Genetic polymorphism: what is it? Polymorphism - what is it? Genetic polymorphism.
) two or more different hereditary forms that are in dynamic equilibrium over several or even many generations. Most often, genetic selection is determined either by varying pressures and vectors (direction) of selection under different conditions (for example, in different seasons), or by the increased relative viability of heterozygotes (See Heterozygote). One of the types of genetic diversity—balanced genetic diversity—is characterized by a constant optimal ratio of polymorphic forms, deviation from which turns out to be unfavorable for the species and is automatically regulated (the optimal ratio of forms is established). The majority of genes are in a state of balanced gene production in humans and animals. There are several forms of genetic diversity, the analysis of which makes it possible to determine the effect of selection in natural populations.
Lit.: Timofeev-Resovsky N.V., Svirezhev Yu.M., On genetic polymorphism in populations, “Genetics”, 1967, No. 10.
Great Soviet Encyclopedia. - M.: Soviet Encyclopedia. 1969-1978 .
See what “Genetic polymorphism” is in other dictionaries:
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Polymorphism polymorphism. The existence of genetically different individuals in a crossing group (population); P. may have a non-genetic (modifying) nature, for example, depending on population density (see.
It is customary to call genes polymorphic if they are represented in a population by several varieties - alleles, which determines the diversity of traits within the species.
Genetic polymorphism (Greek) genetikos- relating to birth, origin; Greek policies- many and morphe - type, form, image) - diversity of allele frequencies of homozygotes. Differences between alleles of the same gene usually involve minor variations in its “genetic” code. A large proportion of genetic polymorphism is made by substitutions of one nucleotide for another and changes in the number of repeating DNA fragments, which occur in all structural elements of the genome: exons, introns, regulatory regions, etc. The scale of genetic polymorphism in humans is such that between DNA sequences There are millions of differences between two people, unless they are identical twins. These differences fall into four main categories:
a) phenotypically not expressed (for example, polymorphic DNA sections used for personal identification using molecular genetic methods);
b) causing phenotypic differences (for example, in hair color or height), but not predisposition to the disease;
c) playing some role in the pathogenesis of the disease (for example, in polygenic diseases);
d) playing a major role in the development of the disease (for example, in monogenic diseases).
Although most known polymorphisms are expressed either in substitutions of a single nucleotide or in changes in the number of repeating DNA fragments, nevertheless, variations affecting the coding fragments of genes and affecting the amino acid sequence of their products are relatively rare and are not related to the specific problem being analyzed. First of all, the possible consequences of polymorphism of nitrons and 5"-terminal non-coding sequences are important. Analysis of this phenomenon largely depends on how variable the intrinsic functions of the protein encoded by different alleles are, which is also true for the enzymes of the formation and metabolism of steroid hormones, about which further discussion will follow.
A locus is said to be polymorphic if two or more alleles of that locus exist in a population. However, if one of the alleles has a very high frequency, say 0.99 or more, then there is a high probability that no other allele will be present in a sample taken from the population unless the sample is very large. Thus, a locus is generally defined as polymorphic if the frequency of the most common allele is less than 0.99. This division is very conditional and other criteria for polymorphism can be found in the literature.
One of the simplest ways to measure the degree of polymorphism in a population is to calculate the average ratio of polymorphic loci and divide their total number by the total number of loci in the sample. Of course, such a measure largely depends on the number of individuals studied. A more accurate measure of genetic variability within a population is AVERAGE EXPECTED HETEROSYGOSITY or GENE DIVERSITY. This value can be derived directly from gene frequencies and is much less susceptible to effects due to sampling error. Gene diversity at this locus is determined as follows:
M h = 1 - SUM x i * i=1 where SUM is the sum, x i is the frequency of allele i and m is the total number of alleles of a given locus.
For any locus, h is the probability that two alleles randomly selected in a population will be different from each other. The average of all h for each locus studied, H, can be used as an estimate of the amount of genetic variation within a population.
The degrees of genetic diversity h and H have been widely used for data obtained from electrophoretic and restriction enzyme analyses. However, they may not always be suitable for data obtained from DNA sequence studies, since the degree of diversity at the DNA level is extremely high. Particularly when long sequences are considered, it is likely that each will differ from other sequences at one or more nucleotides. Then both h and H will be close to 1 and therefore will not differ between loci or populations, thus being uninformative.
When working with DNA, a more appropriate measure of polymorphism in a population is the average number of nucleotide substitutions per position between two randomly selected sequences. This estimate is called nucleotide diversity (Nei M., Li W.-H., 1979) and is denoted p:
P = SUM (x * x * p) i,j i j ij where x i and x j are the frequencies of sequences of the i-th and j-th types, and p ij is the proportion of nucleotide differences between the i-th and j-th sequence types.
Currently, there are several works on the study of nucleotide diversity at the level of DNA sequences. One such work was done for the locus encoding D. melanogaster alcohol dehydrogenase (Adh) (Nei M., 1987).
11 sequences with a length of 2,379 nucleotides were studied. Ignoring deletions and insertions, nine different alleles were identified, one of which was represented by three, and the remaining eight by one sequence. Thus, the frequencies x 1 - x 8 were equal to 1/11, and x 9 = 3/11. Forty-three positions were polymorphic. First, the proportions of nucleotide differences for each pair of sequences were calculated and shown in the table:
For example, the 1-S and 2-S alleles differed at three positions out of 2.379, therefore n 12 = 0.13%. The n value obtained using formula 3.20 turned out to be equal to 0.007.
Genetic polymorphism and hereditary diseases.
In 1902, Garrod proposed that metabolic disorders, such as alkaptonuria, were an extreme expression of the chemical individuality of the organism. The true breadth of genetic diversity first became apparent when electrophoresis of cell extracts (without prior enzyme purification) demonstrated the existence of multiple structural isoforms for many proteins. The presence of isoforms is due to the existence of multiple gene variants (alleles) of this protein in the population. Alleles have identical localization on homologous chromosomes.
Most genes in every organism are represented by two alleles, one inherited from the father and the other from the mother. If both alleles are identical, then the organism is considered homozygous, if different - heterozygous.
