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All India Institute of Medical Sciences

1973 - 1980
PRENATAL DIAGNOSIS CYTOGENETIC STATUS COUNSELLING

1980 - 1989
Banara...
FROM MICROBE TO HUMANS – WE ARE UNIFIED WITH A COMMON LINK OF GENETIC
MATERIAL EVOLVED WITH TIME IN EVOLUTION – i.e., DEOX...
Genetics is the transfer of biological information within a cell, an organism, or a
population. The Levels of Genetics: DN...
HAS ITS OWN
LANGUAGE &
GEOGRAPHY
FULL OF
LANDSCAPES

LOT OF
PUZZLES

FULL OF HISTORY

ESTABLISHING
THE ROOTS

COMPARING WI...
HUMAN GENOME
FULL OF HISTORY

MITOCHONDRIAL

MOTHER TO
DAUGHTERS AND
SONS

ESTABLISHING
THE ROOTS

Y - CHROMOSOMAL

FATHER...
ANCESTRAL

II-LEVEL-DERIVED

MUTATION/VAR
I-LEVEL –DERIVED

MUTATION/VAR
I-LEVEL –DERIVED
MUTATION II-LEVELDERIVED

I-LEVE...
Evolution of mitochondrial Haplogroups

Haplo-group 1 (ancestral)

Haplo-group 2
Haplo-group 3

Haplo-group 4
Haplo-group ...
Biodiversity
&
Human Health
Disease Susceptibility
Genes - Simple and Complex Diseases
Whole Body

Which ?

Where ?

Controls

Behavior ?

Evolutionary

Which genes & why ?
...
GENOME SCREENS AND GENES INVOLVED

 Hypothesis Independent
Approach to find out T2DLinked chromosomal regions
And identif...
HYPOTHESIS INDEPENDENT- GENOME-WIDE ASSOCIATION STUDIES
TCF7L2, SLC30A8, HHEX, CDKAL1
IGF2BP2, CDKN2A/B
WTCCC-7UK WIDE CAS...
GENES CAUSE DISEASE

COMPLEX BIOLOGICAL
SYSTEM - HUMANS

DIFFERENT TIERS OF NETWORKS OPERATE
STRUCTURAL
GENOMIC

GWA & CAN...
GENOMIC PERSPECTIVE & THE QUESTIONS POSED
REGULATION - PHENOTYPE

Nucleus

1014 cells in the body
SIGNALS

STRUCTURAL
GENO...
First Indian report pathogenic mutation E413K in
Exon 7 coding for HTM of the hHb6 gene in 13
affected members of Two Indi...
GENETICS AND GENOME BIOLOGY – LESSONS LEARNT IN EVOLUTION
A SUMMARY
Information available in genetics and genomics is glo...
GENES CAUSE DISEASE

COMPLEX BIOLOGICAL
SYSTEM - HUMANS

DIFFERENT TIERS OF NETWORKS OPERATE
STRUCTURAL
GENOMIC

GWA & CAN...
Genetic susceptibility
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Genetic susceptibility

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Transcript of "Genetic susceptibility"

  1. 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. 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. 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. 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. 5. HUMAN GENOME FULL OF HISTORY MITOCHONDRIAL MOTHER TO DAUGHTERS AND SONS ESTABLISHING THE ROOTS Y - CHROMOSOMAL FATHER TO SONS
  6. 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. 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. 8. Biodiversity & Human Health Disease Susceptibility
  9. 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. 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. 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. 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. 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. 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. 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. 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
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