Articles written in Journal of Genetics

    • Cryptic genes: Evolutionary puzzles

      Mitali Mukerji S. Mahadevan

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      Many microorganisms carry genes that have the potential to code for specific functions but remain inactive during the normal lifetime of the organism. Such genes have been termed cryptic genes and their activation usually requires a mutational event. They are different from pseudogenes which arise as a result of duplication of a functional gene but remain inactivated because of the accumulation of multiple mutations. This review is an attempt to examine some of the well-characterized cryptic genetic systems inEscherichia coli in an effort to understand their functional and evolutionary significance.

    • Utilizing linkage disequilibrium information from Indian Genome Variation Database for mapping mutations: SCA12 case study

      Samira Bahl Ikhlak Ahmed The Indian Genome Variation Consortium Mitali Mukerji

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      Stratification in heterogeneous populations poses an enormous challenge in linkage disequilibrium (LD) based identification of causal loci using surrogate markers. In this study, we demonstrate the enormous potential of endogamous Indian populations for mapping mutations in candidate genes using minimal SNPs, mainly due to larger regions of LD. We show this by a case study of the PPP2R2B gene (∼400 kb) that harbours a CAG repeat, expansion of which has been implicated in spinocerebellar ataxia type 12 (SCA12). Using LD information derived from Indian Genome Variation database (IGVdb) on populations which share similar ethnic and linguistic backgrounds as the SCA12 study population, we could map the causal loci using a minimal set of three SNPs, without the generation of additional basal data from the ethnically matched population. We could also demonstrate transferability of tagSNPs from a related HapMap population for mapping the mutation.

    • Paradigm for disease deconvolution in rare neurodegenerative disorders in Indian population: insights from studies in cerebellar ataxias


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      Cerebellar ataxias are a group of rare progressive neurodegenerative disorders with an average prevalence ranges from 4.8 to 13.8 in 100,000 individuals. The inherited disorders affect multiple members of the families, or a community that is endogamous or consanguineous. Presence of more than 3000 mutations in different genes with overlapping clinical symptoms, genetic anticipation and pleiotropy, as well as incomplete penetrance and variable expressivity due to modifiers pose challenges in genotype–phenotype correlation. Development of a diagnostic algorithm could reduce the time as well as cost in clinicogenetic diagnostics and also help in reducing the economic and social burden of the disease. In a unique research collaboration spanning over 20 years, we have been able to develop a paradigm for studying cerebellar ataxias in the Indian population which would also be relevant in other rare diseases. This has involved clinical and genetic analysis of thousands of families from diverse Indian populations. The extensive resource on ataxia has led to the development of a clinicogenetic algorithm for cost-effective screening of ataxia and a unique ataxia clinic in thetertiary referral centre in All India Institute of Medical Sciences. Utilizing a population polymorphism scanning approach, we have been able to dissect the mechanisms of repeat instability and expansion in many ataxias, and also identify founders, and trace the mutational histories in the Indian population. This provides information for genetic testing of at—risk as well as protected individuals and populations. To dissect uncharacterized cases which comprises more than 50% of the cases, we have explored the potential of next-generation sequencing technologies coupled with the extensive resource of baseline data generated in-house and other public domains. We have also developed a repository of patient-derived peripheral blood mononuclear cells, lymphoblastoid cell lines andneuronal lineages (derived from iPSCs) for ascribing functionality to novel genes/mutations. Through integrating these technologies, novel genes have been identified that has broadened the diagnostic panel, increased the diagnostic yield to over 75%, helped in ascribing pathogenicity to novel mutations and enabled understanding of disease mechanisms. It has also provided a platform fortesting novel molecules for amelioration of pathophysiological phenotypes. This review through a perspective on CAs suggests a generic paradigm from diagnostics to therapeutic interventions for rare disorders in the context of heterogeneous Indian populations.

    • Genomic insights into ayurvedic and western approaches to personalized medicine


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      Ayurveda, an ancient Indian system of medicine documented and practised since 1500 B.C., follows a systems approach thathas interesting parallels with contemporary personalized genomic medicine approaches to the understanding and managementof health and disease. It is based on the trisutra, which are the three aspects of causes, features and therapeutics that areinterconnected through a common organizing principle termed ‘tridosha’. Tridosha comprise three ascertainable physiologicalentities; vata (kinetic), pitta (metabolic) and kapha (potential) that are pervasive across systems, work in conjunction witheach other, respond to the external environment and maintain homeostasis. Each individual is born with a specific proportionof tridosha that are not only genetically determined but also influenced by the environment during foetal development.Jointly they determine a person’s basic constitution, which is termed their ‘prakriti’. Development and progression of differentdiseases with their subtypes are thought to depend on the origin and mechanism of perturbation of the doshas, andthe aim of therapeutic practice is to ensure that the doshas retain their homeostatic state. Similarly, western systems biologyepitomized by translational P4 medicine envisages the integration of multiscalar genetic, cellular, physiological and environmentalnetworks to predict phenotypic outcomes of perturbations. In this perspective article, we aim to outline the shape ofa unifying scaffold that may allow the two intellectual traditions to enhance one another. Specifically, we illustrate how aunique integrative ‘Ayurgenomics’ approach can be used to integrate the trisutra concept of Ayurveda with genomics. Weobserve biochemical and molecular correlates of prakriti and show how these differ significantly in processes that are linkedto intermediate patho-phenotypes, known to take different course in diseases. We also observe a significant enrichment of thehighly connected hub genes which could explain differences in prakriti, focussing on EGLN1, a key oxygen sensor that differsbetween prakriti types and is linked to high altitude adaptation. Integrating our observation with the current literature,we demonstrate how EGLN1 could qualify as a molecular equivalent of tridosha that can modulate different phenotypic outcomes,where hypoxia is a cause or a consequence both during health and diseased states. Our studies affirm that integrationof the trisutra framework through Ayurgenomics can guide the identification of predisposed groups of individuals and enablediscovery of actionable therapeutic points in an individualized manner.

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