The largest US genetic laboratory Reprogenetics, in collaboration with leading scientists from China, a number of New York institutes and medical centers specializing in PGD, published the results of new studies stating that mutations can be detected 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 disproportionately high percent genetic diseases can be detected by 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 parents and even comprehensive screening of carrier parents will not be able to detect them. Standard PGD cannot detect these mutations because the tests are not sensitive enough or focus only on very narrow specific regions of the genome.
"These results represent an important step in the development of whole genome screening to find the healthiest embryos for PGD," says Santiago Munné, Ph.D., founder and director of Reprogenetics and founder of Recombine. "This new approach can detect almost all genome changes, and thereby eliminate the need for further genetic testing during pregnancy or after birth, while ensuring the selection of the healthiest embryo to transfer to an expectant mother."
It is also scientifically confirmed that the new method reduces the error rate by 100 times (compared to previous methods).
"It's remarkable that new (De Novo) mutations can be detected with such high sensitivity and exceptionally low error rates using a small number of embryonic cells," says Brock Peters, Ph.D. and lead scientist on 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 work in this area."
New mutations can lead to serious congenital brain disorders such as autism, epileptic encephalopathies, schizophrenia and others. Since these mutations are unique to the particular sperm and egg involved in the creation of the embryo, genetic analysis of the parents is unable to detect them.
"Up to five percent of newborns suffer from diseases caused by a genetic defect," says Alan Berkley, 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 greatly alleviate some of the emotional and physical stressors of IVF, especially for couples at risk of passing on genetic disorders."
The article was translated specifically for the IVF School program, based on materials
Amniocentesis - a test that is used to obtain a sample for analysis of the genes and chromosomes of the fetus. The fetus is in the uterus surrounded by fluid. This fluid contains a small amount of skin cells from the unborn baby. A small amount of fluid is withdrawn with a thin needle through the mother's abdominal wall (belly). The liquid is sent to a laboratory for analysis. For more detailed information see brochure Amniocentesis.
Autosomal dominant genetic disorder- this is a disease, for the development of which a person needs to inherit one altered copy of the gene (mutation) from one of the parents. At this type 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. In families, vertical transmission of the disease is observed: from one parent to half of the children.
Autosomal recessive geneticdisease - This is a disease in which a person needs to inherit two altered copies of a gene (mutations), one from each parent. With this type of inheritance, a quarter of the children of a married couple are ill. Parents are healthy, but are carriers of the disease. A person who has only one copy of the altered gene will be a healthy carrier. See the booklet Recessive Inheritance for more information.
Autosomal - a trait whose gene is located on autosomes.
Autosomes - Humans have 23 pairs of chromosomes. Pairs 1 to 22 are called autosomes and look the same in men and women. Chromosomes of the 23rd pair differ between men and women and are called sex chromosomes.
Biopsy of chorionic villi, BVP - a procedure during pregnancy to collect cells from the fetus to test 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. See the Chorionic Villus Biopsy brochure for more information.
Vagina - an organ that connects the uterus with the external environment, the birth canal.
Gene - information that an organism 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 testing?
genetic disease - a disease caused by abnormalities in genes or chromosomes.
Deletion - loss of part of the genetic material (DNA); the term can be used to refer to the loss of part of both a gene and a chromosome. See the Chromosomal Disorders brochure for more information.
DNA - the chemical substance of which genes are composed and which contains the information that an organism needs for life.
Duplication - abnormal repetition of a sequence of genetic material (DNA) in a gene or chromosome. See the Chromosomal Disorders brochure for more information.
Measuring the thickness of the collar space (TVP) - Ultrasound of the back of the fetal neck area, which is filled with fluid early in pregnancy. If the child has a congenital disorder (such as Down's syndrome), the thickness of the nuchal space can be changed.
Inversion - change in the sequence of genes on a single chromosome. See the Chromosomal Disorders brochure for more information.
Insertion - insertion of additional genetic material (DNA) into a gene or chromosome. See the Chromosomal Disorders brochure for more information.
Karyotype - a description of the structure of an individual's chromosomes, 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 places of the human body look and perform differently various functions. Each cell (with the exception of eggs in women and sperm in men) contains two copies of each gene.
Ring chromosome is the 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 of a condition in the family, possibly of a hereditary nature.
Mutation- change in 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 violated, and it cannot work correctly. This can lead to the development of a genetic disease.
Miscarriage - p premature termination of a pregnancy before the child is able to survive outside the uterus.
