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Biomedical subjects

R Chakraborty

Publications and source records attributed to R Chakraborty.

At least 109 records · Page 6Linked to original sources
PubMed1995

Cancer predisposition, radiosensitivity and the risk of radiation-induced cancers. II. A Mendelian single-locus model of cancer predisposition and radiosensitivity for predicting cancer risks in populations.

Individuals genetically predisposed to cancer may be more sensitive to cancers induced by ionizing radiation than those who are not so predisposed. Should this be true, under conditions of radiation exposure, a population consisting of cancer-predisposed and non-predisposed individuals will be expected to respond with a higher total frequency of induced cancers than one in which all the individuals are assumed to have the same sensitivity to radiation-induced cancers. To study this problem quantitatively, we have developed a Mendelian autosomal one-locus, two-allele model; this model assumes that one of the alleles is mutant and the genotypes carrying the mutant allele(s) are cancer-predisposed and are also more sensitive to radiation-induced cancer. Formal analytical predictions as well as numerical illustrations of this model show that: (1) when such heterogeneity with respect to cancer predisposition and radiosensitivity is present in the population, irradiation results in a greater increase in the frequency of induced cancers than when it is absent; (2) this increase is detectable only when the proportion of cancers due to genetic predisposition is large and when the degree of predisposition is considerable; and (3) even when the effect is small, most of the radiation-induced cancers will occur in predisposed individuals. These conclusions are valid for models of cancer when predisposition and radiosensitivity may be either dominant or recessive. The published data on breast cancers in Japanese A-bomb survivors show that at 1 Sv, the radiation-related excess relative risk in women irradiated before age 20 is 13 compared to about 2 for those irradiated at later ages. We examined the application of our model to the above data using two assumptions, namely, that the proportion of cancers due to genetic susceptibility at the BRCA1 locus (1/200) and the frequency of the mutant allele (0.0033) estimated for Western populations are valid for Japanese women. With our model, these results can be explained only if there are very large differences in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) of the heterozygotes.

BRCA1 Protein↗
PubMed1995

Population genetics of dinucleotide (dC-dA)n.(dG-dT)n polymorphisms in world populations.

We have characterized eight dinucleotide (dC-dA)n.(dG-dT)n repeat loci located on human chromosome 13q in eight human populations and in a sample of chimpanzees. Even though there is substantial variation in allele frequencies at each locus, at a given locus the most frequent alleles are shared by all human populations. The level of heterozygosity is reduced in isolated or small populations, such as the Pehuenche Indians of Chile, the Dogrib of Canada, and the New Guinea highlanders. On the other hand, larger average heterozygosities are observed in large and cosmopolitan populations, such as the Sokoto population from Nigeria and German Caucasians. Conformity with Hardy-Weinberg equilibrium is generally observed at these loci, unless (a) a population is isolated or small or (b) the repeat motif of the locus is not perfect (e.g., D13S197). Multilocus genotype probabilities at these microsatellite loci do not show departure from the independence rule, unless the loci are closely linked. The allele size distributions at these (CA)n loci do not follow a strict single-step stepwise-mutation model. However, this features does not compromise the ability to detect population affinities, when these loci are used simultaneously. The microsatellite loci examined here are present and, with the exception of the locus D13S197, are polymorphic in the chimpanzees, showing an overlapping distribution of allele sizes with those observed in human populations.

Alleles↗
PubMed1995

D1S80 population data in African Americans, Caucasians, southeastern Hispanics, southwestern Hispanics, and Orientals.

Allele frequencies for the locus D1S80 were determined in African American, Caucasian, Southeastern Hispanic, Southwestern Hispanic, and Oriental sample populations using the polymerase chain reaction and subsequent electrophoresis and silver staining of the amplified products. Due to the presence of anodal and cathodal electrophoretic variants (in reference to the steps in an allelic ladder), allele frequencies were established using a classification protocol based on the steps in the allelic ladder. All sample populations met Hardy-Weinberg expectations for D1S80. In addition, there was no evidence for association of alleles between the loci D1S80 and D1S7. The product of allele frequencies from the data from the sample populations in this study can be used in forensic analyses and paternity tests to estimate the frequency of a D1S80 DNA genotype.

Alleles↗
PubMed1995

A comparative study of genetic variation at five VNTR loci in three ethnic groups of Houston, Texas.

