Difficulties in the differential diagnosis of Noonan syndrome. Types of mutations General questions of the theory of mutations
Reprogenetics, the largest genetic laboratory in the United States, in collaboration with leading scientists from China, a number of New York institutes and medical centers specializing in the field of PGD, have published the results of new studies, which claim that mutations can be found in embryos after in vitro fertilization (IVF) ...
For the study, a small (sparing) biopsy is sufficient, only about 10 embryonic cells, while most of the new (De Novo) mutations that cause a disproportionately high percentage of genetic diseases can be detected using PGD. The uniqueness of the method lies in the development of a new original screening process for the extended whole genome.
New (De Novo) mutations occur only in germ cells and in embryos after fertilization. As a rule, these mutations are not present in the blood of the parents and even comprehensive screening of the carrier parents will not be able to detect them. Standard PGD cannot detect these mutations because the tests are not sensitive enough or are focused only on very narrow specific regions of the genome.
"These results are an important step in the development of whole genome screening to find the healthiest embryos in PGD," said Santiago Munné, Ph.D., founder and director of Reprogenetics and founder of Recombine. "This new approach can detect almost all genomic changes, and thus eliminate the need for further genetic testing during pregnancy or after birth, while ensuring that the healthiest embryo is selected for transfer to the mother-to-be."
It has also been scientifically proven that the new method reduces the error rate by 100 times (compared to previous methods).
“It is remarkable that new (De Novo) mutations can be detected with such high sensitivity and extremely low error rates using a small number of embryonic cells,” says Brock Peters, Ph.D. and lead scientist in the study. "The developed method is effective not only from a medical point of view, but also from an economic point of view, and we look forward to continuing our research in this area."
New mutations can lead to serious congenital brain disorders such as autism, epileptic encephalopathy, schizophrenia and others. Since these mutations are unique to a particular sperm and egg that are involved in the creation of the embryo, genetic analysis of the parents cannot detect them.
"Up to five percent of newborns suffer from diseases caused by a genetic defect," says Alan Berkeley, MD, professor, director of the Department of Obstetrics and Gynecology at the New York University Fertility Center. "Our approach is comprehensive and aims to identify perfectly healthy embryos. This can significantly alleviate some of the emotional and physical stressors of IVF, especially for couples at risk of passing on genetic disorders."
The article was specially translated for the IVF School program, based on materials
All proteins in the body are recorded in the cellular DNA. Only 4 kinds of nucleic bases - and countless combinations of amino acids. Nature made sure that every failure was not critical and made redundant. But sometimes the distortion still creeps in. It's called mutation. This is a violation of the DNA code recording.
Useful - rare
Most of these distortions (over 99%) are negative for the organism, which makes the theory of evolution untenable. The remaining one percent is not able to provide an advantage, since not every mutated organism gives birth to offspring. Indeed, in nature, not everyone has the right to reproduce. Mutation of cells more often occurs in males - and males, as you know, in nature more often die without giving offspring.
Women are to blame
However, man is an exception. In our species, it is most often triggered by the irresponsible behavior of females. Smoking, alcohol, drugs, STDs - and a limited supply of eggs that are negatively impacted from early childhood. If it exists for men, then for women even a small glass can provoke violations of the correct formation of eggs. While European women enjoy freedom, Arab women abstain and give birth to healthy children.
Incorrectly written
Mutation is a permanent change in DNA. It can affect a small area or an entire block in the chromosome. But even a minimal violation shifts the DNA code, forcing completely different amino acids to be synthesized - therefore, the entire protein encoded by this region will be inoperative.
Three types
A mutation is a violation of one of the types - either inherited, or de novo, or local mutation. In the first case, it is In the second - a violation at the level of the sperm or egg, as well as the consequence of exposure to dangerous factors after fertilization. Dangerous factors are not only bad habits, but also an unfavorable environmental situation (including radiation). De novo mutation is a disturbance in all cells of the body, as it arises from abnormal initial ones. In the third case, local, or does not occur at early stages and does not affect all cells of the body, with a high degree of probability it is not transmitted to offspring, in contrast to the first and second types of disorders.
If problems arise in the early stages of pregnancy, then a mosaic violation occurs. In this case, some of the cells are affected by the disease, some are not. With this species, there is a high probability that the child will be born alive. Most of the genetic disorders cannot be seen, because in this case, miscarriages often occur. The mother often does not even notice the pregnancy, it looks like a delayed period. If a mutation is harmless and common, it is called polymorphism. This is how blood groups and iris colors originated. However, polymorphism can increase the likelihood of certain diseases.
Amniocentesis - a study that is used to obtain a sample to analyze the genes and chromosomes of the fetus. The fetus is in the uterus surrounded by fluid. This liquid contains a small amount of skin cells of the unborn child. A small amount of fluid is withdrawn with a thin needle through the mother's abdominal wall (abdomen). The liquid is sent to a laboratory for research. For more information see the Amniocentesis brochure.
