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1973 - 1980
1989 -
1980 - 1989
GENETIC SUSCEPTIBILITYMECHANISMS IN COMPLEX DISEASES
RARE SYNDROMES
PRENATAL DIAGNOSIS -CYTOGENETIC STATUS - COUNSELLING
Banaras Hindu University
All India Institute of Medical Sciences
Jawaharlal Nehru University
2010 - 2013
SHRI MATA VAISHNO DEVI UNIVERSITY, SMVDU
BIODIVERSITYBIODIVERSITYBIODIVERSITYBIODIVERSITYBIODIVERSITYUnderstanding
FROM MICROBE TO HUMANS – WE ARE UNIFIED WITH A COMMON LINK OF GENETICMATERIAL EVOLVED WITH TIME IN EVOLUTION – i.e., DEOXYRIBOSE NUCLEIC ACID -DNA
A COMMON THREAD UNIFYING BIOLOGY
Nucleus
1014 cells in the body
P M
23
2346
ZYGOTE
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
BLUE PRINT OF AN INDIVIDUAL
Chromatin
100s of copies per cell
Mitochondrial DNA
Gene Rich and Gene Poor Regions
Mitochondrion
WHAT ?WHERE ?HOW ?
MEIOSIS MITOSIS
GENESALLELES/NON-ALLELESLOCI
RFLPsSNPsINS/DELCNVSSRs
STRUCTURAL FEATURES TERMINOLOGIES
A
T
G
C
T
A
CELL CELL & GENERATION GENERATION
FULL OF HISTORY
LOT OF PUZZLES
POTENTIAL FOR HUMAN BENEFITS
SOMETHING TO WORRY ABOUT
ESTABLISHING THE ROOTS
COMPARING WITH OTHER SPECIES
BOOK OF LIFE
HAS ITS OWN LANGUAGE & GEOGRAPHY
FULL OF LANDSCAPES
FULL OF HISTORY
HUMAN GENOME
ESTABLISHING THE ROOTSMITOCHONDRIAL Y - CHROMOSOMAL
MOTHER TODAUGHTERS AND SONS
FATHER TO SONS
ANCESTRAL
I-LEVEL -DERIVED
II-LEVEL-DERIVED
MUTATION/VARI-LEVEL –DERIVED
MUTATION/VARI-LEVEL –DERIVED
MUTATION II-LEVEL-DERIVED
Y-CHROMOSOME
MITOCHONDRIA
Haplo-group 1 (ancestral) Haplo-group 2Haplo-group 3
Haplo-group 4
Haplo-group 8
Haplo-group 5
Haplo-group 6
Haplo-group 7
Evolution of mitochondrial Haplogroups
SNPs on mtDNA serve as markers for detection of human evolution and diversity
Mutation + Variations in HVR regions- divide the world population into different “haplogroups”
Whole mitochondrial sequence is being used to elucidate evolution & diversity
Biodiversity &
Human HealthDisease Susceptibility
Genes - Simple and Complex Diseases
Which ?
Where ?
Behavior ?
Evolutionary Functionally
Implications
Whole Body
Different systems & Organs
Cell types
Specific sets of genes active ubiquitous/tissue specific, signals/ transporters etc
Controls
Which genes & why ?
IMPRINTING; ANTICIPATION; ALLELIC HETEROGENEITYLOCUS HETEROGENEITY, SPLICING ERRORS, PROMOTER/ 5’ & 3’ UTR VARIATIONS; MICRO-RNA REGULATORS; POST-TRANSCRIPTIONAL& POST-TRANSLATIONAL MODIFICATIONS; EPIGENETIC CONTROLS; SELECTIONPRESSURE-GENETIC DRIFT
GENOME SCREENS AND GENES INVOLVED
Hypothesis IndependentApproach to find out T2D-Linked chromosomal regionsAnd identify putative, causativeGenetic variants:
2q37.3-CAPN10, 6q22-q23-ENPP1, 20q13.12-HNF4A, 4p16.1-WFS1 12q13-ADC; etc
HYPOTHESIS INDEPENDENT- GENOME-WIDE ASSOCIATION STUDIES
TCF7L2, SLC30A8, HHEX, CDKAL1IGF2BP2, CDKN2A/B
WTCCC-7UK WIDE CASE COHORTSFTO WITH BMI
DIABETES AND GENETICS REPLICATIONAND META-ANALYSIS(DIAGRAM)COMBINED STUDIES OF: WTCCC, DGI,FUSION- IDENTIFIED 6 NEW LOCI:JAFZF1, CDC123-CAMK1D, TSPAN8-LGR5, THADA, ADAMTS9 & NOTCH2IN EAST-ASIAN ANCESTRY:KCNQ1, PTPRD, SRR, 13q13.1, UBE2E2CDC4A, CDC4B
REPLICATION IN ALL POPULATIONS - A PROBLEM
COMPLEX BIOLOGICALSYSTEM - HUMANS
DIFFERENT TIERS OF NETWORKS OPERATESTRUCTURAL
GENOMICFUNCTIONAL
GENOMICi) GENOMIC VARIATION & SIGNATURE
ii) TRANSCRIPTOMIC SIGNATURE / PROFILE
iii) EPIGENOMIC MARKS
iv) METABOLOMIC PROFILE
v) UNDERSTAND NETWORKING OF PATHWAYS
INTERMEDIATE PHENOTYPES
PHYSIOLOGICALVARIATIONS DISEASE
GWA & CANDIDATE
GENES CAUSE DISEASE
~3X109 + ~ 3X109
1014 cells in the body
Chromatin
Nucleus
Mitochondrion
STRUCTURALGENOMIC
FUNCTIONALGENOMIC
PATHWAYS &NETWORKS
SIGNALS
REGULATION - PHENOTYPE
GENOMIC PERSPECTIVE & THE QUESTIONS POSED
Allelic Heterogeneity
Locus Heterogeneity
Same GeneDifferent (spectrum of) mutations
Unrelated Phenotypes/Diseases
Different Genes/LociDifferent mutations
Same Phenotype/ Disease
CLINICAL HETEROGENEITY GENOTYPE-PHENOTYPE
SEM of Scalp Hair
Unaffected Healthy hair
Affectedserration lost
AffectedBeaded form of hair
Ann Genet. 2004: 47, 77-84Ann Genet. 2004: 47, 125-7
Generalized-UnbeadedModerate Severity-Family-2
Localized-Beaded- confined toScalp; Severe Hair Defect –Family-1
First Indian report pathogenic mutation E413K in Exon 7 coding for HTM of the hHb6 gene in 13 affected members of Two Indian Monilethrix Familiesnovel Promoter, HTM and Intronic Polymorphisms in hHb6 and hHb1, the basic keratin gene
GENETICS AND GENOME BIOLOGY – LESSONS LEARNT IN EVOLUTION
Information available in genetics and genomics is global at cellular level – be its Structure, expression, epigenetic regulation, pathways affected and networksfunctional 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.
A SUMMARY
COMPLEX BIOLOGICALSYSTEM - HUMANS
DIFFERENT TIERS OF NETWORKS OPERATESTRUCTURAL
GENOMICFUNCTIONAL
GENOMIC
INTERMEDIATE PHENOTYPES
PHYSIOLOGICALVARIATIONS DISEASE
GWA & CANDIDATE
GENES CAUSE DISEASE
THE ABOVE REQUIRES THE KNOWLEDGE BASE OF PHYSICS, CHEMISTRY,
MATHEMATICS, BIOINFORMATICS, MOLECULAR BIOLOGY etc TO UNDERSTAND THE COMPLEX BIOLOGICAL SYSTEMS