[Analytical estimation of the power of linkage in large pedigrees].

Different approaches to calculation of the power in linkage analysis whose efficiencies have been demonstrated in small pedigrees are described. The possibility of applying them to large pedigrees has been estimated. Equivalence of the analytical estimates of power obtained using different approaches based on analysis of individual pairs of relatives has been shown. The accuracy of the resultant analytical estimation of the power has been analyzed for three large pedigrees and a wide range of inheritance models; the accuracy has been demonstrated to be sufficiently high and equal to the accuracy in the case of small pedigrees.

[Power estimation for in silico mapping].

A fundamentally new approach to gene mapping of complex traits was suggested recently. It consists in computer analysis of existing databases on the phenotypes and single nucleotide polymorphisms (SNPs) in inbred mouse strains and was termed in silico mapping. The power of this method has been studied by simulating quantitative traits controlled by one, two, or three genes. The results have demonstrated that the power of in silico mapping is high in the case of a monogenic trait. The probability of mapping all genes determining a digenic or, especially, trigenic trait is low. If two or three genes make equal phenotypic contributions to a trait, the proportions of experiments where none of them is localized are 17 and 25%, respectively. In the case of a major gene effect, when the phenotypic contribution of one gene considerably exceeds those of the other genes, the probability to map the major gene is 0.95 and 0.80 for the digenic and trigenic models, respectively. This shows that, in the case of polygenic control, the new method could localize only the genes with major effects, while most genes involved in the control of the trait would not be mapped.

[Polymorphism of dental formula and segregation of its variants in a pedigree of kerry blue terrier dogs].

Polymorphism of the dental formula was analyzed in a sophisticated pedigree of Kerry Blue Terrier. A lack of one or more lower premolars was observed in some dogs. Two different patterns of missing teeth were identified. One pattern consisted in agenesis of a second premolar, often in combination with agenesis of neighbor teeth, including the fourth premolar. In the second pattern, agenesis of a fourth premolar was expressed as an isolated abnormality. It was shown previously that the first pattern is inherited as a recessive trait with near complete penetrance. In this work, the control of a major-gene was demonstrated for the second pattern. This abnormality develops in 70-80% of mutant homozygotes and in no more than 20% of heterozygotes and wild-type homozygotes. It was shown that the two dentition abnormalities are controlled by different genes, which were designated LPA2 and LPA4 (Lower Premolar Agenesis).

[Changes in litter size in Kerry blue terrier dogs with abnormal dentition].

The pleiotropic effects of mutations resulting in abnormal dentition were analyzed in Kerry Blue Terrier. A decrease in litter size was demonstrated for dogs with dentition anomalies. The mean litter size was 5.72 puppies when both parents had normal dentition and 3.64 puppies when the parents had hypodontia. Analysis showed that the decrease in litter size cannot be fully explained by the effect of inbreeding and is most probably associated with the pleiotropic effect of the genes controlling teeth development on the embryonic viability.

[Genetic analysis of the predisposition to audiogenic seizure fits in Krushinsky-Molodkina rat strain].

The expression of audiogenic seizure fits has been studied in F1 hybrids between audiogenic seizure-prone Krushinsky-Molodkina rat strain and Wistar rats not prone to audiogenic seizures, as well as in two backcross generations. Only 10% of F1 hybrids exhibit audiogenic seizure fits, whereas the frequency of this character in two generations of their backcrosses with Krushinsky-Molodkina rats is about 50%. A digenic model with incomplete penetrance has been put forward to explain the control of audiogenic seizure fits. This model fits the data obtained: the theoretically expected distributions of the character in offsprings of different crosses do not differ significantly from those observed in experiments. The model explains why the distribution of the character is the same in the first and second backcross offsprings.

[Estimation of allele frequencies in ethnically heterogeneous populations].

A method for reconstructing allele frequencies characteristic of an original ethnically homogeneous population before the start of migration processes is described. Information on both the ethnic group studied and offspring of interethnic marriages is used to estimate the allele frequencies. This makes it possible to increase the informativeness of the sample, which, in the case of ethnic heterogeneity, depends not only on allele frequencies and the total sample size, but also on the ethnic structure of the sample. The problem of estimating allele frequency in an ethnically heterogeneous sample has been solved analytically for diallelic loci. It has been demonstrated that, if offspring of interethnic marriages with the same degree of outbreeding is added to a sample of the ethnic group studied, the sample informativeness does not change. To utilize the information contained in the phenotypes of the offspring of interethnic marriages, representatives of the population from which migration occurs should be included into the sample. The size of the sample ensuring the preassigned accuracy of estimation is minimized at a certain ratio between the numbers of the offspring of interethnic marriages and the "immigrants." To analyze polyallelic loci, a software package has been developed that allows estimating allele frequencies, determining the errors of these estimates, and planning the sample ensuring the preassigned accuracy of estimation. The package is available free at http://mga.bionet.bionet.nsc.ru/PopMixed/PopMixed.html.

[Genetic control of chromosome synapsis in mice heterozygous for a paracentric inversion].