Autosomal dominant genetic disease - This is a disease, for the development of which a person needs to inherit one modified copy of a gene (mutation) from one of the parents. With this type of inheritance, the disease is transmitted to half of the children of a married couple from one of the parents who is sick. Both sexes are equally likely to be affected. Vertical transmission of the disease is observed in families: from one parent to half of the children.
Autosomal recessive geneticdisease - it is such a disease, for the development of which a person must inherit two modified copies of a gene (mutation), one from each of the parents. With this type of inheritance, a quarter of the children of a married couple are ill. The parents are healthy, but they are carriers of the disease. A person with only one copy of the altered gene will be a healthy carrier. For more information see the Recessive Inheritance brochure.
Autosomal -a trait whose gene is located on autosomes.
Autosomes - A person has 23 pairs of chromosomes. Pairs 1 to 22 are called autosomes and look the same in males and females. The chromosomes of the 23rd pair in men and women are different, and are called sex chromosomes.
Chorionic villus biopsy, BVP -a procedure performed during pregnancy to collect fetal cells for testing the genes or chromosomes of the unborn child for certain hereditary conditions. A small number of cells are taken from the developing placenta and sent to a laboratory for testing. For more information see the Chorionic Villus Biopsy brochure.
Vagina -the organ that connects the uterus to the external environment, the birth canal.
Gene -information that the body needs for life, stored in chemical form (DNA) on chromosomes.
Genetic -caused by genes, related to genes.
Genetic research -a study that can help determine if there are changes in individual genes or chromosomes. For more information see the brochure What is Genetic Research?
Genetic disease - a disease caused by abnormalities in genes or chromosomes.
Deletion -loss of part of the genetic material (DNA); this term can be used to refer to the loss of a portion of both a gene and a chromosome. For more information see the Chromosomal Disorders brochure.
DNA -a chemical substance that makes up genes and that contains information that the body needs to function.
Duplication -an abnormal repetition of the sequence of genetic material (DNA) in a gene or chromosome. For more information see the Chromosomal Disorders brochure.
Measurement of the thickness of the collar space (TVP) -an ultrasound scan of the back of the fetus's neck that is filled with fluid early in pregnancy. If the baby has a congenital disorder (such as Down syndrome), the thickness of the collar space may be changed.
Inversion -changing the sequence of genes in a separate chromosome. For more information see the Chromosomal Disorders brochure.
Insertion -insertion of additional genetic material (DNA) into a gene or chromosome. For more information see the Chromosomal Disorders brochure.
Karyotype -a description of the individual's chromosome structure, including the number of chromosomes, the set of sex chromosomes (XX or XY), and any deviations from the normal set.
Cell - The human body is made up of millions of cells that serve as "building blocks". Cells in different parts of the human body look differently and perform different functions. Each cell (with the exception of eggs in women and sperm in men) contains two copies of each gene.
Ring chromosome is a term used when the ends of a chromosome join together to form a ring. For more information see the brochure Chromosomal Translocations.
Uterus -part of a woman's body in which a fetus grows during pregnancy.
Medical genetic counseling - informational and medical assistance to people concerned about the presence in the family of a condition, possibly of a hereditary nature.
Mutation - changing the DNA sequence of a particular gene. This change in the sequence of the gene leads to the fact that the information contained in it is disrupted, and it cannot work correctly. This can lead to the development of a genetic disease.
Miscarriage - npremature termination of pregnancy, which occurred before the moment when the child is able to survive outside the uterus.
Unbalanced translocation -translocation, in which a chromosomal rearrangement leads to the acquisition or loss of a certain amount of chromosomal material (DNA), or simultaneously to the acquisition of additional and loss of part of the original material. May occur in a child whose parent is a carrier of a balanced translocation. For more information see the Chromosome Translocation brochure.
Carrier of chromosomal rearrangement -a person who has a balanced translocation, in which the amount of chromosomal material is not decreased or increased, which usually does not cause health problems.
Media -a person who does not usually have a disease (at present), but carries one modified copy of the gene. In the case of a recessive disease, the host is usually healthy; in the case of a dominant disease with a late onset, the person will fall ill later.
Fertilization -the fusion of an egg and a sperm cell to create the baby's first cell.
Placenta - an organ adjacent to the inner wall of a pregnant woman's uterus. The fetus receives nutrients through the placenta. The placenta grows from a fertilized egg, so it contains the same genes as the fetus.
Positive result -a test result that shows that the examined person has a change (mutation) in the gene.
Sex chromosomes -X chromosome and Y chromosome. The set of sex chromosomes determines whether an individual is male or female. Women have two X chromosomes, men have one X chromosome and one Y chromosome.
Predictive testing -genetic research aimed at identifying a condition that may or will develop during life. When genetic research is aimed at identifying a condition that will almost inevitably develop in the future, such research is called presymptomatic.
