Chromosomes are the main structural elements of the cell nucleus, which are carriers of genes in which hereditary information is encoded. With the ability to reproduce themselves, chromosomes provide a genetic link between generations.
The morphology of chromosomes is associated with the degree of their spiralization. For example, if at the interphase stage (see Mitosis, Meiosis) the chromosomes are maximally unfolded, that is, despiralized, then with the beginning of division the chromosomes are intensively spiralized and shortened. The maximum spiralization and shortening of the chromosome is achieved at the metaphase stage, when relatively short, dense structures are formed that are intensely stained with basic dyes. This stage is most convenient for studying the morphological characteristics of chromosomes.
The metaphase chromosome consists of two longitudinal subunits - chromatids [reveals in the structure of chromosomes elementary filaments (so-called chromonemes, or chromofibrils) 200 Å thick, each of which consists of two subunits].
The sizes of the chromosomes of plants and animals vary considerably: from fractions of a micron to tens of microns. The average lengths of human metaphase chromosomes are in the range of 1.5-10 microns.
The chemical basis of the structure of chromosomes are nucleoproteins - complexes (see) with basic proteins - histones and protamines.
Figure: 1. The structure of a normal chromosome.
A - appearance; B - internal structure: 1-primary constriction; 2 - secondary constriction; 3 - satellite; 4 - centromere.
Individual chromosomes (Fig. 1) are distinguished by the localization of the primary constriction, ie, the location of the centromere (during mitosis and meiosis, the spindle threads are attached to this place, pulling it towards the pole). When the centromere is lost, the chromosome fragments lose their ability to separate during division. The primary constriction divides the chromosomes into 2 arms. Depending on the location of the primary constriction, chromosomes are subdivided into metacentric (both arms are of equal or nearly equal length), submetacentric (arms of unequal length), and acrocentric (the centromere is shifted to the end of the chromosome). In addition to the primary one, less pronounced secondary constrictions can be found in chromosomes. A small end section of chromosomes, separated by a secondary constriction, is called a satellite.
Each type of organism is characterized by its own specific (in terms of the number, size and shape of chromosomes) so-called chromosome set. The set of double, or diploid, set of chromosomes is referred to as a karyotype.
Figure: 2. Normal chromosome set of a woman (two X chromosomes in the lower right corner).
Figure: 3. Normal chromosome set of a man (in the lower right corner - consecutively X- and Y-chromosomes).
Mature eggs contain a single, or haploid, set of chromosomes (n), which is half of the diploid set (2n) inherent in the chromosomes of all other cells in the body. In a diploid set, each chromosome is represented by a pair of homologues, one of which is maternal and the other is paternal. In most cases, the chromosomes of each pair are identical in size, shape, and genetic makeup. The exception is the sex chromosomes, the presence of which determines the development of the body in the male or female direction. The normal human chromosome set consists of 22 pairs of autosomes and one pair of sex chromosomes. In humans and other mammals, the female is determined by the presence of two X chromosomes, and the male is determined by one X and one Y chromosome (Fig. 2 and 3). In female cells, one of the X chromosomes is genetically inactive and is found in the interphase nucleus in the form (see). The study of human chromosomes in health and disease is the subject of medical cytogenetics. It has been established that deviations in the number or structure of chromosomes from the norm that occur in the genital! cells or in the early stages of cleavage of a fertilized egg, cause disturbances in the normal development of the body, causing in some cases the occurrence of a part of spontaneous abortions, stillbirths, congenital malformations and developmental anomalies after birth (chromosomal diseases). Examples of chromosomal diseases include Down's disease (extra G chromosome), Klinefelter syndrome (extra X chromosome in men), and (absence of a Y or one of the X chromosomes in the karyotype). In medical practice, chromosome analysis is carried out either by a direct method (on bone marrow cells), or after short-term cultivation of cells outside the body (peripheral blood, skin, embryonic tissues).
Chromosomes (from the Greek chroma - color and soma - body) are threadlike, self-reproducing structural elements of the cell nucleus, containing in a linear order the factors of heredity - genes. Chromosomes are clearly visible in the nucleus during division of somatic cells (mitosis) and during division (maturation) of sex cells - meiosis (Fig. 1). In both cases, the chromosomes are intensely stained with basic dyes, and are also visible on unstained cytological preparations in phase contrast. In the interphase nucleus, chromosomes are despiralized and not visible under a light microscope, since their transverse dimensions are beyond the resolution of a light microscope. At this time, individual sections of chromosomes in the form of thin filaments with a diameter of 100-500 Å can be distinguished using an electron microscope. Separate non-despiralized sections of chromosomes in the interphase nucleus are visible through a light microscope as intensely staining (heteropycnotic) sections (chromocenters).
