one of them reflects, for example, linear dimensions (this will include all the lengths of the body, arms, legs, etc.), the other - the thickness, the third – thickness unevenness (pronounced waist, hips and bust), the fourth – the relative sizes of the head, the fifth – dark skin, etc. Such features are the most informative, and they have a different contribution to the overall variability of objects, which can also be assessed. However, multivariate analysis methods do not solve the problem of feature duplication, since duplication affects the mentioned relative contribution to the overall variability of the new feature in which they fall. This problem has not been solved in mathematical statistics so far.

Signs can be very different, but they fall into two large classes - quality, or alternative, And quantitative, or continuous. A trait is qualitative in the case when variability manifests itself in the existence of several alternative variants of the trait, that is, in the belonging of an individual to a certain clear class, and its assignment to one of the classes is beyond doubt. For example, we can distinguish two such classes of human individuals as men and women. Women can also be divided into several alternative classes. Suppose a girl is dressed in trousers or her legs are dressed in a single cylindrical piece of matter - a dress or a skirt. We get two classes. The last case can be divided into two classes - dressed in a dress or in a skirt. We get three classes of women. Women can certainly distinguish many alternative classes regarding clothing and at the same time will not experience the slightest difficulty in classifying. Classical examples: pea flowers are white or purple, fruit fly eyes are again white or purple; funny, but both organs can also be pink, and this is another state of a qualitative trait, a separate class. In cases where it is possible to distinguish qualitative (alternative) features, and individuals belonging to different classes (variants) are regularly found in nature, it is customary to talk about polymorphism, and the classes (variants) of these features are usually called morphs, or forms It is originally the same word, in Greek and in Latin, but the meaning of the second is too ambiguous, and it is better to avoid it. Etymologically, both words denote form, but as terms are used for any features, for example, those associated with color. Below are two morphs - with yellow and purple flowers, respectively - of the Altaic Violet, occurring in nature with approximately equal frequency.

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Since we all went to school, we can suspect that the white and purple iris are homozygous for some alleles, and the lilac is heterozygous for these alleles. But we (in particular, I) do not have such information yet, and in any case we must start by ascertaining three color morphs.

We have mentioned three clear classes of pea flower color - white, purple and pink. But apple trees with purple petals grow on Zolotodolinskaya Street. And there are apple trees with pink, with slightly pinkish and white petals. In the case of carnations sold in stalls, it seems to us that the color of the flowers is a quality sign - there are red, white, pink and white petals with a red trim. And flower breeders probably have such a variety of carnations that the trait turns into a quantitative one. You can take a spectrophotometer, extract the anthocyanin pigment from a standard sample of petals and measure the intensity of the purple anthocyanin color, expressing it as a number. And then we get quantitative sign- this is a sign that can be expressed as a real number. One and the same sign in different situations can act as both quantitative and qualitative. For almost any qualitative trait, you can find a way to measure it and thus consider it as a quantitative one. On the contrary, most quantitative characteristics cannot be considered as qualitative, since the values ​​of the measured parameter are rarely grouped into clearly distinguishable classes.

Human height (if we exclude obvious dwarfism) is a typical quantitative trait. How many growth options are there for a normal person? That's right, it's impossible to say - this is a positive real number, and the number of "options" depends on the accuracy with which we measure and what are the physical limits of this quantity. The height of many people can be characterized by its average value. But we also need some characteristics of its variability. To do this, we will have to study the frequency distribution of a quantitative trait. Another textbook example: if we take a lot of people, measure their height to the nearest centimeter and plot them by height so that people with the same height stand in one column, we get the following picture: the length of the columns forms a kind of bell-shaped curve. With sufficient fractionation of measuring height and the number of people, it will reproduce well well-known in probability theory - normal or Gaussian distribution.

Dispersion" href="/text/category/dispersiya/" rel="bookmark">dispersion - the averaged square of deviations of individual values ​​from the mean. Square root from this value gives standard deviation, its dimension coincides with the dimension of the measured quantity, and it can serve as a measure of the spread of a feature. About 70% of all normally distributed objects, no matter how many we measure them, lie in the range of values ​​from the mean minus the standard deviation to the mean plus the standard deviation. If this interval around the average is doubled, then there will be about 90%, if three times, then about 99% of the objects.

The central limit theorem of mathematical statistics states that the distribution of the sum a large number independent random variables approaches normal. And almost any quantitative trait is formed under the influence of a large number of multidirectional and different in strength factors (this is especially true for body size). That is why most of the quantitative characteristics obey the normal distribution.

However, this statement is true only in the first approximation. As is known, in order to assess the acceptability of the model, it is necessary to pay attention to the boundary conditions. The normal distribution is symmetrical and is given on the entire set of real numbers, from - to +, although the probability density falls off rather quickly when moving away from the mean. Let's return as an example to the sign "human height". Indeed, we do not have a hard upper limit on the height of a person, and no matter what record holder we find, there is never a guarantee that sooner or later a taller subject will not be found. But there is even a theoretical lower limit - after all, a person’s height, by definition, cannot be less than zero. This means that the boundary conditions do not allow the Gaussian model for human growth. Moreover, if we take a lot of people, we find that the distribution of their height is slightly asymmetrical and skewed to the right - the physical lower limit at zero makes itself felt! What model can we offer instead of Gaussian as more adequate for the quantitative features of biological objects?