Prenatal diagnosis - a study carried out during pregnancy for the presence or absence of a genetic disease in a child.
Reciprocal translocation - a translocation that occurs when two fragments break off two different chromosomes and change places. For more information see the Chromosome Translocation brochure.
Robertsonian translocation -occurs when one chromosome is attached to another. For more information see the Chromosome Translocation brochure.
Balanced translocation - tranlocation (chromosomal rearrangement), in which the amount of chromosomal material is not reduced or increased, but it is transferred from one chromosome to another. A person with a balanced translocation usually does not suffer from this, but the risk of developing genetic diseases for his children is increased. For more information see the Chromosomal Translocation brochure.
Sex-linked condition - See X-linked inheritance.
Sperm -the father's reproductive cell, the father's contribution to the formation of the cell from which the new child will develop. Each sperm contains 23 chromosomes, one from each pair of the father's chromosomes. The sperm cell fuses with the egg to create the first cell from which the unborn child develops.
Translocation -rearrangement of chromosomal material. It occurs when a fragment of one chromosome breaks off and attaches to another place. For more information see the Chromosome Translocation brochure.
Ultrasound examination (ultrasound) -a painless test in which sound waves are used to create an image of the fetus growing in the mother's uterus. It can be done by moving the scanner head over the surface of the mother's abdominal wall (abdomen) or inside the vagina.
Chromosomes -filamentous structures visible under a microscope that contain genes. Normally, a person has 46 chromosomes. We inherit one set of 23 chromosomes from the mother, the second set of 23 chromosomes from the father.
X-linked disease - a genetic disease resulting from a mutation (change) in a gene located on the X chromosome. X-linked diseases include hemophilia, Duchenne muscular dystrophy, fragile X syndrome, and many others. For more information see the X-linked inheritance brochure.
XX - this is how the set of sex chromosomes of a woman is usually represented. Normally, a woman has two X chromosomes. Each of the X chromosomes is inherited from one of the parents.
X chromosome - One of the sex chromosomes. Women normally have two X chromosomes. Men normally have one X chromosome and one Y chromosome.
Ovary / Ovaries - the organs in the body of a woman that produce eggs.
Ovum -the mother's reproductive cell, which will serve as the basis for creating the first cell of the unborn child. The egg cell contains 23 chromosomes; one from each pair the mother has. The egg cell fuses with the sperm to form the baby's first cell.
De novo - witha combination from the Latin language, meaning "anew". Used to describe changes in genes or chromosomes (mutations) that are newly formed, i.e. none of the parents of a person with a de novo mutation have these changes.
XY - this is how the set of sex chromosomes of a man is usually represented. In nori, males have one X chromosome and one Y chromosome. Males inherit the X chromosome from their mother and the Y chromosome from their father.
Y chromosome - one of the sex chromosomes. Normally, men have one Y chromosome and one X chromosome. A woman normally has two X chromosomes.
Detection of the denovo mutation in the dystrophin gene and its significance for medical genetic counseling in Duchenne muscular dystrophy
(clinical observation)
Muravleva E.A., Starodubova A.V., Pyshkina N.P., Duisenova O.S.
Scientific adviser: d.m.s. Assoc. O. V. Kolokolov
State Budgetary Educational Institution of Higher Professional Education Saratov State Medical University named after IN AND. Razumovsky Ministry of Health of the Russian Federation
Department of Neurology FPK and PPS them. K.N. Tretyakov
Introduction.Duchenne muscular dystrophy (DMD) is one of the most common hereditary neuromuscular diseases. Its prevalence is 2-5: 100,000 of the population, the population frequency is 1: 3500 newborn boys. This form of muscular dystrophy was first described by Edward Meryon (1852) and Guillaume Duchenne (1861).
The disease is characterized by an X-linked recessive mode of inheritance and a severe, progressive course. DMD is caused by a mutation in the dystrophin gene, the locus of which is located at Xp21.2. About 30% of cases are due to de novo mutations, 70% - to the carriage of the mutation by the mother of the proband. Dystrophin is responsible for connecting the cytoskeleton of each muscle fiber to the basal lamina (extracellular matrix) through a protein complex that consists of many subunits. The absence of dystrophin leads to the penetration of excess calcium into the sarcolema (cell membrane). Muscle fibers undergo necrosis, replacement of muscle tissue with adipose tissue and connective tissue occurs.
Modern diagnostics of DMD is based on assessing the compliance of disease manifestations with clinical-anamnestic and laboratory-instrumental (serum creatine kinase (CSK), electroneuromyography (ENMG), histochemical study of muscle biopsy) criteria, genealogical analysis and data of molecular genetic research.
Currently, medical and genetic counseling in many families helps prevent the birth of a sick child. Prenatal DNA diagnostics in early pregnancy in families with a child with DMD will allow the parents to choose further tactics and, possibly, terminate the pregnancy early if the fetus has a disease.
