Genetic susceptibility

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  • 1. All India Institute of Medical Sciences 1973 - 1980 PRENATAL DIAGNOSIS CYTOGENETIC STATUS COUNSELLING 1980 - 1989 Banaras Hindu University 1989 Jawaharlal Nehru University 2010 - 2013 SHRI MATA VAISHNO DEVI UNIVERSITY, SMVDU GENETIC SUSCEPTIBILITY MECHANISMS IN COMPLEX DISEASES RARE SYNDROMES
  • 2. FROM MICROBE TO HUMANS – WE ARE UNIFIED WITH A COMMON LINK OF GENETIC MATERIAL EVOLVED WITH TIME IN EVOLUTION – i.e., DEOXYRIBOSE NUCLEIC ACID -DNA A COMMON THREAD UNIFYING BIOLOGY
  • 3. Genetics is the transfer of biological information within a cell, an organism, or a population. The Levels of Genetics: DNA, Genes, Chromosomes, Genomes, The Cell, The Individual, A Family, The Population 23 46 23 ZYGOTE MEIOSIS MITOSIS BLUE PRINT OF AN INDIVIDUAL WHAT ? WHERE ? HOW ? AG T T C A Nucleus Mitochondrial 100s of copies DNA per cell Chromatin 1014 cells in the body CELL CELL & GENERATION GENERATION Mitochondrion STRUCTURAL FEATURES P M TERMINOLOGIES RFLPs GENES ALLELES/ SNPs INS/DEL NONCNV ALLELES SSRs Gene Rich and Gene Poor Regions LOCI
  • 4. HAS ITS OWN LANGUAGE & GEOGRAPHY FULL OF LANDSCAPES LOT OF PUZZLES FULL OF HISTORY ESTABLISHING THE ROOTS COMPARING WITH OTHER SPECIES POTENTIAL FOR HUMAN BENEFITS SOMETHING TO WORRY ABOUT
  • 5. HUMAN GENOME FULL OF HISTORY MITOCHONDRIAL MOTHER TO DAUGHTERS AND SONS ESTABLISHING THE ROOTS Y - CHROMOSOMAL FATHER TO SONS
  • 6. ANCESTRAL II-LEVEL-DERIVED MUTATION/VAR I-LEVEL –DERIVED MUTATION/VAR I-LEVEL –DERIVED MUTATION II-LEVELDERIVED I-LEVEL -DERIVED Y-CHROMOSOME MITOCHONDRIA
  • 7. Evolution of mitochondrial Haplogroups Haplo-group 1 (ancestral) Haplo-group 2 Haplo-group 3 Haplo-group 4 Haplo-group 6 Haplo-group 5 SNPs on mtDNA serve as markers for detection of human evolution and diversity Haplo-group 8 Haplo-group 7 Mutation + Variations in HVR regionsdivide the world population into different “haplogroups” Whole mitochondrial sequence is being used to elucidate evolution & diversity
  • 8. Biodiversity & Human Health Disease Susceptibility
  • 9. Genes - Simple and Complex Diseases Whole Body Which ? Where ? Controls Behavior ? Evolutionary Which genes & why ? Functionally Different systems & Organs Cell types Specific sets of genes active ubiquitous/tissue specific, signals/ transporters etc Implications IMPRINTING; ANTICIPATION; ALLELIC HETEROGENEITY LOCUS HETEROGENEITY, SPLICING ERRORS, PROMOTER / 5’ & 3’ UTR VARIATIONS; MICRO-RNA REGULATORS; POST-TRANSCRIPTIONAL & POST-TRANSLATIONAL MODIFICATIONS; EPIGENETIC CONTROLS; SELECTION PRESSURE-GENETIC DRIFT
  • 10. GENOME SCREENS AND GENES INVOLVED  Hypothesis Independent Approach to find out T2DLinked chromosomal regions And identify putative, causative Genetic variants:      2q37.3-CAPN10, 6q22-q23-ENPP1, 20q13.12-HNF4A, 4p16.1-WFS1 12q13-ADC; etc