Frequencies of formation of inversion loops and their relative sizes were studied in laboratory mice heterozygous at paracentric inversion In1(1)Rk in chromosome 1, depending on the genetic background. Homozygotes In1/In1 were crossed with mice from five inbred strains (A/HeJ, BALB/cJ, C3H/HeJ, C57BL/6J, DBA2/J). The frequency of formation of inversion loops, their relative sizes, and the dependence of these parameters on the stage of pachitene were analyzed on electron-microscopic slides of spread spermatocytes in first-generation hybrids. It was shown that the genetic background and cross direction statistically significantly influenced the duration of individual pachitene stages and the frequency of inversion loops, but not relative loop size. Using a database on SNP distribution in the inbred strains examined, we carried out in silico mapping of genes affecting the genotype-dependent characters. We have found that the efficiency of synapsis in the inversion does not depend on interstrain differences in homology of the chromosome 1 region involved in the inversion. Genes controlling the inversion loop frequency in the inversion heterozygotes were mapped to chromosome 7, and genes controlling the duration of individual pachitene stages, to chromosomes 2 and 5.

[Inheritance of hypodontia in Kerry Blue Terrier dogs]. / Analiz nasledovaniia gipodontii u kerri-bliu-ter'erov.

Integral segregation analysis, which earlier proved efficient in studying complex hereditary diseases in humans and have been introduced in animal genetics for several years, was used to analyze the inheritance of hypodontia by premolars in Kerry Blue Terrier dogs. Dental formulas have been determined in 598 out of 911 animals united into a single large, complex pedigree. The results of integrated segregation analysis indicated heterogeneous genetic control of different forms of hypodontia. The geneses of different premolars in dogs have been demonstrated to be described by different models of inheritance: the absence of the second premolars can be described by the recessive major-gene model, whereas the agenesis of the fourth premolars have a more complex genetic mechanism and cannot be described by the model of a simple major-gene control.

[Analysis of allelic association: estimation of the criteria power of the TDT]. / Analiz allel'nykh assotsiatsii: otsenka moshchnosti kriteriia TDT.

Analysis of allelic associations is an increasingly more widely used approach to fine mapping of genes of various diseases. To interpret the results correctly, it is necessary to estimate the power of the statistical test used. The principle of the analysis of associations and testing of hypothesis are described, and analytically obtained estimates of the power of the transmission disequilibrium test (TDT), one of the most popular methods of analysis of allelic associations, are presented. These estimates are applicable to arbitrary models of inheritance formulated in terms of relative genotypic risk. The proposed method is illustrated by analysis of the associations of idiopathic scoliosis and aggrecan gene alleles.

[Oligodontia and its inheritance in Kerry blue terrier]. / Oligodontiia i ee nasledstvennaia obuslovlennost' u sobak porody kerri-bliu-ter'er.

Defects of the premolar tooth formula (oligodontia, tooth number reduction) were studied in dogs of the Kerry blue terrier breed. For this purpose, a database including 480 individuals of 96 litters was constructed. The occurrence of oligodontia was investigated in pedigree groups with inbred and outbred crosses. No selective mating choice for the anomaly under study was found in the sample. The results indicate that oligodontia is inherited, which requires comprehensive study of its genetic control and search for corresponding genes.

[A method for estimating penetrance of pathogenic mutations in a mitochondrial genome]. / Metod otsenki penetrantnosti patogennykh mutatsii mitokhondrial'nogo genoma.

Variation in the manifestation age is typical of many mitochondrial diseases. The estimation of penetrance of pathogenic mutations causing such diseases is usually conducted on samples of individuals whose age exceeds the maximum age of the disease manifestation. In the case of rare diseases, samples of sufficient size sometimes cannot be formed. In this study, we propose a method for estimating penetrance involving individuals of any age. The efficiency of the method is demonstrated using Leber hereditary optic neuropathy as an example. It is shown that the method provides an unbiased estimate of penetrance and considerably reduces the error of this estimate in comparison with a sample including individuals whose age exceeds the maximum age of disease manifestation.

[Analysis of polymorphism of the number of tandem repeats in the aggrecan gene exon G3 in the families with idiopathic scoliosis]. / Izuchenie polimorfizma chisla tandemnykh povtorov v ékzone G3 gena agrekana v sem'iakh s idiopaticheskim skoliozom.

In our previous study we showed that the inheritance of pronounced forms of idiopathic scoliosis was described by an autosomal-dominant major gene model assuming incomplete sex- and age-dependent penetrance. In the present study a search for the major gene was carried out by means of testing candidate genes. The aggrecan gene with known polymorphism of the number of tandem repeats in exon G3 was considered to be one of these candidate genes. Various alleles of this gene provide attachment of different number of chondroitin sulfate chains to a proteoglycan core protein, thereby changing functional properties of cartilage. Using the TDT analysis of 33 unrelated families consisting of a proband and his parents, we examined the existence of associations between the aggrecan alleles and the disease. Among nine alleles identified, three alleles with tandem repeats numbers of 25, 26, and 27 prevailed. We did not reveal preferable transmission of any of these alleles to the proband (TDT-statistics for different alleles varied from 0 to 0.71). There was also no correlation between the number of tandem repeats and the disease severity. Thus, either the polymorphism of the number of tandem repeats is not the direct reason for development of idiopathic scoliosis in the families tested, or its effect is too low to be detected using the samples examined.

