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HAPLOGROUP COMPATIBILITY AND HOW mtDNA CAN INFLUENCE TRAITS BEYOND DISEASE Doug Wallace Center for Mitochondrial and Epigenomic Medicine Children’s Hospital.

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Presentation on theme: "HAPLOGROUP COMPATIBILITY AND HOW mtDNA CAN INFLUENCE TRAITS BEYOND DISEASE Doug Wallace Center for Mitochondrial and Epigenomic Medicine Children’s Hospital."— Presentation transcript:

1 HAPLOGROUP COMPATIBILITY AND HOW mtDNA CAN INFLUENCE TRAITS BEYOND DISEASE Doug Wallace Center for Mitochondrial and Epigenomic Medicine Children’s Hospital of Philadelphia

2 THE mtDNA CONTROLS THE MITOCHONDRIAL POWER PLANT CAPACITOR AND THUS IS THE POWER PLANT WIRING DIAGRAM: IT IS NOT TRIVIAL Tissue Specific Manifestations: Brain: Continuous energy demand. 2% body weight but consumes 20% oxygen. Heart>Muscle>Renal>Endocrine>Intestinal: Episodic energy demand.

3 THE mtDNA CAN HARBOR BOTH DISEASE CAUSING AND BENEFICIAL VARIANTS THE MITOCHONDRIAL GENOME: ~ 1500 Dispersed nDNA Genes 37 mtDNA Genes High Mutation Rate (ROS-Repair-etc.) THREE CLASSES OF mtDNA VARIANTS Ancient Functional Polymorphisms Recent Deleterious Mutations Somatic Mutations

4 HUMAN mtDNA CHANGED AS OUR ANCESTORS MIGRATED OUT-OF-AFRICA PERMITTING THEM TO ADAPT TO DIFFERENT ENVIRONMENTS from Mutation rate = 2.2 – 2.9% / MYR Time estimates are YBP

5 Haplogroup H5a: Ancient polymorphism ANCIENT mtDNA VARIANTS CAN BE BOTH GOOD AND BAD DEPENDING ON CONTEXT EUROPEAN tRNA Gln 4336A>G VARIANT BECAME ESTABLISHED BUT NOW REDISPOSES TO ALZHEIMER & PARKINSON DISEASE AD = 3.3%, PD = 5.3%, AD+PD = 6.8%, CNTL = 0.4%

6 ASSOCIATIONS BETWEEN mtDNA HAPLOGROUPS & HUMAN TRAITS NEURODEGENERATIVE DISEASES –Alzheimer Disease –Parkinson Disease –Macular Degeneration –Migraine –Psychiatric Disorders NEUROLOGICAL DISEASES –Stoke METABOLIC DISEASES –Diabetes –Cardiovascular Disease –Metabolic Syndrome INFLAMMATORY & INFECTIOUS DISEASES –Sepsis –IgE Levels –Asthma –AIDS progression –Anti-AIDS HAAT * Lipodystrophy –Osteoarthritis AGING CANCERS ATHLETIC PERFORMANCE (L0>L3>N>H>J-U-T) * HAAT- highly active anti-retroviral therapy H > J = T > U (Uother > U4 = U5a1 > Uk).

7 Differentiated cell Sperm Egg CYTOPLAMIC MIXING TO INCREASE FERTILITY OF INFERTILE EGGS HAS CREATED HETEROPLASMY Infertile Mother Unrelated Younger Donor Recipient oocyte Heteroplasmic child Heteroplasmic zygote ♂ Father ♂ Donor oocyte ♀ Barritt JA, Brenner CA, Malter HE, & Cohen J. Mitochondria in human offspring from ooplasmic transplantation. Human Reproduction 16: (2001). ICSI Ooplasmic Transfer

8 Disaggregate Female ES Cybrids (Heterplasmic NZB- 129 mtDNA) 129 ES Cell Cells Pseudopregnant mother Female Chimera HETEROPLASMY BETWEEN mtDNA HAPLOGROUPS CAN CAUSE NEUROPSYCHIATRIC DISEASES AND LEARNING PROBLEMS HETEROPLASMY OF TWO “NORMAL” (NZB+129) mtDNAs IS ELIMINATED LM(TK-) (mtDNA NZB) Backcross 129 nDNA (NZB mtDNAs) females to B6 males > 9 generations Rhodamine 6G 129 Agouti Mice

