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Biomedical subjects

R Chakraborty

Publications and source records attributed to R Chakraborty.

At least 181 records · Page 10Linked to original sources
PubMed1988

Recombination of haplotypes leads to biased estimates of admixture proportions in human populations.

A population formed by genetic admixture of two or more source populations may exhibit considerable linkage disequilibrium between genetic loci. In the presence of recombination, this linkage disequilibrium declines with time, a fact that is often ignored when considering haplotypes of closely linked systems [e.g., Gm serum group (gamma globulins), HLA, and, more recently, restriction fragment length polymorphisms]. Recombination alters haplotype frequencies over time, and the haplotype-derived measures of admixture proportions from haplotype frequencies in generations following the admixture event become progressively more biased. The direction and extent of this bias can be predicted only when the history of admixture is known. Numerical illustration suggests that this bias is problematic whenever rt greater than 0.05, where r is the recombination rate between linked loci and t is the time (in generations) that has elapsed since the admixture event. In general, even the haplotype frequencies defined by multiple restriction fragment length polymorphism should be used with caution for admixture analysis. When recombination rates or the time since admixture are not precisely known, it is advantageous to consider each restriction fragment length polymorphism site separately for admixture analysis.

Algorithms↗
PubMed1988

Parentage analysis with genetic markers in natural populations. I. The expected proportion of offspring with unambiguous paternity.

Recent studies indicate that polymorphic genetic markers are potentially helpful in resolving genealogical relationships among individuals in a natural population. Genetic data provide opportunities for paternity exclusion when genotypic incompatibilities are observed among individuals, and the present investigation examines the resolving power of genetic markers in unambiguous positive determination of paternity. Under the assumption that the mother for each offspring in a population is unambiguously known, an analytical expression for the fraction of males excluded from paternity is derived for the case where males and females may be derived from two different gene pools. This theoretical formulation can also be used to predict the fraction of births for each of which all but one male can be excluded from paternity. We show that even when the average probability of exclusion approaches unity, a substantial fraction of births yield equivocal mother-father-offspring determinations. The number of loci needed to increase the frequency of unambiguous determinations to a high level is beyond the scope of current electrophoretic studies in most species. Applications of this theory to electrophoretic data on Chamaelirium luteum (L.) shows that in 2255 offspring derived from 273 males and 70 females, only 57 triplets could be unequivocally determined with eight polymorphic protein loci, even though the average combined exclusionary power of these loci was 73%. The distribution of potentially compatible male parents, based on multilocus genotypes, was reasonably well predicted from the allele frequency data available for these loci. We demonstrate that genetic paternity analysis in natural populations cannot be reliably based on exclusionary principles alone. In order to measure the reproductive contributions of individuals in natural populations, more elaborate likelihood principles must be deployed.

Alleles↗
PubMed1988

Population amalgamation and genetic variation: observations on artificially agglomerated tribal populations of Central and South America.

The interpretation of data on genetic variation with regard to the relative roles of different evolutionary factors that produce and maintain genetic variation depends critically on our assumptions concerning effective population size and the level of migration between neighboring populations. In humans, recent population growth and movements of specific ethnic groups across wide geographic areas mean that any theory based on assumptions of constant population size and absence of substructure is generally untenable. We examine the effects of population subdivision on the pattern of protein genetic variation in a total sample drawn from an artificial agglomerate of 12 tribal populations of Central and South America, analyzing the pooled sample as though it were a single population. Several striking findings emerge. (1) Mean heterozygosity is not sensitive to agglomeration, but the number of different alleles (allele count) is inflated, relative to neutral mutation/drift/equilibrium expectation. (2) The inflation is most serious for rare alleles, especially those which originally occurred as tribally restricted "private" polymorphisms. (3) The degree of inflation is an increasing function of both the number of populations encompassed by the sample and of the genetic divergence among them. (4) Treating an agglomerated population as though it were a panmictic unit of long standing can lead to serious biases in estimates of mutation rates, selection pressures, and effective population sizes. Current DNA studies indicate the presence of numerous genetic variants in human populations. The findings and conclusions of this paper are all fully applicable to the study of genetic variation at the DNA level as well.

Alleles↗
PubMed1987

Nonrandom sampling in human genetics: skewness and kurtosis.