Chromosomes continuously exist in the cell nucleus, undergoing a cycle of reversible spiralization: mitosis-interphase-mitosis. The basic patterns of the structure and behavior of chromosomes during mitosis, meiosis and fertilization are the same in all organisms.
Chromosomal theory of heredity... For the first time, chromosomes were described by I. D. Chistyakov in 1874 and E. Strasburger in 1879. In 1901, E. V. Wilson, and in 1902, WS Sutton drew attention to parallelism in the behavior of chromosomes and Mendelian factors of heredity - genes - in meiosis and fertilization and came to the conclusion that genes are located in chromosomes. In 1915-1920. Morgan (T. N. Morgan) and his co-workers proved this position, localized several hundred genes in the chromosomes of Drosophila and created genetic maps of chromosomes. The data on chromosomes obtained in the first quarter of the 20th century formed the basis of the chromosomal theory of heredity, according to which the continuity of the characters of cells and organisms in a number of their generations is ensured by the continuity of their chromosomes.
Chemical composition and autoreproduction of chromosomes... As a result of cytochemical and biochemical studies of chromosomes in the 30s and 50s of the 20th century, it was established that they consist of constant components [DNA (see Nucleic acids), basic proteins (histones or protamines), non-histone proteins] and variable components (RNA and associated acidic protein). The chromosomes are based on deoxyribonucleoprotein filaments with a diameter of about 200 Å (Fig. 2), which can be combined into bundles with a diameter of 500 A.
The discovery by Watson and Crick (J. D. Watson, F. N. Crick) in 1953 of the structure of the DNA molecule, the mechanism of its autoreproduction (reduplication) and the DNA nucleic code and the development of molecular genetics that emerged after that led to the concept of genes as regions of the DNA molecule. (see Genetics). Regularities of autoreproduction of chromosomes were revealed [Taylor (J. N. Taylor) and others, 1957], which turned out to be similar to the regularities of autoreproduction of DNA molecules (semi-conservative reduplication).
Chromosome set - the set of all chromosomes in a cell. Each biological species has a characteristic and constant set of chromosomes, fixed in the evolution of this species. There are two main types of chromosome sets: single, or haploid (in the germ cells of animals), denoted by n, and double, or diploid (in somatic cells, containing pairs of similar, homologous chromosomes from the mother and father), denoted 2n.
The sets of chromosomes of individual biological species differ significantly in the number of chromosomes: from 2 (horse roundworm) to hundreds and thousands (some spore plants and protozoa). The diploid numbers of chromosomes of some organisms are as follows: humans - 46, gorillas - 48, cats - 60, rats - 42, Drosophila - 8.
The sizes of chromosomes in different species are also different. The length of the chromosomes (in the metaphase of mitosis) varies from 0.2 microns in some species to 50 microns in others, and the diameter from 0.2 to 3 microns.
Chromosome morphology is well expressed in the metaphase of mitosis. It is the metaphase chromosomes that are used to identify chromosomes. In such chromosomes, both chromatids are clearly visible, into which each chromosome and centromere (kinetochore, primary constriction) are longitudinally split, connecting the chromatids (Fig. 3). The centromere is visible as a narrowed area that does not contain chromatin (see); to it are attached the threads of the achromatin spindle, due to which the centromere determines the movement of chromosomes to the poles in mitosis and meiosis (Fig. 4).
The loss of a centromere, for example, when a chromosome is broken by ionizing radiation or other mutagens, leads to the loss of the ability of a chromosome piece devoid of a centromere (acentric fragment) to participate in mitosis and meiosis and to its loss from the nucleus. This can cause severe damage to the cell.
The centromere divides the chromosome body into two arms. The location of the centromere is strictly constant for each chromosome and determines three types of chromosomes: 1) acrocentric, or rod-shaped, chromosomes with one long and a second very short arm, resembling a head; 2) submetacentric chromosomes with long arms of unequal length; 3) metacentric chromosomes with arms of the same or nearly equal length (Fig. 3, 4, 5, and 7).
Figure: 4. Scheme of the structure of chromosomes in the metaphase of mitosis after longitudinal cleavage of the centromere: A and A1 - sister chromatids; 1 - long shoulder; 2 - short shoulder; 3 - secondary constriction; 4 - centromere; 5 - spindle fibers.
The characteristic features of the morphology of certain chromosomes are secondary constrictions (not having the function of a centromere), as well as satellites - small sections of chromosomes connected to the rest of its body by a thin thread (Fig. 5). Satellite filaments have the ability to form nucleoli. The characteristic structure in the chromosome (chromomeres) is thickening or more tightly coiled sections of the chromosomal filament (chromonemes). The chromomer pattern is specific to each pair of chromosomes.
