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Recurrent pregnancy loss (RPL) is a severe reproductive pathology with a significant component of unexplained etiology. Extended homozygous regions as a possible etiological factor for RPL were sought in the genomes of embryos. Twenty-two paired first-trimester spontaneously aborted embryos from eleven women with recurrent miscarriage were analyzed. All embryos had normal karyotypes according to metaphase karyotyping and conventional comparative genomic hybridization. SurePrint G3 Human CGH + SNP 4 × 180K microarrays (Agilent Technologies) were used to search for homozygous regions. As a result, 39 runs of homozygosity (ROH) were identified in extraembryonic tissues of 15 abortuses. Verification of recurrent homozygous regions was performed by Sanger sequencing. The presence of occasional heterozygous SNPs was shown in 25 extended ROHs, which may indicate that they did not arise de novo but were inherited from parents. In the course of inheritance in a series of generations, they may accumulate mutations, leading to heterozygosity for several sites in the initially homozygous population-specific regions. Homozygotization of recessive mutations is one of the putative mechanisms of the influence of such inherited ROHs on RPL development. The high frequency of extended ROHs detected in the present study may point to a role of inbreeding in RPL etiology. Homozygous regions may also occur due to uniparental disomy, and abnormalities of genomic imprinting may be another mechanism responsible for the pathological manifestation of ROHs in embryogenesis. Indeed, five predicted imprinted genes were identified within ROHs according to the Geneimprint database: OBSCN, HIST3H2BB, LMX1B, CELF4, and FAM59A. This work reports the first finding of a high frequency of extended ROHs in spontaneously aborted embryos with normal karyotypes from families with RPL.

We demonstrate patterns in the penetrance of the mutant gene and the suppressor gene which control suppressed temperature-dependent chlorophyll defects in F1 hybrid progenies of F. pratensis L. obtained through reciprocal crossings of mother plants of different phenotypes, and the contributions of these genes to the epigenetic variation of plant organisms. In F1 hybrid progenies from reciprocal crossings the mutant gene may demonstrate either the same or differential genomic imprinting. Variations of the effect depended on the degree of the chlorophyll defect in the seedlings at desuppression and the modifying action of the suppressor gene at resuppression. Furthermore, the suppressor gene had a multiplier effect, as it not only suppressed the penetrance of the mutant gene that controlled temperature-dependent chlorophyll defects but also masked the different genomic imprinting in individual F1 hybrid phenotypes.

Genomic imprinting is an epigenetic phenomenon that differentiates maternal and paternal copies of genes in the genome and causes monoallelic expression depending on parental origin. Imprinting is an evolutionary puzzle, as it bears the costs of diploidization without its advantages, namely, protection from recessive mutations. The aim of this review is to answer the question of why genomic imprinting arose and became fixed in the evolution of angiosperms, insects, marsupials, and placental mammals.

As of today, classical genetics has already completed the majority of groundwork to describe the laws of inheritance, identify the causes of many human diseases, and dissect the mechanisms of transfer of genetic information from parents to offspring. However, recent studies indicate that inheritance of phenotypic traits may also occur through nongenetic factors, in particular, through epigenetic factors, that manifest their effects in a transgenerational fashion. This review discusses findings in the area of transgenerational inheritance that open a new era in modern genetics. We discuss the mechanisms of transgenerational inheritance, including DNA methylation, histone modifications, and noncoding RNA transfer, and give an overview of the approaches to detect transgenerational effects in humans.

The current knowledge on multiple epimutations in imprinted genes and their impact on the disturbances of human prenatal development and the emergence of hereditary diseases are reviewed and analyzed. Genetic mechanisms regulating the epigenetic state of imprinted loci in the human genome are discussed.

