Genetics #4 - Mitochondrial Inheritance & Haplogroups Flashcards
What does the mitochondrial genome do
Encodes 13 of 87 proteins of the mitochondrial respiratory chain
Describe the structure of the mtDNA
16569-bp ring-shaped double strand that resembles bacterial genomes
Hypothesis for origin of mitochondria
Mito. originated as separate proteobacteria, which were internalised by the cell as endosymbionts
Relationship between replication of mito. genome and the cell cycle
Independent of each other
Where is there a particularly high number of mtDNA copies
In the mature egg cell (> 100,000 copies)
=> mtDNA represents up to 1/3 of the total DNA content of mature egg cells
Relevance of mitochondria that propel the sperm forward
These specific mitochondria rarely, if ever, contribute to the mitochondrial genomic complement of the conceptus
Difference between nuclear and mitochondrial genome
How many genes in mtDNA
What are their functions
37 genes
13 code for proteins of the Ox. Phos. complex
Remaining 24 are transcribed into 22 transfer RNA (tRNA) and 2 ribosomal RNA (rRNA) molecules that are required for protein synthesis within the mitochondria
What genome encodes the mito. proteins
77 of the 90 mitochondrial respiratory chain proteins, and all other mitochondrial proteins, are encoded by the nuclear genome
What are specific import sequences used for
Transporting proteins into the mitochondria
Cause of most mitochondrial disorders
Caused by mutations of the nuclear genome and are inherited according to the classic mendelian rules of inheritance
From whom does the offspring inherit its mitochondria
Mitochondrial inheritance is purely maternal
- The human zygote receives almost all of its mito. from the oocyte because during fertilisation only the head of the sperm (w/o mitochondria) penetrates the egg
- a mother with mutations in mtDNA will transmit this mutation to all of her offspring, while the father with the same mutation in the mitochondrial genome will not transmit this mutation to any of his offspring
How is the mitochondrial genome different from the nuclear genome
the mitochondrial genome, unlike the nuclear genome, does not have a controlled segregation mechanism
mtDNA is replicated independently of the cell cycle, and the individual copies are randomly distributed to the daughter cells during mitosis
Typical pedigree with mitochondrial inheritance of a disorder
Define heteroplasmy
An mtDNA variant is found only in a portion of the cell’s mitochondria
Frequently, both wild-type and mutant mtDNA sequences at the same locus are found when mitochondrial DNA is studied in a patient
Define homoplasmy
All mtDNA copies have the same sequence (e.g. all mtDNA copies contain a particular mutation)
Name the 3 typical features of mitochondrial inheritance
- Reduced penetrance
- Variable expressivity
- Pleitropy
Define threshold effect
Whether a heteroplasmic mitochondrial mutation is actually expressed phenotypically depends on the proportion of the cells’ normal mtDNA to mutated mtDNA
Is there a change in the proportion of normal and mutated mtDNA copies
It may vary considerably in different organs or in the course of successive cell divisions
Symptoms may change over time
What do mitochondrial mutations affect
Either subunits of the Ox Phos complex
OR
In the case of tRNA or rRNA genes, the efficiency of mitochondrial translation and thus also the function of the ox phos complex
What do mito. mutations affect in terms of metabolism
The cell’s energy metabolism and are especially relevant for tissues that require significant energy, such as the central and peripheral nervous system (including the retina), skeletal muscle, heart muscle, the liver, and kidneys
What are the typical symptoms of mito. mutations
encephalopathy
ataxia
myopathy
cardiomyopathy
external ophthalmoplegia
retinal degeneration
renal tubular dysfunction
What happens to affected individuals during light exercise
What would skeletal muscle histology show
have an insufficient oxidative phosphorylation capacity and suffer lactic acidosis
Shows ragged red fibres representing subsarcolemmal accumulation of mitochondria
Heteroplasmy overview
MELAS Syndrome (mitochondrially inherited disorder)
Mitochondrial Encephalopathy
Lactic Acidosis
Strokelike episodes (hemiparesis and hemianopsia)
- Increasing physical limitations because of progressive myopathy
- small stature, migraine, learning difficulties, deafness, DM
- Caused by m.3243A>G in the mitochondrial tRNALeu gene
MERRF Syndrome
Myoclonic Epilepsy with Ragged Red Fibres
Disorder typically presents symptoms in childhood, with myoclonus progressing into
- generalised epilepsy
- Ataxia
- Dementia
- Short stature
- Hearing loss
- Optic atrophy
- Cardiomyopathy
- Caused by m.8344G>A in the mitochondrial tRNALys gene
NARP Syndrome
Neuropathy
Ataxia
Retinitis Pigmentosa
Caused by m.8993T>G or T>C in the ATPase gene
CPEO
Chronic Progressive External Ophthalmoplegia
Caused by large deletions of mtDNA
Kearns-Sayre Syndrome
CPEO
Retinopathy
Ptosis
Deafness
Cardiac Arrythmias
Ataxia
Caused by large deletions of mtDNA
Pearson Syndrome
Anaemia
Pancytopenia
Exocrine pancreatic function disorder
Hepatopathy
Failure to thrive
Caused by large deletions of mtDNA
When should a mitochondrial disorder be considered
