Sam Rhine - Genetic Update Conferences - www.samrhine.com
Genetics of Common Human Traits and Diseases….. Cloning and Stem Cells…..New Medical Applications
I. CHROMOSOMES - CYTOGENETICS:
A. Metaphase Spread - Karyotype - Autosomes - Sex Chromosomes - XX and XY
1. Chromosome Anatomy - Centromere - p-arm - q-arm - telomeres - chromatids
2. Chromosome Identification - Chromosome Banding - unique sets of stripes
B. Syndrome: a recognizable pattern of anomalies, a group of signs or symptoms,
that occur together and characterize a particular abnormality
C. Chromosome Syndromes: 1 in 160 live births / 50% of a miscarriages
MCA babies (Multiple Congenital Anomalies)
1. Trisomy 16 - most common chromosome syndrome - always miscarries
2. Trisomy 21 - Down Syndrome - 1/800 - Dr John Langdon Haydon Down - 1866
3. Trisomy 18 - Trisomy 13 - Monosomy X = Turner Syndrome - Klinefelter Syndrome
II MONOGENIC INHERITANCE - SINGLE GENE PAIR - MENDEL'S RULES of INHERITANCE
A. Johann Gregor Mendel - Monk at St. Thomas Monastery in Brno, Czech Republic
B. Monogenic Reference Sites:
1. OMIM - http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim
2. Genes and Disease - http://www.ncbi.nlm.nih.gov/books/NBK22183/?depth=2
C. AUTOSOMAL DOMINANT INHERITANCE - AD
1. Brachydactly - Huntington Disease - Neurofibromatosis - Marfan Syn - Alzheimer
D. AUTOSOMAL RECESSIVE INHERITANCE - AR
1. Cystic Fibrosis - Sickle Cell Anemia - Tay-Sachs Disease
E. X LINKED RECESSIVE INHERITANCE - XLR
1. Hemophilia Type A & Type B - Duschenne Musc Dys - Fragile X - Happiness
Genome and Genes Review:
I. INTRODUCTION: Genome / Genes / Gene Control
A. Genome: the sum total of all the genetic information for any biologic organism
1. ~1.5% - 'Coding' DNA
2. ~98.5% - 'Non Coding' DNA..…'Junk' DNA
B. Gene:
1. 'Coding' DNA Genes
- carry the genetic code to make a protein
2. 'Non Coding' DNA Genes - carry a code to make RNA only
C. GENE CONTROL = GENE REGULATION - ON / OFF MECHASNISMS
1. Transcription Factors - turn transcription ON and OFF at the promoter
2. microRNA = miRNA - negative regulators - turn genes OFF at 3' UTR
3. Epigenetics - 'Epi' means upon / on top of / above and beyond the DNA
Epigenetic control mechanism acts on chromatin - Open or Closed Chromatin
D. ENCODE - ENCyclopedia Of Dna Elements - new information as of September 5, 2012
1. International Consortium - 32 Research Institutions - 442 Consortium members
2. New Genome Findings:
a. the 'Junk' contain 'Docking Sites' - 2,890,000 - new gene control areas
b. sncRNAs - small non coding RNAs and lncRNAs - long non coding RNAs:
INTRODUCTION: GENOMIC MEDICINE - NEW ERA of HUMAN GENETICS
A. use knowledge about the entire GENOME - study POPULATIONS of people
1. Genomic Medicine - there is no 'Normal'…..no normal human genome
a. 'Variants' - millions of differences among individuals in a population
b. 'Mutation' - DNA variant that is pathologic / causes disease or cancer
2. Why don't we study the genetics of…..Common Conditions:
Adult Type 2 Diabetes / Macular Degeneration / Hypertension
High Cholesterol / Heart Disease & Stroke / Cancer & Tumors
BiPolar Disorder (Manic/Depressive) / ADHD - Attention Deficit / Alzheimer
Alcohol Dependency / Autism Spectrum - ASD / Epilepsy / Asthma / etc.
…..COMMON DISEASES…..but COMPLEX GENETIC TRAITS
C. HYPOTHESIS that might Explain Complex Diseases:
1. 'COMMON DISEASES / COMMON VARIANTS HYPOTHESIS'
2. Persons with the same Common Disease…..have unique set of DNA Variants in Common
3. HERITABILITY: H - the proportion of Phenotype variation due to Genetics
4. HUMAN QUANTATIVE TRAITS: Height, blood pressure, blood glucose levels
5. Flipping Pennies Model: polygenes are additive - not dominant or recessive
6. Medical Conditions - Threshold effect:
7. TWO perfectly NORMAL parents can have an AFFECTED child!!
D. What would it take to find the Polygenes for Common Diseases? H G P / SNPs & CNPs
E. GWAS - GenomeWide Association Studies - New England Journal Med July 8, 2010
1. Evaluate the entire genome of thousands of people and see if any SNPs might be
Associated with a particular Common Disease
2. GWAS Example: T2D - T1D - Crohn's - Obesity - Height - Blood Lipids - Autism
3. CNPs / CNVs - Copy Number Polymorphisms = Copy Number Variantas
Normal - 2 copies / CNP = 1 copy or 3 copies, etc.
4. de novo CNVs account for 5-8% of autism simplex cases - paternal age effect
5. Obesity & Underweight / Macrocephaly & Microcephaly / Autism & Schizophrenia
Examples of CNVs and Reciprocal Variants - Phenotypic Opposites
6. YOUR PERSONAL GENOME EVALUATION - personal chip - fetal chip
Cloning and Stem Cells…..New Medical Applications
I. Human Embryology - formation of the fetus = Applied Embryology
A. Embryonic Stem Cells…..give rise to four major branches
B. HSCs - Hematopoetic SCs / MSCs - Mesenchymal SCs
ESCs - Endodermal SCs / NSCs - Neural
III. Reproductive cloning: Oocyte Retrieval / Enucleation / SCNT - transfer donor somatic nucleus
Artificial Activation of the egg / ET - Embryo Transfer into the uterus of a surrogate mother
IV. Therapeutic cloning: Human Oocyte Retrieval / Enucleation / SCNT - transfer donor somatic nucleus
Artificial Activation of the egg / grow in lab for 6 days - develop a cell line
"Ethical" Pluripotent Stem Cells …..REPROGRAMMING
1. iPS for: Huntington Dx, Parkinson Dx, Type 1 Diabetes,
2. huESCs from donated blastocysts for Dry MD and Stargardt's
3. RP - Retinitis Pigmentosa - Most Common Inherited Vision Loss
4. Huntington Disease - AD - CAG Triplet Repeat Mutation
5. Also iPSCs for: Alpha-1-Antitrypsin Deficiency / Hutchison Guilford Progeria
Friedreich's Ataxia / Fragile X Syndrome / Rett Syndrome - Autism
6. Man-Made Organs: Teeth / Optic Cup Retina / Cerebral Cortex
Primitive Hypothalamus / Primitive Cerebellum / Heart Vein / Trachea
Cartilage / Cardiac Fibroblasts make new Cardiomyocytes / Fetal Heart Valve
Osteogenesis Imperfecta / Finger Regeneration / burger from muscle stem cells
Made rat pancreas in a mouse embryo…..Human Pancreas??
7. Yamanaka - iPSCs Stock Cell Project in Japan will make iPSCs available for most of the Japanese population