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Biomedical subjects

R Chakraborty

Publications and source records attributed to R Chakraborty.

At least 73 records · Page 4Linked to original sources
PubMed1998

Ionizing radiation and genetic risks. VII. The concept of mutation component and its use in risk estimation for Mendelian diseases.

The responsiveness of Mendelian diseases to an increase in the mutation rate is studied by using the concept of the mutation component (MC) of genetic diseases. Algebraic expressions to evaluate MC at any specific generation following either a one-time or a permanent increase in mutation rate are derived and are illustrated with numerical examples. For a one-time increase in mutation rate, the analysis shows that the first generation MC for autosomal dominant diseases is equal to the selection coefficient; this is also true for X-linked diseases (adjusted for the proportion of X-chromosomes in males). For autosomal recessive diseases the first generation MC is substantially smaller than that for autosomal dominants. In subsequent generations MC gradually decays to zero. Under conditions of a permanent increase in the mutation rate, the MC for autosomal dominant, X-linked and completely recessive autosomal disorders progressively increases to reach a value of one at the new equilibrium. For incompletely recessive autosomal disorders, however, the MC at equilibrium can be larger than one. The rates of approach to the new equilibrium are different for the different classes of diseases, dictated by selection and time (in generations) following radiation exposure. The effects of increases in mutation rate on MC are more pronounced for autosomal dominants, followed by X-linked and are far less for autosomal recessives. Even for autosomal dominants, the early generation effects of radiation exposures would not be appreciable unless the heterozygotes have a severely reduced fitness.

Animals↗
PubMed1998

Application of a time-dependent coalescence process for inferring the history of population size changes from DNA sequence data.

Distribution of pairwise differences of nucleotides from data on a sample of DNA sequences from a given segment of the genome has been used in the past to draw inferences about the past history of population size changes. However, all earlier methods assume a given model of population size changes (such as sudden expansion), parameters of which (e.g., time and amplitude of expansion) are fitted to the observed distributions of nucleotide differences among pairwise comparisons of all DNA sequences in the sample. Our theory indicates that for any time-dependent population size, N(tau) (in which time tau is counted backward from present), a time-dependent coalescence process yields the distribution, p(tau), of the time of coalescence between two DNA sequences randomly drawn from the population. Prediction of p(tau) and N(tau) requires the use of a reverse Laplace transform known to be unstable. Nevertheless, simulated data obtained from three models of monotone population change (stepwise, exponential, and logistic) indicate that the pattern of a past population size change leaves its signature on the pattern of DNA polymorphism. Application of the theory to the published mtDNA sequences indicates that the current mtDNA sequence variation is not inconsistent with a logistic growth of the human population.

Algorithms↗
PubMed1998

Dynamic balance of segregation distortion and selection maintains normal allele sizes at the myotonic dystrophy locus.

Myotonic dystrophy (DM), an autosomal dominant neurological disorder, is caused by CTG-repeat expansions at the DMPK locus, with affected individuals having > or = 50 repeats of this trinucleotide. Reduced reproductive fitness of affected individuals and decreased viability of congenital DM have been noted. Expanded CTG-repeat alleles are highly unstable, predominantly yielding even higher repeat sizes. Preferential transmission of longer alleles from heterozygous mothers within the normal size range of alleles also is observed. In view of these observations, it is worth examining how DM has been maintained in human populations for hundreds of generations. We present an analysis of the dynamic properties of a model of joint effects of segregation distortion and selection (intensity of which increases with allele sizes of an individual's genotype). Our mathematical formulation and numerical analyses demonstrate that a weak segregation distortion during female meiosis, together with selection of comparable intensity (within the normal allele size range), can maintain an equilibrium distribution of allele frequencies. Genetic drift, acting in conjunction with the occasional contraction of alleles by mutation, can contribute to the balance of segregation distortion and mutation, in the sense that even weaker selection can explain the observed allele frequencies. The model is applied to CTG-repeat size distributions at the DMPK locus, observed in normal individuals from world populations.

Alleles↗
PubMed1998

Association of microsatellite markers near the fibrillin 1 gene on human chromosome 15q with scleroderma in a Native American population.