Following the technique of Southern blot restriction fragment length polymorphisms (RFLP) analysis, we generated a database of DNA profiles at five Variable Number of Tandem Repeats loci (D1S7, D2S44, D4S139, D10S28, and D17S79) for 669 individuals of three major ethnic populations (Caucasians, Blacks, and Hispanics) of Houston, Texas. Analysis of fragment sizes at these loci within each sample, as well as their fixed-bin analyses, reveal that the assumptions of independence of allelic occurrences within and between loci are valid for this database. Fixed-bin allele frequency tables, therefore, are the best descriptors of this database for conservative forensic calculations. Finally, we demonstrate that this regional database from Houston, Texas, does not yield any meaningfully different forensic inference than the one obtained from the National database of the respective ethnic groups.

Alleles↗
PubMed1994

Kin selection, social structure, gene flow, and the evolution of chimpanzees.

Hypotheses about chimpanzee social behavior, phylogeography, and evolution were evaluated by noninvasive genotyping of free-ranging individuals from 20 African sites. Degrees of relatedness among individuals in one community were inferred from allele-sharing at eight nuclear simple sequence repeat (SSR) loci. Males are related on the order of half-siblings, and homozygosity is significantly increased at several SSR loci compared to Hardy-Weinberg expectations. These data support the kin-selection hypothesis for the evolution of cooperation among males. Sequence variation patterns at two mitochondrial loci indicate historically high long-distance gene flow and clarify the relationships among three allopatric subspecies. The unexpectedly large genetic distance between the western subspecies, Pan troglodytes verus, and the other two subspecies suggests a divergence time of about 1.58 million years. This result, if confirmed at nuclear loci and supported by eco-behavioral data, implies that P. t. verus should be elevated to full species rank.

Africa↗
PubMed1994

Conservation of human chromosome 13 polymorphic microsatellite (CA)n repeats in chimpanzees.

Tandemly repeated (dC-dA)n.(dG-dT)n sequences occur abundantly and are found in most eukaryotic genomes. To investigate the level of conservation of these repeat sequences in nonhuman primates, we have analyzed seven human chromosome 13 dinucleotide (CA)n repeat loci in chimpanzees by DNA amplification using primers designed for analysis of human loci. Comparable levels of polymorphism at these loci in the two species, revealed by the number of alleles, heterozygosity, and allele sizes, suggest that the (CA)n repeat arrays and their genomic locations are highly conserved. Even though the proportion of shared alleles between the two species varies enormously and the modal alleles are not the same, allelic lengths at each locus in the chimpanzees are detected within the bounds of the allele size range observed in humans. A similar observation has been noted in a limited number of gorillas and orangutans. Using a new measure of genetic distance that takes into account the size of alleles, we have compared the genetic distance between humans and chimpanzees. The genetic distance between these two species was found to be ninefold smaller than expected assuming there is no selection or mutational bias toward retention of (CA)n repeat arrays. These findings suggest a functional significance for these microsatellite loci.

Alleles↗
PubMed1994

Allelic associations of two polymorphic microsatellites in intron 40 of the human von Willebrand factor gene.

At intron 40 of the von Willebrand factor (vWF) gene, two GATA-repeat polymorphic sites exist that are physically separated by 212 bp. At the first site (vWF1 locus), seven segregating repeat alleles were observed in a Brazilian Caucasian population, and at the second (vWF2 locus) there were eight alleles, detected through PCR amplifications of this DNA region. Haplotype analysis of individuals revealed 36 different haplotypes in a sample of 338 chromosomes examined. Allele frequencies between generations and gender at each locus were not significantly different, and the genotype frequencies were consistent with their Hardy-Weinberg expectations. Linkage disequilibrium between loci is highly significant with positive allele size association; that is, large alleles at the loci tend to occur together, and so do the small alleles. Variability at each locus appeared to have arisen in a stepwise fashion, suggesting replication slippage as a possible mechanism of production of new alleles. However, we observed an increased number of haplotypes, in contrast with the predictions of a stepwise production of variation in the entire region, suggesting some form of "cooperative" changes between loci that could be due to either gene conversion, or a common control mechanism of production of new variation at these repeat polymorphism sites. The high degree of polymorphism (gene diversity values of 72% and 78% at vWF1 and vWF2, respectively, and of 93% at the haplotype level) makes these markers informative for paternity testing, genetic counseling, and individual-identification purposes.