Genomic imprinting is one of the most significant epigenetic phenomena, which is involved in the support of eutherians and human embryo development. Molecular mechanisms of imprinting disturbance in the pathology of pre- and postnatal ontogeny are related to a considerable degree to aberrant DNA methylation of imprinted genes. At present time data about multiple abnormalities of DNA methylation arising simultaneously in several imprinted loci are accumulated. This fact brings up the problem of interpretation of imprintome structural and functional organization, as well as interaction of imprinted genes. At present study DNA methylation analysis of 51 imprinted genes in placental tissues of human spontaneous abortions was performed. The presence of several epimutations affected from four to 12 imprinted genes was observed in each embryo. Majority of epimutations (78%) had a postzygotic origin. It was shown for the first time that the total incidence of abnormal DNA methylation of maternal and paternal alleles of imprinted genes, which lead to suppression of embryo development, is significantly higher than the incidence of epimutations, which can lead to stimulation of ontogenesis processes. This fact supports at the epigenetic level the "sex conflict" hypothesis, which explains the appearance of monoallelic imprinted genes expression in the evolution of mammals.

To date, a wide range of assisted reproductive technologies is available for patients with impaired fertility. In general, the current methods of reproductive medicine are considered safe and do not significantly increase the frequency of birth of children with diseases or congenital malformations. However, the evidence has been accumulating in literature on higher risk of genomic imprinting diseases (Beckwith-Wiedemann and Angelman syndromes) as a result of using assisted reproductive technologies. In most cases examined, the appearance of these syndromes was explained by defective methylation status of imprinted genes. It has been suggested that manipulations with gametes and embryos during the period of total epigenetic modification of their genomes may act as potential risk factors of assisted reproductive technologies. Moreover, overcoming many natural reproductive barriers may contribute to the development of some pathological phenotypes. The review summarizes current views on epigenetic risk factors associated with assisted reproductive technologies.

Epigenetic hypothesis of dynamic genomic parental imprinting, explaining the mechanisms of formation and inheritance of quantitative characters in multicellular organisms, is proposed. Method for analyzing the compliance of quantitative characters of organisms with the hypothesis of dynamic genomic parental imprinting is developed. Examples of human characters and characters of other mammals inherited in accordance with the proposed model are given. It is concluded that the hypothesis can be used for studying ontogeny and explaining the mechanisms of inheritance of the morphoses providing the stability and evolution of species. Possible ways of further experimental verification of the hypothesis and areas of its practical application are discussed.

Genomic imprinting is one of the most remarkable and important epigenetic phenomena. A biological ban on parthenogenetic and androgenetic development of mammals is an obvious consequence of genomic imprinting. Genomic imprinting defects may cause malformations, clinical syndromes, and tumor growth in humans and to the large offspring syndrome and an increased mortality after in vitro manipulations with early embryos in mammals. Differential expression of parental alleles during ontogeny implies a mechanism of reversible, selective marking of gene alleles. These relatively stable epigenetic modifications, which do not affect the primary nucleotide sequence of DNA, may be transmitted in somatic cell lines and reproduced in the germ line. The genomic imprinting mechanism may be involved in other epigenetic processes, such as epigenetic inheritance, nonrandom allele segregation, meiotic drive, etc. Artificial modulation of genomic imprinting effects with the use of growth factors and demethylating agents permits partial "normocoping" during the development of parthenogenetic mouse embryos. Targeted changes in the transcriptional activity of imprinted genes provide prerequisites for epigenetic correction of syndromes and diseases caused by genomic imprinting defects.

In female mammals, the process of dosage compensation occurs during early embryonic development. As a result of this, one of X-chromosomes becomes transcriptionally inactive. This process is accompanied by chromatin remodeling on inactivated X-chromosome, providing transcriptional silencing of the genes and maintenance of their inactive state. In the present review, the dynamics of modifications occurring during embryonic inactivation, their distribution over the inactive X-chromosome, interaction, and the role in establishing and maintening the inactive state are discussed. As an illustration, modifications on the inactive X-chromosome of the Microtus common vole are presented.