In some cases, the clinical picture is observed in women - heterozygous carriers of the mutant gene in the form of an increase in the gastrocnemius muscles, moderate muscle weakness, a decrease in tendon and periosteal reflexes, according to paraclinical studies, the level of CCS increases. In addition, the classic clinical manifestations of DMD can occur in women with Shereshevsky-Turner syndrome (genotype 45, XO).
Clinical example. In our clinic, a 7-year-old boy K. is observed, who complains of weakness in the muscles of the arms and legs, fatigue with prolonged walking. The child's mother notes that he has periodic falls, difficulty climbing stairs, a duck-like gait, difficulty getting up from a sitting position, an increase in calf muscles in volume.
The early development of the child was uneventful. At the age of 3 years, those around him noticed impaired motor functions in the form of difficulties when walking up stairs, when getting up, the child did not take part in outdoor games, and began to tire quickly. Then the duck gait changed. Difficulties increased when getting up from a sitting or lying position: step-by-step standing up with an active use of the hands. Gradually, an increase in the calf and some other muscles in volume became noticeable.
In neurological examination, the leading clinical sign is symmetric proximal peripheral tetraparesis, more pronounced in the legs (muscle strength in the proximal upper extremities - 3-4 points, in the distal - 4 points, in the proximal parts of the lower extremities - 2-3 points, in the distal - 4 points). The gait is changed according to the "duck" type. Uses auxiliary ("myopathic") techniques, such as standing up with a "ladder". The muscle tone is reduced, there are no contractures. Hypotrophy of the muscles of the pelvic and shoulder girdle. "Myopathic" features, such as a wide interscapular space. There is pseudohypertrophy of the calf muscles. Tendon and periosteal reflexes - no significant difference in sides; bicypital - low, tricypital and carporadial - medium liveliness, knee and Achilles - low. Based on clinical findings, DMD was suspected.
In the study of CCS, its level was 5379 units / l, which is 31 times higher than the norm (the norm is up to 171 units / l). According to ENMG data, signs were registered that were more characteristic of a moderately current primary muscle process. Thus, the data obtained confirmed the presence of DMD in the patient.
In addition to the proband, his parents and older sister were examined. None of the relatives of the proband had clinical manifestations of DMD. However, the mother showed some increase in calf muscles in volume. According to genealogical analysis, the proband is the only sick person in the family. It cannot be ruled out that the mother of the child and the sibling of the proband are heterozygous carriers of the mutant gene (Fig. 1).
Figure: 1 Pedigree
Within the framework of medical genetic counseling, the family of K. was examined for the presence / absence of deletions and duplications in the dystrophin gene. Molecular genetic analysis in the DNA diagnostics laboratory of the Moscow State Scientific Center of the Russian Academy of Medical Sciences revealed an exon 45 deletion in proband K., which finally confirms the established clinical diagnosis of DMD. In the mother, the deletion of exon 45 detected in the son was not found. As a result of analysis, the exon 45 deletion detected in the brother was not found in the sister. Therefore, in the subject under study, the mutation is most likely of de nоvo origin, but it can also result from germinal mosaicism in the mother. Accordingly, with a de novo mutation, the risk of giving birth to a sick child in the mother will be determined by the population frequency of this mutation (1: 3500, \u003c1%), which is much less than with the X-linked recessive type of inheritance (50% of boys). Since it cannot be completely ruled out that the mutation may result from germinal mosaicism, in which the inheritance according to Mendel's laws is violated, it is recommended that prenatal diagnostics be carried out during subsequent pregnancy in the mother and sister of the proband.
Conclusion. At present, the doctor has a wide arsenal of symptomatic agents used in the treatment of DMD; however, despite the advances in science, the etiological treatment of DMD has not yet been developed, and there are no effective drugs for substitution treatment for DMD. According to recent stem cell research, there are promising vectors that can replace damaged muscle tissue. However, at present, only symptomatic treatment is possible, aimed at improving the patient's quality of life. In this regard, early diagnosis of DMD plays an essential role for the timely conduct of medical genetic counseling and the choice of further family planning tactics. For prenatal DNA diagnosis, chorionic biopsy (CVS) can be performed at 11-14 weeks of gestation, amniocentesis can be used after 15 weeks, fetal blood sampling is possible at about 18 weeks. If testing is carried out in the early stages of pregnancy, early termination of pregnancy is possible if the fetus has a disease. In some cases, it is advisable to carry out preimplantation DNA diagnostics followed by in vitro fertilization.
Findings.To ensure the early detection and prevention of DMD, it is necessary to use more widely the methods of molecular genetic diagnostics; increase the alertness of practicing doctors in relation to this pathology. With a de novo mutation, the risk of having a sick child in the mother is determined by the population frequency of the dystrophin gene mutation. In cases of carriage of the mutation by the mother of the proband, prenatal or perimplantation DNA diagnostics is required for family planning.