During evolution, different alleles arose as a result of mutations from a single predecessor allele; most often they differ from each other by replacing one nucleotide (missense mutation). Typically, proteins encoded by different alleles of the same gene have the same functional properties, that is, the amino acid substitution is neutral or almost neutral from the point of view of natural selection.
The presence of certain alleles is often judged based on analysis of the amino acid sequence of the corresponding proteins. For many genes (for example, the globin beta chain gene), it is possible to isolate a normal allele - the most common in the population, which occurs much more often than others. Sometimes among the alleles there is not a single one that could be considered normal. Extremely high polymorphism is characteristic, for example, of the apoprotein (a) gene and the haptoglobin alpha chain gene. A gene is considered polymorphic if its most common allele occurs in less than 99% of people. This definition reflects only the prevalence of different alleles and not their functional differences.
The concept of polymorphism expanded with the discovery of extraordinary variability in DNA sequences. In the genomes of different people, 1 out of 100-200 nucleotide pairs differs; this is consistent with heterozygosity at 1 in 250–500 bp. Modern methods make it possible to identify single nucleotide substitutions in coding regions that may be nonsense or cause changes in the amino acid sequence. DNA polymorphism is even more pronounced in non-coding regions of the genome, which have little or no effect on gene expression.
In addition to the replacement of individual nucleotides, DNA polymorphism is based on insertions, deletions, and changes in the number of tandem repeats. There are tandem repeats varying in number (long) (minisatellite DNA) and short (tetra-, tri-, di- or mononucleotide) tandem repeats (microsatellite DNA).
The extent of DNA polymorphism is such that there are millions of differences between the DNA sequences of two people, unless they are identical twins. These differences fall into four broad categories:
Phenotypically not expressed (for example, polymorphic DNA sections used for personal identification using molecular genetic methods);
Causing phenotypic differences (for example, in hair color or height) but not predisposition to disease;
Playing some role in the pathogenesis of the disease (for example, in polygenic diseases);
Playing a major role in the development of the disease (for example, with
Polymorphisms are not a direct and obligatory cause of the development of the disease, but may cause a greater or lesser risk of its development under the influence of various external factors.
Therefore, in the presence of polymorphisms, they inform about the increased risk of developing the disease in heterozygous or homozygous carriage of the polymorphism. The risk of developing the disease is measured by the odds ratio (OR).
In Europe, clinical genetic testing of mutations in the following genes is officially carried out: FV (Leiden), F2 (prothrombin), PAI-1, MTHFR.
Mutation Leiden 1691 G->A coagulation factor V (F5)
Physiology and genetics. Coagulation factor V or blood clotting factor V is a protein cofactor in the formation of thrombin from prothrombin. The G1691A Leiden polymorphism (amino acid substitution Arg (R) -> Gln (Q) at position 506, also known as the “Leiden mutation” or “Leiden”) is an indicator of the risk of developing venous thrombosis. This is a point (single-nucleotide) mutation of the gene encoding coagulation factor V that renders the active form of factor V resistant to the degrading action of a specialized regulatory enzyme, the C protein, resulting in hypercoagulability. Accordingly, the risk of blood clots increases. The prevalence of the mutation in European-type populations is 2-6%.
Risk of deep vein thrombosis(TGV): 7 times higher in heterozygous carriers of the Leiden mutation of the F5 Arg506Gln gene and 80 times higher in homozygotes. Additional factors influencing the development of DVT can be divided into 3 groups.
TO first group of factors includes changes in hormonal status:
The use of oral contraceptives additionally increases the risk of developing DVT by 30 times in heterozygotes, 100 times in homozygous carriers.
Pregnancy increases the risk of DVT by 16 times.
Hormone replacement therapy increases the risks by 2-4 times.
Co. second group of factors include vascular damage:
Central venous catheterization increases the risk of DVT by 2-3 times
Surgical interventions - 13 times.
TO third a group of factors includes immobility: bed rest and long air flights. Here only an increase in risk is noted, but the statistics should be more complete:
Infectious diseases and cancer also increase the risk of developing DVT. The risk of developing ischemic stroke in women aged 18-49 years with the presence of the Leiden mutation increases by 2.6 times, and when taking oral contraceptives it increases by 11.2 times.
Clinical data. The presence of the Leiden mutation increases the likelihood of developing a number of pregnancy complications:
Miscarriage in the early stages (risk increases 3 times),
Delayed fetal development
Late toxicosis (gestosis),
Fetoplacental insufficiency.
An increased tendency to thrombus formation can lead to arterial thromboembolism, myocardial infarction and stroke. The presence of the Leiden mutation increases the risk of primary and recurrent venous thrombosis by at least 3-6 times.
The examples below illustrate the connection of the mutation with various types of thrombosis and other cardiovascular diseases.
An 8-year, multicenter study of more than 300 patients with venous thromboembolism (VTE) found a 3.7-fold increased risk of VTE in the presence of the Leiden mutation. In another study, patients with venous thromboembolism were studied for 68 months. During this time, 14% of patients experienced recurrent VTE. Factor V Leiden mutation leads to a fourfold increase in the risk of recurrent VTE. For patients with VTE with the Leiden mutation, longer anticoagulation therapy is recommended compared to patients with normal factor V.
It should be noted that the risk of developing venous thrombosis increases significantly (8-fold increase) if the patient, in addition to the factor V Leiden mutation, also has a mutation of the T polymorphism C677T of the methyltetrahydrofolate reductase gene.
One of the most dangerous complications hormonal contraceptives are thrombosis and thromboembolism. Many women with such complications are heterozygous carriers of the Leiden mutation (genotype G/A). While taking hormonal contraceptives, their risk of thrombosis is increased by 6-9 times. In women using hormonal contraceptives and having a homozygous Leiden mutation (genotype A/A), the risk of developing cerebral sinus thrombosis (CST) is increased by more than 30 times compared to patients who do not have this mutation.