Adult↗
PubMed1994

Linkage disequilibria among (CA)n polymorphisms in the human dystrophin gene and their implications in carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophies.

Four short tandem repeat loci, characterized by length polymorphisms of (CA)n repeats, have been detected within introns 44, 45, 49, and 50 of the human dystrophin gene. The predicted heterozygosities for these loci range from 72 to 93%, and observed allele numbers range from 6 to 19 in 57 normal chromosomes, revealing their high degree of polymorphism. Evidence for significant disequilibria between the loci within introns 49 and 50 is found. These data appear to be consistent with observations of recombination frequencies between these markers and the length of the intron 44 in relation to the entire region. In addition, these four loci are collectively found to be 100% informative in carrier detection/prenatal diagnosis of Becker and Duchenne muscular dystrophies (B/DMD), whereas scoring the (CA)n markers within introns 45 and 49 alone gives a 99.6% success rate.

Alleles↗
PubMed1994

Population genetic characteristics of the D1S80 locus in seven human populations.

We have analyzed the allele frequency distribution at the highly polymorphic variable number of tandem repeat (VNTR) locus D1S80 (pMCT118) in seven ethnic populations (namely, New Guinea Highlanders of Papua New Guinea, Dogrib Indians of Canada, Pehuenche Indians of Chile, American and Western Samoans, Kacharis of Northeast India, and German Caucasians) using the polymerase chain reaction (PCR) technique. In the pooled sample of 443 unrelated individuals 20 segregating alleles were detected. A trimodal pattern of allelic distribution is present in the majority of populations and is indicative of the evolutionary antiquity of the polymorphism at this locus. In spite of the observed high degree of polymorphism (expected heterozygosity 56%-86%), with a single exception--the marginally significant P value (0.04) of the exact test in American Samoans--the genotype distributions in all populations conform to their respective Hardy-Weinberg expectations. Summary statistics indicate that, in general, the allele frequency distribution at this locus may be approximated by the infinite allele model. The data also demonstrate that alleles that are shared by all populations have the highest average frequency within populations. Furthermore, the kinship bioassay analysis demonstrates that the extensive variation observed at the D1S80 locus is at the interindividual within population level, which dwarfs any interpopulation allele frequency variation, consistent with the population dynamics of hypervariable polymorphisms. These characteristics of the D1S80 locus make it a very useful marker for population genetic research, genetic linkage studies, forensic identification of individuals, and for determination of biological relatedness of individuals.

Alleles↗
PubMed1994

D1S80 allele frequencies in a Chinese population.

Allele frequencies for the VNTR locus D1S80 were determined in a Chinese population sample using the polymerase chain reaction and subsequent analysis of the amplified products by polyacrylamide gel electrophoresis and silver staining. A total of 18 nominal D1S80 alleles were observed in 105 unrelated Chinese. The data demonstrate that D1S80 is highly polymorphic in Chinese with a heterozygosity of 90.5%. The D1S80 frequency distribution meets Hardy-Weinberg expectations. This D1S80 data can be used in forensic analyses and paternity tests to estimate the frequency of a DNA profile in a Chinese population.

Alleles↗
PubMed1994

Paternity evaluation in cases lacking a mother and nondetectable alleles.

In parentage testing the formulae for computing paternity index and exclusion probability generally ignores the presence of nondetectable alleles at the loci tested. In contrast, it is now known that even when paternity testing is done with hypervariable DNA markers, nondetectable alleles should not be ignored. This work presents simple formulae needed with this consideration, to analyze paternity evaluation from DNA markers in cases where the mother of the disputed child is unavailable for testing. It is shown that even a modest frequency of nondetectable alleles (e.g., 2-5% per locus) may have a substantial impact on the paternity index when the child and/or the alleged father exhibits a single-banded DNA profile at a locus. Use of such formulae can generate a high probability of exclusion and a high paternity index when multiple independently segregating hypervariable DNA markers are used.

Adult↗
PubMed1994

Paternity testing in the DNA era.

Paternity can be efficiently and effectively tested using multi-allelic variable number of tandem repeat (VNTR) polymorphisms. This can be achieved by using multilocus DNA fingerprinting probes or batteries of single-locus minisatellite probes, or by PCR testing of sets of minisatellite and microsatellite loci. Although some problems of statistics and population genetics remain to be overcome, the informativeness of these hypervariable loci is so high that paternity disputes can be resolved with certainty in virtually every case.