Let's think about this. Signs are formed during the individual development of the organism, which in fact is a very complex chemical reaction that occurs under the control of genes, which at certain moments provide certain concentrations of certain substances. These concentrations act as factors in the equations of rates that make up the individual development of reactions (for example, the Michaelis equations), and the values ​​of the signs directly depend on some of these (or even all) rates. Therefore, the individual contributions of individual genes to a quantitative trait usually do not add up, but are multiplied, that is, each gene increases or decreases the value of the trait by some times. The product of many independent random variables tends to lognormal distribution. As a result, the real distributions of quantitative traits of organisms are not normal, but log-normal. They are really very similar, but still somewhat asymmetrical - more gentle to the right.

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Normal (A and B) and dwarf (C) peas

It is this trait - the relative length of the internode - that is here an alternative trait, while plant growth very rarely behaves like a true alternative trait.

There is another conditionally distinguished class of features, which you need to have a clear idea of. Let's take such a sign as the number of processes on the horns of a deer. The smallest horns are unbranched. In the maximum case, we have 10 processes on both horns. We will not experience any difficulty in assigning this or that horn to a class with a certain number of processes, and on this basis we can think that this is a qualitative feature. But the quality here correlates with an integer, and the number of classes, like a series of integers, is unlimited (no one can guarantee that sooner or later we will not come across a deer with 11 or more processes). Such signs are called countable; they are also called meristic, which can be confusing, since we do not need to measure here, but to count. In fact, there is a simple pattern here - the larger the horn, the more processes it has; just in order for the appendage to be added, the rudiment of the horn needs to gain some critical mass gain. So a countable number of processes is just a measure of the size of the horn. In the case of the number of cells on a dragonfly's wing, this becomes even more obvious. We get the same measure when measuring, when we stop at some of its accuracy. Imagine if we do not count the processes of the antlers of a deer, but the hairs on its young antlers. In fact, we have different measures of the size of the horn, but with different steps (rounding).

They operate with countable signs using the same approaches as with quantitative ones, with some features of mathematical processing. And it would be a mistake to apply to them the same approaches that are applied to alternative features. For example, one Moscow group of scientists studied the number of cells in certain areas of dragonfly wings. They counted the average number of cells, determined the mean and standard deviations, and, for example, found that these means differed statistically significantly in two different water bodies. They concluded that the populations at the two lakes are genetically specific, on the basis that alternative traits must necessarily be determined by hereditary factors, one or a few. But then they operated with their sign as with a quantitative one! Most likely, in one of the reservoirs, dragonflies developed under less favorable conditions and had a smaller wing area, which contained fewer cells, the size of which is rather standardized in ontogeny.

Finally, a third large class of features is often distinguished - rank features. We are talking about those cases when we can rank objects according to the principle "more" / "less" ("better" / "worse"), but we do not have a direct opportunity to express this quality of the superiority of some over others numerically. Situations in which ranking signs appear are quite diverse. On the parade ground, we can easily build soldiers by height without measuring their height; in the same place, by shoulder straps, we easily recognize military ranks, knowing in advance in what order they are ranked relative to each other. In some cases, we are forced to subjectively evaluate some complex integral parameters, for example, the "strength" of individual plants, classifying them into "strong", "medium" and "weak".

It is curious that as soon as we have ranks, we already have a rough numerical measurement of a trait, albeit a very approximate or subjective one. Thus, ranks, being ordinal numbers, are themselves integers. And it is already possible to operate with them as with measurable features. With all the conventionality of such a "measurement", mathematical methods have been developed that make it possible to obtain very reliable conclusions on their basis. Moreover, even undoubted qualitative features can be treated quite approximately as quantitative ones. Suppose, if we have four color morphs, then we can consider them not as one qualitative trait, but as four quantitative traits, each of which can take two values ​​- 0 (the individual does not belong to this morph) and 1 (the individual belongs to given morph). Experience shows that such similar artificial "quantitative features" can be successfully processed.

As examples with the growth of peas show, the same trait can be both quantitative and qualitative. Any quality we distinguish can always be somehow measured (even belonging to the male and female sex can be measured as the ratio of certain hormones). The choice of how to operate with a sign - as a value of a numerical parameter or as an indicator of belonging to a class - is dictated by the characteristics of a particular task. In the case of a bimodal distribution, it is useful to divide all individuals into two classes, at least as a first approximation, even if the two humps of the distribution merge and we cannot uniquely classify the individuals that fall between them, except by formally introducing a threshold value.

Both qualitative and quantitative traits can be inherited to some extent, and therefore, fall into the field of view of genetics. To analyze quantitative and qualitative traits, genetics uses different models. The inheritance of qualitative traits (it was with them that Mendel worked) is described in terms of combinatorics and probability theory in a simpler and more accurate way, and we will mainly deal with it. The inheritance of quantitative traits is described in terms of mathematical statistics and is based mainly on the analysis of correlations and decomposition into variance components. As mentioned above, inheritance of qualitative traits can also be treated as inheritance of quantitative traits, which in some cases turns out to be a very fruitful approach. I hope we will have time to briefly review the beginnings of quantitative trait genetics. In the meantime, a little more terminology.

