PARTHA MAJUMDER

Assessing the genetic causation of a disease, which is of prime importance in medical genetics, is usually done by analysing pedigree data. When gathering such data, it is often more practical to adopt a non-random sampling strategy. However, unless suitable corrections for non-random sampling are made at the time of data analysis, inferences may be grossly affected. For pedigree data ascertained through multiple probands, various correction schemes have been suggested, although the efficiencies of these schemes are unknown. This paper compares such schemes, using Monte Carlo simulation techniques, under a simple genetic model, for pedigrees of fixed sizes and structures and for probands of two types of relationship-parent-offspring, and a pair of siblings. It is found that gene frequencies are grossly overestimated and the penetrance value of heterozygotes slightly underestimated whether or not any correction for non-random sampling of pedigrees is made. Knowledge of the population value of the gene frequency improves the estimate of the penetrance parameter.

Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)-induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N-acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S-transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD-induced hepatotoxicity. In this case-control study, 33 pulmonary tuberculosis patients with ATD-induced hepatotoxicity and 33 pulmonary tuberculosis patients receiving ATD drugs without any evidence of hepatotoxicity were considered as cases and controls, respectively. Point mutations at NAT2 and homozygous 'null' mutations at GSTM1 and GSTT1 genes were looked into genomic DNA, isolated from peripheral blood mononuclear cells by using polymerase chain reaction (PCR). The frequency of homozygous 'null' mutation at the GSTM1 gene was significantly higher among cases (n = 17, 52%) than controls (n = 8, 24%) (P < 0.05, relative risk 2.13, 95% CI: 1.25-3.10). Frequencies of mutations at GSTT1 and NAT2 genes did not differ significantly between cases and controls. Homozygous 'null' mutation at the GSTM1 gene might predispose an individual to ATD-induced hepatotoxicity.

There are various conflicting hypotheses regarding the origins of the tribal groups of India, who belong to three major language groups – Austro-Asiatic, Dravidian and Tibeto-Burman. To test some of the major hypotheses we designed a genetic study in which we sampled tribal populations belonging to all the three language groups. We used a set of autosomal DNA markers, mtDNA restriction-site polymorphisms (RSPs) and mtDNA hypervariable segment-1 (HVS-1) sequence polymorphisms in this study. Using the unlinked autosomal markers we found that there is a fair correspondence between linguistic and genomic affinities among the Indian tribal groups. We reconstructed mtDNA RSP haplotypes and found that there is extensive haplotype sharing among all tribal populations. However, there is very little sharing of mtDNA HVS-1 sequences across populations, and none across language groups. Haplogroup M is ubiquitous, and the subcluster U2i of haplogroup U occurs in a high frequency. Our analyses of haplogroup and HVS-1 sequence data provides evidence in support of the hypothesis that the Austro-Asiatic speakers are the most ancient inhabitants of India. Our data also support the earlier finding that some of the western Eurasian haplogroups found in India may have been present in India prior to the entry of Aryan speakers. However, we do not find compelling evidence to support the theory that haplogroup M was brought into India on an "out of Africa" wave of migration through a southern exit route from Ethiopia. On the contrary, our data raise the possibility that this haplogroup arose in India and was later carried to East Africa from India.

... 1182 Fundamental genomic unity of ethnic India is revealed by analysis of mitochondrial DNA †† Susanta Roychoudhury † , Sangita Roy † , Badal Dey*, Madan Chakraborty*, Monami Roy*, Bidyut Roy*, A. Ramesh # , N. Prabhakaran # , MV Usha Rani ‡ , ...

A modified measure of sex dimorphism for quantitative traits is suggested considering the regions of nonoverlap of the distributions of the trait in the two sex groups. Some inadequacies of an earlier measure that disregards the presence of members of the opposite sex group beyond the threshold value discriminating the two distributions are indicated.

... Mean and variance of the number of samples showing heterozygote excess or deficiency.Majumder, Partha P. ; Chakraborty, Ranajit (1981) Mean and variance of the number of samples showing heterozygote excess or deficiency Heredity, 47 . pp. 259-262. ISSN 0018-067X. ...

It is often of interest to know whether there is increased occurrence of a trait in a pedigree or other structured set of epidemiological data. In answering such questions most current methods use aggregate measures, such as relative risk, that may not relate the outcome for each individual to that individual's risk. In this paper we present a simple method, and its computational algorithm, to overcome this limitation. This new method also permits one to identify high-risk families or subsets of a collection of data, which is not always possible using other approaches.In a study of cancer risk among relatives of retinoblastoma patients, by applying this new method it was found that 11 of 33 families each obtained through a unilateral retinoblastoma patient are at statistically high risk of cancer at all sites combined, while there are 15 of 47 such families obtained through a bilaterally affected proband. These results are unlikely to have occured by chance, indicating an overall excess risk in the ancestors of these retinoblastoma cases.The proposed test procedure does not specify the cause of elevated risk; however, a method is proposed that provides some indication regarding possible causal mechanisms under some circumstances.

Genome-wide screening for localization of disease genes necessitates the efficient reconstruction of haplotypes of members of a pedigree from genotype data at multiple loci. We propose a genetic algorithmic approach to haplotyping and show that it works fast, efficiently and reliably. This algorithm uses certain principles of biological evolution to find optimal solutions to complex problems. The optimality criterion used in the present problem is the minimum number of recombinations over possible haplotype configurations of members of a pedigree. The proposed algorithm is much less demanding in terms of data and assumption requirements compared to the currently used likelihood-based methods of haplotype reconstruction. It also provides multiple optimal haplotype configurations of a pedigree, if such multiple optima exist.