9 91 “129” vs “NZB” mtDNAs differences: 91 “129” vs “NZB” mtDNAs differences: 15 aaΔ +5 tRNA +7 rRNA + 11 CR MIXING TWO NORMAL MOUSE mtDNAs (NZB + 129) CAUSES NEUROPSYCOLOGICAL PHENOTYPES BamH A4276G I I II I II I III II I II III I I I II III I I I II I I II III I I II I II IIIII I IIII II I III I II I I I I IIIIII I II I IIII II I I III Backcrossed 20 generations onto C57BL/6L nDNA. Permitted nZB-129 mtDNAs to segregate. Correlated mtDNA NZB-129 genotypes with behavior. CREATION OF NZB-129 HETEROPLASMIC MICE

10 GENERTATION FROM THE HETEROPLASMIC MICE OF HOMOPLASMIC DERIVATIVES TO ASSESS THE DIFFERENTIAL EFFECTS OF THE HETEROPLASMIC MIXING

11 NZB-129 HETEROPLASMIC MICE EXHIBIT DIMINISHED ACTIVITY, FOOD CONSUMPTION, & METABOLIC RATE BUT HEIGHTEN RESPONSE TO STRESS

12 REDUCED COGNITIVE CAPACITY OF NZB-129 HETEROPLASMIC MICE

13 Mitochondrial DNA modifies cognition in interaction with nuclear genome and age in mice. Roubertoux PL et al. (2003) Nature Genetics 35:65-69 a)Radial Maze: 3 months. b)Krushinsky Test: 3 months. c)Morris Hidden Platform Water Maze: 3, 6, 12 months. d)Probe Test-No Platform: 3 months. H H mtN N mtH N SIMPLY TRANSFERRING mtDNAs FROM ONE NUCLEUS TO ANOTHER HAS MAJOR EFFECTS ON LEARNING AND BEHAVIOR

14 SUGGESTIONS RELATING TO mtDNA HAPLOGROUPS Apply spindle transfer only to women with severe mtDNA mutations, preferably with previous reproductive failure. -Cost-Benefit Ratio justified. -Negative outcome for child otherwise assured. Avoid heteroplasmy. Use haplogroup matched mtDNA donors. - For heteroplasmic women, preferably use female donor on maternal lineage prior to occurrence of mutant mtDNA. -When maternal relatives not available use haplogroup matched donor. Prohibit for now the use of spindle transfer to treat advanced maternal age infertility. -Cost-Benefit Ratio not justified. -Possible long-term risk to society too great if spindle transferred proves deleterious and used for thousands of children.

15 A MITOCHONDRIAL ETIOLOGY OF COMPLEX DISEASE mtDNA Damage & Somatic Mutations ↓ ENERGY,↑ ROS, Δ REBOX, Δ Ca++ PROGRESSIVE BIOENERGETIC DECLINE Apoptosis mtDNA Variants Ancient Adaptive Polymorphisms Recent Deleterious Mutations nDNA Variation Mutations Deleterious Mutations, Mito Gene Polymorphisms Epigenomics Histone Modifications, Signal Transduction, Redox Controls Neuropsychological Blindness, Deafness AD, PD, Depression Muscle Myalgia, Fatigability Cardiomyopathy Renal Failure OXPHOS DYSFUNCTION Environmental Factors Energy Sources Carbohydrates, Fats, Amino Acids Energy Uses Growth, Maintenance, Reproduction Toxins Metabolic Type II Diabetes, Obesity Hypertension, CVD Stress Thermal, Trauma Aging Penetrance & Expressivity Delayed-Onset & Progression, Inflammation, Immunity MS, Type I Diabetes (DAMPs) Infection Predisposition Sepsis, AIDS (Zhang Q et al, 2010, Nature 464:104) Cancer Energy Production, ROS & Redox


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