GENEALOGICAL METHOD (Greek genealogia genealogical) — drawing up and the analysis of family trees for the purpose of establishment of patterns of hereditary transfer of normal and pathological signs.
G.'s essence of m consists in clarification of family relations and in tracing of a sign or a disease among all relatives.
Of m along with cytogenetic, twin, population and statistical methods and method of modeling of hereditary diseases is one of the main methods of studying of heredity of the person. In to medical genetics (see) a method more often call kliniko-genealogical as observe for patol, signs with the help a wedge, inspections. The family tree is formed on one or several signs interesting the specialist.
The consistent patterns of hereditary transfer of signs determined by G. Mendel (see Mendel laws) and the chromosomal theory are the cornerstone of of m heredities (see). Of m is in many respects equivalent to a hybridological method of the general geneticists (see), but differs in the fact that at it instead of carrying out crossings certain marriages choose from population and monitor transfer of the interesting sign in generations. The genealogical method allows to do probabilistic predictions concerning emergence of a certain sign or a disease in a family. Of m belongs to the most universal methods in to genetics of the person (see). It is applied for the purpose of establishment of hereditary character of a sign, definition of type inheritance (see) and penetrances of a gene (see), studying of mutational process, interaction genes (see). couplings of genes (see. Recombination analysis ), mapping of chromosomes (see. Chromosome map ).
Drawing up a family tree for the analysis of inheritance at the person is offered at the end of 19 century the English scientist-anthropologist F. Galton. However empirical overseeing by family trees in which inheritance patol was noted of signs, is known long ago. E.g., dependence on a floor of inheritance of hemophilia found reflection in the Talmud. In the middle of 18 century inheritance of a dominant character of a polydactylia is described and the analysis of splitting of this sign in posterity is given. At the beginning of 19 century J. Adams on the basis of the empirical analysis of family trees described dominant and recessive modes of inheritance. In the same time the analysis of inheritance of hemophilia and color-blindness is given. These and some other facts can be considered as premises of formation of a genealogical method. With development of genetics as G.'s sciences of m it is improved through drawing up family trees and especially concerning methods of a statistical analysis of data. Of m in the Soviet Union began to be applied widely at the beginning of the 30th 20 century by S. N. Davidenkov, T. I. Yudin, Yu. A. Filipchenko, N. K. Koltsov, etc.
In G. the m can conditionally allocate two stages — drawing up family trees and the genealogical analysis, i.e. the analysis of family trees by the principles genetic analysis (see).
The information about perhaps bigger number of relatives — carriers of an ancestral feature or a disease on maternal and fatherly lines is necessary for drawing up a family tree of a proband (the person, with to-rogo begin inspection). An essential condition for clarification of features of inheritance is also sufficient number of families in which the studied sign is traced. Include parents with children in the concept «family». Depending on the purpose the family tree can be full (inclusion in a research of all families of relatives of a proband) or limited (inclusion in a research only of families with sick children). Sources for drawing up a family tree usually are direct inspection, stories of diseases (or extracts from them), results of poll of family members. The information about relatives shall be specified by cross poll.
A basic element of a family tree — genealogical unit — is the individual.
By drawing up family trees the standard symbols (fig. 1) are used. Males are designated by a square, women's — a circle. In Great Britain for designation of males use a symbol of Mars ♂ and women's — a symbol of Venus ♀.
In the presence of several diseases in the studied family the first letters of names of these diseases are used.
Some authors recommend to note age of each member of a family tree on appropriate places of the horizontal line, before designation of age of the dead to put a cross, to mark out the family members inspected personally an exclamation mark what allows to delimit them from persons, data on whom are received from answers of a proband or its relatives.
The graphic representation of a family tree (the genealogical table) is formed so that the persons belonging to one generation were located on one horizontal line. Usually drawing up a family tree is begun with proband (see). In the presence of several children in a family children are represented from left to right, since the senior. Sisters and brothers of one parent couple considered together are called sibsam (see). Each previous generation is located above the line of a proband, and succeeding generation — is lower than the line of a proband. For convenience of drawing up a family tree at first it is possible to draw the genealogical bonds relating to mother of a proband (the maternal line) then represent the fatherly line or on the contrary. Generations are designated by the Roman figures, the persons belonging to one generation — the Arab figures. It is recommended to attach the text description of her certain members to a family tree — a legend.