Final data from the Women's Health Initiative Estrogen Plus Progestin study on the incidence of venous thrombosis during hormone replacement therapy (HRT) were summarized. The study included 16,608 postmenopausal women aged 50 to 79 years, followed from 1993 to 1998. within 5 years. The presence of the Leiden mutation increased the risk of thrombosis during estrogen-progestin hormone replacement therapy by almost 7 times compared to women without this mutation. The presence of other genetic mutations (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, factor V HR2) did not affect the association of HRT and the risk of venous thrombosis. An analysis of more than ten independent studies showed that among patients who had a myocardial infarction before age 55, the prevalence of the Leiden mutation was markedly higher. The average risk of developing myocardial infarction increases by 1.5 times. Moreover, the Leiden mutation leads to a 2.8-fold increase in the number of patients without severe coronary stenosis who develop myocardial infarction.
Polymorphism 20210 G->A prothrombin
Physiology and genetics. Prothrombin (coagulation factor II or F2) is one of the main components of the blood clotting system. During the enzymatic breakdown of prothrombin, thrombin is formed. This reaction is the first stage in the formation of blood clots. The prothrombin gene mutation G20210A is characterized by the replacement of the guanine (G) nucleotide with the adenine (A) nucleotide at position 20210. Due to increased expression of the mutant gene, the level of prothrombin can be one and a half to two times higher than normal. The mutation is inherited in an autosomal dominant manner. This means that thrombophilia occurs even in a heterozygous carrier of the altered gene (G/A).
Thromboembolic diseases(TE) are caused by disorders in the blood clotting system. These disorders also lead to cardiovascular diseases. The G/A genotype is an indicator of the risk of developing thrombosis and myocardial infarction. When thrombosis occurs, the 20210A mutation often occurs in combination with the Leiden mutation. The G/A genotype at position 20210 of the prothrombin gene is a risk factor for the same complications that are associated with the Leiden mutation.
2-3% of representatives of the European race are heterozygous carriers of the gene.
The risk of developing DVT in carriers of the mutant allele (A) of the F2 gene is increased by 2.8 times. The combination of a prothrombin mutation with a Leiden mutation further increases the risks.
According to guidelines for obstetricians and gynecologists (UK, 2000), clinical genetic analysis of FV and prothrombin 20210 is appropriate due to the different risks of homozygotes and heterozygotes.
There are very high, high and medium degree of risk venous thrombosis in pregnant women:
- High the degree of risk in women with an individual and family history of thrombosis and homozygous for the Leiden mutation, the G20210A prothrombin mutation or a combination of these mutations. Such patients are indicated for anticoagulation therapy with low molecular weight heparins from the early to mid-second trimester.
- Average the degree of risk in women with a family history of thrombosis and heterozygous for the Leiden mutation or the G20210A mutation. In this case, anticoagulation therapy is not indicated.
Indications for analysis. Myocardial infarction, increased levels of blood prothrombin, history of thromboembolic diseases, advanced age of the patient, miscarriage, fetoplacental insufficiency, intrauterine fetal death, toxicosis, fetal growth retardation, placental abruption, patients preparing for major abdominal operations (uterine fibroids, cesarean section, ovarian cysts, etc.), smoking.
Clinical data. A study of 500 patients with myocardial infarction and 500 healthy donors showed a more than fivefold increase in the risk of myocardial infarction in patients with the 20210A genotype younger than 51 years of age. Genetic analysis of a group of patients with the first myocardial infarction (age 18-44 years) showed that the 20210A variant is four times more common compared to the healthy group, which corresponds to a 4-fold increase in the risk of heart attack. The likelihood of a heart attack was especially high if you had other cardiovascular risk factors. For example, smoking in the presence of genotype 20210A increases the risk of myocardial infarction by more than 40 times. The 20210A mutation is a significant risk factor for early myocardial infarction.
In a study of patients with a family history of venous thrombosis and a control group of healthy donors, the 20210A mutation was found to lead to a threefold increase in the risk of venous thrombosis. The risk of thrombosis increases for all ages and for both sexes. This study also confirmed a direct link between the presence of the 20210A mutation and increased levels of prothrombin in the blood.
In therapeutic hospitals, where patients with cardiovascular diseases predominate, TE in the form of pulmonary embolism occurs in 15-30% of cases. In many cases, TEs are the direct cause of death, especially in postoperative patients and cancer patients. It has been established that among cancer patients in the presence of TE, mortality increases several times, while the number of TE exceeds the statistical average. The reasons for the increase in TE in cancer patients may need to be sought in the therapy administered, which is inconsistent with the genetic predisposition of the patient. This doesn't just apply to cancer patients. According to post-mortem reports, 60% of patients who die in general hospitals show signs of thromboembolic disease.
Knowledge of the patient’s genotypic characteristics will allow not only to assess the risk of developing life-threatening conditions, but also to correctly determine methods for their prevention and treatment, as well as the possibility of using certain medications.
Heat labile variant A222V (677 C->T) of methylenetetrahydrofolate reductase
Physiology and genetics. Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism. The enzyme catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter is the active form of folic acid necessary for the formation of methionine from homocysteine and then S-adenosylmethionine, which plays a key role in the process of DNA methylation. MTHFR deficiency contributes not only to teratogenic (damaging to the fetus) but also mutagenic (damaging to DNA) effects. In this case, many cellular genes are inactivated, including oncogenes. This is one of the reasons oncologists have become interested in genetic variants of MTHFR. The amino acid homocysteine is an intermediate product of the process of methionine synthesis. Disturbances of the MTHFR enzyme lead to excessive accumulation of homocysteine in the blood plasma - hyperhomocysteinemia.
The MTHFR gene is localized on chromosome 1p36.3. About two dozen mutations of this gene are known that disrupt the function of the enzyme. The most studied mutation is a variant in which the nucleotide cytosine (C) at position 677 is replaced by thymidine (T), which results in the replacement of the amino acid residue alanine with a valine residue (position 222) in the folate binding site. This MTHR polymorphism is designated the C677T mutation. Individuals homozygous for this mutation (T/T genotype) exhibit MTHFR thermolability and a decrease in enzyme activity to approximately 35% of the average value. In general, among the world population, the 677T mutation of the MTHFR gene is quite widespread among representatives of the European (Caucasian) race. The frequencies of two major mutations (C677T and A1298C) among representatives of the US population were studied. The presence of T/T homozygote was shown in 10-16% of Europeans and 10% of people of Spanish origin, and 56 and 52% of the examined individuals were heterozygous carriers of this gene, respectively, i.e. the presence of the 677T variant (genotypes C/T or T/T) was observed in 62-72% of cases. Similar results were found in European population samples. The C677T polymorphism is associated with at least four groups of multifactorial diseases: cardiovascular diseases, fetal defects, colorectal adenoma, and breast and ovarian cancer.
