13 research outputs found
Segmental duplication as one of the driving forces underlying the diversity of the human immunoglobulin heavy chain variable gene region
Background: Segmental duplication and deletion were implicated for a region containing the human
immunoglobulin heavy chain variable (IGHV) gene segments, 1.9III/hv3005 (possible allelic variants of IGHV3-30) and
hv3019b9 (a possible allelic variant of IGHV3-33). However, very little is known about the ranges of the duplication
and the polymorphic region. This is mainly because of the difficulty associated with distinguishing between allelic
and paralogous sequences in the IGHV region containing extensive repetitive sequences. Inability to separate the
two parental haploid genomes in the subjects is another serious barrier. To address these issues, unique DNA
sequence tags evenly distributed within and flanking the duplicated region implicated by the previous studies were
selected. The selected tags in single sperm from six unrelated healthy donors were amplified by multiplex PCR
followed by microarray detection. In this way, individual haplotypes of different parental origins in the sperm donors
could be analyzed separately and precisely. The identified polymorphic region was further analyzed at the nucleotide
sequence level using sequences from the three human genomic sequence assemblies in the database.
Results: A large polymorphic region was identified using the selected sequence tags. Four of the 12 haplotypes were
shown to contain consecutively undetectable tags spanning in a variable range. Detailed analysis of sequences from
the genomic sequence assemblies revealed two large duplicate sequence blocks of 24,696 bp and 24,387 bp,
respectively, and an incomplete copy of 961 bp in this region. It contains up to 13 IGHV gene segments depending on
haplotypes. A polymorphic region was found to be located within the duplicated blocks. The variants of this
polymorphism unusually diverged at the nucleotide sequence level and in IGHV gene segment number, composition
and organization, indicating a limited selection pressure in general. However, the divergence level within the gene
segments is significantly different from that in the intergenic regions indicating that these regions may have been
subject to different selection pressures and that the IGHV gene segments in this region are functionally important.
Conclusions: Non-reciprocal genetic rearrangements associated with large duplicate sequence blocks could
substantially contribute to the IGHV region diversity. Since the resulting polymorphisms may affect the number,
composition and organization of the gene segments in this region, it may have significant impact on the function
of the IGHV gene segment repertoire, antibody diversity, and therefore, the immune system. Because one of the
gene segments, 3-30 (1.9III), is associated with autoimmune diseases, it could be of diagnostic significance to learn
about the variants in the haplotypes by using the multiplex haplotype analysis system used in the present study
with DNA sequence tags specific for the variants of all gene segments in this regio
The genetic influence in fluorosis
Fluorosis, caused by ingestion of excess fluoride, is endemic in at least 25 countries across the globe, China and
India being the worst affected among them. Dental, skeletal and non-skeletal are the major types of fluorosis
affecting millions of people in these countries. A number of genetic epidemiological studies carried out by
investigators have shown the evidence for association between genetic polymorphisms in candidate genes and
differences in the susceptibility pattern of different types of fluorosis among individuals living in the same
community and having the same environmental exposure. These studies have pointed out that genetic variants in
some candidate genes like COL1A2 (Collagen type 1 alpha 2), CTR (Calcitonin receptor gene), ESR (Estrogen
receptor), COMT (Catechol-o-methyltransferase), GSTP1 (Glutathione S-transferase pi 1), MMP-2 (Matrix metallopeptidase
2), PRL (Prolactin), VDR (Vitamin D receptor) and MPO (Myeloperoxidase) could increase or
decrease the risk of fluorosis among the exposed individuals in endemic areas. So, it is increasingly becoming
evident that an individual’s genetic background could play a major role in influencing the risk to fluorosis when
other factors like specific environmental exposures including dietary patterns of fluoride intake and other nutrients
remain the same. The current manuscript presents an up-to-date critical review on fluorosis, focusing
mainly on the genetic association studies that have looked at the possible involvement of genetic factors in
fluorosis