Figure: 5. Scheme of the morphology of the chromosome in the anaphase of mitosis (chromatid. Extending to the pole). A - the appearance of the chromosome; B - internal structure of the same chromosome with two constituent chromonemes (semi-chromatids): 1 - primary constriction with chromomeres making up centromeres; 2 - secondary constriction; 3 - satellite; 4 - satellite thread.
The number of chromosomes, their size and shape at the metaphase stage are characteristic for each type of organism. The combination of these features of a set of chromosomes is called a karyotype. The karyotype can be thought of as a diagram called an idiogram (see below for human chromosomes).
Sex chromosomes... Genes that determine sex are localized in a special pair of chromosomes - sex chromosomes (mammals, humans); in other cases, iol is determined by the ratio of the number of sex chromosomes and all the others, called autosomes (Drosophila). In humans, as in other mammals, the female sex is determined by two identical chromosomes, designated as X chromosomes, the male sex is determined by a pair of heteromorphic chromosomes: X and Y. As a result of reduction division (meiosis) during oocyte maturation (see Ovogenesis) in women all eggs contain one X chromosome. In men, as a result of reduction division (maturation) of spermatocytes, half of the sperm contain the X chromosome, and the other half contains the Y chromosome. The sex of a baby is determined by the accidental fertilization of an egg with a sperm carrying the X or Y chromosome. The result is a female (XX) or male (XY) embryo. In the interphase nucleus in women, one of the X chromosomes is visible as a lump of compact sex chromatin.
Chromosome function and nuclear metabolism... Chromosomal DNA is a template for the synthesis of specific messenger RNA molecules. This synthesis occurs when a given section of the chromosome is despiralized. Examples of local activation of chromosomes are: the formation of despiralized chromosome loops in oocytes of birds, amphibians, fish (the so-called X-lamp brushes) and bulges (puffs) of certain chromosome loci in the multi-filamentous (polytene) chromosomes of the salivary glands and other secretory organs of dipterans (Fig. 6). An example of the inactivation of a whole chromosome, i.e., its exclusion from the metabolism of a given cell, is the formation of one of the X chromosomes of a compact body of sex chromatin.
Figure: 6. Polytene chromosomes of the dipteran insect Acriscotopus lucidus: A and B - the area bounded by dotted lines, in a state of intensive functioning (puff); B - the same section in a non-functioning state. Individual loci of chromosomes (chromomeres) are designated by numbers.
Figure: 7. Chromosome set in the culture of male peripheral blood leukocytes (2n \u003d 46).
Uncovering the mechanisms of functioning of polytene chromosomes such as lamp brushes and other types of spiralization and despiralization of chromosomes is crucial for understanding reversible differential activation of genes.
Human chromosomes... In 1922, T. S. Painter established the diploid number of human chromosomes (in spermatogonia), equal to 48. In 1956, Tio and Levan (H. J. Tjio, A. Levan) used a set of new methods for studying human chromosomes : cell culture; examination of chromosomes without histological sections on total cell preparations; colchicine, leading to the arrest of mitosis at the metaphase stage and the accumulation of such metaphases; phytohemagglutinin, which stimulates the entry of cells into mitosis; treatment of metaphase cells with hypotonic saline. All this made it possible to clarify the diploid number of chromosomes in humans (it turned out to be 46) and to give a description of the human karyotype. In 1960, in Denver (USA), an international commission developed the nomenclature of human chromosomes. According to the commission's proposals, the term "karyotype" should be applied to the systematized set of chromosomes of a single cell (Fig. 7 and 8). The term "idiotram" is retained to represent a set of chromosomes in the form of a diagram based on measurements and description of the morphology of the chromosomes of several cells.
Human chromosomes are numbered (partly serially) from 1 to 22 in accordance with the morphological features that allow their identification. Sex chromosomes have no numbers and are designated as X and Y (Fig. 8).
A connection was found between a number of diseases and birth defects in human development with changes in the number and structure of his chromosomes. (see Heredity).
See also Cytogenetic Studies.
All these achievements have created a solid foundation for the development of human cytogenetics.
Figure: 1. Chromosomes: A - at the stage of anaphase of mitosis in microsporocytes of the trefoil; B - at the stage of metaphase of the first division of meiosis in the mother cells of pollen near Tradescantia. In both cases, the spiral structure of the chromosomes is visible.
Figure: 2. Elementary chromosomal filaments with a diameter of 100 Å (DNA + histone) from interphase nuclei of the calf thymus (electron microscopy): A - filaments isolated from nuclei; B - a thin section through a film of the same preparation.