This review discusses the modern issues in epigenetic regulation in plants related to the imprinting at the levels of genome, locus, and gene. The data described follow the historical order: from the beginning of research into non-crossability of plant forms with different ploidies to the recent communications about allelic imprinting at r1 locus of maize and the control of synthesis of storage proteins with a high forage value. The classical experiments of Kermicle and Lin on the cytogenetic confirmation of the role of parental genome ratio in the endosperm in a successful development of viable caryopses are described in detail. Uniqueness of the experimental technique used by these authors is emphasized. The variants for overcoming the effect of imprinted signal in apomicts and plants with a tetrasporic embryo sac are considered. A considerable attention is paid to the imprinting in the species with polyploid series and to the hypothesis of endosperm balance number. The issues of potential practical application of imprinting in breeding practice are discussed. The results obtained in this direction demonstrate the ways to increase the forage value of maize zeins.

The review gives a definition of epigenetics, considers its history, and describes the relevant phenomena. It is emphasized that epigenetic events agree with the current genetic paradigm, rather than striking its foundation.

The Drosophila melanogaster hdc gene controls trachea branching, which starts during embryo development. Expression in imaginal disks and reproductive organs suggests additional functions for the hdc gene. The gene was demonstrated to have a maternal effect, which was denied previously. Analysis of cell proliferation in imaginal disks with hdc mutations showed that the gene does not possess tumor suppressor properties at the levels of mosaic cuticle clones of adults and transplanted imaginal disks. Transplanted imaginal disks homozygous, but not heterozygous, for an hdc mutation were found to affect oogenesis in the recipient females, implicating the hdc activity in exchanging signals between different organs. Amino acid sequence analysis of the Hdc protein revealed a region homologous to the human HRS proteins, which directly interact with the NF2 tumor suppressor on experimental evidence.

Epigenetic modifications, such as monoallelic DNA methylation, covalent histone modifications, nonhistone proteins, chromatin folding, heterochromatinization, spatial nucleus organization are reviewed with regard to establishment and maintenance of imprinting in mammals. Special attention is paid to repeated DNA sequences as intermediates of the above epigenetic modifications. A suggestion is put forward relative to importance of preimplantation development, in particular, to chromosome organization and segregation in the establishment of imprinting. Some futher directions of imprinting mechanisms are also discussed.

Genomic imprinting belongs by its nature to problems of epigenetics, which studies hereditary changes in gene expression not related to defective sequences of DNA nucleotides. Epigenetic mechanisms of control, including genomic imprinting, are involved in many processes of normal and pathological development of humans and animals. Disturbances of genomic imprinting may lead to various consequences, such as formation of developmental anomalies and syndromes in humans, appearance of the large offspring syndrome and increased mortality upon cloning of mammals, and death of parthenogenetic embryos soon after implantation and beginning of organogenesis. The death of diploid parthenogenetic or androgenetic mammalian embryos is determined by the absence of expression of the genes of imprinted loci of the maternal or paternal genome, which leads to significant defects in development of tissues and organs. A review is provided of the studies aimed at search of possible normalization of misbalanced gene activity and modulation of genomic imprinting effects during parthenogenetic development in mammals.

We studied the effects of three growth factors, fibroblast growth factor (FGF4), transforming growth factor alpha (TGFalpha), and transforming growth factor beta1 (TGFbeta1), on development of diploid parthenogenetic embryos of C57BL/6 mice, which are not capable of developing to somatic stages. Parthenogenetic embryos were treated with growth factors at optimal doses in vitro at the morula--blastocyst stages and transplanted in the uterus of pseudopregnant females. FGF4 and TGFalpha improved the development of parthenogenetic embryos at the preimplantation stages and the number of blastocysts increased under the influence of TGFalpha. All three growth factors improved the implantation of embryos in the uterus. When FGF4 or TGFbeta1 were added to the nutrient medium, 2.4 or 1.6%, respectively, of parthenogenetic embryos reached the somatic stages in utero. No somitic embryos were observed in the control. The treatment of parthenogenetic embryos with two growth factors, FGF4 and TGFbeta1, simultaneously increased the amount of somatic embryos to 7.5%, while combination of three growth factors in creased the amount of such embryos to 16.7%. In the latter case, some parthenogenetic embryos reached the stage of 25-27 pairs of somites and were 2.0-2.5 mm long. The data we obtained suggest that, when combined, the growth factors FGF4, TGFalpha, and RGFbeta1 possessed a synergistic effect leading to a significant improvement of the development of parthenogenetic C57BL/6 embryos.