Chromosome Mapping↗
PubMed1994

Population dynamics of DNA fingerprint patterns within and between populations.

DNA fingerprint is a pattern of a variable number of bands (DNA fragments) with different sizes on a Southern gel for each individual, generated by one or many VNTR loci. Genetic divergence between individuals within and between populations can be studied in terms of number of shared bands between individuals. Using a population genetic model we show that the expectations of measures of genetic distance between populations based on band sharing data from DNA fingerprint patterns are functions of composite parameters M = 4Nv, and time of divergence (t) between populations, where N is the effective size of the populations, and v, the mutation rate. The expected genetic distance remains linear with time of divergence at least up to N generations as long as the average heterozygosity at the DNA fingerprint loci remains at or below 90%. Neither incomplete knowledge of the allele frequencies at each locus, nor the unknown number of loci underlying DNA fingerprint pattern, compromise these evolutionary dynamics of DNA fingerprint patterns. Applications of this theory to data on three human populations, and review of literature indicate that co-migration of alleles, and the presence of syntenic loci underlying the fingerprint pattern have little impact of the reliability of evolutionary conclusions from DNA fingerprint studies.

DNA Fingerprinting↗
PubMed1994

Estimation of genetic distance and coefficient of gene diversity from single-probe multilocus DNA fingerprinting data.

DNA fingerprinting exhibits multilocus genotypes of individuals, detected by the use of a single multilocus probe. Consequently, population data on DNA fingerprinting do not provide a complete characterization of the genetic variation in terms of allele-frequency distributions, since neither the number of loci nor the locus affiliation of alleles is directly observable. Yet DNA fingerprinting has been proved to be a cost-effective method of detecting hypervariable polymorphisms in several organisms, where the traditional loci fail to detect enough variation for microevolutionary studies. In the present paper we demonstrate that the above-mentioned features of DNA fingerprinting data do not cause any serious problem when they are used in evolutionary studies. Bias-corrected estimators of Nei's standard and minimum genetic distances are derived, and, by an application of this theory to data on seven short tandem repeat loci in three major human populations, it is shown that these modified measures of genetic distances based on DNA fingerprint patterns are quite close to Nei's distances based on locus-specific allele frequencies. Empirical as well as theoretical support of the adequacy of such genetic distances from DNA fingerprinting data is also discussed, and it indicates that the technical limitations of DNA fingerprinting should not deter the use of the method for short-term evolutionary studies.

Alleles↗
PubMed1994

Phylogeny of mitochondrial DNA clones in tassel-eared squirrels Sciurus aberti.

The tassel-eared squirrel, Sciurus aberti, includes six subspecies which occupy restrictive and apparently identical habitats in Ponderosa pine forests in the south-western United States and Mexico; the strict habitat requirement of this species is based on dietary requirements which are only fulfilled in these forests. To examine evolutionary relationships among certain subspecies of S. aberti, we obtained estimates of nucleotide diversity within subspecies as well as nucleotide divergence between subspecies using mitochondrial DNA (mtDNA) analysis. Restriction site polymorphisms were identified in samples of the four US subspecies: S. a. aberti (Abert), S. a. kaibabensis (Kaibab), S. a. ferreus (Ferreus), and S. a. chuscensis (Chuska) Fourteen mtDNA clones were resolved that were, with one exception, uniquely subspecific. Dendrograms constructed by neighbour-joining and maximum parsimony methods revealed two major assemblages: (1) an Abert/Kaibab group; and (2) a Ferreus/Chuska group. The Abert vs. Ferreus clones exhibited the greatest net nucleotide divergence, with a lineage separation estimate approximating 572,000 years ago assuming a nucleotide substitution rate of 7.15 x 10(-9)/year/site. Five out of ten Chuska squirrels shared a clone with one Abert sample; the relative sizes of these two populations and their respective ranges as well as their close proximity support the proposal for relatively recent intermixing of Abert and Chuska populations resulting in what appears to be Abert-->Chuska migration. Nucleotide diversity within subspecies ranked as Kaibab < Ferreus < Abert < Chuska; the relatively high diversity for the Chuska sample is based on the apparent introgression of Abert mtDNA. The relative diversity exhibited by Kaibab, Ferreus and Aberti samples corresponds to the range size of the respective subspecies.

Animals↗