Indications for analysis. Increased blood homocysteine levels (hyperhomocysteinemia), cardiovascular diseases (in particular, coronary heart disease (CHD) and myocardial infarction), atherosclerosis, atherothrombosis. Antiphospholipid syndrome. Cancer chemotherapy before or during pregnancy. Family predisposition to pregnancy complications leading to congenital malformations: defects of the fetal nervous system, anencephaly, deformities of the facial skeleton (cleft palate, cleft lip), prenatal fetal death. Intestinal polyposis, colorectal adenoma due to alcohol consumption, rectal cancer. Family predisposition to cancer, presence of BRCA gene mutations. Cervical dysplasia, especially in combination with papillovirus infections.
Clinical data. Defects in this gene often lead to various diseases with a wide range of clinical symptoms: mental and physical developmental delays, prenatal death or fetal defect, cardiovascular and neurodegenerative diseases, diabetes, cancer and others. Carriers of C/T heterozygotes experience folic acid deficiency during pregnancy, which can lead to defects in the development of the neural tube in the fetus. Smoking increases the effect of the mutation. Carriers of two T/T alleles (homozygous state) are especially at risk of developing side effects when taking drugs used in cancer chemotherapy.
Hyperhomocysteinemia (HH) is an independent risk factor for atherosclerosis and atherothrombosis (independent of hyperlipidemia, hypertension, diabetes mellitus, etc.). It has been established that 10% of the risk of developing coronary atherosclerosis is due to an increase in the level of homocysteine in the blood plasma. In a study of a group of patients with HH and a group of healthy donors, the homozygous form 677T was found in 73% of patients with HH and only in 10% of healthy donors. The presence of the homozygous 677T form leads to an almost 10-fold increase in the risk of HH. Patients with HH also had lower levels of folic acid and vitamin B12, consumed more coffee, and smoked more often than healthy donors. Normal homocysteine levels are 5-15 µmol/l, moderately elevated levels are 15-30 µmol/l. In severe HH, a 40-fold increase in homocysteine levels is possible. Researchers attribute the cause of severe forms of HH to other mutations and factors - homozygous mutation of the Cb S gene, the most common are I278T and G307S, although the frequency of their manifestation varies greatly in different countries, much less often the causes of severe HH are the T/T genotype of MTHFR, methionine synthetase deficiency and impaired methionine synthetase activity due to genetic disorders of vitamin B12 metabolism. Correction of HH can be carried out by supplying cofactors necessary for the metabolism of homocysteine (folic acid, vitamins B12, B1 and B6 (features of HH vitamin therapy). In carriers of the T/T genotype MTHFR, with optimal folate intake, homocysteine levels are moderately increased (up to 50%). Although In severe HH, the combination of 2.5 mg folic acid, 25 mg vitamin B6 and 250 mcg vitamin B12 per day is known to reduce the progression of atherosclerosis (measured in carotid plaque), but whether homocysteine-lowering therapy prevents significant vascular complications remains to be confirmed in persons with moderate HS.
The importance of the GG problem is indicated by the fact that the US Department of Health in 1992 recommended that women who may become pregnant take 400 mcg of folic acid per day. The US Food and Drug Administration requires that cereals be fortified with folic acid in concentrations that can provide an additional 100 mcg per day. However, the daily dose of folic acid needed to maximally reduce homocysteine levels is 400 mcg, meaning higher doses of dietary folic acid supplementation may be justified.
The pathogenesis of neural tube birth defects includes, in particular, genetic and dietary factors. In a study of 40 children from Southern Italy with a congenital neural tube defect and healthy donors, it was shown that the 677C genotype in the homozygous state (C/C) leads to a twofold increase in the risk of developing defects, while the mutant homozygote T/T corresponds to an almost tenfold reduction in risk . In a study of a sample of the Irish population (395 patients and 848 healthy ones), it was found that the occurrence of the T variant was increased in patients with a congenital neural tube defect. It is difficult to say whether these contrasting study results are due to population changes or whether other risk factors are not taken into account. Therefore, it is not yet possible to determine whether the T variant is a protective or, conversely, a pathogenic factor for this disease. An increase in the frequency of the 677T genotype was noted not only with late toxicosis (preeclampsia), but also with other complications of pregnancy (placental abruption, fetal growth restriction, prenatal fetal death). The combination of the 677T mutation with other risk factors leads to an increased likelihood of early miscarriage. When examining the relationship between the 677T mutation and cardiovascular disease, it was found that the homozygous 677T mutation is much more common in patients with cardiovascular disease than in healthy donors. In young patients with arterial ischemia, homozygote T/T is 1.2 times more common.
A statistical analysis of 40 independent studies (meta-analysis) of patients with coronary artery disease, summarizing data on 11,162 patients and 12,758 healthy donors, showed a 1.16-fold increase in the risk of developing coronary artery disease in the presence of a T/T homozygote. The low degree of risk is associated with the heterogeneity of the analyzed population samples. When studying homogeneous population samples (individual studies rather than meta-analyses), risk estimates are significantly higher. Thus, the difference in the frequency of occurrence of T/T homozygotes in patients and healthy donors corresponded to a 3-fold increase in the risk of cardiovascular diseases at an early age. The presence of the 677T mutation in the MTHFR gene in patients with antiphospholipid syndrome correlates with the recurrent course of thrombosis.
A definite, albeit complex, relationship has been identified between MTHFR variants and the development of precancerous and cancerous conditions of the colorectal region. A study was conducted on a large group of patients with colon polyposis. RBC folate levels were determined, along with an assessment of the MTHFR C/T genotype. Previous results have shown an association between low folate levels and the risk of developing adenomatosis. Multivariate analysis showed that smoking, folate status, and MTHFR genotype were significant components of high risk of adenomatosis. This risk turned out to be very high in individuals with low folate levels and carriage of the 677T allele in homo- or heterozygous form. These data showed a strong interaction between dietary and genetic factors in the development of precancerous conditions.