Schizophrenia is one of the most mysterious and complex diseases in many ways. It is difficult to diagnose - there is still no consensus on whether it is one disease or many similar to each other. It is difficult to treat it - now there are only drugs that suppress the so-called. positive symptoms (like delusions), but they do not help return the person to a fulfilling life. Schizophrenia is difficult to study - no other animal except humans suffers from it, therefore there are almost no models for its study. Schizophrenia is very difficult to understand from a genetic and evolutionary point of view - it is full of contradictions that biologists cannot yet resolve. The good news, however, is that in recent years, things have finally gotten off the ground. We have already discussed the history of the discovery of schizophrenia and the first results of its study by neurophysiological methods. This time, we will focus on how scientists are looking for genetic causes of the disease.
The importance of this work is not even that almost every hundredth person on the planet suffers from schizophrenia, and progress in this area should at least radically simplify diagnostics, even if it is impossible to create a good medicine right away. The importance of genetic studies is that they are already changing our understanding of the fundamental mechanisms of inheritance of complex traits. If scientists still manage to understand how such a complex disease as schizophrenia can "hide" in our DNA, this will mean a radical breakthrough in understanding the organization of the genome. And the significance of such work will go far beyond clinical psychiatry.
First, a few raw facts. Schizophrenia is a severe, chronic, disabling mental illness that usually affects young people. It affects about 50 million people worldwide (just under 1% of the population). The disease is accompanied by apathy, lack of will, often hallucinations, delirium, disorganized thinking and speech, and motor disorders. Symptoms usually cause social isolation and decreased performance. The increased risk of suicide in patients with schizophrenia, as well as concomitant somatic diseases, lead to the fact that their overall life expectancy is reduced by 10-15 years. In addition, people with schizophrenia have fewer children: men have an average of 75 percent, women - 50 percent.
The last half century has been a time of rapid progress in many areas of medicine, but this progress has hardly affected the prevention and treatment of schizophrenia. Not least of all, this is due to the fact that we still do not have a clear idea of \u200b\u200bwhat kind of violation of biological processes is the cause of the development of the disease. This lack of understanding has led to the fact that since the introduction of the first antipsychotic drug chlorpromazine (trade name: Aminazine) on the market more than 60 years ago, there has not been a qualitative change in the treatment of the disease. All currently approved antipsychotics for the treatment of schizophrenia (both typical, including chlorpromazine, and atypical) have the same basic mechanism of action: they reduce the activity of dopamine receptors, which eliminates hallucinations and delusions, but, unfortunately, has little effect on negative symptoms like apathy, lack of will, thinking disorders, etc. We do not even mention the side effects. A general disappointment in schizophrenia research is that pharmaceutical companies have long been cutting back on antipsychotic funding - even as the total number of clinical trials is growing. However, the hope for clarification of the causes of schizophrenia came from a rather unexpected side - it is associated with unprecedented progress in molecular genetics.
Collective responsibility
Even the first schizophrenic researchers noticed that the risk of getting sick is closely related to the presence of sick relatives. Attempts to establish the mechanism of inheritance of schizophrenia were undertaken almost immediately after the rediscovery of Mendel's laws, at the very beginning of the 20th century. However, unlike many other diseases, schizophrenia did not want to fit into the framework of simple Mendelian models. Despite the high heritability, it was not possible to associate it with one or several genes, therefore, by the middle of the century, the so-called. psychogenic theories of disease development. In agreement with psychoanalysis, which was extremely popular by the middle of the century, these theories explained the apparent heritability of schizophrenia not by genetics, but by the peculiarities of upbringing and an unhealthy atmosphere within the family. There was even such a thing as “schizophrenogenic parents”.
However, this theory, despite its popularity, did not live long. The final point in the question of whether schizophrenia is a hereditary disease was put by psychogenetic studies carried out already in the 60-70s. These were primarily twin studies, as well as studies of adopted children. The essence of twin studies is to compare the probabilities of manifestation of a sign - in this case, the development of a disease - in identical and fraternal twins. Since the difference in the effect of the environment on twins does not depend on whether they are identical or fraternal, the differences in these probabilities must be mainly due to the fact that identical twins are genetically identical, and fraternal twins have, on average, only half of the common variants of genes.
In the case of schizophrenia, the concordance of identical twins was found to be more than 3 times that of fraternal twins: for the former, it is approximately 50 percent, and for the latter, less than 15 percent. These words should be understood as follows: if you have an identical twin brother with schizophrenia, then you yourself will get sick with a probability of 50 percent. If you and your brother are fraternal twins, then the risk of getting sick is no more than 15 percent. Theoretical calculations, which additionally take into account the prevalence of schizophrenia in the population, estimate the contribution of heritability to the development of the disease at the level of 70-80 percent. By comparison, height and body mass index are inherited in much the same way - traits that have always been considered closely related to genetics. By the way, as it turned out later, the same high heritability is characteristic of three of the other four major mental illnesses: attention deficit hyperactivity disorder, bipolar disorder, and autism.