OBJECTIVE: To localize disease genes for scleroderma, or systemic sclerosis (SSc), in a population of Choctaw Native Americans with a high prevalence of SSc, in which there is evidence of a possible founder effect. METHODS: A candidate gene approach was used in which microsatellite alleles on human chromosomes 15q and 2q, homologous to the murine tight skin 1 (tsk1) and tsk2 loci, respectively, were analyzed in Choctaw SSc cases and race-matched normal controls for possible disease association. Genotyping first-degree relatives of the cases identified potential disease haplotypes, and haplotype frequencies were obtained by expectation-maximization and maximum-likelihood estimation methods. Simultaneously, the ancestral origins of contemporary Choctaw SSc cases were ascertained using census and historical records. RESULTS: A multilocus 2-cM haplotype was identified on human chromosome 15q homologous to the murine tsk1 region, which showed a significantly increased frequency in SSc cases compared with controls. This haplotype contains 2 intragenic markers for the fibrillin 1 (FBN1) gene. Genealogical studies demonstrated that the SSc cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-eighteenth century. The probability that the SSc cases share this haplotype due to familial aggregation effects alone was calculated and found to be very low. There was no evidence of any microsatellite allele disturbances on chromosome 2q in the region homologous to the tsk2 locus or the region containing the interleukin-1 family. CONCLUSION: A 2-cM haplotype on chromosome 15q that contains FBN1 is associated with scleroderma in Choctaw Native Americans from Oklahoma. This haplotype may have been inherited from common founders about 10 generations ago and may contribute to the high prevalence of SSc that is now seen.

Alleles↗
PubMed1998

Mutations in the BRCA1 gene: implications of inter-population differences for predicting the risk of radiation-induced breast cancers.

The effects of cancer predisposition and increased tumorigenic radiosensitivity of the predisposed genotypes on radiation cancer risks (in the general population and in sisters and first cousins of affected probands) are studied using an autosomal dominant model of cancer predisposition and radiosensitivity. The model assumes that the predisposing alleles, which confer enhanced tumorigenic radiosensitivity, are incompletely penetrant. In addition, the model also allows for sporadic cancers, unrelated to the predisposing locus. The predictions of the model are illustrated using current estimates of BRCA1 mutant gene frequencies; the estimates of the strength of predisposition and radiosensitivity differentials used are based on animal and human studies. It is shown that, unless both the strength of predisposition and radiosensitivity differential are large (say, > 100-fold in comparison with normal homozygotes), (i) the effect of risk heterogeneity on cancer risk is marginal; (ii) dose-dependent radiation effect remains virtually the same as in a homogeneous irradiated population that has no predisposed subgroups; (iii) for the same radiation dose, relatives of affected probands show an enhancement of cancer risks; and (iv) most extra cancers in relatives can be attributed to radiosensitivity differentials. This simple model can give an upper bound of the effect of risk heterogeneity on radiation-induced breast cancer risks even when the cumulative breast cancer risk is age-dependent. Further, our model predicts that the benefits of mammography outweigh the risks.

BRCA1 Protein↗
PubMed1998

Macrophage mannosyl fucosyl receptor: its role in invasion of virulent and avirulent L. donovani promastigotes.

The interaction of leishmania parasites with macrophages is known to be receptor mediated. Previous study from this laboratory (J. Parasitol. 82:632, 1996) showed the significant involvement of LPG and gp63 receptors in the recognition of virulent strains onto the macrophages. The role of carbohydrate receptors the other major receptors besides LPG and gp63 receptors, in the recognition of both virulent (strains AG83 and GE1) and avirulent (strain UR6) leishmania onto the host macrophages has been the major focus of the present investigation. Various neoglycoproteins were used as efficient ligands to preblock the carbohydrate receptors on the macrophage surface. Similarly, various sugar specific lectins were used to preblock the corresponding carbohydrate ligands on the parasite surface. When these preblocked macrophages or parasites were used to study their mode of recognition, it was obvious from the findings that avirulent leishmania promastigotes possibly use the mannosyl fucosyl receptors (MFR) more avidly for their initial attachment and subsequent internalization into the macrophages whereas the virulent leishmania exhibits limited use of this receptor. When a macrophage-like cell line (J774), lacking in MFR, was purposely selected to test the previous findings, as expected, the attachment of avirulent promastigotes (UR6) onto the cell line was found to be negligible when compared to the peritoneal macrophages. Thus, it appears that avirulent leishmania promastigotes probably utilize MFR significantly for their initial recognition and subsequent internalization by macrophages.