When a multivariate normal sample is chosen from a truncated space of one of its components one can no longer make use of the normality assumption for the sample observations or for the estimates derived from them. In this paper, skewness and kurtosis for each component are derived analytically under a broad class of nonrandom sampling. It is shown that the distortions in skewness and kurtosis produced by nonrandomness are negligible, except those for the component with respect to which the selection of sampling regions is based. The usual tests of normality from sample values of skewness and kurtosis measures remain valid under nonrandom sampling, except for the selection variable. The implications of these analytical results in the context of commingling analysis in genetic epidemiology are discussed. It is recommended that when samples of families are obtained through nonrandomly ascertained probands, a commingling analysis should treat each relative class separately, since such analyses based on the pooled sample of individuals may involve unspecified bias in the levels of the test procedure.

Genetics, Medical↗
PubMed1987

Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria.

Eight polymorphic restriction enzyme sites at the phenylalanine hydroxylase (PAH) locus were analyzed from the parental chromosomes in 33 Danish nuclear families with at least one phenylketonuric (PKU) child. Determination of haplotypes of 66 normal chromosomes and 66 chromosomes bearing mutant allele(s) demonstrated that there are at least two haplotypes which occur predominantly on PKU chromosomes and rarely otherwise. Overall, the relative frequencies of the various haplotypes are significantly different on PKU- and normal-allele bearing chromosomes, even though there is no predominantly occurring unique haplotype which can characterize the PKU chromosomes. In addition, no significant association (linkage disequilibrium) between any single polymorphic site and the mutant allele(s) was observed. The results suggest that either the phenylketonuric mutation was very ancient so that the polymorphic sites and the mutation have reached linkage equilibrium or the mutant allele(s) are the results of multiple mutations in the phenylalanine hydroxylase gene in man. Furthermore, a crude relationship between standardized linkage disequilibria and physical map distances of the polymorphic sites indicates that there is no apparent recombination hot-spot in the human phenylalanine hydroxylase gene, since the recombination rate within the locus appears to be uniform and likely to be occurring at a rate similar to that within the HLA gene cluster. The limitations of this later analysis are discussed in view of the sampling errors of disequilibrium measure used, and the potential utility of the PAH haplotypes for prenatal diagnosis and detection of PKU carriers is established.

Alleles↗
PubMed1987

Genetic differentiation of quantitative characters between populations or species. II: Optimal selection in infinite populations.

Using a new and more general genetic model called the discrete-allelic state model and assuming discrete-time process, the evolutionary changes of genetic variation of quantitative characters, controlled by a few loci, within and between populations during the process of genetic differentiation of populations or species, are studied under the effects of mutation and centripetal selection in infinitely large populations. While in a finite population and ignoring selection, the rate of change of additive genetic variance depends on mutation and effective population size, traits under optimal selection in infinitely large populations go through the dynamics of a rather complicated form depending on the relative intensities of selection and mutation. When a population, which has reached steady-state by mutation-selection balance, splits into two, in one of which the same optimum genotype holds but in the other the optimum shifts a few standard deviations away from the original optimum, the corresponding daughter population starts differentiating from its sister population by favouring certain class of mutant alleles and discarding others which were originally favoured. During this process of turn over of genes, both the intra- and inter-populational variances undergo a complicated change, and the ratio of the former to the latter is a non-linear function of time of divergence. This pattern is qualitatively very different from the case when selection is absent. The intra-population distribution of genotypic values, during this transition, is shown to deviate considerably from normality. The presence of linkage seems to retard the accumulation of intra-populational genetic variance. The implications of these results are discussed in comparison with the earlier findings of evolutionary models of quantitative traits.

Alleles↗
PubMed1987

Biochemical heterozygosity and phenotypic variability of polygenic traits.

Using the theory of additive genetic variability of a polygenic trait, it is shown that an individual's heterozygosity at the loci governing the trait cannot be determined accurately from observations on phenotypes alone. Furthermore, the negative association between heterozygosity and phenotypic variance, and a positive correlation of the frequency of the modal class of a phenotypic trait and the extent of heterozygosity can be explained by additive allelic effects. It is argued that while the number of heterozygous loci in an individual may not be a good indicator of the individual's genomic heterozygosity, there is evidence that some of the biochemical loci may reflect genetic variation at the loci controlling phenotypic polymorphism. Thus the observed relationship between biochemical heterozygosity and phenotypic variance may not constitute hard evidence of heterosis, overdominance, or associative overdominance.