Figure: 3. Chromosome set Vicia faba (horse beans) in the metaphase stage.
Figure: 8. Chromosomes of the same as in fig. 7, kits classified according to Denver nomenclature into homologous pairs (karyotype).
Sex chromosome pathologies can be caused by a violation of their number (aneuploidy) or structural defects.
The most common sex chromosome aneuploidies are: 45, X (Turner Syndrome); 47, XXY (Klinefelter Syndrome); 47, XYY; and 47, XXX. Sex chromosome mosaicism with the presence of cells with a normal genotype in the body is not uncommon. The two most common types of sex chromosome mosaicism are 45, X / 46, XX and 45, X / 46, XY. The severity of phenotypic manifestations in patients with mosaicism corresponds to the proportion of abnormal cells.
Structural pathologies of the X and Y chromosomes primarily include isochromosomes, deletions, duplications, ring chromosomes, and translocations.
One example of a genomic disorder is gene duplication MECP2 in men, expressed in the presence of muscle hypotension, severe mental retardation, delayed speech development, impaired swallowing, frequent respiratory infections, and convulsive seizures (tonic-clonic seizures that cannot be treated).
Chromosome abnormalities (aneuploidy)
The most common sex chromosome aneuploidies are 45, X (Shereshevsky-Turner syndrome); 47, XXY (Klinefelter Syndrome); 47, XYY and 47, XXX with an occurrence of approximately 1/2500, 1/500 to 1/1000, 1/900 to 1500 and 1/1000, respectively. Sex chromosome mosaicism with the presence of cells with a normal genotype in the body is not uncommon. The two most common types of sex chromosome mosaicism are 45, X / 46, XX and 45, X / 46, XY. The severity of phenotypic manifestations in patients with mosaicism corresponds to the percentage of abnormal cells.
Monosomy on the X chromosome (45, X, or Shereshevsky-Turner Syndrome)
Most patients with Shereshevsky-Turner syndrome have monosomy on the X chromosome, karyotype 45, X. Other forms of the syndrome include mosaicism on the X chromosome, for example 45, X / 46, XX or 45, X / 46, XY with partial deletion of the Y chromosome. Some patients have a structural abnormality of the second X chromosome (for example, isochromosomy of the long arm of the X chromosome or deletion of the short arm). Deletions involving the distal part of the short arm of the Y chromosome are also associated with the Turner syndrome phenotype, since in this case the patients lack the so-called anti-Turner genes (SHOX, RPSY4, and ZFY). Deletions of the short arm of the X chromosome have also been associated with the Turner syndrome phenotype. Most are isolated cases.
Shereshevsky-Turner syndrome is characterized by short stature and some of the following manifestations: facial dysmorphia, including low-set ears, skin folds in the neck, shield-like chest (wide, with a large distance between the nipples), lymphedema, valgus deformity of the elbow joint, short fourth metacarpal bone hypoplasia of the nail plates, age spots and congenital heart defects. Among the heart defects, the typical and most common are vascular defects and coarctation of the aorta. In addition, patients with Turner syndrome develop striate gonads, impaired ovulation, and delayed sexual development. There are also defects in the development of the kidneys (horseshoe kidney). Lymphedema of the lower extremities may be the only clinical sign seen in newborns. Individuals with Turner syndrome who carry the genetic material of the Y chromosome have an increased risk of developing gonadoblastoma.
47, XXY Klinefelter Syndrome
Klinefelter's syndrome is the most common sex chromosome abnormality that causes primary hypogonadism. Karyotype 47, XXY is the result of nondisjunction of sex chromosomes and can be both maternal and paternal in origin. Most cases of the disease are detected postnatally and diagnosed by determining the causes of infertility, identifying gynecomastia, cryptorchidism, or neurological disorders.
Figure: Nondisjunction of sex chromosomes
Newborn boys with karyotype 47, XXY are phenotypically normal, with physiologically normal male external genitalia and no visible dysmorphia. The main clinical manifestations of Klinefelter syndrome, including tall stature, small testes, and infertility (azoospermia), become pronounced in the post-pubertal period. Patients with Klinefelter syndrome are at increased risk of mental disorders, autism disorders, and social problems. In patients diagnosed with Klinefelter's syndrome, neurological status should be assessed and referred to an endocrinologist.
47, XYY
Persons with karyotype 47, XYY are tall, they may have a moderate delay in motor and speech development. Many of them require increased attention to education, but, as a rule, they all study in the main general education schools. Sexual development is normal and most boys are fertile. Due to the lack of expression of the phenotype and the absence of associated health problems, many individuals with the 47, XYY karyotype remain undiagnosed throughout their lives.