Two no less broad concepts than a sign, without which, however, one cannot do - genotype And phenotype. These terms themselves, like the term " gene", introduced in 1909 by the Danish geneticist Wilhelm Ludwig Johansen. The phenotype is everything that concerns the characteristics of the organisms in question, the genotype is everything that concerns their genes. It is clear that there can be an infinite number of signs, and there are tens of thousands of genes. Moreover, no one registers the vast majority of traits, and no one knows the vast majority of genes. But the phenotype and genotype are working concepts, the content of which in each case is dictated by a genetic experiment. A genetic experiment usually consists in the fact that someone is crossed with someone, often over many generations, and they follow the signs of the offspring, which can be selected, crossed, etc., in accordance with these signs. Or a sample of individuals is removed from nature , register their features, find out which variants are represented by some genes, observe the dynamics of their frequencies. In each case, we are looking for well-defined traits and genes, often a few. And when we talk about the phenotype, we mean the values ​​or states of precisely these traits, and when we talk about the genotype, then the set of these genes. There is a dependence of the first on the second, but, as we will see, not the most direct one. Genetics largely consists in elucidating this dependence. And only if the DNA sequence itself appears as a feature, the phenotype coincides with the genotype.

Only recently has it become possible to conduct high-tech experiments on tracking all known genes of those objects in whom they are known (for example, humans) - for example, by the presence or absence of all messenger RNA or all proteins in a particular tissue. The corresponding areas were named, respectively, "proteomics" and "transcriptomics", and the totality of all proteins or messenger RNA present in a particular object, respectively - proteome and transcriptome.

1.3. The concepts of "gene", "locus", "allele", "ortholog", "paralog", "mutation".

Based on our preliminary assertion that there is a lot of mathematics in genetics, we should expect terminological rigor in it. Unfortunately, it is also an empirical science that exists on a huge and heterogeneous experimental material, made by many scientists of different specializations (and different education!), And this led to the existence of various terminological "dialects" in the genetics, including in things very important. Let's move on to a concept that may seem central to genetics, but which in reality turned out to be too vague for this. Tell me what is gene? It's actually a very unlucky concept, so it now has multiple meanings. In classical genetics a gene is an inherited factor that affects the traits of an organism. Once it was considered as further an indivisible unit of heredity. After the discovery of the structure of DNA, it quickly became clear that many classical genes are sections of DNA encoding a certain protein, for example, an enzyme, which determines the inherited trait. This was a huge breakthrough in science, and on this wave it initially seemed that All the genes of classical genetics are just that. The following formula was developed: One gene - one polypeptide chain". It was proposed, in the original formulation "one gene - one enzyme", in 1941 (that is, 12 years before the decoding of the structure of DNA by Watson and Crick) by George Beadle and Edward Tatham (you will find portraits of these and many other scientists in the textbook) who worked with neurospore mold strains that differed in their ability to carry out certain biochemical reactions and found that each gene is responsible for one specific biochemical reaction, that is, for a certain stage of mold metabolism. For these works they received the Nobel Prize in 1948. Note that at that stage the gene was still understood quite classically, but active research was carried out to find out what it physically represents. And after the discovery of the structure of DNA, everything seemed to fall into place and the genome began to be called the DNA segment encoding the polypeptide chain.

However, over time, it was found that next to the coding sequence there are always regulatory DNA sequences that do not encode anything themselves, but affect the switching on and off and the intensity of transcription of this gene. You know them well: this is the promoter - the landing site of RNA polymerase, the operators - the landing sites of regulatory proteins, also enhancers- also sites for regulatory proteins that promote transcription, but are located at some, sometimes significant, distance from the coding sequence, and silencers- sequences that prevent transcription, etc. Sometimes they are located hundreds and thousands of nucleotides (on the scale of the chromosome, this is not so much), but still function as cis-factors (i.e., nearby), physically located nearby due to a certain DNA stacking. All this economy began to be considered as belonging to a gene that encodes something. Thus, in the molecular genetics of eukaryotes a gene is a coding region of DNA together with adjacent regions of DNA that affect its transcription.

For such a site in 1957, S. Benzer proposed a clarifying term cistron, which was also unlucky, since this term began to denote only the coding region of DNA (the so-called open reading frame), and sometimes the DNA region between the promoter and the terminator, from which a single RNA molecule is read. You remember that in prokaryotes, in which molecular genetic mechanisms began to be elucidated earlier, the operon organization of genes is widespread, when sequences encoding several polypeptide chains have common regulation and are read as part of a single mRNA. This does not allow the use of the above definition of the term "gene". On the other hand, the term "cistron" is of little use here: being defined as a DNA region from which a single RNA is read, it will include regions encoding several different proteins, which, on the other hand, was once called the "polycistronic principle of organization of genetic material." As a result, the use of the terms "gene" and "cistron" without explanation (at least which kingdom is in question) is currently fraught with misunderstandings.

Note that in the molecular biological sense, the gene turned out to be subdivided into parts - exons, introns, operators, enhancers, and finally - individual nucleotides. And the regulatory sequence of DNA, taken as such, has lost the right to be called a gene, since it does not encode anything itself. But due to the effect on the transcription of the gene, this sequence can also affect some trait (i.e., the phenotype) that will be inherited along with this sequence. And it can be separated by recombination from the coding sequence, especially if it is a remote enhancer. In other words, the regulatory sequence is also a special hereditary factor, which also has its own place on the chromosome. Some regulatory sequences, such as enhancers, can affect the transcription of several genes at once, i.e., occupy their specific place in the regulatory network that controls the development and functioning of an organism. There are all signs of a gene in the understanding of classical genetics.

