The Nallur B. Ramachandra Laboratory

Genetics and Genomics Lab - University of Mysore

About me                                                      

The contributions of Dr. N. B. Ramachandra, to science have been recognized by the State Government and he has been awarded Sir C. V. Raman Young Scientist State Award for the Year 2007. He worked for Ph.D from 1982-1988 in the Department of Zoology, University of Mysore. After his post doctoral work at Canada, he joined as a Lecturer, in the Department of Zoology, University of Mysore, Mysore during 1992. Since then he has worked with Prof. H. A. Ranganath as a collaborator as well as independently. He currently serves as the Chairman of Department of studies in Genetics and Genomics, University of Mysore, Mysuru.

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His significant research contributions are as follows:

Hybridization and evolution of new races in Drosophila: 

A fundamental question in evolutionary biology is to understand how new species are formed and whether speciation is gradual or punctuated. This question has been difficult to evaluate critically because the evolutionary history of most plant and animal species is poorly known. The role of hybridization in the evolution of new species in animals has been debated and not much evidence has been recorded. To understand the process of anagenesis, Ramachandra has conducted long range interracial hybridization experiments in Drosophila nasuta system and evolved 16 new karyotypically stabilized cytoraces and a new nasuta - albomicans complex of Drosophila which would have taken million of years in nature. The cytoraces, the gold mine, are being investigated further to understand the molecular basis of raciation / speciation. The variations are the currency of evolution and the conserved genes usually shows less number of variation in species but rapidly evolving genes shows a great number of changes between species. The REGs are usually sex and reproduction related genes of Drosophila. One of the REGs studied in nasuta-albomicans complex of Drosophila has shown positive selection whereas all the other species of Drosophila has neutrally evolved.

Isolation and Characterization of Genes involved in muscle development in Drosophila:

Dr. Ramachandra’s analysis of 16 Indirect Flight Muscles mutants in Drosophila which are located on chromosome 2 involved in myoblast proliferation, template splitting, myoblasts fusion, muscle differentiation and late muscle development is new to science.

Molecular genetic analysis of complex human disorders (Congenital heart diseases, Dyslexia, Asthma, Down Syndrome, Parkinson Disease and Tuberculosis):

The genetic analysis of the above said commonly found complex disorders in our population are being investigated. Down syndrome (DS) is a chromosomal anomaly associated with mental retardation which is due to the occurrence of free trisomy 21 (92-95%), mosaic trisomy 21 (2-4%) and translocation (3-4%). Advanced maternal age is a well documented risk factor for maternal meiotic nondisjunction. In India, three children with DS are born every hour and 91.3% of children with DS are born to young age mothers than to advanced age mothers, which is in congruence with his investigation. Besides the known risk factors, mother's age, father's age, the age of the maternal grandmother at the time of birth of the mother is also a risk factor for the occurrence of DS. Further investigations at the larger samples are being initiated in this direction. We are currently working on molecular analysis of recombination machinery and folate metabolism that play a role in the etiology of DS. The cellular mechanism with reference to nondisjunction in Drosophila and humans are similar and investigation on oogenesis and fertilization in human system is difficult to address. Therefore, Drosophila serves as a potent model system to understand and investigate the mechanisms that contribute to increased levels of meiotic nondisjunction in oocytes as a result of aging or factors that influence cohesion degradation with age in both aged and young flies that produce more of aneuploids.

Studies on congenital heart diseases (CHD) through SNP genotyping revealed Indian specific SNPs involved in causing CHDs in three genes – NKX2.5, GATA4, CRELD1, and also a lack of association of existing SNPs in TFAP2B in specifically Patent ductus arteriosus patients were. Dyslexia, an educational problem, seen in 10% of school children, exhibits high frequency of autosomal dominant inheritance and less cholesterol level. An association with specific SNPs in dyslexia has been identified. Further, whole genome scan on dyslexic families indentified 5 new genes involved in the manifestation of this complex disorder. In addition, an attempt has also been made to visualize the ongoing cellular processes with an aim to understand the functional role of the candidate genes identified. Although dyslexia has long been thought as a neuronal migration disorder, he suggests that dyslexia may also as be viewed as a disorder due to defects in neurotransmission and cell adhesion processes. He has also reported allelic unequal recombination between the XTR region Yp11.2 and Xq21.3, indicating the presence of a new PAR, which was named PAR3.