Direct molecular genetic testing carried out in 59 Huntington's disease patients belonging to 46 families from Bashkortostan revealed the (CAG)n repeat expansion in exon 1 of the IT15 gene in 57 of them. By use of this analysis the disease status was not confirmed in two patients with atypical form of the disease and negative family history. The (CAG)n repeat expansion was identified in 27 out of 127 asymptomatic at-risk individuals. Analysis of the mutant (CAG)n allele inheritance demonstrated extremely high instability and high mutation rate predominantly leading to the appearance of the alleles with increasing number of (CAG)n repeats in subsequent generations. The instability was mostly observed in cases of paternal transmission. Almost complete linkage disequilibrium between the (CCG)7 mutant alleles and the del2642 deletion was demonstrated. Three major haplotypes revealed, (CCG)7/del-, (CCG)7/del+, and (CCG)10/del-, implied the existence of at least three sources of the origin of Huntington's disease in Bashkortostan. The identified haplotype frequency distribution patterns displayed similarities with those in European populations. The contribution of a number of genetic factors to the age of onset of Huntington's disease was analyzed.

Analysis of markers mtDNA in a population of Nogays (n = 206), living on Nothern Caucasus and speaking on language of Turkic branch of the Altaic linguistic family, has shown, that the level of their genetic differentiation is high (H = 0.99). Among the found haplotypes there is all the basic Western Eurasian haplogroups, most often of which are clusters H (22%) and U (21%), however, the percentage of the lineages specific only for populations of East Eurasia (40%) is highest. In a population of Nogays there are also variants mtDNA, belonging to haplogroup M1, characteristic for North East Africa, and gaplogroup U2, typical for populations of India. This testifies about presence in a gene pool of Nogays people of components of a various parentage.

Effect of chromosomal rearrangements on the expression of mutations was studied in Drosophila melanogaster regulatory genes. These were facultative dominant lethals and recessive lethals on the X chromosome obtained by the classical Muller-5 method. Chromosomal rearrangements drastically changed the expression of regulatory gene mutations. Rearrangements either caused the lethal effect of mutations or suppressed the already present lethality. The action of rearrangements exhibited the maternal or paternal effect. Irrespective of the presence in the genome of mutations at regulatory genes, a rearrangement acted as a factor decreasing fertility of the organism. The rearrangement effect is identical to the expression of regulatory genes per se. It is concluded that the chromosomal rearrangement affects the examined regulatory genes indirectly through a change in the operation of regulatory genes located within the rearrangement. Thus, rearrangements gain great importance for the definition of the pattern of genome functional activity. Widespread distribution of rearrangements in individual genotypes and their effectivity in the process of speciation are thus explained.

The review considers the epigenetic defects and their diagnostics in several hereditary disorders and tumors. Aberrant methylation of the promoter or regulatory region of a gene results in its functional inactivation, which is phenotypically similar to structural deletion. Screening tests were developed for Prader-Willi, Angelman, Wiedemann-Beckwith, and Martin-Bell syndromes and mental retardation FRAXE. The tests are based on allele methylation analysis by methylation-specific or methylation-sensitive PCR. Carcinogenesis-associated genes (RB1, CDKN2A, ARF14, HIC1, CDI, etc.) are often methylated in tumors. Tumors differ in methylation frequencies, allowing differential diagnostics. Aberrant methylation of tumor suppressor genes occurs in early carcinogenesis, and its detection may be employed in presymptomatic diagnostics of tumors.