This contradiction between the classical and molecular biological concept of a gene, which arose at a time when it seemed that all classical genes are transcribed sections of DNA encoding a protein or RNA, has not been overcome so far, which, however, is not particularly important, since the word "gene" has not been used as a strict term for a long time. In connection with the rapid development of molecular biology, the molecular biology wins: a gene is a transcribed section of DNA along with its regulatory DNA sequences. However, the classical concept that a gene is a hereditary factor (no matter how it functions, what it is and what it consists of) was historically the first, lasted more than half a century and turned out to be extremely fruitful. You need to be aware of this contradiction and learn to understand what is being said from the context.

In practice, this contradiction is resolved in two ways: either before using the word "gene" its meaning is preliminarily specified, or it is not used as a term. An example of the first case: in the section "materials and methods" in an article devoted to counting genes in the genome, it will be written by what criterion the gene was determined - for example, the number of open reading frames was counted. In the next article they will write: we analyzed the expression and showed that some of the potential reading frames found are never transcribed and, apparently, are not genes, but pseudogenes. An example of the second situation: a locus is being studied, from which several thousand proteins are made due to the fact that there are three alternative promoters, three alternative terminators and a dozen introns subject to alternative splicing. Where is the gene here and how many genes are at this locus? In this case, the word "gene" will be mentioned only in the introduction, as a synonym for the word "locus". If we take a phrase containing the word "gene" from the population genetic context and insert it into the molecular biological context, then we will get a loss of meaning.

Different variants of the same gene, in any sense, are denoted by the term alleles. In this form, the term was proposed by W. Johansen in 1926, on the basis of the term "allomorphic pair" introduced by W. Batson in 1902). The concept of "allele" appeared when nothing was known about the structure of DNA, and it was introduced precisely as Alternative option gene. This concept is especially important for diploid organisms, which receive the same set of genes from father and mother and, as a result, each of them is present in the genome in two copies, which may be identical or differ, but not to such an extent that it cannot be said that it is "same gene". These two copies are called alleles.

It's funny, but with regard to the term "allele", there is no unambiguous solution to such a simple question as the grammatical gender of this word in Russian. Moscow, as well as Kiev and Novosibirsk schools, believe that the allele is masculine, Leningrad (St. Petersburg) - that is feminine. You can see that even in the two recommended textbooks this word is used in different ways.

The term "alleles" was originally introduced to refer to variants of a gene responsible for a particular trait that are associated with the state of that trait. However, it turned out that genes independent of each other can influence the same trait in the same way. This raises the problem of distinguishing between alleles of the same or different genes. Fortunately, even earlier it became clear that genes are located in a strictly defined sequence in linear structures - as it turned out, in chromosomes - so that each gene occupies a strictly defined place on one of the chromosomes. Therefore, each gene could be identified not only by its influence on the trait, but also by its place on a particular chromosome. It turns out that each place on the chromosome responsible for some trait - locus- is occupied by one of the alleles - individual variants of the gene. The diploid nucleus contains two alleles of each locus, obtained from mother and father, different or identical. Locus can be defined as position on a chromosome occupied by a certain hereditary factor, A allele- How variant of a certain hereditary factor, and since it is the locus that gives certainty to the hereditary factor, but the allele is variant of a hereditary factor located at a particular locus. Obviously, this definition is given from the point of view of classical genetics. In this case, it is better to say "locus on the chromosome." and not the “locus of the chromosome”, because in the second case it may seem that the chromosome is composed only of such loci that have genetic meaning. Although a gene in the classical sense really corresponds to a certain segment of DNA of a chromosome, and although very often non-coding segments of DNA can affect something at least indirectly (for example, the presence of a block of repeats can contribute to the compaction of chromatin and thereby affect the intensity of transcription of coding segments DNA located even at a considerable distance from it), nevertheless, there certainly exist extended sections of DNA that do not have any genetic content, that is, they do not affect anything and are not genes in any sense.

But the terms 'locus' and 'allele' also have a funny expansive meaning. If we study the DNA sequence itself, which in this case is both our trait and our gene, since it literally encodes itself, we can call any part of it that can be recognized in any way as a locus, and its variant as an allele. For example, in the genome there are so-called "microsatellites" - sequences of very short, consisting of two or three letters, tandem (arranged one after another) repeats. The number of these repeats changes very easily due to mechanisms associated with slippage during replication or incorrect recombination. Actually, due to these mechanisms, they “start up” in the genome, while they have no function of their own and they are not genes in the molecular sense. Due to their high variability, microsatellites like to study evolutionary genetics - since the number of copies of repeats can be used with a certain degree of certainty to judge relationship. So, in this case, it is also customary to talk about alleles, denoting by this word sequences of microsatellites of different lengths (that is, with a different number of copies of repeats).

It turned out that the word "gene" in classical genetics can be abandoned altogether. There is a locus - a place on the chromosome, which is always occupied by one of the alleles. The relationship between a locus and an allele is the same as the relationship between a variable and its value. Moreover, in accordance with the classical definition, both the locus is a gene (as a generic concept), and the allele is a gene (as an individual concept). You can often hear "these genes are non-allelic to each other", that is, they talk about allelic and non-allelic genes, that is, about alleles of one locus and alleles of different loci. In the practice of genetics, a not very rigid tradition has been established to use the word "gene" as a synonym for the word "locus", and such examples will also be found in our text.

