Cystic fibrosis (CF) is the most common potentially lethal disorder of Caucassians. Its frequency in India is not known. We diagnosed 30 cases of CF based on sweat chloride testing. The clinical profile and frequency of delta F508 mutation was studied. The frequency of F508 mutation was 27% (16 chromosomes) which is much lower as compared to that patients in the Western world. Eight patients carried other mutations, three of them were new mutations.

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This was a period prevalence study carried out in 4 hospitals in Baroda from October 93 to February 97 covering over 30,000 deliveries. This study, a part of the multicentric SOMDI Project, aimed at dermining the prevalence of malformations in the population and the overall risk figures for Down Syndrom (DS) as well as its maternal age specific prevalence. The hospitals chosen for the study had delivery rates such that the study in the end was expected to comprise of 50% Government i.e. poor socioeconomic strata (SES) and 50% Private sector i.e, an upper SES. Total number of births recorded were 31,775, with the Government Sector having 15,652 and the Private sector have 16,123. The total number of malformations was 651 with the overall incidence of malformation being 2.05% and the incidence the Government and private sectors being 2.57% and 1.54% respectively. The significantly lower incidence in the private sector was probably because of an upper SES and because of early detection and termination. Increasing maternal age showed a rising trend in the percentage of malformations with incidence in the age group from 15-19 years being 2.07% that at an age more than or equal to 40 being 4.92%. Still births had 6.3 times higher incidence of malformations than that in live births (10.43% in still births Vs 1.68% in live births). Malformations were found to be significantly higher in rural (3.1%) compared to urban (1.8%) populations and in children of Consanguinous (5.0%) compared to non-consanguinous marriages (2.06%). Pre terms had a significantly higher (5.6%) incidence of malformations compared to term (1.75%) babies. In male and female babies, incidence of malformations was not significantly different (2.12% and 1.75% respectively). A previous history of malformations was present in 53 incidences (out of total deliveries); out of 53, as many as 31 had a previous history of a neural tube defect (NTD) and in 2 of these there was a recurrence of NTD in this particular pregnancy. In the systemwise distribution of malformation, CNS anomalies were the most common, followed by the musculoskeletal system and gastrointestinal system. An interesting association noted was a large number of babies having a combination of midline defects viz. cleft lip and/or cleft palate and NTD and/or hyrocephalus. A total of 33 Down syndrome cases were encountered with an overall prevalence of 1.04% per 1000 and an overall risk of DS of 1 per 962 births. Maternal age specific prevalence of DS increased from 0.54/1000 at age 15-19 years to 15.6/1000 at age > 40 years. The corresponding age specific risks for DS were 1/1825 births and 1/64 births respectively.

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“In an endemic environment, all susceptibles will develop the disease.� South India, like the rest of the country is known for its caste system. The origin, level of inbreeding, endogamy and sympatric isolation amongst the caste system will lead to divergence of their gene pool and Ir (Immune response) genes are no exception to this. These differences may result in differential susceptibility at the population level. The lessons from inbred strains of animals explain this phenomenon and no immunologist or geneticist of today would like to carry out an experiment by mixing up the different strains of a species. In human populations in general, and in Indian caste groups in particular, the population dynamics like migration, miscegenation, social taboos and marriage patterns skew the picture and mask the differences between these populations particularly the prevalence and susceptibility to disease. Most of the research workers are disabled having a limited knowledge and even more limited facilities to do an 'ideal' experimental study in humans. Thus, in any clinical disease or immunological study in humans, a (case), caste, sex, nativity and haplotype (HLA or Ir gene) matched controls may need to be studied to understand the immunogenetic basis of disease susceptibility. The studies hitherto carried out at Madurai have revealed: i) different caste groups possess different haplotypes, some characteristic to a caste whereas others were common to many of them, ii) genetic distance calculated based on allele frequency brought out their affinity to each other; iii) not many Brahmin populations of India, have the same of the gene pool, presumably because of their origin, though they have all adopted the Hindu philosophy and religion, iv) numerically larger and geographically adjacent patrilineal clans of a tribe are genetically closer to each other; v ) a given HLA disease association transcend ethnic barrier (eg. pulmonary tuberculosis, leprosy), due to Ir gene dependant immunogeneric predisposition, vi) a few other HLA disease associations found in some populations or caste groups and not in others (eg. psoriasis) may be due to a linked gene and hitch hike phenomenon. Another new dimension is added to this genetic epidemiology: settlements, population size and the microbial world and infections increase in size as a function of time over the decades, resulting in faster transmission of a disease. The epidemiology is also changing over a period in the same place. As a result the newborn of today are subjected to a newer set of stress and selections than they were a generation ago. The epidemiology is known to affect the thymic education of lymphocytes through MHC, resulting in a different repertoire among children brought up in different environments. This has had great implications in subsequent environmental challenges and infections. Today any problem should be investigated and tackled by a group of open minded, knowledgeable scientists cutting across the barriers of their field of specializations. This is the need of the hour in this country.

