Transcript Human Mitochondrial DNA

HAPLOGROUP COMPATIBILITY AND HOW mtDNA CAN
INFLUENCE TRAITS BEYOND DISEASE
Doug Wallace
Center for Mitochondrial and Epigenomic Medicine
Children’s Hospital of Philadelphia
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.
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
HUMAN mtDNA CHANGED AS OUR ANCESTORS MIGRATED
OUT-OF-AFRICA PERMITTING THEM TO ADAPT TO DIFFERENT
ENVIRONMENTS
from http://www.mitomap.org
Mutation rate = 2.2 – 2.9% / MYR
Time estimates are YBP
ANCIENT mtDNA VARIANTS CAN BE BOTH
GOOD AND BAD DEPENDING ON CONTEXT
EUROPEAN tRNAGln 4336A>G VARIANT BECAME
ESTABLISHED BUT NOW REDISPOSES TO
ALZHEIMER & PARKINSON DISEASE
Haplogroup H5a: Ancient polymorphism
AD = 3.3%,
PD = 5.3%,
AD+PD =
6.8%,
CNTL = 0.4%
ASSOCIATIONS BETWEEN mtDNA HAPLOGROUPS & HUMAN TRAITS
H > J = T > U (Uother > U4 = U5a1 > Uk).
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NEURODEGENERATIVE DISEASES
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Alzheimer Disease
Parkinson Disease
Macular Degeneration
Migraine
Psychiatric Disorders
NEUROLOGICAL DISEASES
– Stoke
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METABOLIC DISEASES
– Diabetes
– Cardiovascular Disease
– Metabolic Syndrome
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INFLAMMATORY & INFECTIOUS DISEASES
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–
–
–
–
–
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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
CYTOPLAMIC MIXING TO INCREASE FERTILITY OF INFERTILE
EGGS HAS CREATED HETEROPLASMY
Father ♂
Sperm
Recipient
oocyte
Egg
♀
ICSI
Donor
oocyte
Ooplasmic
Transfer
Heteroplasmic
zygote
Infertile
Mother
Heteroplasmic
child
Unrelated
Younger
Donor
Differentiated cell
Barritt JA, Brenner CA, Malter HE, & Cohen J. Mitochondria in human offspring from
ooplasmic transplantation. Human Reproduction 16: 513-516 (2001).
HETEROPLASMY BETWEEN mtDNA HAPLOGROUPS CAN CAUSE
NEUROPSYCHIATRIC DISEASES AND LEARNING PROBLEMS
HETEROPLASMY OF TWO “NORMAL” (NZB+129) mtDNAs IS ELIMINATED
LM(TK-) (mtDNA NZB)
Disaggregate
129 Agouti Mice
129 ES Cell Cells
Rhodamine 6G Female ES Cybrids
(Heterplasmic NZB129 mtDNA)
Backcross 129 nDNA (NZB + 129 mtDNAs)
females to B6 males > 9 generations
Female Chimera
Pseudopregnant
mother
MIXING TWO NORMAL MOUSE mtDNAs (NZB + 129) CAUSES
NEUROPSYCOLOGICAL PHENOTYPES
CREATION OF NZB-129 HETEROPLASMIC MICE
BamH A4276G
M
NW
91 “129” vs “NZB” mtDNAs differences: 15 aaΔ +5 tRNA +7 rRNA + 11 CR
0
I
2000
I II
I
4000
II I III II I II III I I
6000
I II III I I I II
8000
I
I II III
10000
I I
II I II IIIII I IIII
12000
II
I
14000
16000
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.
GENERTATION
FROM THE
HETEROPLASMIC
MICE OF
HOMOPLASMIC
DERIVATIVES TO
ASSESS THE
DIFFERENTIAL
EFFECTS OF THE
HETEROPLASMIC
MIXING
NZB-129 HETEROPLASMIC MICE EXHIBIT DIMINISHED ACTIVITY, FOOD
CONSUMPTION, & METABOLIC RATE BUT HEIGHTEN RESPONSE TO STRESS
REDUCED COGNITIVE CAPACITY OF NZB-129 HETEROPLASMIC
MICE
SIMPLY TRANSFERRING
mtDNAs FROM ONE
NUCLEUS TO ANOTHER
HAS MAJOR EFFECTS
ON LEARNING AND
BEHAVIOR
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.
Mitochondrial DNA modifies
cognition in interaction with
nuclear genome and age in mice.
Roubertoux PL et al. (2003)
Nature Genetics 35:65-69
H H
N N
mtH
mtN
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.
A MITOCHONDRIAL ETIOLOGY OF COMPLEX DISEASE
Environmental Factors
Energy Sources
Carbohydrates,
Fats, Amino Acids
Energy Uses
Growth,
Maintenance,
Reproduction
Toxins
Metabolic
Type II Diabetes, Obesity
Hypertension, CVD
Stress
Thermal, Trauma
mtDNA Variants
Ancient Adaptive Polymorphisms
Recent Deleterious Mutations
OXPHOS
DYSFUNCTION
↓ENERGY,↑ ROS,
Δ REBOX, Δ Ca++
mtDNA Damage &
Somatic Mutations
PROGRESSIVE
BIOENERGETIC
DECLINE
Apoptosis
Inflammation, Immunity
MS, Type I Diabetes
(DAMPs)
Infection Predisposition
Sepsis, AIDS
(Zhang Q et al, 2010, Nature 464:104)
Aging
Penetrance & Expressivity
Delayed-Onset & Progression,
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
Cancer
Energy Production,
ROS & Redox