[Radiation mapping of the short arm of swine chromosome 2]. / Radiatsionnaia karta korotkogo plecha khromosomy 2 svin'i.

In recent years, maps of mammalian genomes have been acquiring increasingly higher resolution. Integration of maps of different types has become possible. As a tool in integrating maps of mammalian genomes of different types, high-resolution mapping with radiation-induced hybrids (RH) is used. Here, we present an RH6000 map of the short arm of porcine chromosome 2. The map contains 15 microsatellites and five genes (for parathyroid hormone, lactate dehydrogenase A, myogenic factor, follicle-stimulating hormone beta, and calpain I). The RH panel was obtained on the basis of a hybrid cell line bearing the single porcine chromosome 2 against the background of mink chromosomes. The mean frequency of preserving markers examined in the panel was 18.3%. Integration of four genes in the panel and a comparison of gene order in homologous regions of human and porcine chromosomes are presented.

[Pedigree analysis in evaluating gene frequency in aboriginal populations of Siberia]. / Analiz rodoslovnykh pri otsenke chastot allelei v populiatsiiakh korennykh zhitelei Sibiri.

Procedure is described to estimate allele frequencies in indigenous populations of Siberia using phenotype data not only for "pure-blood" representatives of the ethnic groups examined, but also for the descendants of mixed marriages. Implementation of the method requires reconstruction of the data on relatives for the sample examined. Inclusion of the data on descendants of mixed marriages into the analysis increases the sample information content and decreases variance of the estimates obtained. The advantages of the method are illustrated using an example of Tundra Nentsy, for whom it was shown that variance of estimates at the analysis of the blood groups allele frequencies can be diminished approximately by a factor of 1.5.

[Mapping of genes determining animal quantitative traits: a method for partitioning variances]. / Kartirovanie genov, determiniruiushchikh kolichestvennye priznaki zhivotnykh: metod razlozheniia dispersii.

The method of quantitative trait loci (QTL) mapping based on the partitioning of variance was further developed. This extended possibilities of this method to include its use in the analysis of the data material obtained in the interbreed or interpopulation animal crosses, which provide information for genetic studies of QTL subjected to natural or artificial selection.

[Radiation hybrid mapping: statistical criteria and their properties]. / Radiatsionnoe gibridnoe kartirovanie: statisticheskie kriterii i ikh svoistva.

Statistical tests specially developed for radiation hybrid (RH) mapping, modified likelihood-ratio test and Akaike's information content, are proposed. They allow several most likely gene orders to be identified to a certain accuracy. The properties of the proposed tests that characterize the accuracy of gene ordering as dependent on the number of genes mapped, the position of the selective gene, and the sample size have been studied. Recommendations as to the practical use of these tests are presented.

[Genetic relationships between catalepsy and pendulum movements in rats]. / O geneticheskikh vzaimootnosheniiakh katalepsii i maiatnikoobrazhnyikh dvizhenii u krys.

Predispositions to pendulum movements (PMs) and catalepsy was studied in rat strains selected for predisposition to catalepsy and for enhanced or suppressed PMs. Positive correlation between PMs and catalepsy at earlier stages of selection changed to negative at later stages. Based on these data, it was hypothesized that the genes that determine the predisposition to catalepsy affect the expression of the gene determining PMs in such a way that different PM alleles become dominant in the cases of moderate and strong effects of the catalepsy genes.

[An efficient algorithm for estimation of functions of a pedigree with short inbred loops]. / Effektivnyi algoritm podscheta funktsii pravdopodobiia rodoslovnykh s korotkimi inbrednymi petliami.

The study is a further development of the methods for genetic analysis using pedigree data. Methods for approximation of the likelihood based on cutting of all loops are often used in analysis of large pedigrees with multiple loops. In this study, a fast efficient algorithm for calculating likelihood is proposed. This algorithm allows short inbred loops to be processed without cutting them and, hence, prevents the loss of genetic information. The approach proposed may be important for analysis of the pedigrees of farm and laboratory animals, where inbred crosses resulting in short inbred loops are common. The results of a stochastic genetic experiment agree with this suggestion: the use of the algorithm proposed considerably increases the accuracy of estimation of model parameters and testing of genetic hypotheses.

[Inheritance of pendulum movements in rats]. / Nasledovanie "maiatnikoobraznykh dvizhenii" u krys.

Inheritance of predisposition to pendulum movements (PMs) in rats was studied by two methods: segregation analysis of binary traits (on pedigrees recorded in the selection archives for cataleptic strain GC) and the classical Mendelian analysis of hybrids between strains PM+ and PM- selected for pronounced PMs and the absence of PMs, respectively. Both methods yields the same result: it was found that predisposition to PMs exhibited a monogenic dominant inheritance with incomplete penetrance.