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DNA level studies, based on SSOP hybridization of HLA class II PCR products have revealed considerable diversity in HLA among Asian Indians. High resolution typing of specific alleles such as DR2 and DR4 in the HLA class II region and their DR-DQ haplotypes have helped to detect unique haplotypes and novel alleles which have subsequently been confirmed by sequencing. Incidentally, remarkable stability is maintained in several other DRBI alleles, viz DR1, DR7, DR9 and DR10. Further characterization of new alleles will be carried out by sequencing of mRNA. The ARMS-PCR technology has been found to be particularly useful for typing difficult HLA-A, HLA-B and all HLA-Cw alleles. These technologies are remarkably superior over serological methods. Our studies have shown appreciable heterogeneity of common HLA-A and B alleles in Asian Indians. Molecular subtypes of HLA-A2 revealed that subtype A*0211 is found only in the Indian population and may be the result of a selection pressure in this population. Investigations into polymorphism in the HLA-B27 gene revealed that subtypes common both to the western Caucasoids and orientals occur in the Indian population. It is apparent that the population of the Indian subcontinent, placed as it is between the Caucasoids and Negroids on one hand and Australoids and Mongoloids on the other, provides a rich source of many HLA haplotypes. While the most frequent Caucasian haplotypes occurred with a reasonable frequency in Asian Indians, those found predominantly in other ethnic groups (e.g., Australian Aborigines and populations of Oceania, China and Japan) are also detected. Knowledge on this is most important for donor selection during organ and bone marrow transplantation and for designing MHC targeted vaccines in specific diseases. The major histocompatibility complex (MHC) encompasses two major classes of molecules: the MHC classes I and class II, both of which appear to have originated from a common ancestor gene. The major biological function of the MHC is to bind peptide fragments derived from protein antigens (viruses, peptides etc) and display them on the surface of antigen presenting cells (APCs), evoking effector responses upon recognition by the antigen specific receptors on T lymphocytes. This process requires an efficient intracellular machinery to fragment the protein antigens into smaller peptides capable of binding to a host MHC molecule. Since the number of peptides that can theoretically be generated is very large, there is need for an extensive MHC gene pool. Thus the HLA system which is the MHC of man is extremely polymorphic. Although the general rules for peptide-MHC interactions for both classes of MHC molecules are essentially similar; there are two fundamental differences: i) MHC class I ligands originate from endogenous sources, mainly from proteins of the cytosol or the nucleus and are delivered by the 'endogenous processing pathway: In contrast, the MHC class II ligands are generated by the degradation of proteins from the extracellular compartment. These distinctions are also reflected in the responding T cells: CD8 positive T cells being restricted by class I-peptide complexes, and CD4 positive T cells by class II-peptide complexes. ii) In accordance with the distribution of hydrogen bonds in the peptide binding groove of the MHC, the anchor residues are placed at the terminal ends of the class I groove. Contrarily, the binding forces are distributed throughout the class II groove and ensure bonds between the peptide's backbone and class II molecule (Madden et al, 1993; Stern et al, 1994; Stern and Wiley 1994). The specificity of the interaction is determined by pockets in the MHC groove that have a fixed spacing from each other and which also have specificity for anchoring particular side chains of the peptide's amino acids.