Alleles↗
PubMed1987

Further considerations of difficulties of estimating familial risks from pedigree data.

In elucidating the etiology of complex diseases through various epidemiologic and genetic analyses, it is necessary to define the expected risks for each member of a pedigree collected through an affected individual. It is shown that several factors are to be considered without which such expected risk estimates may be biased. The presence of secular trends in disease incidence introduces a bias in familial relative risk estimates, the magnitude and direction of which may be judged from the nature of the secular trends and the age and cohort composition of the individuals included in the study. Nonrandom follow-up time of the relatives, on the contrary, produces a bias in relative risk estimates, the magnitude and direction of which cannot be ascertained without any prior assumption about the distribution of follow-up time. In addition, competing causes of diseases and risk heterogeneity among different relatives and among families are also sources of indeterminate biases, which must be removed in order to interprete the results of relative risk studies and segregation analysis of discrete disease traits.

Chronic Disease↗
PubMed1987

Population genetic study in ten endogamous groups of West Bengal, India.

Ten endogamous population groups of West Bengal (India)--Rabhas, Garos, Mechs, Rajbanshis, Jalia Kaibartas, Bagdis, Lodhas, Mundas, Brahmins, Vaidyas--have been typed for twelve polymorphic systems: ABO, Gm, Km, Hp, Cp, Tf, Alb, Hb, aP, EsD, AK and PGM1. The results are compared with those obtained on other Indian populations. Serological and anthropometric data, which have been included into population comparisons, reveal a considerable genetic variability of the groups under study. This variability is obviously connected with the population history of West Bengal.

Blood Group Antigens↗
PubMed1986

Studies on the effect of reserpine on the peroxidase activity of submaxillary gland.

In an earlier report we have described how the administration of reserpine (0.5 mg/kg) stimulates the peroxidase activity of rat and mouse submaxillary gland [R. Chakraborty, B. Mukherjee and R. N. Hati, Life Sci. 35, 1913 (1984)]. Further studies have been carried out in this area. This stimulation of the enzyme activity started from 0.02 mg reserpine/kg body wt. The effect of reserpine was found in all subcellular fractions of submaxillary gland. Iodinating activity of the enzyme preparation was also increased by reserpine treatment. Kinetic studies indicate that reserpine increased the Vmax of the enzyme without altering Km. Protein synthesis inhibitors inhibited the increase of the enzyme activity by reserpine. Dibutyryl c-AMP, theophylline or both drugs together did not alter the peroxidase activity. The effect of reserpine was also found in experiments using slices and single cell preparations of submaxillary gland, suggesting that the drug is probably acting directly on the acinar cells.

Animals↗
PubMed1986

Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria.

Restriction fragment length polymorphisms (RFLPs) detected in the human genome by means of a cDNA clone of phenylalanine hydroxylase (PAH) segregate concordantly with phenylketonuria (PKU) in several families. To establish the usefulness of these DNA polymorphisms for prenatal diagnosis of PKU the genotypes and chromosomal haplotypes of eight RFLPs at the PAH locus were determined in 46 families, each with one or more affected children. 34 of these families were informative for linkage analysis, giving a maximum probability of 10(9):1 in favour of tight linkage between PKU and the PAH RFLP haplotypes. Thus the deficiency of hepatic PAH in PKU patients is caused by mutations in the PAH gene itself, and the RFLPs could be used effectively for prenatal diagnosis and carrier detection of PKU in affected families. Use of the PKU haplotypes based on these eight RFLPs would establish disease status in approximately 87% of siblings at risk, although three RFLPs alone (detected with the restriction enzymes Pvu II, Xmn I, and EcoR R) are nearly as effective.

Alleles↗
PubMed1986

An adoption study of human obesity.

We examined the contributions of genetic factors and the family environment to human fatness in a sample of 540 adult Danish adoptees who were selected from a population of 3580 and divided into four weight classes: thin, median weight, overweight, and obese. There was a strong relation between the weight class of the adoptees and the body-mass index of their biologic parents - for the mothers, P less than 0.0001; for the fathers, P less than 0.02. There was no relation between the weight class of the adoptees and the body-mass index of their adoptive parents. Cumulative distributions of the body-mass index of parents showed similar results; there was a strong relation between the body-mass index of biologic parents and adoptee weight class and no relation between the index of adoptive parents and adoptee weight class. Furthermore, the relation between biologic parents and adoptees was not confined to the obesity weight class, but was present across the whole range of body fatness - from very thin to very fat. We conclude that genetic influences have an important role in determining human fatness in adults, whereas the family environment alone has no apparent effect.