We studied the effect of the growth factor LIF on the development of parthenogenetic mouse embryos (CBA x C57BL/6)F1. LIF was added to the culture medium at 10, 50, 100, and 250 ng/ml at the morula stage and parthenogenetic embryos were cultivated in vitro until the late blastocysts stage and then transplanted in the uterus of pseudopregnant females, which were then sacrificed on day 12 of pregnancy. All the LIF doses used improved the development of parthenogenetic mouse embryos at the preimplantation stages and increased the amount of blastocysts by 16%, on average, as compared to the control. LIF at 50 and 100 ng/ml increased approximately twice the number of embryos that reached the somatic stages. Some of them reached the stage of 32-45 somites and had fore and hind limb buds. No such embryos were found in the control. Well formed placenta was observed in 6% of the embryos treated with LIF and the most pronounced effect was recorded at 100 ng/ml. The data we obtained suggest that exogenous LIF can improve pre- and postimplantation development of parthenogenetic mouse embryos due, possibly, to increased survival rate of embryonic stem cells derived from the inner cell mass of blastocysts. LIF improves not only the development of the parthenogenetic embryo per se, but also the formation of its extraembryonic envelopes, which leads to the development of a larger placenta in LIF-treated parthenogenetic embryos, as compared to the control.

The mutants referred to as facultative dominant lethals were selected in the progeny of gamma-irradiated Drosophila males. The mutant males were viable and fertile, though their crosses with females of the yellow line yielded no daughters. The mutations obtained differed from the common mutations by (1) extremely varying penetrance of F1 hybrids from crosses with various lines; (2) the uncertain relationships between the mutant and normal alleles; (3) the different expression in somatic and germ cells; (4) the dependence of the expression on the sex of the parent carrying the donor mutations; (5) the mass morphosis formation and (6) the frequent reversal to the norm. These mutations are assigned to the regulatory group and their specific expression (see above) can be helpful in identifying regulatory gene mutations. We assume that the specific expression of the mutations studied is related to specific properties of the regulatory genes. These properties are as follows: (1) only one out of two homologous regulatory genes located on one homolog is in an active state, (2) in the haploid chromosome set the regulatory gene is represented by several alleles (cys-alleles); (3) only one allele ensures the regulatory gene activity.

We studied the effects of fibroblast growth factor 2 (FGF2) and insulin-like growth factor 2 (IGF2) on the development of parthenogenetic mouse embryos (CBA x C57BK/6)F1. The parthenogenetic embryos were treated in vitro during the preimplantation period and, at the blastocyst stage, transplanted into the uterus of pseudopregnant females. The addition of FGF2 at an optimal dose (2.5 ng/ml) to the culture medium increased twofold the number of embryos developed in utero to the somite stages as compared to the control: 18 and 43%, respectively. The parthenogenetic embryos (18-21 somites), treated and nontreated with FGF2 during the preimplantation period, were explanted for further development in vitro and treated with IGF2 at 2.5 micrograms/ml. As a result, many more parthenogenetic embryos (> 87%) of both groups developed in vitro to the stage of 30 or more somites as compared to the control (59%). The treatment of the parthenogenetic embryos with FGF2 alone at the preimplantation stages did not improve their development in vitro at the postimplantation stages. The results we obtained suggest that the treatment of parthenogenetic embryos in vitro with FGF2 during the preimplantation period increased twofold the number of somite embryos in utero, while their subsequent treatment in vitro with IGF2 leads to a significant prolongation of their development, as compared to the control.

Clonal analysis of parthenogenetic chimeric mouse embryos C57B1/6(PG)<-->BALB/c has shown that parthenogenetic cell clones C57BL/6 are present in the brain, liver, and kidneys of 14- and 18-day-old embryos. The content of the parthenogenetic component (PG) in these organs on day 18 was lower than on day 14, and, in some 18-day-old embryos, parthenogenetic cell clones were absent from the liver and/or kidneys. These data suggest that, during the embryogenesis of parthenogenetic chimeras, parthenogenetic cell clones of mostly endodermal and mesodermal origins were actively eliminated. Therefore, in such parthenogenetic adult chimeras, parthenogenetic clones of mostly ectodermal origins were preserved. In parthenogenetic chimeras CBA(PG)<-->BALB/c, parthenogenetic cell clones were actively eliminated at early embryonic stages, and, as a result, they were absent at the post-implantation stages. Hence, during development of parthenogenetic cell clones, the effects of genomic imprinting are expressed unequally in C57BL/6 and CBA mice.