Earlier it was reported that men with 47, XYY have increased aggression, which is reflected in their aggressive behavior. However, subsequent large-scale joint studies of European and American geneticists showed that the statistics of increased criminal activity in men with XYY correlated with their low socioeconomic status due to their low IQ value (about 10 points), which led to certain difficulties with the law and, more often, insignificant offenses. Individuals with 47, XYY have higher rates of attention deficit hyperactivity disorder, as well as autistic disorders. These patients are advised to evaluate their neuropsychic development, given the widespread prevalence of learning difficulties and behavioral problems.
47, XXX
47, XXX (aka trisomy on the X chromosome) is the most common sex chromosome abnormality in women. Trisomy on the X chromosome is diagnosed in utero during genetic screening. Women with karyotype 47, XXX do not have an increased risk of developing a fetus with chromosomal abnormalities.
A survey of 155 women with karyotype 47, XXX showed that 62 percent of them were physically normal. Thus, for the majority of individuals with karyotype 47, XXX, the diagnosis is never made. Women with 47, XXX have high growth; (The average head circumference varies between the 25th and 35th percentile, but by adolescence, for many, it can reach the 80th percentile). Sexual maturity and fertility are most often normal, but premature ovarian failure may occur.
In the next survey of eleven infants with the 47, XXX karyotype, it was shown that the IQ of girls from birth was 15-20 points lower than that of their brothers. Therefore, it is recommended to monitor developmental delays and identify the presence of psychological problems in the future.
Other diseases
More than one hundred cases of karyotype 49, XXXXY have been reported, at least twenty cases 49, XXXXX and a few 49, XYYYY. There is a direct relationship between the number of additional sex chromosomes and the severity of phenotypic manifestations in patients. In the study of tetra- and pentasomy of sex chromosomes, it was concluded that polysomy on the X chromosome is associated with more serious consequences than polysomy on the Y chromosome. It has been shown that the level of intelligence IQ decreases by 10 points with each extra X chromosome from their normal number.
49, XXXXY The characteristic clinical features of the XXXXY karyotype are sunken bridge of the nose with a wide or raised tip of the nose, widely spaced eyes, eyelid-nasal folds, skeletal pathologies (especially radial ulnar synostosis), congenital heart disease, endocrine disorders, and a high degree of hypogonadism and hypogenitalism. Severe mental retardation and moderate short stature are also common. Although individuals with this karyotype are often referred to as cases of Klinefelter's syndrome, all the characteristic features of XXXXY quite clearly indicate this particular phenotype.
49, XXXXX Women with karyotype 49, XXXXX (X-chromosome pentasomy) always have mental retardation. Other manifestations, such as scoop-facial, cardiovascular, and skeletal pathologies, are rather variable. Patients with X-chromosome pentasomy may exhibit similarities to those seen in Down syndrome. Radioluminal synostosis is also common in patients with a large number of X chromosomes. Some patients have mosaicism 48, XXXX and 49, XXXXX.
Mosaicism 45, X / 46, XX
This is the most common sex chromosome mosaicism and is diagnosed with amniocentesis and prenatal karyotyping. Individuals with this type of mosaicism have milder clinical features of Turner syndrome. Many women went through puberty and were able to reproduce offspring.
Of 156 prenatally diagnosed cases of mosaicism, 45, X / 46, XX, 14% of cases had an abnormal outcome. Two stillbirths and 20 cases of an abnormal phenotype were reported (12 had some features of Turner syndrome, and the remaining 8 were of the nature of anomalies, possibly unrelated to it). More than 85% of girls had a normal phenotype at birth, or it was established based on the results of medical termination of pregnancy. However, the main features of Turner syndrome (such as short stature and lack of secondary sexual characteristics) appeared only in childhood or adolescence, and were not noticed in infancy. In some women with a normal phenotype, with impaired ovarian function, mosaicism 45, X / 46, XX is detected.
Mosaicism 45, X / 46, XY
Mosaicism with 45, X / 46, XY has a wide phenotypic spectrum. For example, in a retrospective series of 151 postnatally diagnosed cases of mosaicism 45, X / 46, XY, 42% of patients are girls by phenotype, with the presence of typical or atypical Turner syndrome. Another 42% had indeterminate external genitalia and asymmetric gonads (mixed gonadal dysgenesis), finally, 15% had a male phenotype with incomplete masculinization. Thus, all cases diagnosed postnatally were phenotypically pathological. On the contrary, among 80 prenatally diagnosed cases of mosaicism 45, X / 46, XY 74, 92.6% were phenotypically normal boys. This may explain the fact that children or adults with mosaicism but a normal phenotype are unlikely to seek medical attention (referral error).