But there are situations when the word "gene" is difficult to avoid. For example, they treated peas with red flowers with a chemical mutagen and got peas with white flowers. It was established that the trait "flower color" is inherited as determined by one locus - in such cases it is customary to talk about monogenic sign (although the non-existent term "monolocal" would be more accurate). However, white-flowered peas have already been known and this trait is determined by an allele of a well-known locus. The question is, did we get the same allele at the same locus, or a different (at the DNA sequence level) allele at the same locus, which, however, also leads to white flowers? Or an allele of a new, previously unknown locus - which may, say, for a completely different stage of pigment synthesis? Until this is established, one has to lazily say: "We got the white-flowering gene." By the way, a real situation from the life of our laboratory is described - we received a gene that determines white-flowering, which turned out to be allelic to a not widely known locus responsible for the anthocyanin color of a flower a, but to a little-known locus a2 .

The terms locus and allele can also be applied to a gene in the molecular genetic sense - namely, to a specific nucleotide sequence. Here the meaning of the terms "locus" and "gene" is the same, and allele will mean specific nucleotide sequence of a given gene. However, within the framework of molecular genetics, the need for these terms does not arise very often, since molecular biological consideration is usually diverted from the existence in a diploid organism of a second such gene, with an identical or slightly different sequence, in a homologous chromosome.

You probably know from molecular biology about the existence multigene families: when in the genome there are several genes in the molecular sense that encode a protein product of the same type - the same enzyme, for example. Moreover, they may differ somewhat in their primary structure: both in DNA and in the protein product, as well as in some physical and chemical properties protein product - the intensity of the molecular function, as well as the features of expression - that is, the place, time and intensity of synthesis. The same pea has seven genes (in the molecular sense) for histone H1, each of which encodes a special variant of the molecule, one of which is present only in actively dividing cells and disappears from the chromatin of cells that have completed division. Any sequence of any of these genes would be a variant of the H1 histone gene. But within the same genome, these seven genes occupy different loci, so only different variants of a particular locus will be alleles. You must be familiar with the concept homology- similarity based on common origin, and homologues- objects that have such a similarity. In molecular genetics, two types of gene homology are distinguished. Homologous but non-allelic genes in the same haploid genome occupying different loci are called paralogs(from the Greek "para" - near, near). Individual variants of the same locus in different individuals are called orthologs(from the Greek "ortho" - directly, opposite; remember the ortho-para isomers in organic matter). Basically, orthologs are alleles. However, the term "ortholog" is commonly used by molecular biologists when studying genes. different types- in cases where it can be unequivocally established that they have the same locus, while the term "allele" is applied only to a gene variant in the same species, or in closely related species, which, nevertheless, able to interbreed (e.g. wheat and its wild relatives). Thus, an allele is a genetic concept; alleles are spoken of when, in principle, they can participate in crossing.

Let's ask ourselves a question - where did paralogs come from? It is logical and correct to assume that they arose as a result of gene duplication - that is, rare cases of "reproduction" of a gene in the genome. Naturally, any such event, however rare, occurs within the limits of any one species. As a result, we have a situation where some individuals of the same species have two loci in the genome that are identical in their primary structure (it can accumulate differences over time), while others have only one. Let us assume that two copies of the propagated gene are located side by side, so that both new loci are located in the same place where one old one was located. And so they begin to accumulate differences. Where and what are alleles here? We have considered the situation when the concept of "allele" fails, and this is very good, since in doing so we traced the limit of its applicability.

By the way, an unexpectedly non-trivial question is what are different and identical alleles. In the early stages of the development of genetics, alleles were recognized only by phenotype, and only those that lead to different phenotypes were considered different alleles. Most often, there were two alleles - normal and defective (mutant), so that in the early stages of the development of genetics, the “presence-absence theory” (of a certain function) was popular. However, as genetics developed, more and more cases became known when the same trait has several heritable variants, which ultimately led to the appearance famous aphorism Thomas Morgan: "One presence cannot correspond to several absences." And in the case of quantitative traits determined by many genes at once, there is no special phenotypic manifestation of a single allele at all. As a result, they settled on the fact that alleles were considered obviously different if in this experiment they were not obviously inherited from the same individual, that is, they were not identical in origin or such identity was not established. For example, we catch one hundred seemingly identical individuals in nature in order to study the small nuances of the phenotypic manifestation of a certain gene, cross them with special tester lines, transfer the studied gene obtained from them to an identical gene background, measure the trait of interest to us - and at the same time we believe that one hundred different (by origin) normal (!) alleles participate in the experiment (all of them are obtained from nature from viable individuals).

You understand that when it became possible to decipher the primary structure of the studied genes, the question of the identity of alleles ceased to be theoretical and was reduced to the identity of their primary structure (nucleotide sequence). If there is at least one substitution, the alleles are different; if not, they are the same, since they are completely identical molecules. Given the possibility of accumulation of nucleotide substitutions, many of which do not affect the function of the locus, in practice this approach differs little from a priori considering any alleles independently obtained from different individuals to be different. However, the rate of occurrence of substitutions varies greatly from locus to locus - for example, in some loci we observed an identical nucleotide sequence even in alleles obtained from different pea subspecies (wild and cultivated).