The first stage of the genealogical analysis (the analysis of a family tree) is establishment of hereditary character of a sign. In each family tree also features of inheritance of a certain sign shall be tracked. In the analysis of a sign it is necessary to consider its possible modifications as result of interaction of the gene and the environment controlling it. So, some diseases can be shown only under certain conditions the environment; in other conditions carriers patol, a sign can be considered as healthy. The sign can depend on several genes. Externally similar signs are not always identical genetically. So, e.g., the atrophy of muscles can be the main manifestation myopathies (see) and to develop owing to nutritional dystrophy (see); an incomplete dislocation of a crystalline lens in some cases — one of the main signs of a syndrome of Marfan (see. Marfana syndrome ), but can be a traumatic origin. The signs having identity at one level, napr, physiological can be various on another, napr, biochemical. It is also important to establish whether two signs matching with each other are result of action of one gene or are caused by action of several genes. After full identity of signs, studying of ancestors and posterity on the chosen markers is established allows to establish with a certain degree of reliance distribution of the corresponding genes among family members. At detection of repeated repeatability patol, a sign or a disease in a family tree the careful genetic analysis is necessary for differentiation of hereditary pathology from phenotypical similar disturbances of other etiology. E.g., the nanocephalia in combination with mental retardation can be a consequence of rare recessive mutation; at the same time some drugs accepted by mother during pregnancy x-ray radiation of a fruit can cause similar defects. The rubella transferred by the woman to the first three months of pregnancy causes diverse changes in a fruit (deafness, heart diseases, damage of eyes) reminding signs of the known hereditary diseases. Sometimes (poorly expressed rubella) mother does not know about the disease transferred it. In this case it is necessary to carry out serol, inspection of mother and child to find out, than signs at the child are caused patol: influence of an infection or influence of a mutant gene (see. Mutation ).
After establishment of the hereditary nature of the analyzed sign * pass to establishment of a mode of inheritance. For the solution of this question use various methods of statistical data processing of a family tree.
The choice of a method of processing of genealogical data in many respects is defined by way of collecting material.
At full registration of families the direct a priori method of Bernstein or a simple method of sibs — Veynberg's method is more often used (see. Population genetics ). At a direct a priori method the expected number of patients in a family with a certain number of posterity proceeding from a dominant or recessive mode of inheritance is found, and comparison of the available distribution of sick children in families with theoretically expected is carried out. At a simple method of sibs the relation of sick sibs of a proband to number of all sibs in a family then statistical comparison of the received relation with expected is carried out, proceeding from a dominant or recessive mode of inheritance is defined.
It is necessary to consider that the simple relation of number of sick children to healthy will not give the correct idea of a mode of inheritance because the analyzed material did not include families carriers in which normal children were born. Often the fact that registration goes from the patient is the reason of it. Therefore, it is necessary to enter allowance for into calculations of a ratio of sick and healthy children a share of uninspected families. At incomplete poodinochny registration of material W. Weinberg's amendment is used. The essence of the amendment is that exclude from each family on one sick child and define a share of the remained sick children to all remained children in a family.
The statistical analysis allows to establish a ratio between the obtained data and theoretically expected proportions of splitting of a mutant gene, and also how empirically found ratio corresponds to Mendelian laws of splitting, to reveal a proportion of genotypes and other genetic patterns.
In a wedge, the practician G. of m promotes clarification of the main patterns of hereditary transfer patol, signs and diseases, to establishment of types of their inheritance.
At an autosomal and dominant mode of inheritance (fig. 2) transfer of a hereditary disease or a sign is traced from generation to generation (inheritance down). One of parents of a proband is usually sick (more rare both) or the erased symptoms of a disease are found in it; both floors with an identical frequency are surprised. Probability of appearance of the sick child in a family at full penetrance of a mutant gene (see. Penetrance of a gene ) makes 50%. In the presence of a mutant gene at both parents at children with probability of 25% the mutant gene appears in a homozygous state. It leads to especially expressed manifestation of a sign. E.g., at polydactylism at both parents children with very heavy defects of bone system can be born.
It is necessary to consider that action of a gene in many respects depends on the modifying influence of other genes and environmental factors. As penetrance of a gene can vary over a wide range, in a certain dependence the frequency of detection patol, signs in posterity changes. At verification of genetic data on inheritance of a dominant gene in the analysis of a family tree it is necessary to make allowance for the frequency of a sign in population.
On autosomal dominantly type such diseases as are inherited Alporta syndrome (see), spider finger (see), marble disease (see), bone formation imperfect (see), Pelgera anomaly (see), Pernicious anemia (see), tuberous sclerosis (see), favism (see), Sharko — Mari amyotrophy (see. Atrophy muscular ), etc.