The results of twin studies were fully confirmed in the study of children who were born to patients with schizophrenia and were adopted in early infancy by healthy adoptive parents. It turned out that the risk of developing schizophrenia in them is not reduced in comparison with children raised by their schizophrenic parents, which clearly indicates the key role of genes in etiology.
And here we come to one of the most mysterious features of schizophrenia. The fact is that if it is so strongly inherited and at the same time has a very negative effect on the fitness of the carrier (recall that patients with schizophrenia leave at least half the number of offspring than healthy people), then how does it manage to survive in the population at least for ? This contradiction, around which the main struggle between different theories is taking place, is called the "evolutionary paradox of schizophrenia"
Until recently, it was completely unclear to scientists what specific features of the genome of patients with schizophrenia predetermine the development of the disease. For decades, heated debate was conducted not even about which genes are changed in patients with schizophrenia, but about what is the general genetic "architecture" of the disease.
The following is meant. The genomes of individuals are very similar to each other, the average difference is less than 0.1 percent of nucleotides. Some of these distinctive features of the genome are quite widespread in the population. It is conventionally believed that if they occur in more than one percent of people, they can be called common variants or polymorphisms. It is believed that such common variants appeared in the human genome more than 100,000 years ago, even before the first emigration of the ancestors of modern humans from Africa, so they are usually present in most human subpopulations. Naturally, in order to exist in a significant part of the population for thousands of generations, most of the polymorphisms should not be too harmful to their carriers.
However, in the genome of each of the people there are other genetic features - younger and rarer. Most of them do not provide carriers with any advantage, so their frequency in the population, even if they are fixed, remains insignificant. Many of these traits (or mutations) have a more or less pronounced negative effect on fitness, so they are gradually removed by negative selection. Instead of them, as a result of a continuous mutational process, other new harmful options appear. In total, the frequency of any of the new mutations almost never exceeds 0.1 percent, and such variants are called rare.
So, the architecture of a disease means which genetic variants - common or rare, having a strong phenotypic effect or only slightly increasing the risk of developing a disease - predetermine its appearance. It was around this issue that until recently the main debate about the genetics of schizophrenia was conducted.
The only fact indisputably established by molecular genetic methods regarding the genetics of schizophrenia over the last third of the 20th century is its incredible complexity. Today, it is obvious that predisposition to disease is determined by changes in dozens of genes. At the same time, all the proposed "genetic architectures" of schizophrenia during this time can be combined into two groups: the "common disease - common variants" (CV) model and the "common disease - rare variants" model ("common disease - rare variants ", RV). Each of the models offered their own explanations for the "evolutionary paradox of schizophrenia."
RV vs. CV
According to the CV model, the genetic substrate of schizophrenia is a set of genetic traits, a polygen, akin to what determines the inheritance of quantitative traits such as height or body weight. Such a polygen is a set of polymorphisms, each of which only slightly affects physiology (they are called "causal", because, although not alone, they lead to the development of the disease). In order to maintain a rather high incidence rate characteristic of schizophrenia, it is necessary that this polygen consists of common variants - after all, it is very difficult to collect many rare variants in one genome. Accordingly, each person has dozens of such risky options in his genome. In total, all causal variants determine the genetic liability of each individual to the disease. For qualitative complex traits such as schizophrenia, it is assumed that there is a threshold of predisposition, and the disease develops only in those people whose predisposition exceeds this threshold.
Disease susceptibility threshold model. The normal distribution of the predisposition is shown, plotted along the horizontal axis. People whose predisposition exceeds the threshold value develop the disease.
For the first time such a polygenic model of schizophrenia was proposed in 1967 by one of the founders of modern psychiatric genetics, Irving Gottesman, who also made a significant contribution to proving the hereditary nature of the disease. From the point of view of adherents of the CV model, the persistence of a high frequency of causal variants of schizophrenia in a population over many generations may have several explanations. Firstly, each individual such variant has a rather insignificant effect on the phenotype; such “quasi-neutral” variants may be invisible for selection and remain common in populations. This is especially true for populations with low effective numbers, where the influence of chance is no less important than selection pressure - this also applies to the population of our species.
On the other hand, suggestions were made about the presence in the case of schizophrenia of the so-called. balancing selection, ie, the positive influence of "schizophrenic polymorphisms" on healthy carriers. It's not that hard to imagine. It is known, for example, that schizoid individuals with a high genetic predisposition to schizophrenia (of which there are many among the close relatives of patients) are characterized by an increased level of creativity, which can slightly increase their adaptation (this has already been shown in several works). Population genetics allows a situation where the positive effect of causal variants in healthy carriers may outweigh the negative consequences for those people who have too many of these "good mutations", which led to the development of the disease.