Unbalanced translocation - translocation, in which 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 Brochure Chromosomal Translocations.
Carrier of chromosomal rearrangement - a person who has a balanced translocation, in which the amount of chromosomal material is not reduced or increased, which usually does not cause health problems.
carrier - a person who does not normally have a disease (currently) but carries one altered copy of a gene. In the case of a recessive disease, the carrier is usually healthy; in the case of a dominant disease with a late onset, the person will become ill later.
Fertilization - the fusion of an egg and a sperm to create the baby's first cell.
Placenta- an organ adjacent to the inner wall of the uterus of a pregnant woman. 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 a 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 develop 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 from two different chromosomes and switch places. For more information see the Brochure Chromosomal Translocations.
Robertsonian translocation - occurs when one chromosome is attached to another. For more information see the Brochure Chromosomal Translocations.
Balanced translocation - t ranlocation (chromosomal rearrangement), in which the amount of chromosomal material is not reduced or increased, but it is moved 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 Brochure Chromosomal Translocations.
Sex-linked condition- See X-linked inheritance.
Spermatozoon - paternal germ cell, paternal contribution to the formation of the cell from which it will develop new baby. Each sperm contains 23 chromosomes, one from each pair of paternal chromosomes. The sperm fuses with the egg to create the first cell from which the unborn child develops.
Translocation - rearrangement of chromosomal material. Occurs when a fragment of one chromosome breaks off and attaches to another place. For more information see the Brochure Chromosomal Translocations.
Ultrasound examination (ultrasound) - a painless examination in which sound waves are used to create an image of a fetus growing in the mother's uterus. It can be performed by moving the scanner head over the surface of the mother's abdominal wall (belly) 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 our mother, the second set of 23 chromosomes from our 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. See the brochure X-linked Inheritance for more information.
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- Organs in a woman's body that produce eggs.
Ovum - the mother's germ cell, which will serve as the basis for creating the first cell of the unborn child. The egg contains 23 chromosomes; one of each pair the mother has. The egg fuses with the sperm to form the baby's first cell.
De novo - with combination of Latin 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 has these changes.
XY- this is how the set of sex chromosomes of a man is usually represented. 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, males have one Y chromosome and one X chromosome. A woman normally has two X chromosomes.
Schizophrenia is one of the most mysterious and complex diseases, and in many ways. It is difficult to diagnose - there is still no consensus on whether this disease is one 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 delirium), but they do not help return the person to a full life. Schizophrenia is difficult to study - no other animal except humans suffers from it, so there are almost no models for studying it. Schizophrenia is very difficult to understand from a genetic and evolutionary point of view - it is full of contradictions that biologists cannot yet resolve. However, the good news is that in last years Finally, things seem to have moved off the ground. We have already talked about the history of the discovery of schizophrenia and the first results of its study by neurophysiological methods. This time we will talk about how scientists are looking for the 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 diagnosis, even if we create good medicine it won't work right away. The importance of genetic research lies in the fact that they are already changing our understanding of the fundamental mechanisms of inheritance of complex traits. If scientists do 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, some raw facts. Schizophrenia is a severe, chronic, disabling mental illness that usually affects people at a young age. It affects about 50 million people worldwide (slightly less than 1% of the population). The disease is accompanied by apathy, lack of will, often hallucinations, delirium, disorganization of thinking and speech, and motor disorders. Symptoms usually cause social isolation and reduced performance. An increased risk of suicide in patients with schizophrenia, as well as concomitant somatic diseases, leads to the fact that their overall life expectancy is reduced by 10-15 years. In addition, patients 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. Last but not least, this is due to the fact that we still do not have a clear idea about the violation of which biological processes is the cause of the development of the disease. This lack of understanding has meant that since the introduction of the first antipsychotic drug chlorpromazine (trade name: Aminazine) to 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 ones) have the same main 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, thought disorders, etc. side effects we don't even mention. A common disappointment in schizophrenia research is that drug companies have long been cutting funding for antipsychotics, even as the total number of clinical trials continues to rise. However, the hope for clarification of the causes of schizophrenia came from a rather unexpected direction - it is associated with unprecedented progress in molecular genetics.
Collective responsibility
Even the first researchers of schizophrenia 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 made 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 more genes, therefore, by the middle of the century, the so-called "syntheses" began to become more and more popular. 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 characteristics 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 last long. The final point on the question of whether schizophrenia is a hereditary disease was put by psychogenetic studies conducted 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 the manifestation of some sign - in this case, the development of the 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 should mainly come from the fact that identical twins are genetically identical, while fraternal twins have, on average, only half the common variants of genes.