Let's touch on such non-strict, popular terms as "wild-type alleles", "mutant alleles" and "null alleles". The above "theory of presence-absence" in many cases is quite applicable. Let's take the same peas for example. Pea flowers have a pigment - anthocyanin, which colors them in pink-red (purple) color. If any of the proteins involved in the biochemical chain of anthocyanin synthesis is defective or absent, anthocyanin is not synthesized and the flowers remain white. Suppose there is a locus in a certain chromosome, let's denote it A, which contains the DNA sequence that codes for one of these proteins. Usually they say less strictly, but more simply - in a certain chromosome there is a gene A, which encodes one of these proteins (Peas do have such a gene with this designation and encode a regulatory protein that binds to DNA, and not an enzyme involved in the synthesis of anthocyanin). Let this gene have two alleles, let's denote them A And a. allele A encodes a normal functional protein. allele A does not encode a functional protein. How this is possible - we will talk later, for us now it is important that this allele simply "does not work" - does not fulfill its molecular function, even if it is unknown to us. In such cases, the normal allele is called wild type/ On the example of peas, this term is doubly correct. Peas are both cultivated and wild (representatives of the same species continue to exist in the wild). And all wild peas have purple flowers, while cultivated ones have both purple and white flowers, but white ones predominate in vegetable and grain varieties of European selection. For an allele that is not capable of forming a functional protein product, the term is often also used. null allele.

There are cases when the concept of "wild type" or "null allele" is not applicable. For example, in a two-pointed ladybug Adalia bipunctata There are two forms - red with black flecks and black with red. (By the way, this is one of the classic objects of population genetics, introduced into this science by Timofeev-Resovsky.) Both are represented in the European part of Russia, none is better than the other (in Novosibirsk, however, only the second is found). None of them can be called wild type in contrast to the other. However, it is possible that one of these alleles is associated with the loss of the molecular function of the protein product of this locus, which, like other genes of individual development, is likely to be a factor influencing the expression of other genes.

Then there is a popular term in genetics - mutation. Historically, the concept was introduced by Hugo De Vries in a sense approaching that which now exists in horror films - a sudden change in hereditary inclinations, leading to a radical change in the phenotype. De Vries worked with one of the types of primrose ( Oenothera), which, as it turned out later, has a highly original cytogenetics: due to multiple chromosomal rearrangements, the entire genome is inherited as one allele. However, the word has become a widely used term, and not just in Hollywood. Sergei Sergeevich Chetverikov, one of the founders of population genetics, used the term "genovariation", which is more correct, but did not take root (although Chetverikov was one of the domestic geneticists who had a significant impact on world genetics, actually founding population genetics). Currently under mutation understood any change in the primary structure of DNA- from the replacement of one nucleotide to the loss of huge parts of chromosomes. I would like to draw your attention to the fact that the word "mutation" refers to the event of change itself. However, in a non-strict but tenacious genetic practice, the same word "mutation" is often applied to its result, that is, to the allele that arose as a result of the mutation. They say: “Drosophila participate in the experiment - carriers of the mutation white". No one recorded the mutational event itself, which led to the emergence of this classic mutation - by the way, it is associated with the insertion of a mobile genetic element into the enzyme gene copia, which moves exceptionally rarely - but everyone keeps saying "mutation" instead of "mutant allele". It is understood that once there was a mutation that spoiled the normal allele, resulting in a mutant one. It is easy to understand that the “mutant allele” is also the antonym of the expression “wild-type allele”, but wider than “null allele”, since it allows various deviations from the wild-type allele, both leading to a complete loss of molecular function (the very same “ several absences!), and not leading.

There is another very nasty terminological situation that some of you will have to deal with in human genetics. As we shall see later, human genetics in general, terminologically, deviated quite a lot from general genetics. The reason is that, on the one hand, this specialized field of science belongs both to biology and medicine and is purely institutionally isolated from all other genetics, and in this sense it boils in its own juice. On the other hand, due to its practical significance, this area is very large in terms of volume - the number of researchers and their studies, journals, articles - which makes its internal traditions resistant to external influences, including those from the "mother" general genetics. Modern human genetics has advanced so far that in many cases it has realized the age-old dream of geneticists, namely, it turned out to be able to associate certain signs (including pathological ones) with the presence of certain nucleotides in specific positions of specific genes. But it was here that an unfortunate terminological substitution occurred. When we compare many alleles in relation to the primary structure of DNA, it turns out that in some positions there is always the same specific nucleotide, and in some positions nucleotide substitutions are possible. (There is a suspicion that in the genomes of all people of mankind you can find any nucleotide in any position, which raises a funny philosophical question - what is the human genome). They were correctly named. polymorphic positions- and indeed, each such position exhibits alternative variability - that is, polymorphism - in relation to which of the four nucleotides it can be occupied. But here, somehow, there was a substitution of concepts. "Polymorphism" came to be called a specific nucleotide at a specific polymorphic position (what should be called a "morph"). They began to say something like this: “We sequenced such and such a gene in so many people and found twelve polymorphisms, two in positions such and such, six in such and such, and four in such and such. Two of the polymorphisms in such-and-such a position showed a significant association with the syndrome of such-and-such. Most likely, such a substitution took place at the level of laboratory slang, which exists in any scientific work and consists in simplifying terminology, often illiterate. Students who come to the lab sometimes mistake slang for terminology and begin to use it in all seriousness. At some point, it happens that both the author of the article and the reviewers in a scientific journal are used to the same slang, then it penetrates the scientific press and, with some probability, is fixed. (The picture, by the way, is more than familiar from population genetics and completely replicates the process of speciation - when random occurrences occur in an isolated population, they coincide in different sexes and anomalies in the recognition system of suitable sexual partners are fixed, which become the norm in a new species and lead to its non-crossing with the old .) In addition to the etymological contradiction (one single morph is called a word indicating that there are many morphs) and bad taste, such a substitution also has the consequence that researchers using this jargon have deprived themselves of the term "polymorphism" in its correct meaning. And when it becomes necessary to express the corresponding concept (which has not disappeared), instead of an unambiguous term, they have to resort to verbose descriptions. Suppose, in situations for which the term "balanced polymorphism" exists - when one of the morphs has an advantage in some conditions, the other - in others, so they coexist and do not displace one another - they always have to resort to long descriptions like the one above.

