Sujoy Ghosh

Bio: Sujoy Ghosh is an academic researcher from University of Calcutta. The author has contributed to research in topics: Nondisjunction & Meiosis II. The author has an hindex of 8, co-authored 29 publications receiving 283 citations. Previous affiliations of Sujoy Ghosh include West Bengal University of Technology.

Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations

Abstract: Down syndrome caused by meiotic nondisjunction of chromosome 21 in humans, is well known to be associated with advanced maternal age, but success in identifying and understanding other risk factors has been limited. Recently published work in a U.S. population suggested intriguing interactions between the maternal age effect and altered recombination patterns during meiosis, but some of the results were counter-intuitive. We have tested these hypotheses in a population sample from India, and found that essentially all of the results of the U.S. study are replicated even in our ethnically very different population. We examined meiotic recombination patterns in a total of 138 families from the eastern part of India, each with a single free trisomy 21 child. We genotyped each family with a set of STR markers using PCR and characterized the stage of origin of nondisjunction and the recombination pattern of maternal chromosome 21 during oogenesis. Our sample contains 107 maternal meiosis I errors and 31 maternal meiosis II errors and we subsequently stratified them with respect to maternal age and the number of detectable crossover events. We observed an association between meiosis I nondisjuncion and recombination in the telomeric 5.1 Mb of chromosome 21. By contrast, in meiosis II cases we observed preferential peri-centromeric exchanges covering the proximal 5.7 Mb region, with interaction between maternal age and the location of the crossover. Overall reduction of recombination irrespective of maternal age is also evident in meiosis I cases. Our findings are very consistent with previously reported data in a U.S. population and our results are the first independent confirmation of those previous reports. This not only provides much needed confirmation of previous results, but it suggests that the genetic etiology underlying the occurrence of trisomy 21 may be similar across human populations.

Telomere length is associated with types of chromosome 21 nondisjunction: a new insight into the maternal age effect on Down syndrome birth.

Abstract: Advanced maternal age is a well-documented risk factor of chromosome 21 nondisjunction in humans, but understanding of this association at the genetic level is still limited. In particular, the state of maternal genetic age is unclear. In the present study, we estimated maternal genetic age by measuring telomere length of peripheral blood lymphocytes among age-matched mothers of children with Down syndrome (cases: N = 75) and mothers of euploid children (controls: N = 75) in an age range of 18–42 years. All blood samples were taken within 1 week of the birth of the child in both cases and controls. The telomere length estimation was performed by restriction digestion—Southern blot hybridization method. We stratified the cases on the basis of centromeric STR genotyping into maternal meiosis I (N = 48) and maternal meiosis II (N = 27) nondisjunction groups and used linear regression to compare telomere length as a function of age in the euploid, meiosis I and meiosis II groups. Our results show that all three groups have similar telomere length on average for younger mothers. As age increases, all groups show telomere loss, but that loss is largest in the meiosis II mother group and smallest in the euploid mother group with the meiosis I mother group in the middle. The regression lines for all three were statistically significantly different from each other (p < 0.001). Our results do not support the theory that younger women who have babies with Down syndrome do so because are ‘genetically older’ than their chronological age, but we provide the first evidence that older mothers who have babies with Down syndrome are “genetically older” than controls, who have euploid babies at the same age. We also show for the first time that telomere length attrition may be associated in some way with meiosis I and meiosis II nondisjunction of chromosome 21 and subsequent Down syndrome births at advanced maternal age.

Epidemiology of Down Syndrome: New Insight Into the Multidimensional Interactions Among Genetic and Environmental Risk Factors in the Oocyte

Abstract: Down syndrome birth is attributable to multiple maternal risk factors that include both genetic and environmental challenges, but there is limited understanding of the complicated interactions among these factors. In the present study, a case-control analysis of approximately 400 infants with or without suspected Down syndrome reported between 2003 and 2009 and their parents in and around Kolkata, India, was conducted. Maternal exposure to 2 environmental risk factors (smokeless chewing tobacco and oral contraceptive pills) was recorded, and families were genotyped with microsatellite markers to establish the origin of nondisjunction errors as well as recombination patterns of nondisjoined chromosome 21. With logistic regression models, the possible interactions among all of these risk factors, as well as with maternal age, were explored. Smokeless chewing tobacco was associated with significant risk for meiosis II nondisjunction and achiasmate (nonexchange) meiosis I error among young mothers. By contrast, the risk due to oral contraceptive pills was associated with older mothers. Study results suggest that the chewing tobacco risk factor operates independently of the maternal age effect, whereas contraceptive pillrelated risk may interact with or exacerbate age-related risk. Moreover, both risk factors, when present together, exhibited a strong age-dependent effect. contraceptives, oral; Down syndrome; maternal age; nondisjunction, genetic; recombination, genetic; tobacco, smokeless

Comparison of therapeutic response of lycopene and curcumin in oral submucous fibrosis: A randomized controlled trial.

Abstract: OBJECTIVES To evaluate and compare the therapeutic response of lycopene and curcumin with placebo in patients suffering from oral submucous fibrosis (OSMF) and to correlate the habit variables of smoked and smokeless tobacco products in OSMF. METHODS A randomized placebo-controlled parallel clinical study was conducted on ninety OSMF patients, who were divided into three treatment groups using computer-generated randomization. Group A patients (n = 30) were given curcumin tablet (300 mg) twice daily, Group B patients (n = 30) received lycopene capsules (8 mg) twice daily, and for Group C (n = 30), placebo capsules were given once daily for a period of six months. Both the participant and outcome assessor were blinded. Pre- and post-treatment comparison of mouth opening, burning sensation, tongue protrusion, and cheek flexibility was analyzed at periodic follow-up of 9 months. RESULTS The overall improvement in mouth opening, burning sensation, tongue protrusion, and cheek flexibility was 3.9 ± 4.9 mm, 4.8 ± 2.6, 5.0 ± 7.2 mm, & 0.36 ± 0.71 mm, respectively, for curcumin and 4.1 ± 4.2 mm, 5.0 ± 2.3, 2.4 ± 3.5 mm, & 0.66 ± 0.80 mm, respectively, for lycopene with the p value <0.05. CONCLUSION Statistically significant improvement in clinical findings was observed in both curcumin and lycopene treatment groups in comparison with placebo. However, the therapeutic efficacy of curcumin and lycopene was found to be almost equal in OSMF patients.