Based on the reports of UNSCEAR for the period from 1958 to 2001 the paper presents a retrospective analysis of the use of direct methods and the doubling dose method for quantitative determination of the genetic risk of human exposure expressed as different hereditary diseases. As early as 1962 UNSCEAR estimated the doubling dose (a dose causing as many mutations as those occurring spontaneously during one generation) at 1 Gy for cases of exposure to ionizing radiations with low LET at a low dose rate and this value was confirmed in the next UNSCEAR reports up to now. For cases of acute irradiation the doubling dose was estimated at 0.3-0.4 Gy for the period under review. The paper considers the evolution of the concepts of human natural hereditary variability which is a basis for assessing the risk of exposure by the doubling dose method. The level of human natural genetic variability per 1,000,000 newborns is estimated at 738,000 hereditary diseases including mendelian, chromosomal and multifactorial ones. The greatest difficulties in assessing the doubling dose value were found to occur in the case of multifactorial diseases the phenotypical expression of which depends on mutational events in polygenic systems and on numerous environmental factors. The introduction in calculations of the potential recoverability correction factor (PRCF) made it possible to assess the genetic risk taking into account this class of hereditary diseased. The current estimate of genetic risk is 3000-4700 genetic diseases in the first generation per 1,000,000 newborns after exposure of the parental generation to 1 Gy at low dose rate. A certain part of genetic changes after exposure of the parental generation to radiation will express themselves in the second generation, in grandchildren (1150-3200 cases or 56% of the effect predicted for the first generation), and in succeeding generations.

A review of the data on the mechanisms and effects of genomic imprinting, an epigenetic phenomenon regulating the development in placentate mammals, is presented. In contrast to the majority of gene loci with biallelic expression, the expression of imprinted loci is monoallelic. In humans and mice, more than 300 imprinted loci have been identified, in which maternal or paternal alleles may either be expressed or be found in a repressed state during ontogeny. Imprinting is established during gametogenesis, and the repression of an allele of the imprinted locus is determined by methylation of the key regulatory element of this allele. Both the maternal and paternal chromosome sets are required for normal development in mammals. This is why parthenogenesis and androgenesis in these animals are impossible in nature. As a result of differential gene expression of many imprinted loci, the balance of gene activity is established, which is necessary for normal proliferation and differentiation of various cell clones in embryogenesis. Many human developmental abnormalities and syndromes are determined by defective genomic imprinting. In particular, the loss of imprints, which is followed by the occurrence of biallelic expression of some imprinted loci, may cause malignant tumors.

Methylation is a modification that changes the structure and functional status of DNA. Hence it is interesting to study the effect of methylation on basic processes occurring in living cells. In this review, the role of DNA methylation in recombination, replication, transcription regulation, imprinting, tumorigenesis, and tumor progression is considered.

This is a review of the data of clonal analysis of developing tissues in parthenogenetic and androgenetic chimeric mice. The time and causes of death of the parthenogenetic and androgenetic cell clones in chimeras are considered. The data obtained suggest that the development of cell clones, derivatives of the mesoderm and endoderm, is determined by the expression of alleles of the imprinted loci of paternal chromosomes, while the formation of cell clones, derivatives of the ectoderm, depends on the expression of other imprinted loci of maternal chromosomes. The death of androgenetic and parthenogenetic (gynogenetic) mammalian embryos is due to the lack of the expression of certain imprinted loci of the maternal and paternal genome, respectively.