If several members of a family have an unspecific, multisystem disorder with involvement particularly of the nervous system and skeletal muscles (even a migraine can be a minimal symptom)
LHON
Leber Hereditary Optic Neuropathy
Not a multisystem disorder but only affects the optic nerve
It involves acute to subacute progressive neuropathy of the optic nerve which typically presents as acute, painless loss of vision, striking “out of the blue”
A large central scotoma occurs
Initially, this is monocular, but within weeks to months, it also affects the 2nd eye
There may be partial recovery but the disorder usually progresses to severe optic atrophy
Males are more frequently affected - gender biased penetrance
Usually occurs between 15-35 but can range from 8-60
Mutations in mtDNA genes coding proteins of complex I of the respiratory chain
Common mutations are m.11778G>A, m.3460G>A, and m.14484T>C
Leigh Syndrome
A severe neurological disorder that usually becomes apparent in the 1st year of life
Typical onset occurs after a viral infection
Progressive loss of mental & movement abilites (psychomotor regression)
Typically results in death within 2-3 years, usually due to respiratory failure
A small number of individuals do not develop symptoms until adulthood or have symptoms that worsen more slowly
The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and dysphagia, which causes failure to thrive
Affected individuals commonly develop hypotonia, dystonia, and ataxia
Peripheral neuropathy is common and makes movement difficult
Weakness or paralysis of the muscles that move the eyes (ophthalmoparesis); rapid, involuntary eye movements (nystagmus); or optic atrophy can occur
Severe breathing problems progress until they cause acute respiratory failure
Some affected individuals develop hypertrophic cardiomyopathy
What substance is found in the blood, urine or CSF of those with Leigh Syndrome
Elevated lactic acid
What is Leigh Syndrome characterised by
MRI necrotizing lesions in the midbrain [basal ganglia (movement); the cerebellum (balance)] and the brainstem (swallowing and breathing)
Bilateral symmetrical degeneration occurs and often is accompanied by demyelination, which reduces the ability of the nerves to activate muscles used for movement or relay sensory information from the rest of the body back to the brain
Occurence of Leigh Syndrome
More common in certain populations
How many genes can the mutation be in
> 75 genes => mito. disorder with the broadest clinical genetic heterogeneity
What is the type of the majority of mutations associated with Leigh’s
What is the most common inheritance pattern
Mostly involves mutations in NUCLEAR DNA (80%) as opposed to mtDNA (20%) - matrilineal, MT-ATP6
Genes associated are involved in the process of energy metabolism
Many of the gene mutations associated with Leigh syndrome reduce or eliminate the activity of proteins in the 5 protein complexes (I-V) of oxidative phosphorylation or disrupt their assembly
However, genes in the pyruvate dehydrogenase (PDH) complex (citric acid (Krebs) cycle) are also involved
=> Leigh’s has different inheritance patterns
Most common = autosomal recessive => both copies of the gene in each cell have mutations (applies to most of Legh syndrome associated genes contained in nuclear DNA)
How can a small number of affected individuals (Leigh’s) inherit it
In an X-linked recessive pattern, including the majority of PDH complex deficiencies
Define haplogroups
- individual branches – or closely related groups of branches – on the genetic family tree of all humans
- A haplogroup is a group of individuals who can trace their ancestry back to a single common ancestor
- Haplogroups pertain to a single line of descent
- As such, membership of a haplogroup, by any individual, relies on a relatively small proportion of the genetic material possessed by that individual
What are the 2 types of haplogroups
What do they indicate
Paternally inherited Y-chromosome DNA (Y-DNA)
Maternally inherited mitochondrial DNA (mtDNA)
Indicate the agnatic (or patrilineal) and cognatic (or matrilineal) ancestry
Why can Y-DNA and mtDNA be used to trace ancestry
because differences that occur in them are due to variation in nucleotide sequence (polymorphisms) over time, as opposed to recombination during crossing over in meiosis
There is no crossing over in mtDNA or in Y chromosomal DNA (except for the PARs), both have a linear pattern of inheritance
What can Y-DNA haplogroups determine
How is this done
Whether 2 apparently unrelated individuals sharing the same surname do indeed descend from a common ancestor in a not too distant past (3 to 20 generations)
achieved by comparing the haplotypes through the Short Tandem Repeat (STR) markers. Deep SNP testing allows to go back much farther in time, and to identify the ancient ethnic group to which one’s ancestors belonged
What is the mitochondrial most recent common ancestor of all living humans
mtMRCA
What sort of DNA is mtDNA
Coding DNA
Hence mtDNA subclades are mostly determined by mutations in the coding region of the DNA
It is possible that one or several mutations found in a particular haplogroup or subclade have a positive or negative effect on health
What are many mtDNA mutations associated with
Energy related conditions but also osteoporosis, Alzheimer’s disease and Parkinson’s disease