Structural chromosome abnormalities
Structural pathologies primarily include isochromosomes, deletions, duplications, ring chromosomes, and translocations.
Isochromosome Xq
The isochromosome of the long arm of the X chromosome, isoXq or i (Xq), in the presence of which the short arm (p) is excluded (absent / reduced) and replaced with an exact copy of the long arm (q), is the most common sex chromosome abnormality.
The presence of structural pathology is not associated with an increased age-related risk of parents. Isochromosomy 46, X, i (Xq) can be an expression of mosaicism, when two genetically different cell populations are present in the body: normal - 46, XX and 45, X.
Isochromosomes Xq and Xy are associated with Turner syndrome, possibly because the main anti-Turner gene SHOX is located on the distal part of the short arms of the X and Y chromosomes (on pseudoautosomal regions). Isochromosome Xq is also detected in patients with one of the variations of Klinefelter syndrome, 47, X, i (Xq), Y.
Xp22.11 deletion
Xp22.11 deletion includes the gene PTCHD1... Identification has been reported in several families with autism spectrum disorders, as well as in three families with mental retardation. Gene PTCHD1 is a candidate gene for X-linked mental retardation with or without autism. The function and role of this gene is unknown.
Xp22.3 deletion
Deletion of this area is often associated with microphthalmia and linear skin defects (MLS) syndrome and is an X-linked dominant disorder, that is, fatal for men and therefore traced only in women. The gene in this region encodes mitochondrial cytochrome c synthase ( HCCS). The clinical manifestation of MLS is expressed by the presence of microphthalmia and anophthalmia (one- or two-sided) and linear skin defects, mainly of the face and neck, which disappear over time. Structural pathologies of the brain, developmental delay and seizures (seizures) are also part of the clinical picture. Cardiac disorders (such as hypertensive cardiomyopathy and arrhythmia), short stature, hernia of the diaphragm, nail dystrophy, preauricular fistula, hearing loss, urogenital malformations (malformations, malformation) are also common clinical manifestations.
Screening assessments include ophthalmologic and dermatologic examinations, general developmental assessments, echocardiogram, magnetic resonance imaging of the brain (MRI), and electroencephalogram (EEG).
Xp22 SHOX deletions
The Xp22 deletion includes the SHOX gene, a mutation of which causes idiopathic short stature. The SHOX gene is located in the pseudo-autosomal region 1 of the X and Y chromosomes. This gene is believed to be responsible for short stature in Turner syndrome, and a haploinsufficiency of this gene causes Lery-Weill dyschondrosteosis. Lery-Weill dyschondrosteosis is characterized by short stature, most pronounced in women, as well as chronic subluxation of the hand (deformation of the wrist bones, Madelung's deformity). Homozygous deletions of the SHOX gene cause Langer's dysplasia, a more severe form of metaphyseal dysplasia. Deletions of the SHOX gene are easily detected in patients with short stature, without any other specific features in the structure of their skeleton. More than 60% of SHOX rearrangements are gene deletions; in the absence of deletions, comparative genomic hybridization followed by sequencing to identify and identify point mutations is a clinical examination of idiopathic short stature.
Xp11.22 deletions
Deletions in the Xp11.22 region include the PHF8 gene (which encodes the PHD8 finger protein), which mutations have been associated with mental retardation, cleft lip / palate, and autistic disorders.
Mutations with a deletion of the PHF8 gene are associated with X-linked mental retardation syndrome, Siderius-Hamel syndrome (Siderius-Hamel syndrome).
Duplicates Xp.22.31
Duplications at the Xp.22.31 locus are often described in the literature. There has been much debate as to whether this duplication is pathogenic or benign, given the difficulty of determining the consequences of variation in gene copy number. This duplication affects the steroid sulfatase gene. As a result, a genetic defect, a mutation in the gene of steroid sulfatase, which is expressed in a decrease in its activity or the absence of its synthesis. Deletion of this gene is associated with X-linked ichthyosis in men. This duplication is observed in patients with mental retardation. However, it is detected both in healthy relatives of these patients and in the general population. Although duplications of this gene may not be phenotypic, triplications have been consistently associated with mental disorders. FISH diagnostics ultimately makes it possible to differentiate duplications from triplications (to recognize an increase in gene copy number).