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A total of 23,367 children born at Safdarjung hospital, New Delhi were examined for the incidence of congenital malformations as a part of multicentric project (SOMDI) funded by DAE. The study revealed 3.1% of still births, 1.46% of malformations. The frequency of malformations was more in babies born to rural mothers cum parents who were blood relatives. Amongst the malformations recorded central nervous system (Neural tube defect) malformations were more frequent (7.87/1000 births) followed by muscutoskeletal cum gastrointestinal type (3.08/1000 births) and multiple malformations (1.67/1000 births)

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We describe a new G to A transition polymorphism, designated Apt, on the human Y chromosome. The A allele chromosomes and the most closely related G allele chromosomes have been found only in India, where they make up about 1.3% of the population. They are found in several different social groups and show considerable microsatellite, minisatellite and major satellite diversity, suggesting that they do not have a recent origin.

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A total of 26,237 deliveries were monitored for twinning and malformations at the 4 government hospitals catering to the population of Kollam and Alapuzha-districts of South Kerala. Among these 7.8 per thousand were twin births showing an increase in the incidence with maternal age. The twin births were high among children of consanguineous marriages (11.7 per thousand) as compared to non-consanguineous marriages (7.7 per thousand). Still births and malformations were also higher in twin deliveries as against singleton deliveries. A large data base is being built to establish a twin registry.

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Congenital cataracts constitute a major cause of blindness in infancy. It is caused by the loss of transparency of the lens, hampering normal vision. Affected infants become visually handicapped necessitating effective management. Cataracts result when normal lens formation during embryogenesis and its subsequent development are affected. Based on the location and morphology of the opacities, different phenotypic forms of cataracts are identified which are under the control of different genes and follow autosomal dominant, autosomal recessive and X-linked inheritance. Crystallins (a, b and g) which constitute 90% of the water soluble proteins are responsible for the maintenance of the refractive property of the lens. Hence structural variations in these proteins have been associated with cataracts. Intrinsic membrane proteins which are water insoluble and expressed in the terminal differentiation of the lens epithelium are also implicated in cataract formation. Cataracts are found to be associated with maternal infections during pregnancy (rubella infection), several clinical syndromes, metabolic disorders, chromosomal disorders, (triploidy, trisomies, monosomy, deletions, duplications and translocations), and gene disorders. Autosomal dominant forms are found to be more common among the gene disorders and exhibit intrafamilial, interfamilial and interocular variations. More than a dozen genes have been mapped for cataracts showing the locus and allelic heterogeneity and two of them are associated with mutations in the crystallin genes. One of them with over expression of gE gene on chromosome 2 causes Coppock like cataract while a chain termination mutation in the crystallin BB2 locus on chromosome 22 causes Cerulean cataract. Experiments on animals suggest crystallins as strong candidates for the study of cataracts in man. Other candidate loci include intrinsic membrane proteins (MIP), developmental genes (PAX6) and connexin gap junction proteins (CX46). Surgical extraction of cataracts though is considered as the best treatment for cataracts, the prognosis is poor when it comes to infantile forms. Hence risk predictions and counseling based on the mode of inheritance and other factors seems to be the best approach in the management of cataracts. Recently prenatal detection of cataracts through ultrasonography has been reported which can be made a part of the routine anatomical study specially when family history for severe genetic disorder assoicated with cataracts exist.