Similar assumptions were made by scientists who examined a large cohort of patients with colon cancer and showed a significant relationship between the risk of developing cancer, the age of patients, age-related folate deficiency and the T/T genotype of MTHFR. A study of 379 patients with colorectal adenoma and 726 healthy donors showed that male carriers of the T/T genotype who consumed a lot of alcohol had a 3.5 times higher risk of developing adenoma. However, some researchers believe that without alcohol consumption as a risk factor, the 677T mutation is a protective factor.
Thus, a study of patients with proximal colorectal cancer showed that the presence of a T/T homozygote in a patient leads to a 2.8-fold reduction in the risk of developing colorectal cancer. These findings require testing in other populations. Most likely, the significance of a low-active mutant MTHFR can be considered aggravating against the background of the other listed risk factors, since this gene defect can reduce genome stability due to DNA hypomethylation. The C677T polymorphism affects the effectiveness of cancer chemotherapy. Fluorouracil is widely used for chemotherapy of colorectal cancer. The likelihood of positive dynamics in response to chemotherapy for colorectal adenocarcinoma if the patient had the 677T genotype increased almost threefold. The results suggest that genotyping for the C677T polymorphism will allow the development of more effective chemotherapy courses. However, a study of small samples (up to 50) of breast cancer patients showed that in the presence of a T/T homozygote, the risk of developing side effects when using methotrexate (an antimetabolite, the action of which is associated with inhibition of the activity of the MTHFR enzyme) increases tenfold.
There are few studies of MTHFR genotype in gynecological cancers. The C677T polymorphism of the MTHFR gene was studied in a large group of Jewish women with breast and ovarian cancer, including hereditary forms associated with BRCA gene mutations. With such an unfavorable genetic background, the presence of the T/T genotype in patients turned out to be a significant factor in the aggravation of the disease. The frequency of the T/T genotype was 2 times higher (33% versus 17%, P = 0.0026) among women with bilateral breast cancer and ovarian cancer, compared with the main group of patients. Women with the heterozygous C/T genotype had a double risk of cancer, and in patients with the homozygous T/T genotype, the risk was three times higher than in the control group. At the same time, reduced dietary folate intake increased genetic risk by up to five times compared with controls. The authors also confirmed the fact that HPV (papilloma virus) infection in patients is the most important risk factor for the development of cervical dysplasia. At the same time, the special significance of the combination of HPV infection with the T/T variant of MTHFR is emphasized.
Polymorphism Arg353Gln (10976 G->A) coagulation factor VII (F7)
Physiology and genetics. In the active state, factor VII interacts with factor III, which leads to the activation of factors IX and X of the blood coagulation system, that is, coagulation factor VII is involved in the formation of a blood clot. The 353Gln variant (10976A) leads to a decrease in the productivity (expression) of the factor VII gene and is a protective factor in the development of thrombosis and myocardial infarction. The prevalence of this variant in European populations is 10-20%.
Indications for analysis. Risk of myocardial infarction and fatal outcome due to myocardial infarction, level of coagulation factor VII in the blood, history of thromboembolic diseases.
Clinical data. High levels of coagulation factor VII in the blood have been associated with an increased risk of death from myocardial infarction. The presented data on the clinical significance of the mutation are confirmed by studies in other European populations. In particular, the presence of the 10976A variant was associated with a reduced risk of fatal myocardial infarction.
In a study of patients with coronary artery stenosis and myocardial infarction, it was found that the presence of the 10976A mutation leads to a 30% decrease in the level of factor VII in the blood and a 2-fold decrease in the risk of myocardial infarction, even in the presence of significant coronary atherosclerosis.
In the group of patients who did not have myocardial infarction, an increased incidence of hetero- and homozygous genotypes 10976A, G/A and G/G, respectively, was observed.
Polymorphism - -455 G->A fibrinogen
Physiology and genetics. When blood vessels are damaged, fibrinogen turns into fibrin, the main component of blood clots (thrombi). The -455A fibrinogen beta (FGB) mutation is accompanied by increased gene performance (expression), which leads to increased levels of fibrinogen in the blood and increases the likelihood of blood clots. The prevalence of this variant in European populations is 5-10%.
Indications for analysis. Elevated levels of plasma fibrinogen, high blood pressure, history of thromboembolic diseases, stroke.
Clinical data. An increased tendency to form blood clots can lead to thrombosis and cardiovascular diseases. The level of fibrinogen in the blood is determined by a number of factors, including medications, smoking, alcohol intake and body weight. However, both genotypes G and A correspond to a noticeable difference in blood fibrinogen levels (10-30% according to various studies).
In a study of a group of healthy donors, it was found that the -455A mutation leads to increased levels of fibrinogen in the blood. The large-scale EUROSTROKE study found that the risk of stroke (ischemic or hemorrhagic) increases 2-3 times with increasing blood fibrinogen levels. The risk further increases with elevated systolic blood pressure (>160 mmHg). These data are confirmed by studies of non-European populations.
With high blood pressure, the presence of the -455A genotype increases the risk of ischemic stroke.
Stroke patients with the -455A genotype are characterized by multifocal lesions: they may have three or more lacunar cerebral vascular infarctions, on average, the risk of stroke increases by 2.6 times.
With elevated blood pressure in patients with the mutation, the risk of multifocal stroke increases by more than 4 times (Finland).
Polymorphism - IIeMet (66 a-g) Mutation of methionine synthetase reductase
Physiology and genetics. The MTRR gene encodes the enzyme methionine synthase reductase (MSR), which is involved in a large number of biochemical reactions associated with methyl group transfer. One of the functions of MCP is the reverse conversion of homocysteine to methionine. Vitamin B12 (cobalamin) takes part as a cofactor in this reaction.
The I22M A->G polymorphism is associated with an amino acid substitution in the MCP enzyme molecule. As a result of this replacement, the functional activity of the enzyme decreases, which leads to an increased risk of fetal developmental disorders - neural tube defects. The effect of polymorphism is aggravated by vitamin B12 deficiency. When the I22M A->G polymorphism in the MTRR gene is combined with the 677C->T polymorphism in the MTHFR gene, the risk increases.