Genetic analysis of asthma revealed an autosomal recessive pattern of inheritance; parental consanguineous marriage and serum intracellular cell adhesion molecule-1 were significantly associated with asthma. Serum levels of interleukin-13 and interferon-gamma from adult patients with asthma through ELISA has revealed a nonsignificant difference of serum cytokines with the duration of asthma, number of allergens, and severity of sensitization. Presently, we are continuing with the research on polymorphisms on ADAM33 gene and 2 interleukins which have been found to be significantly associated with asthma severity.
Research in Parkinson disease (PD) genetics is also being conducted to determine and identify variants which will help in identifying regions that are responsible for the increased susceptibility and other candidate genes that are responsible for the disease development. Further, tests will be developed which can be performed on the “at-risk” patients to detect their susceptibility for the development of PD. The identification of genetic mutations also provides the rationale to develop new treatments for disease.

We are also working on an international collaborative project with McMaster University, Canada, towards the design of a compact, low cost diagnostic unit for Tuberculosis, one of the largest and most common diseases to plague the modern world. The device has specific Mycobacterium tuberculosis markers allowing for a relatively faster identification of TB in patients. The low cost aims at making it a tool of choice in developing and under developed countries with poor resource settings.

Genomics:

A UOM-Human olfactory Receptor Database at University of Mysore, Manasagangotri, Mysore was constituted under my convenorship. This data base provides information regarding the structure, function and evolution of entire OR gene superfamily. This also provides information about OR genomic organization and a comprehensive summary of constantly evolving olfactory receptor genes in the human genome.

In a population study, we performed genome-wide genotyping using high-resolution arrays and identified 44109 CNVs from 1715 genomes across 12 populations. The study unravelled the force of independent evolutionary dynamics on genome-organizational plasticity across chromosomes and populations. We established the first drafts of population-specific CNV maps providing a rationale for prioritizing chromosomal regions. We further demonstrated the use of CNV tool to study human migration and identified a second major settlement establishing new migration routes in addition to existing ones. We established complex relationship of CNVs on genes and their physical interacting partners which helped unravel many complexities involved in phenotype expression. We also propose four mechanisms unraveling the many complexities in miRNA genes, targets and co-regulated miRNA genes towards establishment of phenotypic diversity. Dr. Ramachandra also constituted a UOM-Human olfactory Receptor Database at University of Mysore, Manasagangotri, Mysore.

Personalised Genomic medicine:

Human disorders and its association of molecular markers have led to the identification of genes responsible for several heritable disorders. Atherosclerosis is a complex genetic disorder with a high frequency. Whole-genome sequencing (WGS) is a promising tool for identifying all genetic variants in a given genome sample. Therefore, we propose the following – to analyze the DNA variants – SNPs, Indels, and CNVs in the genome of this patient by Whole-genome sequencing, to identify the candidate genes for diseases in the genome, to establish gene-protein interaction network and pathway using identified genes, to validate the identified genetic variants in parents and unaffected controls, and to establish genotype-phenotype relationship. This will help in genetic diagnosis, treatment, counseling and management of the disease.

The problems of genetic disorders are enormous and about 1/6th of the world population are suffering from inherited diseases and have a significant socioeconomic impact. The prevalence of atherosclerosis is increasing in the Indian population. Molecular genetic markers namely, SNPs, Microsatellites, Insertion/deletion polymorphisms (Indels) and Copy number variations (CNVs) are the most powerful tools for the analysis of genomes and enable the association of heritable traits with underlying genomic variation. The improvement in techniques in sequencing the human DNA and in bioinformatics, especially genome-wide studies can help detect combinations of various DNA variants and relate to diverse phenotypes. Implementation of whole genome sequencing enables the identification of all types of genetic variations in a single experiment.

Therefore, with the availability of the next-generation sequencing instruments, identification of all the variants within an individual will help to understand the causal factors and other contributing factors towards the development of effective strategies to identify individuals who are at high risk and to further design effective remedies. In this context, we plan to examine the genetic influence and effective medicines on the manifestation of such a rare condition of this patient. These investigations will help us to identify susceptible genes and DNA markers linked to AVSD and aid in identifying the targets for Drug Discovery to perform personalized medication and to prescribe genomic medicine.

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