The problem of the functioning specificity of sex chromosomes during the early stages of embryogenesis in man and the associated problem of the sex ratio in spontaneous and induced abortions, as well as in newborns, remains open. We have conducted a cytogenetic examination of 342 spontaneous abortions divided into three clinical groups on the basis of the severity of the developmental disturbances of the embryo: spontaneous abortions sensu stricto with a developed embryo without any significant intrauterine delay of development (n = 100), nondeveloping pregnancies (n = 176), and anembryonic fetuses (n = 66). The frequency of chromosomal mutations in these groups was 22.0, 48.3, and 48.5%, respectively. Statistical analysis has demonstrated significant differences between the studied groups in the frequencies of the normal and abnormal karyotypes: the major contributions to these differences were associated with autosomal trisomy, triploidy, and 46,XY karyotype. The presence of 46,XY may reflect specific genetic mechanisms of prenatal mortality of embryos with normal karyotype, associated with sex and/or with the imprinting of X-chromosomes. The sex ratio in spontaneous abortions with normal karyotype was as follows: 0.77 for spontaneous abortions with well-developed embryos without any significant intrauterine delay of development; 0.60 for non-developing pregnancies; and 0.31 for anembryonic fetuses. An analysis of DNA from the embryos and their parents has demonstrated a low probability of contamination of cell cultures with mother cells as a possible source of prevalence of embryos with 46,XX karyotype among spontaneous abortions. Nondeveloping pregnancies and anembryonic fetuses showed statistically significant differences in the sex ratio (1.11) from the control group consisting of medical abortions. Differences in the sex ratio were due to an increasingly lower proportion of embryos with karyotype 46,XY (relative to the expected one) among the fetuses with an increased severity of developmental disturbances. The statistical "chances ratio" index also provided evidence that embryos with 46,XY karyotype had a higher propensity to produce a well-formed fetus as compared with the female embryos. We propose that the expression of genes of the maternal X-chromosome in XY embryos supports a more stable development during early embryogenesis as compared with XX embryos. In the latter case, normal development is coupled with the operation of an additional mechanism for compensation of the dose of X-linked genes. Operation of this mechanism increases the probability of disturbances in female embryos. A higher viability of XY embryos during the early stages of ontogenesis in man appears to explain their underrepresentation in samples of spontaneously aborted embryos and appears to be the major factor responsible for the deviation of the sex ratio from the theoretically expected value.

In populations of Harmonia axyridis Pall. from Novosibirsk and Kyzyl, females (three out of 34 studied) that produce exclusively female progeny were found. In one of the families studied, the inheritance of the male-killing trait was monitored over five generations. The male-killing trait was maternally inherited. The beetles of this family were infected with the bacteria that, according to the sequence analysis of the gene fragment for 16S rRNA, belong to the genus Spiroplasma (VI group).

A key problem of honeybee (Apis mellifera mellifera) breeding in the Southern Urals is its cross-breeding with the Caucasian honeybee Apis mellifera caucasica. Mitochondrial DNA (mtDNA) in these subspecies differ in the length of a fragment localized between genes CO-I and CO-II, which can be used as a marker. A pair of 20-mer primers for PCR was chosen by means of computer design in order to determine the fragment size in both of the subspecies. The amplified fragment was shown to have a length of 350 bp in A. m. caucasica and 600 bp in A. m. mellifera. The difference in length results from the different ratio between two main elements P and Q, which comprise a major part of this sequence in these subspecies: a copy of P element and two copies of Q element in A. m. mellifera, and a copy of Q element only in A. m. caucasica. This sharply defined distinction allows us to use PCR for differentiating the subspecies, estimating the heterogeneity in the colonies, and rejecting queens in the selection process because of the maternal inheritance of the studied character. The nucleotide sequence of the amplified mtDNA fragment of A. m. mellifera was determined.

The phenotypic expression of the mutation Uns (gene Pax-1) were studied in the progeny of heterozygous mice. In all crosses, the sex ratio close to 1:1 was observed in the progeny. However, among sons and daughters the segregation for the mutant character depended on the variant of the cross variant. When the Uns/+ mice were intercrossed, the ratio of mutant to normal females was 3:1, while the corresponding ratio among males was 0.9:1. Studying preimplantation development in vitro and postimplantation development in vivo revealed no significant mortality in embryos obtained by crossing heterozygous mice. Ultrastructural analysis revealed no distortions in synapsis and desynapsis of axial elements of the autosomal chromosomes in Uns/+ mice. The segregation found seems to result either from different fertilizing ability of normal sperm and sperm carrying the Uns mutation or, which is more probable, from the genetic imprinting of the gene Uns.