The I22M A->G polymorphism in the MTRR gene also enhances hyperhomocysteinemia caused by the 677C->T polymorphism in the MTHFR gene. The A66G (Ile22Met) polymorphism in the MTRR gene in both heterozygous (AG) and homozygous (GG) variants significantly increases homocysteine concentrations only when combined with the MTHFR 677TT genotype.
The MTRR 66 A-G polymorphism increases the risk of having a child with Down syndrome by 2.57 times. The combination of polymorphisms in the MTHFR and MTRR genes increases this risk to 4.08%.
Polymorphism - 675 5G/4G Plasminogen activator inhibitor (PAI) mutation 1
Physiology and genetics. This protein (also known as SERPINE1 and PAI-1) is one of the main components of the thrombolytic plasminogen-plasmin system. PAI-1 inhibits tissue and urokinase plasminogen activators. Accordingly, PAI-1 plays an important role in determining susceptibility to cardiovascular diseases. The homozygous variant 4G of the -675 4G/5G polymorphism is a risk factor for the development of thrombosis and myocardial infarction. The prevalence of the homozygous form of this variant in Caucasian populations is 5-8%. The PAI-1 gene differs from all known human genes in its maximum response to stress. The association of the 4G mutant allele with an increased risk of DVT has been analyzed in many studies, but their results are inconsistent.
According to Russian researchers (St. Petersburg), the risk of developing cerebral thrombosis increased 6 times in individuals with a family history of cardiovascular diseases in the presence of the 4G allele. An association of carriage of the 4G polymorphism with recurrent miscarriage has been shown.
Clinical aspects. The 4G variant results in increased gene expression and therefore increased levels of PAI-1 in the blood. Consequently, the thrombolytic system is inhibited and the risk of thrombosis increases.
In a study of large population samples (357 patients and 281 healthy donors), it was found that the 4G/4G variant increases the risk of thrombosis by an average of 1.7 times. The increased risk was much higher for the subgroups of patients with portal vein thrombosis and visceral thrombosis. However, no statistically significant correlations were found for the subgroups of patients with deep vein thrombosis, cerebral or retinal thrombosis. The 4G variant has been associated with an increased risk of myocardial infarction. In the presence of the 4G variant in PAI-1 and L33P in the ITGB3 gene, the average risk of developing myocardial infarction increased by 4.5 times; in men, the risk increased by 6 times in the presence of these two variants.
A study of 1179 healthy donors and their close relatives showed the 4G variant is associated with a family history of coronary artery and/or heart disease. In this study of a large population sample, the average increase in risk in the presence of homozygotes was 1.6 times. Variants of the 4G/5G polymorphism correlate particularly strongly with mean blood levels of PAI-1 in the presence of obesity. It has been suggested that the effect of the 4G variant is related to central rather than peripheral obesity. Since patients with central obesity are particularly at risk for cardiovascular disease, the effect of polymorphisms on blood PAI-1 levels may lead to an additional increase in risk.
Indications for analysis polymorphism. Portal vein thrombosis, visceral thrombosis, myocardial infarction, family history of myocardial infarction, coronary artery/heart disease, blood PAI-1 level, obesity.
Genetic diversity or genetic polymorphism is the diversity of populations according to traits or markers of genetic nature. One of the types of biodiversity. Genetic diversity is an important component of the genetic characteristics of a population, group of populations or species. Genetic diversity, depending on the choice of genetic markers under consideration, is characterized by several measurable parameters:
1. Average heterozygosity.
2. Number of alleles per locus.
3. Genetic distance (to assess interpopulation genetic diversity).
Polymorphism happens:
Chromosomal;
Transition;
Balanced.
Genetic polymorphism occurs when a gene is represented by more than one allele. An example is blood group systems.
Chromosomal polymorphism - there are differences between individuals on individual chromosomes. This is the result of chromosomal aberrations. There are differences in heterochromatic regions. If the changes do not have pathological consequences - chromosomal polymorphism, the nature of the mutations is neutral.
Transitional polymorphism is the replacement of one old allele in a population with a new one, which is more useful under given conditions. Humans have a haptoglobin gene - Hp1f, Hp 2fs. The old allele is Hp1f, the new allele is Hp2fs. HP forms a complex with hemoglobin and causes the adhesion of red blood cells in the acute phase of diseases.
Balanced polymorphism occurs when none of the genotypes receives an advantage, and natural selection favors diversity.
All forms of polymorphism are very widespread in nature in populations of all organisms. In populations of organisms that reproduce sexually, there is always polymorphism.
Invertebrate animals are more polymorphic than vertebrates. The more polymorphic a population is, the more evolutionarily plastic it is. In a population, large pools of alleles do not have maximum fitness in a given location at a given time. These reserves occur in small quantities and in a heterozygous state. After changes in living conditions, they can become useful and begin to accumulate - transitional polymorphism. Large genetic reserves help populations respond to their environment. One of the mechanisms that maintain diversity is the superiority of heterozygotes. With complete dominance, there is no manifestation; with incomplete dominance, heterosis is observed. In a population, selection maintains a genetically unstable heterozygous structure, and such a population contains 3 types of individuals (AA, Aa, aa). As a result of natural selection, genetic death occurs, reducing the reproductive potential of the population. The population is falling. Therefore, genetic death is a burden for the population. It is also called genetic load.
Genetic load is part of the hereditary variability of a population, which determines the emergence of less fit individuals that are subject to selective death as a result of natural selection.
There are 3 types of genetic load.
1. Mutation.
2. Segregation.
3. Substitutional.
Each type of genetic load correlates with a certain type of natural selection.
Mutation genetic load is a side effect of the mutation process. Stabilizing natural selection removes harmful mutations from a population.
Segregation genetic load is characteristic of populations that take advantage of heterozygotes. Less well-adapted homozygous individuals are removed. If both homozygotes are lethal, half of the offspring die.
Substitutional genetic load - the old allele is replaced by a new one. Corresponds to the driving form of natural selection and transitional polymorphism.
genetic polymorphism creates all the conditions for ongoing evolution. When a new factor appears in the environment, the population is able to adapt to new conditions. For example, insect resistance to various types of insecticides.