The second basic model of the genetic architecture of schizophrenia is the RV model. She suggests that schizophrenia is a collective concept and each individual case or family with a history of the disease is a separate quasi-Mendelian disease associated in each case with unique changes in the genome. Within the framework of this model, causal genetic variants are under very strong selection pressure and are quickly removed from the population. But since a small number of new mutations occur in each generation, a certain balance is established between selection and the emergence of causal variants.
On the one hand, the RV model can explain why schizophrenia is very well inherited, but its universal genes have not yet been found: after all, each family inherits its own causal mutations, and there are simply no universal ones. On the other hand, if one is guided by this model, then one has to admit that mutations in hundreds of different genes can lead to the same phenotype. After all, schizophrenia is a common disease, and the occurrence of new mutations is rare. For example, data on the sequencing of father-mother-child triplets show that in each generation, for 6 billion nucleotides of the diploid genome, only 70 new single-nucleotide substitutions arise, of which, on average, only a few theoretically can have any effect on the phenotype, and mutations of other types - an even rarer phenomenon.
However, some empirical evidence indirectly supports this model of the genetic architecture of schizophrenia. For example, in the early 1990s, it was found that about one percent of all schizophrenic patients have a microdeletion in one of the regions of chromosome 22. In the vast majority of cases, this mutation is not inherited from the parents, but occurs de novo during gametogenesis. One in 2,000 people is born with this microdeletion, which leads to a variety of disorders in the body, called "DiGeorge syndrome." Those suffering from this syndrome are characterized by serious impairments of cognitive functions and immunity, often accompanied by hypocalcemia, as well as heart and kidney problems. A quarter of patients with Di Giorgi syndrome develop schizophrenia. It is tempting to assume that other cases of schizophrenia are due to similar genetic disorders with disastrous consequences.
Another empirical observation indirectly confirms the role de novo mutations in the etiology of schizophrenia is the relationship of the risk of getting sick with the age of the father. So, according to some data, among those whose fathers were more than 50 years old at the time of birth, there are 3 times more patients with schizophrenia than among those whose fathers were less than 30. On the other hand, hypotheses have been put forward for a long time about the connection between the father's age and the occurrence of de novo mutations. Such a relationship, for example, has long been established for sporadic cases of another (monogenic) hereditary disease - achondroplasia. This correlation was recently confirmed by the aforementioned triplet sequencing data: de novo mutations are associated with the age of the father, but not with the age of the mother. According to scientists' calculations, a child receives on average 15 mutations from a mother, regardless of her age, and from a father - 25 if he is 20 years old, 55 if he is 35 years old and more than 85 if he is over 50. That is, the number de novo mutations in the child's genome increases by two every year of the father's life.
Together, these data seemed to indicate a key role de novo mutations in the etiology of schizophrenia. However, the situation actually turned out to be much more complicated. Already after the separation of the two main theories, the genetics of schizophrenia were in stagnation for decades. Almost no reliable reproducible data was obtained in favor of one of them. Neither the general genetic architecture of the disease, nor the specific options that affect the risk of developing the disease. A sharp leap has occurred over the past 7 years and it is primarily associated with technological breakthroughs.
Looking for genes
Sequencing of the first human genome, the subsequent improvement of sequencing technologies, and then the emergence and widespread introduction of high-throughput sequencing finally made it possible to get a more or less complete picture of the structure of genetic variability in the human population. This new information immediately began to be used for a full-scale search for genetic determinants of predisposition to certain diseases, including schizophrenia.
Similar studies are built like this. First, a sample of unrelated sick people (cases) and approximately the same size sample of unrelated healthy individuals (controls) are collected. All these people determine the presence of certain genetic variants - just in the last 10 years, researchers have had the opportunity to determine them at the level of entire genomes. Then the frequency of occurrence of each of the defined variants is compared between the groups of sick people and the control group. If at the same time it is possible to find a statistically significant enrichment of a particular variant in carriers, it is called an association. Thus, among the vast number of existing genetic variants are those that are associated with the development of the disease.
An important value characterizing the effect of a disease-associated variant is OD (odds ratio, risk ratio), which is defined as the ratio of the chances of getting sick in carriers of a given variant compared to those who do not have it. If the OD of a variant is 10, it means the following. If we take a random group of carriers of a variant and an equal group of people who do not have this variant, it turns out that in the first group there will be 10 times more patients than in the second. Moreover, the closer OD is to one for a given variant, the larger the sample is needed in order to reliably confirm the fact that the association really exists, that this genetic variant really affects the development of the disease.
Such works have made it possible to date to find over a dozen submicroscopic deletions and duplications associated with schizophrenia throughout the genome (they are called CNV - copy number variations, one of the CNVs just causes the already known DiGeorge syndrome). For the discovered CNVs that cause schizophrenia, OD ranges from 4 to 60. These are high values, but due to their extreme rarity, even in total, they all explain only a very small part of the heritability of schizophrenia in the population. What is responsible for the development of the disease in everyone else?