Direct Detection of Insertion/Deletion Polymorphisms in an Autosomal Region by Analyzing High-Density Markers in Individual Spermatozoa
Direct polymerase chain reaction (PCR) detection of insertion/deletion (indel) polymorphisms requires sample homozygosity. For the indel polymorphisms that have the deletion allele with a relatively low frequency in the autosomal regions, direct PCR detection becomes difficult or impossible. The present study is, to our knowledge, the first designed to directly detect indel polymorphisms in a human autosomal region (i.e., the immunoglobulin V(H) region), through use of single haploid sperm cells as subjects. Unique marker sequences (n=32), spaced at ∼5-kb intervals, were selected near the 3′ end of the V(H) region. A two-round multiplex PCR protocol was used to amplify these sequences from single sperm samples from nine unrelated healthy donors. The parental haplotypes of the donors were determined by examining the presence or absence of these markers. Seven clustered markers in 6 of the 18 haplotypes were missing and likely represented a 35–40-kb indel polymorphism. The genotypes of the donors, with respect to this polymorphism, perfectly matched the expectation under Hardy-Weinberg equilibrium. Three V(H) gene segments, of which two are functional, are affected by this polymorphism. According to these results, >10% of individuals in the human population may not have these gene segments in their genome, and ∼44% may have only one copy of these gene segments. The biological impact of this polymorphism would be very interesting to study. The approach used in the present study could be applied to understand the physical structure and diversity of all other autosomal regions
Polymorphisms in DNA repair and multidrug resistance genes among Sindhis of Central India
Polymorphisms in DNA repair and multidrug resistance genes might contribute to interindividual and
interethnic differences in DNA repair capacity and drug disposition respectively. In the present study, we
determined the allele and genotype frequencies of four single nucleotide polymorphisms (SNPs) located
in the DNA repair genes, XRCC1, XRCC3, XPD, OGG1, namely XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD
Lys751Gln, and OGG1 Ser326Cys, respectively and two SNPs located in the multidrug resistance gene,
ABCB1, namely ABCB1 C3435T and ABCB1 C1236T, in 33–35 healthy and unrelated Sindhi individuals,
residing in the Vidarbha region of Central India and compared them with the Maharashtrian population
from the same geographical region and some other HapMap populations from the HapMap database. The
study findings reveal that the Indian Sindhis are closely related to the Maharashtrians as well as Utah
residents with Northern and Western European ancestry and Gujarati Indians in Houston, Texas in the
HapMap database
Frequency and genotype distribution of ABCB1 gene polymorphisms among Maharashtrian population of Central India
1. Apart from conferring multidrug resistance to cancer cells, P-glycoprotein (P-gp) encoded by
the gene ABCB1 (also, known as Multidrug resistance gene, MDR1), plays a major role in drug
disposition. Single nucleotide polymorphisms (SNPs) in the ABCB1 gene might contribute to
inter-individual and ethnic differences in drug disposition and thereby, could influence the
outcome and prognosis of certain diseases.
2. India is one of the most ethnically and genetically diverse regions of the world. This study
was undertaken with a view to determine the allele and genotype frequencies of C3435T
and C1236T polymorphisms in the ABCB1 gene among the Maharshtrian population,
residing in the Vidarbha region of central India and compare them with HapMap and other
Indian populations. The common synonymous C3435T polymorphism has been found to be
associated with lower P-gp functional expression and drug uptake, alone or in conjunction
with a few other linked SNPs like C1236T.
3. The genotypes of C3435T and C1236T SNPs were determined by PCR-RFLP in 222 healthy
and unrelated Maharashtrian individuals.
4. According to the findings of this study, the Maharashtrians were found to be not
significantly different from the Gujarati Indians in Houston, Texas in the HapMap database
DNA repair gene polymorphisms at XRCC1, XRCC3, XPD, and OGG1 loci in Maharashtrian population of central India
Reduction in DNA repair capacity is associated with increased rates of birth defects, cancer, and accelerated
ageing. Genetic polymorphisms in DNA repair genes might influence the repair activities of the
enzymes predisposing individuals to cancer risk. Owing to the presence of these genetic variants,
inter-individual and ethnic differences in DNA repair capacity have been observed in various populations.
