Population and molecular-genetic aspects of Haemophilia A and Haemophilia B in Uzbekistan

The present study summarizes results of retrospective epidemiological and molecular-genetic investigations of Haemophilia A and Haemophilia B in Uzbekistan. In the period from 1991 to 2004, a combined total of 1304 cases of Haemophilia A and Haemophilia B were recorded in the republic. The morbidity index varied from 0.75 to 1.46 per 10000 newborn male infants. The mean birth rate of patients with Haemophilia A and Haemophilia B amounted to 1: 8735 (1.14 × 10^?4) of newborn male infants. Features of certain DNA-polymorphisms in the genes of blood coagulation factors VIII and IX in the Uzbek population were analyzed. The frequencies of alleles were studied and the information value of these genetic markers for ascertaining genetic carriage and prenatal diagnosis of Haemophilia A and Haemophilia B was determined. Results of DNA diagnosis of Haemophilia A and Haemophilia B are summarized.     

Trypsin clotting time (K-test) in hemophilia A and in hemophilia B1

In investigations made in 32 patients with haemophilia A and 28 patients with haemophilia B the possibility of utilizing the trypsin clotting time (K-test) was tested in diagnosing both diseases. 23 plasmas of healthy test persons were used as controls and revealed a mean value of the K-test amounting to 24.52 +/- 0.75 seconds. With a mean value amounting to 30.025 +/- 2.88 seconds the K-test was clearly and from a statistical point of view significantly prolonged in hemophilia B contrary to hemophilia A with a slight prolongation amounting to 26.95 +/- 2.03 seconds. Possible causes for the response of the trypsin clotting tie are discussed.     

Segregation analysis of hemophilia A and B.

We analyzed a sample of 1,485 families with hemophilia A and B and with unknown diagnosis. The frequency of sporadic cases was estimated to be .166 and .078 for the two types of hemophilia, respectively. The sex ratio of mutation rates did not differ significantly from unity. The average age of maternal grandfathers of probands at birth of mothers with a single child, affected by hemophilia B, and of maternal grandfathers of probands at birth of mothers with more than one child affected by hemophilia B, was higher than the age in appropriate control groups.     

Spemann's organizer--it's origin and derivatives (cellular-tissue and molecular-genetic aspects)

In 1924 H. Spemann and H. Mangold discovered that a piece of the dorsal lip of a blastopore from Triturus cristatus, after transplantation to the ventral side of another embryo, was able to cause the neighbouring tissues to change their fate and participate in the formation of a new embryo. The dorsal lip was termed "the organizer". Since then, for as long as 75 years, attempts have been made to establish the intimate mechanisms of the organizer activity. However, no real advance was achieved in their understanding. Within the last 15 years, genetic and molecular techniques have been vastly improved, to help in tracing the fate of many cell lineages, and in compiling more exactly the fate maps for different parts of the embryo. Using these data, I have attempted to trace the fate of Spemann's organizer after the early gastrula stage. Analysis of data on inductive abilities of the organizer cells, on the use of markers, and on the observation of expression of specific genes allowed to conclude that Spemann's organizer in amphibia and its homologues in other vertebrates too are heterogeneous: they are composed of distinct cell populations able to induce primarity the development of either the head or trunk parts of the embryo. These population, determined to become the head of the trunk organizers still at the blastula stage, may be located either in the single continuous cell layer (as in amphibia and birds) or separated among different tissue germs (as in mammals). When the dorsal-ventral orientation of the embryo is established and the organizer is switched on the very early invaginating cells of the dorsal blastopore lip (in the case of amphibia) move in advance of the entire invaginating mesoderm and by the end of gastrulation occupy the place just in front of the notochord. It is supposed that the early dorsal lip and the prechordal mesoderm (PCM) are one and the same cell population, i.e. during gastrulation Spemann's organizer transfers from the lip of blastopore to the prechordal zone. The PCM seems to play an exclusive role in the formation of a head in vertebrate, because some mutations in genes expressed in the PCM result in the entire head deletion. It is supposed that spreading of differentiating signals from the PCM occurs along the main body axis in both caudal and rostral directions. After the main body plan formation the PCM is replaced by adenohypophysis. This conclusion is drawn not only from the same topology of both these structures, but also from the similarities of a set of specific genetical markers expressed in these, that makes it possible to suppose the existence of deep connections and succession between them. The adenohypophysis seems to arise directly from the PCM, or cells of the ectoderm influenced by the PCM may be subsequently transformed into humoral cells of adenohypophysis. In this interpretation, adenohypophysis and the much earlier established PCM may be considered as derivatives of Spemann's organizer. This inference is supported by the fact that all the three above structures first originate in vertebrates only.     