Animals↗
PubMed1998

Signatures of population expansion in microsatellite repeat data.

To examine the signature of population expansion on genetic variability at microsatellite loci, we consider a population that evolves according to the time-continuous Moran model, with growing population size and mutations that follow a general asymmetric stepwise mutation model. We present calculations of expected allele-size variance and homozygosity at a locus in such a model for several variants of growth, including stepwise, exponential, and logistic growth. These calculations in particular prove that population bottleneck followed by growth in size causes an imbalance between allele size variance and heterozygosity, characterized by the variance being transiently higher than expected under equilibrium conditions. This effect is, in a sense, analogous to that demonstrated before for the infinite allele model, where the number of alleles transiently increases after a stepwise growth of population. We analyze a set of data on tetranucleotide repeats that reveals the imbalance expected under the assumption of bottleneck followed by population growth in two out of three major racial groups. The imbalance is strongest in Asians, intermediate in Europeans, and absent in Africans. This finding is consistent with previous findings by others concerning the population expansion of modern humans, with the bottleneck event being most ancient in Africans, most recent in Asians, and intermediate in Europeans. Nevertheless, the imbalance index alone cannot reliably estimate the time of initiation of population expansion.

Genetics, Population↗
PubMed1998

Simultaneous estimation of all the parameters of a stepwise mutation model.

Minisatellite and microsatellite are short tandemly repetitive sequences dispersed in eukaryotic genomes, many of which are highly polymorphic due to copy number variation of the repeats. Because mutation changes copy numbers of the repeat sequences in a generalized stepwise fashion, stepwise mutation models are widely used for studying the dynamics of these loci. We propose a minimum chi-square (MCS) method for simultaneous estimation of all the parameters in a stepwise mutation model and the ancestral allelic type of a sample. The MCS estimator requires knowing the mean number of alleles of a certain size in a sample, which can be estimated using Monte Carlo samples generated by a coalescent algorithm. The method is applied to samples of seven (CA)n repeat loci from eight human populations and one chimpanzee population. The estimated values of parameters suggest that there is a general tendency for microsatellite alleles to expand in size, because (1) each mutation has a slight tendency to cause size increase and (2) the mean size increase is larger than the mean size decrease for a mutation. Our estimates also suggest that most of these CA-repeat loci evolve according to multistep mutation models rather than single-step mutation models. We also introduced several quantities for measuring the quality of the estimation of ancestral allelic type, and it appears that the majority of the estimated ancestral allelic types are reasonably accurate. Implications of our analysis and potential extensions of the method are discussed. SINCE the discovery that a large number of loci with tandemly repeated sequences in human and many eukaryote species are highly polymorphic because of copy number variation of the repeats in different individuals (Jeffreys 1985; Litt and Luty 1989; Weber and May 1989), allele size data from such loci are rapidly becoming the dominant source of genetic markers for genome mapping, forensic testing, and population studies. Loci with repeat sequences longer than 5 bp are generally referred to as minisatellite or variable number tandem repeat loci, and those with repeat sequences between 2 to 5 bp are referred to as microsatellite or short tandem repeat loci (Tautz 1993). Because mutations change the copy number of such loci in a stepwise fashion, rapid accumulation of population samples from minisatellite and microsatellite loci has resurrected the interest of the stepwise mutation model (SMM), which was popular in the 1970s.

Chi-Square Distribution↗
PubMed1998

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. IV. Prediction of risks in relatives of cancer-predisposed individuals.

