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