In the case of schizophrenia, it turned out that the concordance of identical twins is more than 3 times higher than the concordance of fraternal twins: for the first it is approximately 50 percent, and for the second - less than 15 percent. These words should be understood as follows: if you have an identical twin brother suffering from 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. For 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 four other major mental illnesses: attention deficit hyperactivity disorder, bipolar disorder and autism.
The results of twin studies have been 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 their risk of developing schizophrenia is not reduced compared to 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 as many offspring as healthy people), then how does it manage to remain in the population for at least ? This contradiction, around which in many respects the main struggle between different theories takes place, has been 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, there has been a heated debate not even about which genes are changed in patients with schizophrenia, but about what is the general genetic "architecture" of the disease.
It means the following. The genomes of individual people are very similar to each other, with differences averaging less than 0.1 percent of nucleotides. Some of them distinctive features genomes are quite widespread in the population. It is conventionally considered 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 ancestors from Africa. modern people, so they are commonly 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, as a result of a continuous mutation process, other new harmful variants appear. In sum, 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 exactly which genetic variants - common or rare, having a strong phenotypic effect, or only slightly increasing the risk of developing a disease - predetermine its occurrence. It is 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 the predisposition to the disease is determined by changes in dozens of genes. At the same time, all the "genetic architectures" of schizophrenia proposed 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 gave its own explanation of 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 polygene, akin to what determines the inheritance of quantitative traits such as height or body weight. Such a polygene is a set of polymorphisms, each of which only slightly affects the physiology (they are called "causal", because, although not alone, they lead to the development of the disease). To maintain the characteristic of schizophrenia is quite high level morbidity, it is necessary that this polygene consists of common variants - after all, it is very difficult to assemble many rare variants in one genome. Accordingly, each person has dozens of such risky variants in his genome. In sum, all causal variants determine the genetic predisposition (liability) of each individual to the disease. It is assumed that for qualitative complex features, such as schizophrenia, there is a certain threshold value of predisposition, and only those people whose predisposition exceeds this threshold value develop the disease.
Threshold model of disease susceptibility. shown normal distribution predisposition, plotted on 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 the population over many generations can have several explanations. First, each individual such variant has a rather minor effect on the phenotype, such "quasi-neutral" variants may be invisible to selection and remain common in populations. This is especially true for populations with low effective size, where the influence of chance is no less important than selection pressure - this includes the population of our species.
On the other hand, assumptions have been made about the presence in the case of schizophrenia of the so-called. balancing selection, i.e., the positive effect of "schizophrenic polymorphisms" on healthy carriers. It's not that hard to imagine. It is known, for example, that for schizoid individuals with a high genetic predisposition to schizophrenia (of which there are many among close relatives of patients), it is characteristic elevated level creative abilities, which may slightly increase their adaptation (this has already been shown in several works). Population genetics allows for 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 that each individual case or family history of the disease is a separate quasi-Mendelian disease associated in each individual case with unique changes in the genome. In 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 we are guided by this model, then we have 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 sequencing of father-mother-child triplets show that in each generation, only 70 new single-nucleotide substitutions occur per 6 billion nucleotides of the diploid genome, of which, on average, only a few can theoretically have any effect on the phenotype, and mutations of other types - an even rarer occurrence.
However, some empirical evidence indirectly supports this model of the genetic architecture of schizophrenia. For example, in the early 1990s, it was discovered that about one percent of all patients with schizophrenia had a microdeletion in one of the regions of the 22nd chromosome. In the vast majority of cases, this mutation is not inherited from parents, but occurs de novo during gametogenesis. One in 2,000 people is born with this microdeletion, which leads to a variety of abnormalities in the body, called "DiGeorge syndrome." Those suffering from this syndrome are characterized by severe impairment of cognitive functions and immunity, they are often accompanied by hypocalcemia, as well as problems with the heart and kidneys. A quarter of people with DiGeorge syndrome develop schizophrenia. It would be tempting to suggest that other cases of schizophrenia are due to similar genetic disorders with catastrophic consequences.
Another empirical observation indirectly supporting 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 over 50 years old at the time of birth, there are 3 times more patients with schizophrenia than among those whose fathers were under 30. de novo mutations. Such a connection, for example, has long been established for sporadic cases of another (monogenic) hereditary disease - achondroplasia. This correlation has most recently been 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 the calculations of scientists, on average, a child receives 15 mutations from the mother, regardless of her age, and from the 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 with each year of the father's life.