Individuals carrying cancer-predisposing germline mutations are known to be at a higher risk for cancers than those who do not carry them. This is also true of their biological relatives because they have a higher probability of being carriers of such mutant genes than unrelated individuals in the population. Further, there are now sufficient grounds for assuming that cancer-predisposed individuals may also be at a higher risk for cancers induced by ionizing radiation. In our earlier work, we examined the impact of this heterogeneity (with respect to cancer predisposition and radiosensitivity differentials) on risks of radiation-induced cancer at the population level. This paper is focused on the question of risks of radiation-induced cancer in relatives of cancer-predisposed individuals. Using an autosomal dominant model of cancer predisposition and radiosensitivity developed earlier and applying it to breast cancer risks associated with mutations in the BRCA1 gene, we show that: (1) The risk ratio (i.e. the ratio of risk of radiation-induced cancer in relatives to that in unrelated individuals) in the population increases with the degree of biological relatedness of the relative, being higher for close than for distant relatives; incomplete penetrance of the mutant gene "dilutes" this risk ratio. (2) The proportion of excess radiation-induced cancers in relatives (i.e. the attributable fraction) is higher than in unrelated individuals. (3) In relatives, the proportion of excess cancers due to radiosensitivity differentials alone depends on the strength of predisposition, the radiosensitivity differentials assumed, the radiation dose, the proportion of cancers due to predisposition, the mutant gene frequency and the penetrance of the mutant gene. This is in contrast to the situation for unrelated individuals, for whom the above-mentioned proportion is dependent on the first three but not on the last three of these factors. Further, even when the proportion of excess cancers is small, most of it is due to radiosensitivity differential alone both in unrelated individuals and in relatives. (4) For values of predisposition strength and radiosensitivity differential <10, even when the estimated frequency of a mutant BRCA1 gene is 0.0047 and the proportion of breast cancers due to these mutations is 38% (as is the case for Ashkenazi Jewish women under age 30), the increase in breast cancer risks is only marginal even for first-degree relatives. (5) These findings support the conclusion that increases in radiation risks to relatives (compared to those in unrelated individuals), to be detectable epidemiologically, will occur only when the mutant alleles are common and the strength of predisposition and radiosensitivity differentials are conjointly dramatic.

Breast Neoplasms↗
PubMed1998

Development of a highly polymorphic STR marker for identity testing purposes at the human androgen receptor gene (HUMARA).

We developed a non-isotopic method which improves the technical quality of the X-linked HUMARA locus typing process. The use of formamide and a low concentration of acrylamide increased resolution and sharpness of HUMARA alleles in silver-stained polyacrylamide gels. In addition, the construction of an allelic ladder containing amplified sequence of 9 alleles (even-numbered alleles) of the HUMARA locus, allows confident, rapid and precise assignment of discretely defined alleles. Allele and genotype frequencies for the HUMARA locus were determined in a French Canadian population sample. Observed genotype frequencies in females conformed to Hardy-Weinberg expectations. Furthermore, the HUMARA locus is highly polymorphic with 18 observed alleles and an heterozygosity value of 89.3%. Also, this locus has average powers of discrimination of 97.8% and 88.7% for testing samples of female and male origin, respectively. In the French Canadian population, the average probability of excluding a random man as the father in paternity analysis when both mother and daughter are tested for this locus is 88.0%. Together, the results indicate that the HUMARA locus provides a highly discriminatory system that is appropriate for the purposes of forensic identification and paternity testing involving a female child.

Alleles↗
PubMed1997

Relative mutation rates at di-, tri-, and tetranucleotide microsatellite loci.

Using the generalized stepwise mutation model, we propose a method of estimating the relative mutation rates of microsatellite loci, grouped by the repeat motif. Applying ANOVA to the distributions of the allele sizes at microsatellite loci from a set of populations, grouped by repeat motif types, we estimated the effect of population size differences and mutation rate differences among loci. This provides an estimate of motif-type-specific mutation rates up to a multiplicative constant. Applications to four different sets of di-, tri-, and tetranucleotide loci from a number of human populations reveal that, on average, the non-disease-causing microsatellite loci have mutation rates inversely related to their motif sizes. The dinucleotides appear to have mutation rates 1.5-2 times higher than the tetranucleotides, and the non-disease-causing trinucleotides have mutation rates intermediate between the di- and tetranucleotides. In contrast, the disease-causing trinucleotides have mutation rates 3.9-6.9 times larger than the tetranucleotides. Comparison of these estimates with the direct observations of mutation rates at microsatellites indicates that the earlier suggestion of higher mutation rates of tetranucleotides in comparison with the dinucleotides may stem from a nonrandom sampling of tetranucleotide loci in direct mutation assays.