After relatively unsuccessful attempts to find such CNVs that would cause the development of the disease not in a few rare cases, but in a significant part of the population, the supporters of the "mutational" model pinned great hopes on another type of experiments. They compare in schizophrenic patients and healthy controls not the presence of massive genetic rearrangements, but the complete sequences of genomes or exomes (sets of all protein-coding sequences). Such data, obtained using high-throughput sequencing, allows finding rare and unique genetic features that cannot be detected by other methods.
The reduction in the cost of sequencing has made it possible in recent years to experiment of this type on rather large samples - including in recent studies several thousand patients and the same number of healthy controls. What's the result? Alas, so far only one gene has been found, rare mutations in which are reliably associated with schizophrenia - this is the gene SETD1A, encoding one of the important proteins involved in the regulation of transcription. As with CNV, the problem is the same: mutations in the gene SETD1Acannot explain any significant part of the heritability of schizophrenia due to the fact that they are simply very rare.
Relationship between the prevalence of associated genetic variants (along the horizontal axis) and their impact on the risk of developing schizophrenia (OR). In the main graph, red triangles show some of the disease-associated CNVs found to date, and blue circles show SNPs from GWAS. The incision in the same coordinates shows areas of rare and frequent genetic variants.
There are indications that other rare and unique variants exist that influence predisposition to schizophrenia. And a further increase in the samples in experiments using sequencing should help to find some of them. However, despite the fact that the study of rare variants may still provide some valuable information (especially this information will be important for creating cellular and animal models of schizophrenia), most scientists now agree that rare variants play only a minor role in heritability. schizophrenia, and the CV model is much better at describing the genetic architecture of the disease. The conviction in the fidelity of the CV model came primarily with the development of studies such as GWAS, which we will discuss in detail in the second part. In short, this type of research has revealed the very common genetic variation that accounts for a significant proportion of the heritability of schizophrenia predicted by the CV model.
Additional evidence for the CV model for schizophrenia is the link between the level of genetic predisposition to schizophrenia and so-called schizophrenic spectrum disorders. Even early schizophrenic researchers noticed that among the relatives of schizophrenic patients there are often not only other schizophrenic patients, but also "eccentric" individuals with oddities of character and symptoms similar to schizophrenic, but less pronounced. Subsequently, such observations led to the concept that there is a whole set of diseases, which are characterized by more or less pronounced disturbances in the perception of reality. This group of diseases is called schizophrenic spectrum disorders. In addition to various forms of schizophrenia, they include delusional disorders, schizotypal, paranoid and schizoid personality disorders, schizoaffective disorder, and some other pathologies. Gottesman, proposing his polygenic model of schizophrenia, suggested that people with subthreshold values \u200b\u200bof susceptibility to disease may develop other pathologies of the schizophrenic spectrum, and the severity of the disease correlates with the level of predisposition.
If this hypothesis is correct, it is logical to assume that genetic variants found to be associated with schizophrenia will be enriched among people with schizophrenic spectrum disorders. To assess the genetic predisposition of each individual, a special value is used, called the polygenic risk score. The level of polygenic risk takes into account the total contribution of all common risk variants identified in the GWAS, present in the genome of a given person, to the predisposition to the disease. It turned out that, as predicted by the CV model, the values \u200b\u200bof the level of polygenic risk correlate not only with schizophrenia itself (which is trivial), but also with other diseases of the schizophrenic spectrum, with higher levels of polygenic risk corresponding to severe types of disorders.
And yet one problem remains - the phenomenon of the “old fathers”. If most of the empirical evidence supports the polygenic model of schizophrenia, how can we reconcile with it the well-known association between age at parenthood and children's risk of developing schizophrenia?
An elegant explanation of this phenomenon in terms of the CV model has once been put forward. It was assumed that late paternity and schizophrenia are not, respectively, cause and effect, but are two consequences of a common cause, namely the genetic predisposition of late fathers to schizophrenia. On the one hand, a high level of predisposition to schizophrenia may be correlated in healthy men with later paternity. On the other hand, it is obvious that a high predisposition of the father predetermines an increased likelihood that his children will develop schizophrenia. It turns out that we can deal with two independent correlations, which means that the accumulation of mutations in the precursors of spermatozoa in men may have almost no effect on the development of schizophrenia in their offspring. Recent simulations that include epidemiological data as well as recent molecular frequency data de novo mutations are in good agreement with just such an explanation of the phenomenon of the "old fathers".
Thus, at the moment it can be considered that there are almost no convincing arguments in favor of the "mutational" RV model of schizophrenia. So the key to the etiology of the disease lies in which set of common polymorphisms causes schizophrenia in accordance with the CV model. The second part of our story will be devoted to how genetics are looking for this set and what they have already discovered.
Arkady Golov