Adoption↗
PubMed1986

Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas.

The ethnic and geographic distributions of several common chronic diseases show distinct patterns that are consistent with the distribution of genes and genetic admixture. For example, diabetes and gallbladder disease occur most frequently among Amerindians, while those genetically admixed with them (such as Mexican-Americans) have intermediate rates, and lowest rates are found among Whites and Blacks. Because there will be heterogeneity from individual to individual in ancestral affinity within an admixed population, a method is developed for estimating each person's admixture probability. Results confirm that there is substantial heterogeneity of individual admixture among Mexican-Americans in Starr County, Texas, with a mean value indicating that 65% of genes in this population are Caucasian derived and 35% Amerindian derived. The individual estimates are shown to be unrelated to the probability of being diabetic and only marginally related to gallbladder disease, with those having the most Amerindian affinity being at increased risk. These results are a consequence of the independent assortment of loci and indicate that unless the markers employed are related (including linkage) to the disease of interest, the method will have limited utility. Individual admixture estimates will be useful, however, for examining aspects of population structure and will find increased utility for predicting disease and examining disease associations as more and more of the genome is represented by markers, a very probable prospect with the abundance of DNA polymorphism being identified by restriction enzymes.

Adolescent↗
PubMed1986

Diversity in palmar pattern ridge counts among 12 Iranian populations.

Bilateral palmar prints of 604 male individuals from 12 Iranian groups, six Mongoloid and six Caucasoid, have been analyzed for palmar pattern ridge counts (PPRC). Highly significant variation has been observed in the size of the palmar patterns in all the configurational areas among the Iranian groups. The distance analysis based on PPRCs differentiated the Iranian Mongoloid from the Iranian Caucasoid groups into distinct clusters. The pattern of differentiation based on PPRCs explained the ethnohistoric relationships between the Iranian groups as well as between the Iranian and the 20 Caucasoid groups from India much better than the palmar pattern frequencies. The results of this study demonstrate the existence of variation in the size of the palmar patterns across different populations within an ethnic group, as well as that among different ethnic groups, and seems to be a better indicator of interpopulational diversity than the palmar pattern frequencies.

Asian People↗
PubMed1986

Frequencies of complex diseases in hybrid populations.

Diseases of complex etiology demonstrate considerable variation in their frequencies in different ethnic populations. Noninsulin-dependent diabetes mellitus (NIDDM), rheumatoid arthritis, and several cardiovascular diseases constitute examples of such disorders. In genetic studies involving hybrid populations of known ancestry, it is of interest to compare and correlate disease prevalence with the admixture proportion, the latter estimated from a number of polymorphic genetic markers. Theoretical formulations are provided relating disease prevalence in a hybrid population to the admixture proportion under different models of disease transmission. It is shown that the relationship between admixture proportion and disease frequency provides discriminatory power regarding the mode of inheritance. This method is illustrated with an example comparing the proportion of Amerindian ancestry in Mexican-Americans and the prevalence of NIDDM. It is found that genetic factors are involved in susceptibility to NIDDM, but the mode of inheritance cannot be explained by any simple genetic model, and the role of sporadic events cannot be totally ruled out.

Diabetes Mellitus, Type 2↗
PubMed1986

Gene differentiation among ten endogamous groups of West Bengal, India.

Ten endogamous populations of West Bengal, India have been surveyed for genetic variation in 12 systems. These populations encompass all social ranks in the caste hierarchy and cover almost the entire geographic area of the state. Gene diversity analysis suggests that these groups exhibit significant allele frequency variation at all but three loci. The overall genetic difference is not, however, in accord with the classification based on caste. Two low-ranking scheduled caste groups are, in fact, in close proximity with the high-caste ones, suggesting evidence of past generations of gene flow among them. Three different clusters of groups emerge from the present data, providing support for the anthropologic assertion that in Bengal Proto-Australoid, Caucasoid, and Mongoloid racial elements generally coexist. However, these three components are not uniformly present in all groups. Geographic separation of the groups is a strong determinant of the gene differentiation that exists among these populations.

Alleles↗