Population genetics study of hemoglobinopathies in Uzbekistan. II. Population dynamics of hemoglobinopathies

It was shown that on comparing variability of selective neutral genetic marker systems with that of the beta-thalassemia system for the populations of different hierarchical level, the relative importance of selection and genetic drift could be evaluated. The genetic differentiation of the beta-thalassemia gene frequencies in elementary populations (villages) could be solely explained by genetic drift. On the other hand, the differentiation of district populations (the sizes of the populations being 10(6] for beta-thalassemia gene frequencies could be explained by selection forces. This is supported by the fact that the genetic distances and FST values are only significant for the beta-thalassemia gene and not for the neutral genetic systems, when the district populations are compared.     

Genetic aspects of microphylogeny of black-and-white cattle of Uzbekistan

The genetic aspects of microphylogeny of herds of black and white cattle of Asian and European populations have been studied on the basis of distribution analysis of frequency in 62 antigens of 11 systems of blood groups.     

Epidemiological characterisation of acute and chronic hepatitis B in Uzbekistan

The epidemiological survey of 126 foci with patients having acute hepatitis B (AHB) and 120 foci with patients having chronic hepatitis B (CHB) was conducted. The observation of the susceptible members of the family showed that a significantly higher level of infection was found in persons having contacts with CHB patients (44.4 +/- 2.3%) in comparison with the members of the families of AHB patients (33.2 +/- 2.3%). The study revealed that children under 14 years were actively involved into the epidemic process; in these children the highest levels of infection were observed in the families of AHB patients (40.2 +/- 3.7%) and CHB patients (57.1 +/- 3.5%). High detection rate of HbsAg were noted in brothers and sisters in the foci of AHB (42.3 +/- 6.4%) and the foci of CHB (52.3 +/- 5.4%), also in parents: 32.4 +/- 5.2% and 46.5 +/- 4.2%, in children: 28.8 +/- 3.4% and 35.6 +/- 3.6% respectively.     

Incidence of hepatitis B in hemophilia patients

Hepatitis represents a serious complication in the transfusion of blood and blood products. In examining patients from the haemophilia centre in Jena HBsAg was identified in no case, HBsAK, however, in 80% of them. The rate of hepatitis infection increased here with the increasing frequency of transfusion. It should be determined by regularly checking HBsAG, HBsAK and transferases within the scope of prophylactic examinations.     

The human genes for hemophilia A and hemophilia B flank the X chromosome fragile site at Xq27.3.

Two DNA recombinant clones, shown by separate studies to contain DNA sequences homologous to the genes coding for the human blood coagulation Factors VIII and IX, were hybridized in situ to metaphases or prometaphases derived from patients with the fragile-X syndrome and from a normal control. The results of these experiments indicate that (i) both genes are located in the subtelomeric region of the long arm of the human X chromosome flanking the fragile site at Xq27.3, (ii) the resolution of this localization is approximately 0.5% the length of the human haploid genome, i.e., 1.8 X 10(7) bp, (iii) the linear order of loci within the above region is Factor IX-fragile site-Factor VIII-Xqter. Both the localization and the linear order of these loci have been confirmed by Southern blotting studies using the same molecular probes and a panel of rodent-human somatic cell hybrids known to have retained different segments of the human X chromosome. The findings described herein and the knowledge that Factor IX deficiency recombines freely with at least two loci of the G6PD cluster support our hypothesis that the chromosomal region which includes the fragile-X site is normally a region of high meiotic recombination.     

A new MspI restriction fragment length polymorphism in the hemophilia B locus

Summary Using a partial cDNA probe for human coagulation factor IX, we have detected a new restriction fragment length polymorphism in human DNA digested with MspI. The frequency of the minor allele is 0.20±0.05 and average heterozygosity is about 0.32. The MspI RELP is in strong linkage disequilibrium with the TaqI RFLP previously described, but should nevertheless be useful in segregation analysis in case of homozygosity for the TaqI minor allelc.     

Population aspects of forensic genetics

The paper presents the methodology of forensic genetics as a synthesis of population genetics and forensic medicine. Main population genetic problems, appearing in calculation of probability statistics and interpretation of the results of forensic genetic investigations, are discussed in detail.     

Population aspects of cancer genetics

A number of relatively rare, high-risk genes have been identified which predispose to common cancers such as breast, colon, and melanoma. Although these are clearly important in the clinical setting, it is also relevant to discuss the impact of these genes at the population level and to contrast these with that which could be ascribed to more common genetic variants which only confer a modest increased risk of cancer. In this review, we examine inferences about the role of genetics in cancer from ecological studies of incidence patterns from a number of population-based studies of familial and attributable risk. The relationship between the genetic model (genotypic risk, allele frequency, mode of inheritance) and the expected impact in the population in terms of both attributable risk and familial risk is presented. The advantages and limitations of using cancer occurrence in twins to measure the genetic contribution to specific cancer sites is discussed. The potential role of lower-penetrance genes in the overall cancer burden may be significant but may pose significant problems in the public health arena.     

Population aspects of forensic genetics

The paper presents the methodology of forensic genetics as a synthesis of population genetics and forensic medicine. Main population genetic problems, appearing in calculation of probability statistics and interpretation of the results of forensic genetic investigations, are discussed in detail.