Chromosome 21 non-disjunction and Down syndrome birth in an Indian cohort: analysis of incidence and aetiology from family linkage data

Abstract: We analysed the family linkage data obtained from short tandem repeat (STR) genotyping of 212 unrelated Indian families having a single Down syndrome (DS) baby each, in order to explore the incidence and aetiology of this human aneuploidy in our cohort. The estimated values of maternal meiotic I and meiotic II non-disjunction (NDJ) errors of chromosome 21 (Ch 21) were approximately 78 and approximately 22%, respectively. Within the paternal outcome group, about 47 and 53% were accounted for NDJ at meiosis I and meiosis II, respectively. We estimated only approximately 2% post-zygotic mitotic errors. The comparison of average age of conception between controls and DS-bearing mothers revealed a significant difference (P or=35 years) and found linear decrease in the frequency of achiasmate meiosis from the young to the old group. In contrary, a linear increase in the multiple chiasma frequency from the young to the old group was observed. Considering these results together, we propose that the risk factors for Ch 21 NDJ are of two types, one being 'maternal age-independent' and the other being 'maternal age-dependent'. Moreover, a comparison of our present Indian dataset with that of other published data of ethnically different populations suggested that the genetics that underlies the NDJ of Ch 21 is probably universal irrespective of racial difference across human populations. The present study is the first population-based report on any DS cohort from the Indian subcontinent and our work will help future workers in understanding better the aetiology of this birth defect.

Human pre-implantation embryo development

Abstract: Understanding human pre-implantation development has important implications for assisted reproductive technology (ART) and for human embryonic stem cell (hESC)-based therapies. Owing to limited resources, the cellular and molecular mechanisms governing this early stage of human development are poorly understood. Nonetheless, recent advances in non-invasive imaging techniques and molecular and genomic technologies have helped to increase our understanding of this fascinating stage of human development. Here, we summarize what is currently known about human pre-implantation embryo development and highlight how further studies of human pre-implantation embryos can be used to improve ART and to fully harness the potential of hESCs for therapeutic goals.

Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes

Abstract: During female meiosis, bivalent chromosomes are thought to be held together from birth until ovulation by sister chromatid cohesion mediated by cohesin complexes whose ring structure depends on kleisin subunits, either Rec8 or Scc1. Because cohesion is established at DNA replication in the embryo, its maintenance for such a long time may require cohesin turnover. To address whether Rec8- or Scc1-containing cohesin holds bivalents together and whether it turns over, we created mice whose kleisin subunits can be cleaved by TEV protease. We show by microinjection experiments and confocal live-cell imaging that Rec8 cleavage triggers chiasmata resolution during meiosis I and sister centromere disjunction during meiosis II, while Scc1 cleavage triggers sister chromatid disjunction in the first embryonic mitosis, demonstrating a dramatic transition from Rec8- to Scc1-containing cohesin at fertilization. Crucially, activation of an ectopic Rec8 transgene during the growing phase of Rec8 TEV/TEV oocytes does not prevent TEV-mediated bivalent destruction, implying little or no cohesin turnover for $ 2w k during oocyte growth. We suggest that the inability of oocytes to regenerate cohesion may contribute to agerelated meiosis I errors.

Meiotic Origins of Maternal Age-Related Aneuploidy

Abstract: Chromosome segregation errors in female meiosis lead to aneuploidy in the resulting egg and embryo, making them one of the leading genetic causes of spontaneous abortions and developmental disabilities in humans. It is known that aneuploidy of meiotic origin increases dramatically as women age, and current evidence suggests that most errors occur in meiosis I. Several hypotheses regarding the cause of maternal age-related aneuploidy have been proposed, including recombination errors in early meiosis, a defective spindle assembly checkpoint in meiosis I, and deterioration of sister chromatid cohesion with age. This review discusses findings in each area, and focuses especially on recent studies suggesting that deterioration of cohesion with increasing maternal age is a leading cause of age-related aneuploidy.

Meiosis and Maternal Aging: Insights from Aneuploid Oocytes and Trisomy Births

Abstract: In most organisms, genome haploidization requires reciprocal DNA exchanges (crossovers) between replicated parental homologs to form bivalent chromosomes. These are resolved to their four constituent chromatids during two meiotic divisions. In female mammals, bivalents are formed during fetal life and remain intact until shortly before ovulation. Extending this period beyond ∼35 years greatly increases the risk of aneuploidy in human oocytes, resulting in a dramatic increase in infertility, miscarriage, and birth defects, most notably trisomy 21. Bivalent chromosomes are stabilized by cohesion between sister chromatids, which is mediated by the cohesin complex. In mouse oocytes, cohesin becomes depleted from chromosomes during female aging. Consistent with this, premature loss of centromeric cohesion is a major source of aneuploidy in oocytes from older women. Here, we propose a mechanistic framework to reconcile data from genetic studies on human trisomy and oocytes with recent advances in our understanding of the molecular mechanisms of chromosome segregation during meiosis in model organisms.