Together, these data seemed to indicate quite clearly the key role de novo mutations in the etiology of schizophrenia. However, the situation actually turned out to be much more complicated. Even after the separation of the two main theories, for decades the genetics of schizophrenia stagnated. Almost no reliable reproducible evidence has been obtained in favor of one of them. Neither about the general genetic architecture of the disease, nor about specific variants that affect the risk of developing the disease. A sharp jump has occurred over the past 7 years and it is associated primarily with technological breakthroughs.
Looking for genes
The sequencing of the first human genome, the subsequent improvement in sequencing technologies, and then the advent and widespread introduction of high-throughput sequencing finally made it possible to gain a more or less complete understanding 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 structured like this. First, a sample of unrelated sick people (cases) and a sample of unrelated healthy individuals (controls) of approximately the same size are collected. All these people are determined by the presence of certain genetic variants - just in the last 10 years, researchers have the opportunity to determine them at the level of entire genomes. Then, the frequency of occurrence of each of the identified variants is compared between groups of sick people and a control group. If at the same time it is possible to find a statistically significant enrichment of one or another 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 measure that characterizes the effect of a disease-associated variant is OD (odds ratio), which is defined as the ratio of the chances of getting sick in carriers of this variant compared to those people who do not have it. If the OD value of a variant is 10, this means the following. If we take a random group of carriers of the 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. At the same time, the closer the OD is to one for a given variant, the larger the sample is needed in order to reliably confirm that the association really exists - that this genetic variant really affects the development of the disease.
Such work has now made it possible to detect more than 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 DiGeorge syndrome already known to us). For the CNVs that have been found to cause schizophrenia, the 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, supporters of the "mutation" model assigned great expectations for a different type of experiment. They compare in patients with schizophrenia and healthy controls not the presence of massive genetic rearrangements, but the complete sequences of genomes or exomes (the totality of all protein-coding sequences). Such data, obtained using high-throughput sequencing, makes it possible to find rare and unique genetic features that cannot be detected by other methods.
The cheapening of sequencing has made it possible in recent years to conduct experiments of this type on rather large samples, including several thousand patients and the same number of healthy controls in recent studies. What is the result? Alas, so far only one gene has been found, in which rare mutations are reliably associated with schizophrenia - this is the gene SETD1A, encoding one of the important proteins involved in the regulation of transcription. As in the case of CNV, the problem here is the same: mutations in the gene SETD1A cannot 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 (horizontal axis) and their impact on the risk of developing schizophrenia (OR). In the main plot, the red triangles show some of the disease-associated CNVs identified so far, the blue circles show the SNPs from GWAS. The incision shows areas of rare and frequent genetic variants in the same coordinates.
There are indications that there are other rare and unique options that influence susceptibility to schizophrenia. And further increase in samples in experiments using sequencing should help to find some of them. However, while 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 confidence in the correctness of the CV model came first of all with the development of GWAS-type studies, which we will discuss in detail in the second part. In short, studies of this type have uncovered the very common genetic variability that describes a large proportion of the heritability of schizophrenia, the existence of which was predicted by the CV model.
Additional support for the CV model for schizophrenia is the relationship between the level of genetic predisposition to schizophrenia and the so-called schizophrenia spectrum disorders. Even early researchers of schizophrenia noticed that among the relatives of patients with schizophrenia, there are often not only other patients with schizophrenia, but also "eccentric" personalities 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 that are characterized by more or less pronounced disturbances in the perception of reality. This group of diseases is called the schizophrenia spectrum disorder. In addition to various forms of schizophrenia, these 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 of predisposition to the 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 would be logical to assume that the genetic variants found to be associated with schizophrenia would also be enriched among people with schizophrenia spectrum disorders. To assess the genetic predisposition of each individual, a special value is used, called the level of polygenic risk (polygenic risk score). The level of polygenic risk takes into account the total contribution of all common risk variants identified in the GWAS that are present in the genome this person, in predisposition to disease. It turned out that, as predicted by the CV model, the values of the polygenic risk level correlate not only with schizophrenia itself (which is trivial), but also with other diseases of the schizophrenia spectrum, and higher levels of polygenic risk correspond to severe types of disorders.
And yet one problem remains - the phenomenon of "old fathers". If much of the empirical evidence supports the polygenic model of schizophrenia, how does one reconcile with it the long-established association between age at fatherhood and children's risk of developing schizophrenia?