In terms of introducing you to the traditional and not always consistent genetic terminology, it is necessary to mention a rather funny term marker. This term was introduced for loci that are important to us not in themselves, but insofar as they mark a certain region of the chromosome. The appearance of such a term was associated with a long period of time when not very many genetic loci were known. It was needed in situations where it was necessary to stake a newly discovered gene or, paradoxical as it may sound, to work with genes that have not yet been discovered. For example, the nature of the genes that control economically valuable quantitative traits of plants and animals was completely unknown for a long time, and even now little is known about them. At the same time, there was no doubt that these genes exist and are located on the chromosomes. Manipulating with known loci - markers - it was possible to identify regions of chromosomes with which certain effects on quantitative traits are associated, and use them in breeding work. Initially, these were mostly "visible markers" - loci that had alleles with a visible effect. However, in the future, this approach was seriously developed due to the involvement in genetic analysis of biochemical traits (as a rule, also not functionally related to economically valuable traits), and later due to the emergence of the opportunity to work with the polymorphism of chromosome DNA itself. This led to the emergence of the concept of "molecular marker". Thus, the term "marker" is only a synonym for the term "locus", but emphasizes that this locus is of interest to us not as such, but only as a landmark on the chromosome. However, the term became so accustomed that it began to be used in cases where the locus is a directly studied object. Paradoxically, in molecular phylogeny studies, the analyzed sequences themselves are also commonly referred to as markers. Here it could be implied that they are just landmarks in time and nucleotide substitutions in them mark evolutionary events, which, of course, are not limited to changes only in the analyzed sequences.

Genes (more precisely, loci) are usually denoted by abbreviations consisting of Latin letters, as well as numbers. However, behind these designations are the full names of genes, Latin or, more often, English. Both full names and abbreviations for genes are always written in italics. For genes with visible expression, this is usually a word describing the mutant phenotype: w – white(white eyes of a fly), y – yellow(yellow body in a fly), a – anthocyanin inhibition(for peas) op – ovula pistilloida(for peas) bth – bithorax- not a very good name for a mutation in Drosophila, in which a second pair of wings appears on the metathorax (metothorax) (as on mesothorax) - but it is written as if the thoracic tagma had doubled. There is even a Drosophila mutation with an official name fushi tarazu(abbreviated symbol - ftz) - Japanese. Cheerful Americans named one of the genes mothers against decapentaplegic, by analogy with organizations such as "mothers against the war in Iraq" - in female fruit flies, carriers of this mutation, descendants carrying the gene will not survive decapentaplegic. The abbreviation for this gene sounds just as good: Mad. Occasionally, and not in the most popular objects, the official name of the gene and its abbreviation are not related to each other: the mutation that turns the tendrils of peas into leaves has the designation tl(from tendrilless), and the title is clavicula. If a gene is known by its molecular product (protein or RNA), then this gene itself will be named after its product: mtTrnK – mitochondrial transportation RNA for lysine, Rbcl – ribulose biphosphate carboxylase large subunit. It is important that each species has a completely independent official nomenclature of gene symbols, which leads to some difficulties at the present time, when the number of objects with developed private genetics has increased, and the number of objects in which genes are studied not by genetic experiments, but by direct reading of DNA sequences – grows like an avalanche (for example, the project “10,000 Vertebrate Genomes” is already in operation).

Genetics began with cases where only two alleles were known at each locus and it was possible to distinguish them by writing with a capital or small letter, which was initiated by Mendel. A capital letter was used for the dominant allele (you know what this means from school, we will touch on the phenomenon of dominance in more detail later) - this is usually the wild-type allele; as we would now say - an allele with a normal, unimpaired molecular function. At the same time, the locus was designated with a small letter, that is, its designation coincided with that of a recessive, that is, mutant, non-functional allele, because it was by the existence of such an allele that scientists first learned about the existence of the locus. In rare cases, when the mutant allele turned out to be dominant, both it and the locus itself were designated with a capital letter.

When, and very soon, it became clear that there are many alleles in a locus (now we know that there are a lot of them), allele designations were introduced, which are written in a superscript after the designation of loci. The “+” symbol is often used as such an index for the wild-type allele, sometimes there is no index. Suppose, at the very first known Drosophila locus white (w) the wild-type allele is denoted w+ , the allele responsible for white eyes w, and responsible for apricot - wa (full name - whiteapricot).