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Haemophia A is one of the commonest bleeding disorders occurring with a frequency of 1 in 5000 to 10,000 male births. 52 haemophilic patients 150 unrelated control women from non-haemophilic families were studied for allelic frequencies and heterozygosity rates of intragenic factor VIII gene related RELPs (Bcl I, Hind 111, 13 (CA)n repeats 22(AG)n (GT)n repeats XbaI/Kpnl) and extragenic markers (Bg III and Tag-I). Based on the results it is suggeted that Carrier screening and prenatal diaguosis for haemophilia A in Indian population should be to analyse these polymorphisms and in severe cases for inversion of intron 22 of factor VlII gene.

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HbS is not merely confined to tribes, but also exists in other caste populations. As far as the distribution in tribes in concerned, three distinct foci are discernible conforming to three distinct major tribal clusters. However; wide variability exists within populations. The populations of mixed origin have elevated HbS frequencies. Overall correlation of plasmodium falciparum with HbS incidence is negligible, but significant positive correlation with % population spread of HbS to castes is an important observation. The Orissa situation needs special mention. The HbS gene is found in various caste populations including high castes and those with an AFI index of above 25% 0 with -thalassemia, it is expected that HbS frequency is in the process of increasing in these caste populations. Significant correlations obtained between districtwise distribution of HbS and latitude, % tribal population, % tribal cultivators and % tribal literacy are important from the point of view of understanding the population dynamics of HbS distribution in the Indian population.

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As a part of the multicentric BRNS project on the incidence of congenital malformations and Down syndrome, Mumbai centre examined a total of 42,304 babies delievered at K.E.M. Hospital and Nowrosjee Wadia Maternity Hospital (NWMH). Among the major malformations recorded 5.58 were of musculoskeletal system 5.22 of gastrointestinal system, 4.89 of gastrointestinal system, 2.88 of urinogenital system, 1.82 cardiovascular system and other less than 1 per 1000 birth. Among the minor varieties of dismorphism hand and feet showed maximum frequency followed by ears and eyes. Details of these malformations with reference to clinical features; chromosmal analysis and demographic data are discussed.

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Several studies on genetic polymorphism of apolipoprotein B (ApoB) in the Taiwanese population are reviewed in this report. ApoB, the main protein component of low-density lipoprotein, contains 4536 amino acids in mature protein and 27 residues the signal peptide. Four polymorphisms, A59IV, T2488T, R3611Q, E4154K in ApoB mature protein could be detected by changes in restriction enzyme digestions, however, length polymorphism defined signal peptide (SP) and 3' variable number tandem repeat (VNTR) regions of APOB. Taiwanese exhibited 0.86 Val591, 0.99 Thr2488 (XbaI type), 1.00 Arg3611 and 0.98 Glu4154; homozygous genotype was present in most of the population which was in contrast to higher heterozygous genotype frequencies in Caucasians. The signal peptide SP27 and SP24 alleles in Taiwanese did not differ statistically from the Caucasians in frequency distribution; both groups showed SP27 homozygous genotype in most of the population. Of the 16 VNTR alleles found in normal population, Taiwanese exhibited 0.58 VNTR35, 014 VNTR37 and VNTR33; these were quite distinct from the 0.37 VNTR37, 0.25 VNTR35 and 0.10 VNTR31 reported in Caucasians. Sequence variation of these repeats mainly resided in the middle portion of the region and linkage disequlibrium was observed between VNTR and some restriction enzyme site polymorphisms. Coronary heart disease patients had greater chance to deviate from the normal trends in the polymorphic region.

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By studying 908 males from 33 locations of Europe, North Africa and West Asia, the variation of two Y-linked dinucleotide microsatellites was analyzed within three major chromosomal frames defined by mutations that are in or approach the condition of non-recurrence. Among the 223 haplotypes found, we selected a set of the ten most common haplotypes, representing 47.6% of the entire sample. We observed that they detect most of the information on inter-population differences. We calculated partial regression coefficients for haplotype frequencies as a function of latitude and longitude of the sampling locations and showed that some of them are distributed according to a cline. Furthermore, the incidence of the selected haplotypes was heterogenous, denoting the extremely high structuring of populations. These results indicate that Y chromosomal types defined by these markers here described can be considered optimal for population studies also because reliable frequency estimates can be obtained in small samples.