At an autosomal and recessive mode of inheritance (fig. Z) action of a mutant gene is found only in a homozygous state (in a heterozygous state the normal allele dominates), both floors to the same extent are surprised, 25% of children in a family are sick, 50% of children phenotypical are healthy, but are heterozygous carriers of a mutant gene (as well as their parents), 25% have no mutant gene. The disease is quite often noted at brothers and sisters while their parents and close relatives remain clinically healthy — distribution of a hereditary disease across. The probability of the birth of the sick child at two heterozygous parents makes 25%; at limited number of children in a family, napr, two, the probability of the birth of two sick children makes 6,25% (i.e. 0,25 X 0,25 X 100%). The probability of the birth of sick children considerably increases in a case of a consanguineous relation of parents as at the same time the possibility of a combination in one zygote of two mutant genes raises. This probability (at the penetrance equal of 100%) is defined by a formula q 2 + Fqp, where q — the frequency of a recessive allele in population, r — the frequency of a normal allele, F — the coefficient equal 1/4 (the brother and the sister, the father and the daughter), 1/8 (the uncle and the niece), 1/16 (the cousin brother and the sister), 1/64 (the three times removed brother and the sister). E.g., if parents — cousin sibsa, the risk of the birth of the sick child with a fenilketonuriya makes 1:1600 whereas it is equal in marriage of the persons who are not relatives to 1:10 000. In marriage of homozygous and heterozygous carriers (aa X aa) the number of sick children in a family increases to 50%, and a half of children will be heterozygous carriers of a mutant gene that reminds an autosomal and dominant mode of inheritance (pseudo-dominance). Marriage of homozygous carriers of a mutant gene (aa x dd) leads to the birth of children, being also homozygous carriers of this gene and having a wedge, symptoms of a disease. In some cases children can be healthy phenotypical that can indicate controllability of the studied sign or a disease by different genes (genokopirovaniye).
On autosomal recessively type are inherited: alkaptonuria (see), albinism (see), amaurotic idiocy (see), galactosemia (see), hepatocerebral dystrophy (see), lactacidemia (see), mucoviscidosis (see), Nimanna-Pika disease (see), progeria (see), Refsuma syndrome (see), etc.
At recessive linked with a hollow mode of inheritance a mutant gene it is localized in X-chromosome or a Y-chromosome. Inheritance of the genes localized in X-and Y - lame catfishes, happens on the consistent patterns determined for gonosomes. Features of inheritance vary depending on localization of a gene in a homologous or nonhomologous X-segment and Y-chromosomes. So, the golandrichesky gene (the gene which is absolutely linked to a Y-chromosome) causing a pereponchatost of fingers, pilosis of auricles and some other signs is inherited on the fatherly line and shows the action only at males. Transfer of hereditary defect from the father to all his sons happens at full penetrance of a mutant gene.
At localization of a mutant gene in X-chromosome of the woman — carriers of a mutant gene remain phenotypical healthy because the mutant gene is resisted by a normal allele of the second X-chromosome. Action of the mutant gene localized in X-chromosome is shown only at males, except for extremely exceptional cases when both X-chromosomes bear a mutant gene. In a family a half of boys can be sick, and a half of girls — can be carriers of a mutant gene (fig. 4). Sick men give a gene to daughters and do not transfer to sons. On the recessive type linked to a floor are transferred: agammaglobulinemia (see), Viskotta — Aldrich a syndrome (see), hemophilia (see), daltonism (see. Color sight ), Lowe syndrome (see), Fabri disease (see), etc.
In the analysis of family trees it is necessary to consider a possibility of a polygenic mode of inheritance. At the same time the quantity of the genes controlling a certain sign can be very considerable. The hereditary basis of such signs as growth, intellectual development, temperament is polygenic. Influence of the environment significantly affects their manifestation also.
Of m allows to specify the nature of hereditary transfer that matters for timely diagnosis of a disease and performing therapy at early stages of a disease, the solution of a number of questions in medikogenetichesky consultation (see). So, drawing up a detailed family tree is necessary, in particular, for definition of the forecast of posterity. Indications to G.'s use m in similar cases — existence in families of persons with a hereditary disease or instructions on the burdened heredity. Of m defines indications to the choice of an additional (paraclinic) method of inspection that is of great importance for identification of a heterozygous carriage of a mutant gene.