ME2CP Duplication Syndrome
Mutations in the gene encoding methyl-binding-CpG terminal protein 2 ( ME2CP), located at Xq28, responsible for Rett syndrome. Duplication of this region has little or no phenotypic significance for women, probably due to inactivation of the abnormal X chromosome. Men with this mutation are severely weakened. The presence of duplication is clinically expressed in the presence of severe muscular hypotension, severe mental retardation, delayed speech development, impaired swallowing (difficulty eating), frequent respiratory infections and convulsive seizures up to tonic-clonic, sometimes not amenable to treatment. Many patients with this duplication have been diagnosed with autism or a similar disorder. Similar to what is observed in Rett syndrome, patients with duplication ME2CP are experiencing developmental regression. In addition, they develop ataxia, and progressive muscle spasticity in the lower body often results in a loss of locomotion. Gastrointestinal problems and severe constipation were noted. Duplication often affects the interleukin 1 receptor antagonist gene ( IRAK1), which may play a role in the appearance of immune pathologies noted in this group of patients. The prognosis is poor, and most men with this duplication die before age 30 due to secondary respiratory infections. Triplication of this region is manifested by an even more severe phenotype in men.
Screening examinations of these patients involve EEG, assessment of swallowing function, assessment of humoral and cellular immunity. Treatment may include treating muscle hypotension and spasticity, speech therapy (speech therapy), using a gastronomic tube (gastrostomy tube) for nutritional problems, and treating respiratory infections.
The translation of materials from the UpTodate website was prepared by specialists of the Center for Immunology and Reproduction.
Male Y chromosome
Brief information (video, English): ,
Women and men each have 23 pairs of chromosomes. Of each pair, one was received from the father and one from the mother. Unlike autosomal chromosomes, named in order from "1" to "22", the two "sex" chromosomes are designated by letter. XX for women and XY for men. From the mother - always the X chromosome. From the father, the child will inherit either the X chromosome (girl) or the Y chromosome (boy). The X chromosome from the father turns into a combination of XX - and this is female. The Y chromosome from the father turns into the XY combination, and sets the male gender. Almost all chromosomes undergo mixing (recombination) - a process where each pair of chromosomes exchange different fragments with each other. Since each male has only one Y chromosome, unlike the X chromosomes, it does not recombine. For these reasons, genealogical analysis of X chromosomes becomes much more complicated. We also inherit mitochondrial DNA (mtDNA) from our mother, and none from our father.
The main tools of DNA genealogy are analyzes of mutations, their number and location in mtDNA and Y chromosomes. The Y chromosome, due to the very low frequency of mutations and the lack of mixing (recombinations), in contrast to mitochondrial DNA, is transmitted almost unchanged from generation to generation. According to variations of mutations, chromosomes are divided into haplotypes, which are combined into haplogroups and subclades (subgroups). The letter designations of haplogroups are alphabetical and show the time of the next mutation. That is, haplogroup A (the Y-chromosome of the so-called Adam, appeared about 75,000 years ago, is localized today, mainly in South Africa) is older (about 30,000 years ago), etc. alphabetically.
Estimated distribution of Y-DNA haplogroups 2000 BC e.
Spread of Y-DNA haplogroups
Distribution of Y-DNA haplogroups in Europe
As you know, the cells of men contain a pair of sex chromosomes - the female X chromosome and the male Y chromosome. However, if the Y chromosome is really male, then the X chromosome is rather common: after all, representatives of both sexes have it, but in men receiving it from their mother, it is only in one copy. The X chromosome contains many genes that are necessary for the life of any organism, regardless of gender. It also contains genes, mutations in which lead to serious diseases such as hemophilia, Duchenne muscular dystrophy, color blindness. These diseases, associated with the X chromosome, in the overwhelming majority of cases are manifested in men, since they have only one X chromosome.
In women, the defective gene is compensated by a healthy gene on the paired X chromosome, while in men there is nothing to compensate for it. Therefore, men most often suffer from hemophilia or color blindness, although they receive these diseases from their mothers.
It turns out that this female sex chromosome has a region with a completely unexpected function: it carries genes specialized for the production of sperm.
Along with the discovery of the unknown function of the X chromosome, scientists have found out another property of it. Until now, it was believed that, unlike the Y chromosome, the X chromosome is stable. Now biologists have found out that it was undergoing fairly rapid evolutionary changes. Taken together, these results force us to reconsider its biological and medical significance.
The X chromosome was considered to be very well studied - also because it is associated with the diseases listed above. However, when scientists began to carefully analyze the nucleotide sequence of the X chromosome, they found details that had previously eluded attention. Professor's laboratory David Page , where the discovery took place, was known for her work in the study of the Y chromosome. And so they took up the other sex chromosome, setting the task of comparing its nucleotide sequence in humans and mice. The aim of the work was to test the opinion that the X chromosome is conservative and therefore is practically the same in all mammals, which is well-established among specialists.