Genetic variability limited to one species (Homo sapiens in our case) is called genetic polymorphism (GP).
The genomes of all people, with the exception of identical twins, are different.
Pronounced population, ethnic and, most importantly, individual differences in genomes both in their semantic part (exons) and in their non-coding sequences (intergenic spaces, introns, etc.) are caused by various mutations leading to HP. The latter is usually defined as a Mendelian trait that occurs in a population in at least 2 variants with a frequency of at least 1% for each. The study of GP is the main task of the rapidly growing program “Human Genetic Diversity” (see Table 1.1).
GP can be qualitative, when nucleotide substitutions occur, or quantitative, when the number of nucleotide repeats of different lengths varies in DNA. Both types of GPs are found both in sense (protein-coding) and extragenic sequences of the DNA molecule.
High-quality GP is represented predominantly by single-nucleotide substitutions, the so-called single nucleotide polymorphism (SNP). This is the most common GP. Already the first comparative study of genomes in representatives of different races and ethnic groups showed not only the deep genetic relatedness of all people (genomic similarity - 99.9%), but also made it possible to obtain valuable information about the origin of man, the routes of his settlement on the planet, and the paths of ethnogenesis. Solving many problems of genogeography, human origins, genome evolution in phylogeny and ethnogenesis - this is the range of fundamental problems facing this rapidly developing field.
Quantitative GP is represented by variations in the number of tandem repeats (STR - Short Tandem Repeats) in the form of 1-2 nucleotides (microsatellite DNA) or 3-4 or more nucleotides per core (repeating) unit. This is the so-called minisatellite DNA. Finally, DNA repeats can have a large length and an internal structure variable in nucleotide composition - the so-called VNTR (Variable Number Tandem Repeats).
As a rule, quantitative GP concerns non-sense non-coding (coding) regions of the genome. The only exceptions are trinucleotide repeats. Most often this is CAG (citosine-adenine-guanine) - a triplet encoding glutamic acid. They can also occur in the coding sequences of a number of structural genes. In particular, such GPs are characteristic of “expansion disease” genes (see Chapter 3). In these cases, upon reaching a certain copy number of the trinucleotide (polynucleotide) repeat, GPs cease to be functionally neutral and manifest themselves as a special type of so-called “dynamic mutations”. The latter are especially characteristic of a large group of neurodegenerative diseases (Huntington's chorea, Kennedy's disease, spinocerebellar ataxia, etc.). The characteristic clinical features of such diseases are: late manifestation, anticipation effect (increasing the severity of the disease in subsequent generations), lack of effective treatment methods (see Chapter 3).
All people inhabiting our planet today are truly genetically brothers and sisters. Moreover, interindividual variability, even when sequencing the genes of representatives of the white, yellow and black races, did not exceed 0.1% and is mainly due to single nucleotide substitutions, SNP (Single Nucleotide Polymorphisms). Such substitutions are very numerous and occur every 250-400 bp. Their total number in the genome is estimated at 10-13 million (Table 1.2). It is assumed that about half of all SNPs (5 million) are located in the sense (expressed) part of the genome. It is these substitutions that turn out to be especially important for the molecular diagnosis of hereditary diseases. They play a major role in human GP.
Today it is well known that polymorphism is characteristic of almost all human genes. Moreover, it has been established that it has pronounced ethnic and population specificity. This feature allows the widespread use of polymorphic gene markers in ethnic and population studies. Polymorphism affecting the semantic parts of genes often leads to the replacement of amino acids and to the appearance of proteins with new functional properties. Substitutions or repeats of nucleotides in the regulatory (promoter) regions of genes can have a significant impact on the expression activity of genes. Inherited polymorphic gene changes play a decisive role in determining the unique biochemical profile of each person, in assessing his hereditary predisposition to various common multifactorial (multifactorial) diseases. The study of medical aspects of HP constitutes the conceptual and methodological basis of predictive medicine (see 1.2.5).
As studies have shown in recent years, single nucleotide substitutions (SNPs) and short tandem mono-, di- and trinucleotide repeats are the dominant, but by no means the only variants of polymorphism in the human genome. It was recently reported that about 12% of all human genes are present in more than two copies. Therefore, the actual differences between the genomes of different people are likely to significantly exceed the previously postulated 0.1%. Based on this, it is currently believed that the proximity of unrelated genomes is not 99.9%, as previously thought, but approximately equal to about 99 0%. Particularly surprising was the fact that not only the number of copies of individual genes, but even entire chromosome fragments with sizes of 0.65-1.3 Megabases (1 Mgb = 10 6 bp) can vary in the genome. In recent years, using the method of comparative genomic hybridization on chips containing DNA probes corresponding to the entire human genome, amazing data have been obtained proving the polymorphism of individual genomes in large (5-20 Mgb) DNA fragments. This polymorphism is called Copy Number Variation; its contribution to human pathology is currently being actively studied.
According to modern data, quantitative polymorphism in the human genome is much more widespread than previously thought; The main qualitative variant of polymorphism is single nucleotide substitutions - SNPs.
1.2.З.1. International Project “Haploid Genome” (HapMar)
A decisive role in the study of genomic polymorphism belongs to the international project for the study of the human haploid genome - “Haploid Map” - HapMap.
The project was launched at the initiative of the Human Genome Research Institute (USA) in 2002. The project was implemented by 200 researchers from 6 countries (USA, UK, Canada, Japan, China, Nigeria), who formed the Scientific Consortium. The goal of the project is to obtain a genetic map of the next generation, which should be based on the distribution of single nucleotide substitutions (SNPs) in the haploid set of all 23 human chromosomes.
The essence of the project is that when analyzing the distribution of already known SNPs (SNPs) in individuals of several generations, neighboring or closely located SNPs in the DNA of one chromosome are inherited in blocks. Such a SNP block is a haplotype - an allelic set of several loci located on the same chromosome (hence the name of the HapMar project). In this case, each of the mapped SNPs acts as an independent molecular marker. To create a genome-wide map of SNPs, however, it is important that the genetic linkage between two neighboring SNPs be highly reliable. Based on the linkage of such SNP markers with the studied trait (disease, symptom), the most likely localization sites of candidate genes are determined, the mutations (polymorphism) of which are associated with a particular multifactorial disease. Typically, several SNPs that are closely linked to an already known Mendelian trait are selected for mapping. Such well-characterized SNPs with a frequency of rare alleles of at least 5% are called marker SNPs (tagSNPs). It is expected that ultimately, of the approximately 10 million SNPs present in each person's genome, only about 500,000 tagSNPs will be selected during the project.