Analysis of Variance↗
PubMed1997

Cloning and characterization of a high-copy-number novel insertion sequence from chemolithotrophic Thiobacillus ferrooxidans.

Two distinct families of repetitive DNA elements (1.4 and 1.2 kb) were identified from S1 nuclease-treated genomic DNA of four strains of Thiobacillus ferrooxidans. The 1.4-kb fragment hybridized with IST2, an insertion sequence of T. ferrooxidans. The 1.2-kb fragment was cloned and sequenced. The sequence (IST445), 1219 bp in length, with features characteristic of an insertion element, has a terminal inverted repeat of 8 bp, which can be further extended to 23 or 48 bp with 9 and 26 mismatches, respectively. It displays 54.4% identity in 967 nucleotides of overlap with ISAE1 of Alcaligenes eutrophus. The IST445 contains three open reading frames which have codon usage almost similar to 56 different coding genes of T. ferrooxidans. In Southern blots of restricted genomic DNAs probed with IST445, each of the several strains of T. ferrooxidans gives a distinctive fingerprint. IST445 is present in the range of 10-20 copies per genome in the four strains studied.

Amino Acid Sequence↗
PubMed1997

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. III. Effects of incomplete penetrance and dose-dependent radiosensitivity on cancer risks in populations.

Recent studies have identified a number of genes in the human genome at which germinal mutations predispose the individuals to one or another type of cancer. These studies also show that not all individuals carrying the mutant genes develop cancers (i.e., the mutant genes are not fully penetrant). At least some of these predisposed genotypes also have a higher sensitivity to cancers induced by ionizing radiation than those who are not so predisposed, which may be dependent on dose. This paper presents an analysis of the impact of such heterogeneity on estimates of cancer risks for an irradiated population. This is done by extending the Mendelian one-locus, two-allele model of cancer predisposition and radiosensitivity developed earlier to allow for incomplete penetrance and dose dependence of radiosensitivity differentials among genotypes. The model is applied to recently published data for breast cancer and hereditary non-polyposis colon cancer using a range of possible values for the strength of predisposition and radiosensitivity differentials. It is shown that, after radiation exposures, the ratio of cancer risks in a heterogeneous population relative to that in a homogeneous population increases with increasing dose, but that the dose dependence of the relative risk diminishes at higher doses. Likewise, the attributable risk (i.e. the proportion of the increase in risk that is due to both increased susceptibility and increased radiosensitivity) and the proportion of attributable risk due to increased radiosensitivity also increase with dose, and the dose dependence of each measurement also diminishes at higher doses. However, when the proportion of cancers due to the susceptible genotypes is small (<10%) (as is likely to be the case for breast cancer in non-Ashkenazi women), the increases in the relative risk and attributable risk are marked only when there are very large increases in cancer susceptibility (>1000-fold) and radiosensitivity (>100-fold) in the susceptible group. When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%) (as may be the case for breast cancer in Ashkenazi Jewish women), there may be large increases in the relative risk and attributable risk for comparatively modest increases in cancer susceptibility (>10-fold) and radiosensitivity (>100-fold) in the susceptible subpopulation. For any given combination of strength of predisposition and radiosensitivity differential, incomplete penetrance dilutes the effect.

Breast Neoplasms↗
PubMed1997

Historical genetics in Uruguay: estimates of biological origins and their problems.