An elegant explanation of this phenomenon was once put forward in terms of the CV model. It has been suggested that late fatherhood and schizophrenia are not cause and effect, respectively, 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 susceptibility to schizophrenia may correlate in healthy men with later fatherhood. On the other hand, it is clear that a father's high predisposition 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 male spermatozoa precursors may have almost no effect on the development of schizophrenia in their offspring. Recent modeling results, taking into account epidemiological data, as well as fresh molecular data on frequency de novo mutations are in good agreement with this explanation of the phenomenon of "old fathers".
Thus, at the moment we can assume 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 particular set of common polymorphisms causes schizophrenia in accordance with the CV model. How geneticists are looking for this set and what they have already discovered will be the subject of the second part of our story.
Arkady GolovAll body proteins are written in cellular DNA. Only 4 types of nucleic bases - and countless combinations of amino acids. Nature made sure that each failure was not critical and made redundant. But sometimes the distortion still creeps in. It's called mutation. This is a violation in the recording of the DNA code.
Useful - rare
Most of these distortions (more than 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 offspring. Indeed, in nature, not everyone has the right to reproduce. Cell mutation occurs more often in males - and males, as you know, die more often in nature without giving offspring.
The 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 affected by early childhood. If it exists for men, then for women, even a small glass can provoke violations of the proper formation of eggs. While European women enjoy freedom, Arab women abstain - and give birth to healthy children.
Not spelled correctly
Mutation is a permanent change in DNA. It can affect a small area or a whole block in the chromosome. But even a minimal violation shifts the DNA code, forcing the synthesis of completely different amino acids - therefore, the entire protein encoded by this site will be inoperative.
Three types
A mutation is a violation of one of the types - either inherited, or a de novo mutation, or a local mutation. In the first case, it is. In the second, it is a violation at the level of the sperm or egg, as well as a consequence of exposure to hazardous factors after fertilization. Hazards are not only bad habits, but also unfavorable environmental conditions (including radiation). A de novo mutation is a disturbance in all the cells of the body, as it arises from an abnormal source. In the third case, local, or does not occur in the 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 arose in the early stages of pregnancy, then a mosaic disorder 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 the mutation is harmless and occurs frequently, it is called a polymorphism. This is how blood types and colors of the iris originated. However, polymorphism can increase the likelihood of certain diseases.
There are the following types of mutations:
a) genomic mutations, leading to a change in the number of chromosomes. Genomic mutations often occur in plants. In this case, the multiplication of entire sets of chromosomes (polyploidy) or an increase (trisomy) or decrease (monosomy) in the number of individual chromosomes can occur;
b) chromosomal mutations(see section 2.2), in which the structure of chromosomes is disturbed, and their number in the cell remains unchanged. Chromosomal mutations can be detected by microscopic examination.
in) gene mutations, not leading to changes in chromosomes detected by a microscope; these mutations can only be detected by genetic analysis of phenotypic changes (see Section 3.6).
The study of mutations in humans at the level of proteins and DNA (especially mutations in hemoglobin genes) has made a great contribution to understanding their molecular nature. The results of these studies and the results of the analysis of the structure of chromosomes by high resolution methods of differential staining led to the blurring of the line between chromosomal and gene mutations. We now know that deletions and insertions are possible at the molecular level, and that unequal crossing over can change the microstructure. Differential staining methods made it possible to detect previously indistinguishable chromosomal rearrangements under the microscope. It should be remembered that chromosome changes detected by differential staining differ by several orders of magnitude.
5 Mutations 143
from changes such as deletions of structural genes. Therefore, the distinction between structural chromosomal aberrations and gene mutations is useful for practical purposes.
Cells in which mutations occur. Except type genetic damage, its extremely important localization. Mutations can occur in both sex and somatic cells. Those that arise in germ cells are transmitted to individuals of the next generation and, as a rule, are found in all cells of the descendants who have become their carriers. Somatic mutations can only be detected in the offspring of the corresponding mutant cell, which leads to a "mosaic" of the individual. Phenotypic consequences will manifest themselves only if these mutations interfere with the implementation of specific functions inherent in these mutant cells.
Mutation frequencies. One of the parameters most commonly used in the study of the mutation process is frequency occurrence mutations(or mutation rate). In relation to a person, it is defined as the probability of a mutational event occurring during the lifetime of one generation. As a rule, this refers to the frequency of mutations in fertilized eggs. The issue of mutation frequencies in somatic cells is discussed in Sec. 5 1.6.