But this number is quite enough to cover the entire human genome with the OZ map. Naturally, the gradual saturation of the genome with such point molecular markers, convenient for genome-wide analysis, opens up great prospects for mapping many still unknown genes, the allelic variants of which are associated (linked) with various serious diseases.
The first stage of the NarMar project, worth $138 million, was completed in October 2005. More than a million NCDs (1,007,329) were genotyped in 270 representatives of 4 populations (90 European Americans, 90 Nigerians, 45 Chinese and 45 Japanese). The result of the work was a haploid SNP map containing information on the distribution and frequencies of marker SNPs in the studied populations.
As a result of the second stage of the HapMap project, which ended in December 2006, the same sample of individuals (269 people) was genotyped for another 4,600,000 SNPs. To date, the next generation genetic map (NaM) already contains information on more than 5.5 million NCDs. In its final version, which, given the ever-increasing speed of SNP mapping, will become available in the near future, there will be information on 9,000,000 SNPs of the haploid set. Thanks to HapMar, which includes not only SNPs of already mapped genes with known phenotypes, but also SNPs of not yet identified genes, scientists have in their hands a powerful universal navigator necessary for an in-depth analysis of the genome of each individual, for fast and efficient mapping of genes whose allelic variants predispose to various multifactorial diseases, to conduct large-scale studies on human population genetics, pharmacogenetics and individual medicine.
According to Francis Collins, director of the National Human Genome Research Institute (USA): “Already when discussing the Human Genome Program 20 years ago, I dreamed of a time when the genomic approach would become a tool for diagnosing, treating and preventing severe common diseases that affect sick people are overwhelming our hospitals, clinics, and doctors' offices. Success
The NarMar project allows us to take a serious step towards this dream today” (http://www.the-scientist.com/2006/2/1/46/1/).
Indeed, using the HapMar technique, it was possible to quickly map the gene responsible for macular degeneration, identify the main gene and several gene markers of heart disease, identify chromosome regions and find genes associated with osteoporosis, bronchial asthma, type 1 and type 2 diabetes , as well as with prostate cancer. Using the HapMar technology, it is possible not only to conduct genome-wide screening, but also to study individual parts of the genome (fragments of chromosomes) and even candidate genes. The combination of Nar-Mar technology with the capabilities of high-resolution hybridization DNA chips and a special computer program made genome-wide association screening available and made a real revolution in predictive medicine in terms of effective identification of susceptibility genes to various MDs (see Chapters 8 and 9).
Considering that genetic polymorphism is by no means limited to OCD, and molecular variations of the genome are much more diverse, scientists and publishers of the scientific journal Human Mutation Richard Cotton (Australia) and Haig Kazazian (USA) initiated the Human Variom Project, the goal of which is to create a universal bank data, which includes information not only on mutations leading to various monogenic diseases, but also on polymorphisms predisposing to multifactorial diseases - http://www.humanvariomeproject.org/index.php?p = News. Considering the fairly conventional boundaries between “polymorphism” and “mutations,” the creation of such a universal library of genome variations can only be welcomed.
Unfortunately, we have to admit that, if in the case of the Human Genome project in Russia some attempts were still made to participate in joint research, then in the implementation of the international project NarMar, domestic scientists were practically not involved. Accordingly, using genome-wide SNP screening technology in Russia in the absence of the necessary hardware and software is very problematic. Meanwhile, taking into account the population characteristics of genetic polymorphism, the introduction of GWAS technology in Russia is absolutely necessary (see Chapter 9).
It is with deep regret that we have to state that the already existing colossal gap between domestic and advanced world science in the field of studying the human genome will only rapidly increase after the completion of the NarMar program.
1.2.З.2. New projects to study the human genome
The NarMar project is far from the only one, although it is the most advanced in research into the structural and functional organization of the human genome in our time. Another international project is ENCODE “Encyclopedia of DNA Elements”, initiated by the National Institute of Human Genome Research (NIHGR). Its goal is to accurately identify and map all protein-synthesizing genes and functionally significant elements of the human genome. As a pilot study, the project intends to repeatedly sequence and study in detail a genome fragment measuring up to 1% of the total DNA length. The most likely candidate is a genomic region of about 30 Megabases (million bp) in the short arm of chromosome 6. It is there that the HLA locus, which is very complex in structural and functional terms and is responsible for the synthesis of histocompatibility antigens, is located. It is planned to sequence the HLA region in 100 patients with autoimmune diseases (systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, bronchial asthma, etc.) and in 100 somatically healthy donors in order to understand the molecular nature of gene features in these pathologies. In a similar way, it is expected to identify candidate genes in loci that exhibit a non-random association with frequent severe diseases of a multifactorial nature. The results of the ENCODE project have already been partially published, however, the HLA locus is not included in it.
Another project - NIHGR "Chemical Genomics" - aims to create a publicly accessible library of chemical substances, mainly organic compounds, convenient for studying the main metabolic pathways of the body, directly interacting with the genome and promising for the creation of new drugs.
The Genome to Life Project focuses on the metabolic features and organization of the genomes of single-celled organisms that are pathogenic to humans. It is assumed that the result of its implementation will be computerized models of the reaction of microbes to external influences. Research will focus on four main areas: bacterial proteins, regulatory mechanisms of gene function, microbial associations (symbiosis), interaction with the human body (www.genomestolife.org).
Finally, the main organization for funding scientific projects in the UK, the Wellcome Trust, has created the Structural Genomic Consortium. Its goal is to use data from the study of the human genome to increase the efficiency of the search and synthesis of new targeted drugs.
The Environmental Genome Project, which is being developed in the USA and Western Europe, is also directly related to predictive medicine and pharmacogenetics. Some details of this project will be discussed in the next chapter.