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Congenital adrenal hyperplasia (CAH) is one of the most common outosomal recessive condition causing ambiguous genitalia in females. Often, it's a life threatening condition occurring with 1 in 5000 to 15000 live births and caused due to mutations in CYP21 gene encoding the enzyme 21-hydroxylase. 25 cases of CAH reporting at All India Institute of Medical Sciences, New Delhi, were analysed for mutations in the gene CYP21 and the results are discussed.

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The ability to retrieve DNA from ancient specimens has been one of the greatest achievements of the past decade, and has opened a totally new field of research with applications in seemingly distant domains such as archeobotany, the molecular phylogeny of extinct genomes, human paleopathology and the genetics of ancient human populations. However, extraction of ancient DNA often has a very low rate of success, prompting researchers to develop screening methods for the selection of promising specimens. With this goal in mind, we studied the amino acid content of nine human bones of ancient origin. We demonstrate that a single HPLC chromatogram is indicative of integrity of ancient bone proteins. Among five specimens containing amplifiable DNA, four exhibited a protein content similar to that of contemporary bone. Three of the four specimens, from which we were unable to extract any amplifiable DNA, had an amino acid content strikingly different from that of contemporary bone. A non-parametric statistical test, Kendall's tau, was used to show that protein content and PCR products, are probably correlated (at a 95% confidence level).In addition, the D/L Asp and D/L Glu racemization ratios obtained are indicative of the presence of ancient organic compounds. We propose that protein analysis should be systematically performed in studies where there are many samples, in order to select the specimens that are most likely to contain retrievable ancient DNA.

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The minisatellite locus D1S80 was studied in five ethnic populations, namely, Konkanastha Brahmins and Marathas of Maharashtra; Nairs, Ezhavas and Muslims from Kerala, to compare the allele and genotype frequencies. DNA isoleted from blood samples collected from 364 unrelated healthy donors was amplified by PCR and subjected to polyaerylamide gel electrophones. A total of 20 alleles and 71 genotypes were observed from the above population groups. A bimodal pattern was observed in the allele frequency distribution representing 18 and 24 as predominant ones. The observed heterozygosity was in the range of 65% to 82%. All the five population groups conformed to Hardy- Weinberg equilibrium expectations.

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Recently, Y-linked markers have been found extremely useful tools in population genetics and evolutionary biology. We have studied a tetranucleotide marker, DYS19 and a bialleleic marker DYS287, an Alu polymorphic marker (YAP) in five ethnic groups of India. Blood samples were collected from 215 random healthy males and DNA was extracted by using a simple salt precipitation method. DNA samples, after amplification by polymerase chain reaction (PCR), were electrophoresed. The detection of alleles was done by silver staining and reconfirmed by using a fragment analyser programme in an ALF express sequencer (Pharamacia). A total of four alleles were observed at DYS19 locus in all the five ethnic groups. Allele 194bp was found to be the predominant one in all the groups. The absence of YAP was found in all the groups.

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The ApoB VNTR locus was analyzed in two distinct ethnic groups of Maharashtra to determine, the distribution of allele and genotype frequencies. Blood samples were collected from 183 random, unrelated, healthy donors. DNA was extracted by using a simple salt precipitation method, amplified by polymerase chain reaction (PCR) and the products were electrophoresed in 4% PAGE followed by silver staining. A total of 14 alleles and 38 genotypes were observed. Allele 37 and 39 were found to be the predominant alleles showing a bimodal distribution. Both the population groups conformed to Hardy-Weinberg Equilibrium expectations.

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The D17S5 is a highly informative minisatellite locus and shows extensive interpopulation allelic variability. However in many cases, it shows preferential amplification of shorter alleles, which has hampered the full potential of this minisatellite from being realized. This study explores the use of the Expand Long Template PCR system to circumvent this problem.

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