I draw your attention to the fact that for traditional genetic objects with developed private genetics, different traditions still coexist in writing the designations of loci and their alleles. So far I have found three of them:

Loci with visible manifestation are written with a small or capital letter, depending on whether the locus is described by a recessive or dominant allele in relation to the wild type; and capitalized if the locus is known from molecular function. At the same time, for loci with visible manifestation and dominance, the tradition is preserved to write recessive alleles with a small letter, and dominant alleles with a capital letter. Such is the genetic nomenclature, for example, in peas and mice. For example, the pea locus a, responsible for the color of the flowers has alleles A And a.

As in the previous case, but the capital and small letters in the designation of the locus and its alleles are rigidly fixed. Such a system is used in Drosophila. Here the designations w And W belong to completely different loci. white And Wrinkled. The wild-type allele is always denoted by the index "+" here. (It is curious that Drosophila and mouse geneticists, who are accustomed to the system adopted by their subjects, are usually not even aware of the existence of another system for naming loci.)

All letters in the designations of loci are always capital. Such a system is now used in human genetics, and it has been adopted quite recently.

The same allele designations are used for phenotypes, but always without italics. So, if you describe the results of an experiment in which you observed so many pea plants with purple flowers and so many with white flowers, and you know that white-flowering in the experiment is associated with the locus a, then you will designate purple-flowered and white-flowered plants with the letters A and a in the table of occurrence, even if you do not know their genotype. The same is done if you determine the presence of electrophoretic variants of some isoenzyme: there the correspondence of the phenotype to the genotype is greater, but even it is not always unambiguous.

1.4. The concepts of "homozygote", "heterozygote", "hemizygote".

In each diploid organism, each chromosome (except for the sex chromosomes) is represented in two copies - homologues received from the father and mother, respectively. Each of the homologues has the same set of loci, and in each of the homologues, each locus is occupied by some allele. Therefore, each diploid organism carries two alleles of each locus. When recording its genotype, the designations of the two alleles present in the locus (locuses) of interest to us are written in a row, for example, if there is in the locus a pea alleles A And a There are three possible genotypes: A A, A a And a a.

If in both homologues the locus is represented by the same allele, then the individual is said to be homozygous at this allele, or at this locus. Moreover, when they say that they are homozygous for a locus, the emphasis is on the fact that in both homologues there are no differences in it, when they say that they are homozygous for an allele, the emphasis is on which allele. If in both homologues the locus is represented by different alleles, then the individual heterozygous for this locus. For simplicity, homozygous and heterozygous individuals are called respectively homozygous And heterozygote. Considering what was said above about the identity/differences of alleles, true homozygotes in nature are not very common. However, in a particular experiment, no one bothers to ignore the differences that are not detected or cannot be detected in this experiment, and to consider individuals in which both copies of the locus have an identical phenotypic manifestation as homozygotes. In studies involving related individuals, known homozygotes are encountered - individuals in which both alleles of some locus are identical in origin. Such studies often use the notion average heterozygosity is the proportion of heterozygous loci among all loci.

Let's add another term hemizygote- this is an individual in which not two, but only one allele is obviously present. Well, for example, you probably know that men have only one sex X chromosome, and the second sex chromosome, the Y chromosome, is not homologous to it (with the exception of small areas), since it is not devoid of most areas saturated with genetic information. Therefore, alleles from those regions of the X chromosome that are not represented on the Y chromosome do not have homologues in the nucleus, that is, they are in the hemizygote. Sometimes a chromosome loses some of its fragment along with the genes (or one gene) in it. In this case, the alleles of these genes in the homologous chromosome are also in the hemizygote. However, in a genetic experiment, we often do not know what happened in the chromosomes, and we judge genes only by the phenotype. In this case, the absence of a gene may not differ from its "breakdown" - the loss of its function. And until we know, let's say, the molecular background, but somehow conclude that the molecular function is lost, we will just talk about the allele, or "null allele."

Distinguishing between homozygote, heterozygote, and hemizygote can be important in diploid organisms because dose the corresponding allele in the genome in this case differs by half (for example, in the case of a locus in the X chromosome, two copies per genome in women and one in men), which may be important. Molecular genetics usually digresses from the homozygosity/heterozygosity of its subjects. However, the concept is often used here. gene doses, that is, the number of alleles with unimpaired molecular function in the genome - usually it varies from 0 to 2, but can be increased by gene modification, that is, artificial introduction of additional copies into the genome.

In the case of haploid organisms, it is customary to say that in general all alleles of all genes are in the hemizygote. What kind of haploid organisms do we have? Prokaryotes, lower fungi and ascomycetes, plant gametophytes. Let's note one detail - haploids are not those who have strictly one haploid genomes in a cell. In most bacterial cells, there are several nucleoids that have not yet had time to separate - but they are all identical (up to de novo mutations). In lower fungi, the hyphae are often not subdivided into individual cells at all. It is important that a haploid organism has a single variant of the haploid genome in its cells. Finally, some animals - such as Hymenoptera - have a haploid sex - you probably know that bee drones are haploid. At the same time, in somatic cells, the set of chromosomes doubles, from which they do not cease to be haploids. Mitochondria and plastids are more often inherited only from the mother, so the cells are hemizygous for the genes located in the genomes of these organelles. However, in many plants, plastids sometimes have biparental inheritance, in others this happens occasionally, and paternal mitochondria also penetrate the zygote extremely rarely. In such cases, the offspring receives from both parents a certain varying proportion of these organelles, not necessarily equal to 1/2. In such cases, it is customary to speak of heteroplasmy.