G.'s accuracy of m is limited by a small amount of children in a family. Mistakes during the use of a method can be caused also by the wrong diagnosis of a disease (sign); the wrong definition of paternity due to illegitimate bonds. The wrong diagnosis is usually connected with an insufficient differentiation feno-and genocopies, with insufficiency of the received data because of extensiveness of a family tree, insufficient knowledge the analyzed signs interviewed about this or that at relatives. Often inspected do not know the relatives or try to hide existence of a hereditary disease, patol, a sign, to shift them to other line. G.'s inaccuracy of m can also occur owing to registration of families with various number of patients, absence of sick children at heterozygous carriers. Incomplete penetrance of a dominant gene or semidominance can imitate recessive inheritance. Of m in some cases does not supply with the authentic information allowing to differentiate the dominance limited to a floor from the recessive inheritance linked to a floor as, e.g., at the sick father clinically healthy daughter has the sick son. Besides, it is difficult to distinguish again arisen mutation from earlier being available in a family tree. Penetrance and expressivity of a mutant gene vary at heterozygous carriers at an autosomal and dominant mode of inheritance. In these cases the account even of the erased and atypical symptoms of a disease and a paraclinic research matters that helps the correct establishment of a mode of inheritance.
Thus, the analysis of family trees precedes clinical and laboratory inspection of patients and their relatives. Of m gives the chance to define a mode of inheritance patol, a sign or a disease and by that quite often to specify its form as for each hereditary disease transfer preferential on a certain type is characteristic. The features of transfer of a hereditary disease established by means of G. to m allow to exercise judgment in the analysis early a wedge, the symptoms revealed at some members of the studied family have differential and diagnostic value. So, in initial stages diagnosis of the main forms of a myopathy is complicated: psudohypertrophic, juvenile and a shoulder - scapular and front. Studying of genealogical data can correctly help to estimate a wedge, symptoms of a disease, to define its form as the mode of inheritance linked to a floor is characteristic of a psudohypertrophic form, for juvenile — autosomal and recessive, a for a shoulder - scapular and front — autosomal and dominant. From these positions these G. m quite often matter for timely diagnosis of hereditary diseases — before development of the expressed stages of a disease. Of m can instruct on a cause of illness in separate clinically difficult cases. So, the child having the signs of defeat of a nervous system reminding fenilketonuriya (see). While biochemical defect is absent, can be born from marriage of the woman, a sick fenilketonuriya and earlier treated, with the healthy man (toxic effect of phenylalanine on a brain of a fruit). Of m gives the chance to define group of people, needing detailed researches for identification of a heterozygous carriage of a mutant gene, first of all — close relatives of a proband, persons with the burdened anamnesis. A wedge, the proband shall have a complex inspection of the last, with the address of special attention to identification of the microsymptoms identical to that. The analysis of genealogical data is a basis for the choice of a necessary method of a paraclinic research: gematol, inspection at diseases of blood, biochemical, methods at disbolism, an electromyography at neuromuscular diseases, the electroencephalography at epilepsy etc. of G. m allows to reveal also a role of heredity in development of a number of widespread not hereditary diseases: cardiovascular, rheumatism, psychological and some other.
Of m helps to track features of inheritance throughout a lineage, to note influence of external factors, blood marriages on a proyavlyaemost of a mutant gene and degree of manifestation of its properties. In recent years for studying of a family tree computers begin to be used more and more widely. The practical value of G. of m increases with increase in accuracy of drawing up family trees; it is promoted by fuller registration of genealogical data and identification of teterozigotny carriers of a mutant gene by means of comprehensive inspection.
See also Hereditary diseases .
Bibliography: Badalyan L. O., Tabolin V. A. and Veltishchev Yu. E. Hereditary diseases at children, M., 1971; Davidenkovs. H. Hereditary diseases of a nervous system, M., 1932; it e, Clinical lectures on nervous diseases, century 4, M of 1961 Grooms B. V. Biologich * which modeling of hereditary diseases chr l About centuries, M., 1969; Makkyosak In the Geneticist of the person, the lane with English, M., 1967; it, Ancestral features of the person, the lane with English, M., 1976, bibliogr.; Dzh. V. and Shell U. J. Nasledstvennost of the person, the lane with English, M., 1958; Problems of medical genetics, under the editorship of V. P. Eph-roimsona, etc., M., 1970; Stern K. Fundamentals of genetics of the person, the lane with English, M., 1965; Efroimson V. P. Introduction to medical genetics, M., 1968; Roberts G. A. An introduction to medical genetics, L., 1963.
E. I. Gusev.