The efficiency of different methods of the directed extension of the pedigrees that are used to analyze the linkage of recessive genes was studied. It was demonstrated that the addition of parents' relatives with abnormal phenotypes into the pedigree allowed the total sample size to be considerably decreased. All other methods of pedigree extension are efficient only when they take into account the phenotypes of the added relatives: at least one relative should have an abnormality. The generally accepted notion that three-generation pedigrees are optimal for linkage analysis was disproved for the case of recessive abnormal traits. A choice between two alternatives for construction of pedigree samples was discussed: (1) the use of only nuclear pedigrees strictly tested for informative value with respect to linkage analysis and (2) the introduction of any nuclear pedigree carrying an abnormality into the sample and the subsequent extension of the pedigree.

Genetic imprinting is an epigenetic phenomenon by which the parental germline confers a sex-specific mark on the some chromosomal regions which provide for monoallelic gene expression in the offspring. This paper examine the relation of genetic imprinting with human diseases. Collection of data on uniparental disomy cases in human diseases and early embryonic lethality, identification intragenic deletions and point mutations in patients who have some syndromes due to a parental imprint switch failure is providing our understanding of phenomenon of genetic imprinting and have important clinical implications.

Published and our own data, included in the CHRODYS database, on the dependence of phenotypic abnormalities in mono-, di-, and trisomics at human chromosome 15 on its parental origin are reviewed. The concept is confirmed that Prader-Willi and Angelman syndromes result from the combined effect of gene or chromosome mutations impairing the expression of syndrome-specific genes and from genomic imprinting, i.e., repression of corresponding genes received from one of the parents.

The term genomic imprinting is used to designate the phenomenon of functional nonequivalence of alleles whose activities depend on their parental origin. A functional hemizygosity of the gene is characteristic for genomic imprinting. However, activities of alleles also depend on their parental origin in some cases of diallelic gene expression. These cases are described in the literature as possible examples of imprinting. In this paper, different manifestations of genomic imprinting are analyzed, and a hypothesis is suggested about the murine genome as a set of genes with different expressions of homologous alleles, whose activities depend on their parental origin.

The possibility of using the phenotypic characteristics of parents for identifying the linkage phase in offspring is analyzed. It is demonstrated that parents with similar phenotypes (or marker genotypes) carry no information about the gene linkage phase in diheterozygous offspring. The probability of a certain linkage phase remains the same in all informative crossings. It depends on the model of inheritance of the analyzed alternative trait and is similar for di- and polyallelic markers. The frequencies of informative crossings and the probability of the linkage phase for different models of inheritance of the analyzed and marker traits are estimated.

The frequency of recessive sex-linked lethal mutations (RSLLM) induced in chromosome Muller-5 of mature sperms by treatment with ethyleneimine (EI) or methyl methanesulfonate (MMS) was shown to increase when male pronucleus or zygote was formed in the oocyte cytoplasm of the mutagen-sensitive line mus(2)201G1. The increase in the total number of mutations in the mutant cytoplasm was accompanied by a transformation of damages causing mosaic mutations into damage to the genome, which are recorded as complete mutations.

The mutagenic effect of the paracentromeric heterochromatin deletion MS2-10 was studied in direct and reciprocal crosses of laboratory and wild-type lines of Drosophila melanogaster. The effect of deletion MS2-10 depended on the opposite chromosome. This was shown for the combination of autosome MS2-10 with autosome 2 from the Berlin wild line, but when MS2-10 was combined with an autosome from lines Canton S and pr pk cn, the effect was absent. When deletion MS2-10 was inherited from the female parent and the opposite chromosome from the male parent, the effect of the deletion was present, but it was absent in males heterozygous for MS2-10, obtained in reciprocal crosses. In maternal effect, this case of mutagenesis is similar to hybrid dysgenesis. However, the pattern of P-M dysgenesis was shown to differ from the type of mutagenesis described in the present work.