  • 11. HYPOTHESIS INDEPENDENT- GENOME-WIDE ASSOCIATION STUDIES TCF7L2, SLC30A8, HHEX, CDKAL1 IGF2BP2, CDKN2A/B WTCCC-7UK WIDE CASE COHORTS FTO WITH BMI DIABETES AND GENETICS REPLICATION AND META-ANALYSIS(DIAGRAM) COMBINED STUDIES OF: WTCCC, DGI, FUSION- IDENTIFIED 6 NEW LOCI: JAFZF1, CDC123-CAMK1D, TSPAN8-LGR5, THADA, ADAMTS9 & NOTCH2 IN EAST-ASIAN ANCESTRY: KCNQ1, PTPRD, SRR, 13q13.1, UBE2E2 CDC4A, CDC4B REPLICATION IN ALL POPULATIONS - A PROBLEM
  • 12. GENES CAUSE DISEASE COMPLEX BIOLOGICAL SYSTEM - HUMANS DIFFERENT TIERS OF NETWORKS OPERATE STRUCTURAL GENOMIC GWA & CANDIDATE FUNCTIONAL GENOMIC i) GENOMIC VARIATION & SIGNATURE ii) TRANSCRIPTOMIC SIGNATURE / PROFILE iii) EPIGENOMIC MARKS iv) METABOLOMIC PROFILE v) UNDERSTAND NETWORKING OF PATHWAYS PHYSIOLOGICAL VARIATIONS INTERMEDIATE PHENOTYPES DISEASE
  • 13. GENOMIC PERSPECTIVE & THE QUESTIONS POSED REGULATION - PHENOTYPE Nucleus 1014 cells in the body SIGNALS STRUCTURAL GENOMIC Chromatin Mitochondrion ~3X109 + ~ 3X109 CLINICAL HETEROGENEITY GENOTYPE-PHENOTYPE Allelic Heterogeneity Same Gene Different (spectrum of) mutations PATHWAYS & NETWORKS FUNCTIONAL GENOMIC Unrelated Phenotypes/Diseases Locus Heterogeneity Different Genes/Loci Different mutations Same Phenotype/ Disease
  • 14. First Indian report pathogenic mutation E413K in Exon 7 coding for HTM of the hHb6 gene in 13 affected members of Two Indian Monilethrix Families Ann Genet. 2004: 47, 77-84 Ann Genet. 2004: 47, 125-7 novel Promoter, HTM and Intronic Polymorphisms in hHb6 and hHb1, the basic keratin gene SEM of Scalp Hair Unaffected Healthy hair Affected serration lost Generalized-Unbeaded Moderate SeverityFamily-2 Affected Beaded form of hair Localized-Beaded- confined to Scalp; Severe Hair Defect – Family-1
  • 15. GENETICS AND GENOME BIOLOGY – LESSONS LEARNT IN EVOLUTION A SUMMARY Information available in genetics and genomics is global at cellular level – be its Structure, expression, epigenetic regulation, pathways affected and networks functional in cellular physiology & metabolism – yet the whole organism (systems) level understanding is not complete. This also relates to genotype – phenotype correlations; our genetic make-up and susceptibilities or social/behavioural influences. Thus it makes the system complex to analyze and we need help of concepts in physics, chemistry, mathematics, engineering etc. Understanding these in the evolutionary context provides a deep understanding of who we are and how we function.
  • 16. GENES CAUSE DISEASE COMPLEX BIOLOGICAL SYSTEM - HUMANS DIFFERENT TIERS OF NETWORKS OPERATE STRUCTURAL GENOMIC GWA & CANDIDATE FUNCTIONAL GENOMIC THE ABOVE REQUIRES THE KNOWLEDGE BASE OF PHYSICS, CHEMISTRY, MATHEMATICS, BIOINFORMATICS, MOLECULAR BIOLOGY etc TO UNDERSTAND THE COMPLEX BIOLOGICAL SYSTEMS PHYSIOLOGICAL VARIATIONS INTERMEDIATE PHENOTYPES DISEASE