The relative contribution of Europeans, Africans, and Amerindians to the gene pool of two Uruguayan populations (Montevideo and Tacuarembó) was estimated using several approaches. For Montevideo 8 genetic systems were considered, and for Tacuarembó 18 systems were used. A preliminary investigation of the most probable parental groups, using genetic distances, yielded four combinations of European populations, four combinations of African populations, and five combinations of Amerindian populations. Afterward, 240 possible combinations from the possible parental groups were considered for the quantitative estimations of interethnic admixture using the gene identity method. The most inclusive combinations furnished the following admixture estimates: (1) Montevideo, 92% European, 7% African, and 1% Amerindian; (2) Tacuarembó, 65% European, 15% African, and 20% Amerindian. The modal values obtained within each ethnic category did not differ by much (2-3%), the exception being the Amerindian contribution to Tacuarembó, where a higher diversity was observed (up to 14%). Comparison with a maximum-likelihood method of admixture estimation was hampered by the fact that not all markers can be used to obtain these alternative numbers. Evaluations using six systems for Montevideo and seven for Tacuarembó yielded values that were closer to the previous estimates for Montevideo (largest difference, 7% in the Amerindian component) but somewhat higher for Tacuarembó, amounting to 11% for the European and Amerindian contributions. It is clear, however, that the two populations show significant biological heterogeneity, resulting partly from diverse patterns of historical formation.

Ethnicity↗
PubMed1997

Analysis of allele distribution for six short tandem repeat loci in the French Canadian population of Québec.

Short tandem repeat (STR) loci represent a rich source of highly polymorphic markers in the human genome which are useful for the purposes of forensic identification and determination of biological relatedness of individuals. Here, as a part of an ongoing extensive study, we report the analysis of a multilocus genotype survey of 642 to 870 chromosomes in the French Canadian Caucasian population of Québec at six STR loci. The loci HUMCSF1PO, HUMTPOX, HUMTH01, HUMF13A01, HUMFESFPS, and HUMvWA were typed using two multiplex polymerase chain reactions (PCR). Amplified DNA samples were subsequently analyzed by polyacrylamide gel electrophoresis followed by silver staining. The heterozygote frequencies of the loci range from 0.614 to 0.820 (0.661 to 0.818 expected) and the number of alleles from 7 to 12 per locus. Although statistically significant deviation from Hardy-Weinberg expectations of genotype frequencies was noted at some loci by one or more tests, in general, the genotype frequencies are well estimated from the product of allele frequencies at all loci. The most frequent six-locus genotype is expected to occur in the French Canadian population with a frequency of 3.50 by 10(-5) and together, these six loci have an average probability of discrimination of 0.9999985. The study presented here indicates that these six STR loci are informative genetic markers for identity testing purposes in the French Canadian Caucasian population of Québec.

Adult↗
PubMed1996

Estimation of mutation rates from parentage exclusion data: applications to STR and VNTR loci.

Nonpaternity is a common source of bias in estimating mutation rates when they are obtained from family data showing discordance of parental and children's genotypes. With the availability of hypervariable DNA markers, this source of bias can be largely eliminated. However, the proportion of cases where parentage exclusion is caused by presumed mutation(s) of parental alleles must be adjusted to obtain a valid mutation rate estimate. The present work derives the basis of this adjustment factor, called the proportional bias. This proportional bias depends upon the allele frequency distribution at the locus. The maximum and minimum bounds of the proportional bias depend on the number of alleles at the locus. Using data from Caucasian populations at tandem repeat loci commonly used for parentage testing and forensic identification purposes, we show that when mutation rates are estimated at these loci, the proportional bias is generally very close to the maximum possible value for the observed number of alleles (or binned fragment sizes) at each locus. The expected proportional bias decreases with increasing mutation rate at a locus. For the short tandem repeat loci, without bias correction, the direct count method can result in an underestimation of up to 60% of their true value. In contrast, for the minisatellite VNTR loci, even with crude measurements on allele sizes, we show that the absolute proportional bias is generally below the coefficient of variation of the direct estimates.

Chromosome Mapping↗
PubMed1996

Oxygen-dependent leishmanicidal activity of stimulated macrophages.

Peritoneal macrophages pretreated with different stimulants were analysed and compared with their respective controls for their ability to kill intracellular pathogenic L. donovani, (MHOM/IN/1983/AG83) an isolate from Indian subcontinent. Stimulation of macrophages by zymosan showed a higher microbicidal activity as compared to that by PMA. A correlation between microbicidal activity of the macrophages and the parameters related to respiratory burst activity such as liberation of O2-, production of H2O2 and consumption of O2 was sought. All the parameters showed a decrease in case of infected macrophages in comparison to those of the non-infected ones. Thus, it is possible that the impairment of macrophage activation by intracellular Leishmania contributes to their survival in the toxic environment of the host.

Animals↗