India harbors enormous genetic, cultural and linguistic diversity. The present study was undertaken to
determine the allele and genotype frequencies of four non-synonymous SNPs, XRCC1 Arg399Gln (C > T,
rs25487), XRCC3 Thr241Met (G > A, rs861539), XPD Lys751Gln (T > G, rs13181), and OGG1 Ser326Cys
(C > G, rs1052133) in the Maharashtrian population, residing in the Vidarbha region of central India
and to compare them with HapMap and other Indian populations. The variant alleles of these polymorphisms
have been found to be positively associated with different forms of cancer in several genetic epidemiological
studies. The basic prevalence of these polymorphisms in the general population must be
known to evaluate their significance in risk assessment in cancer and other phenotypes. About 215
healthy and unrelated individuals from the Maharashtrian population were genotyped for each of these
four polymorphisms using PCR–RFLP. The allele and genotype frequency distribution at the four DNA
repair gene loci among Maharashtrians revealed a characteristic pattern. To the best of our knowledge,
this is the first report of these DNA repair gene polymorphisms in a central Indian populatio
Arsenic in groundwater of West Bengal, India: A review of human health risks and assessment of possible intervention options
This paper reviews how active research in West Bengal has unmasked the endemic arsenism that has detrimental effects on the health of millions of people and their offspring. It documents how the pathways of exposure to this toxin/poison have been greatly expanded through intensive application of groundwater in agriculture in the region within the Green Revolution framework. A goal of this paper is to compare and contrast the similarities and differences in arsenic occurrence in West Bengal with those of other parts of the world and assess the unique socio-cultural factors that determine the risks of exposure to arsenic in local groundwater. Successful intervention options are also critically reviewed with emphasis on integrative strategies that ensure safe water to the populalion, proper nutrition, and effective ways to reduce the transfer of arsenic from soil to crops. While no universal model may be suited for the vast areas of the world affected with by natural contamination of groundwater with arsenic, we have emphasized community specific sustainable options that can be adapted. Disseminating scientifically correct information among the population coupled with increased community level participation and education are recognized as necessary adjuncts for an engineering intervention to be successful and sustainable. (C) 2017 Elsevier B.V. All rights reserved
Genetic polymorphism of CYP2D6*2 C? T 2850, GSTM1, NQO1 genes and their correlation with biomarkers in manganese miners of Central India
Manganese (Mn) intoxication is most often regarded as an occupational manifestation and occurs in
places such as manganese mines, dry cell battery plants and ceramic industries. In the present study,
the influence of genetic polymorphism in cytochrome P450 2D6 (CYP2D6*2), glutathione S-transferase
M1 (GSTM1) and NAD(P)H quinone oxidoreductase 1 (NQO1) genes on blood manganese and plasma prolactin
concentrations in manganese miners was investigated. Genotyping of CYP2D6*2 C ? T 2850 and
NQO1 C ? T 609 was carried out using polymerase chain reaction–restriction fragment length polymorphism
(PCR–RFLP) whereas the genotyping of GSTM1 was carried out by multiplex PCR using beta globin
as an internal control. Manganese miners with CYP2D6*2 C ? T 2850 variant genotype had relatively low
Mn concentration [GM: 21.4 ± 8.9 lg L1
] than the subjects with wild (GM: 36.3 ± 8.5 lg L1
) and heterozygous
(GM: 34.4 ± 6.9 lg L1
) genotypes. Miners with CYP2D6*2 variant genotypes showed low prolactin
levels (GM: 13.13 ± 1.6 ng mL1
) compared to the wild (GM: 16.4.4 ± 1.5 lg L1
) and heterozygous
(GM: 18.7 ± 1.6 ng mL1
) genotypes. Gene–gene interaction studies also revealed that the subjects with
CYP2D6*2 C ? T 2850 variant genotypes had low levels of Mn and prolactin. Our new findings suggest
that CYP2D6*2 C ? T 2850 variant genotypes can regulate plasma prolactin levels in manganese miners
of Central India and could be involved in the fast metabolism of blood manganese, compared to wild and
heterozygous genotypes.
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