To make an accurate comparison, the team re-sequenced the human X chromosome using Page's original method, developed in collaboration with the University of Washington, St. Louis. They improved the sequencing accuracy, which allowed them to fill in the previously existing gaps in the nucleotide sequence. In addition, the researchers discovered the so-called palindromes - regions in which the nucleotide sequence is repeated upside down, like in a mirror. The standard approach ignored these areas. The refined structure of the X chromosome was made public by biologists for use in the scientific community.
By making a comparison, the scientists found that the X chromosomes of humans and mice share approximately 95% of genes in common, and almost all of these genes are expressed in both sexes. Along with this, they discovered 340 genes that distinguish humans from mice. Obviously, they formed over the 80 million years that have passed since the time of the common ancestor of the mouse and man.
Analysis of their expression revealed that these genes are active almost exclusively in the cells of the testes, where they are involved in the production of sperm.
Further research is needed to better understand their work.
“This group of genes is extremely important for medical genetics,” says Jakob Müller, the first author of the article. - Since they are located on the X chromosome, they are not inherited by mendel's laws ... Now that we have found their location, we can begin to analyze their biological significance. "
Scientists believe these genes are likely to play an important role in diseases associated with male reproduction, infertility, and possibly testicular cancer.
“The X chromosome was considered to be the most studied chromosome in the human genome,” said David Page. - But its still unknown side is that it is rapidly evolving and, apparently, is involved in the reproductive function of men. Our results demonstrated the dual role of the X chromosome. This is a new book that has yet to be written. "
Our cells. Chromosomes determine everything from hair color and eye color to gender. Whether you are male or female depends on the presence or absence of certain chromosomes. Human chromosomes contain 23 pairs, or a total of 46 chromosomes.
There are 22 pairs of autosomes (non-sex chromosomes) and one pair of gonosomes (sex chromosomes). The sex chromosomes are the X and Y chromosomes.
Sex cells
During human sexual reproduction, two separate gametes merge and a zygote is formed. are those produced by a type of cell division called. They contain only one set of chromosomes and are called.
The male gamete, called the sperm, is relatively mobile and usually has. The female gamete, called the ovum, is immobile and relatively large compared to the male gamete. When haploid male and female gametes combine in a process called fertilization, they develop into a zygote. A zygote, which means that it contains two sets of chromosomes.
Sex chromosomes XY
Male gametes or sperm in humans and other mammals are heterogametic and contain one of two types of sex chromosomes.
Sperm cells carry either X or Y chromosomes. However, female gametes or eggs contain only the X chromosome and are homogametic. In this case, the sperm cell determines the sex of the individual. If a sperm cell containing an X chromosome fertilizes an egg, the resulting zygote will be XX - female. If the sperm cell contains a Y chromosome, then the resulting zygote will be XY, male.
The Y chromosomes are essential for the development of male or testicles. Individuals that lack the Y chromosome (XO or XX) develop female gonads or ovaries. Two X chromosomes are required for the development of fully functioning ovaries.
Genes located on the X chromosome are called X-linked genes, and they determine X-linked recessive inheritance. A mutation in one of these genes can lead to the development of altered traits. Since males only have one X chromosome, the altered trait will always be expressed in males. In females, the trait will not always be expressed, since they have two X chromosomes. An altered trait can be masked if only one X chromosome has the mutation and the trait is recessive.
Sex chromosomes XX
Grasshoppers, cockroaches, and other insects have a sex determination system similar to humans. Adult males lack the Y chromosome and only have an X chromosome. They produce sperm cells that contain an X chromosome or a sexless chromosome called O. Females have an XX and produce eggs containing an X chromosome.
If sperm cell X fertilizes an egg, the resulting zygote will be XX - female. If a sperm cell that does not contain a sex chromosome fertilizes an egg, the resulting zygote will be XO - male.
Sex chromosomes ZW
Birds, insects such as butterflies, frogs, snakes and some fish have different sexing systems. In these animals, it is the female gamete that determines the sex. Female gametes can contain either the Z chromosome or the W chromosome. Male gametes contain only the Z chromosome. In these species, the combination of chromosomes ZW means female, and ZZ means male.
Parthenogenesis
What about animals like most wasps, bees and ants that don't have sex chromosomes? How is gender determined? In these species, gender determines. If the egg is fertilized, a female will emerge from it. A male may emerge from an unfertilized egg. The female is diploid and contains two sets of chromosomes, while the haploid male contains only one set of chromosomes. This development of a male from an unfertilized egg and a female from a fertilized egg is a type of parthenogenesis known as arrhenotokal parthenogenesis.
Environmental gender determination
In turtles and crocodiles, sex is determined by the ambient temperature during a certain period of development of the fertilized egg. Eggs that are incubated above a certain temperature develop into one sex, while eggs incubated below a certain temperature develop into the other sex.
