Genetics #4 - Mitochondrial Inheritance & Haplogroups

Question 1

What does the mitochondrial genome do

Answer 1

Encodes 13 of 87 proteins of the mitochondrial respiratory chain

Question 2

Describe the structure of the mtDNA

Answer 2

16569-bp ring-shaped double strand that resembles bacterial genomes

Question 3

Hypothesis for origin of mitochondria

Answer 3

Mito. originated as separate proteobacteria, which were internalised by the cell as endosymbionts

Question 4

Relationship between replication of mito. genome and the cell cycle

Answer 4

Independent of each other

Question 5

Where is there a particularly high number of mtDNA copies

Answer 5

In the mature egg cell (> 100,000 copies)

=> mtDNA represents up to 1/3 of the total DNA content of mature egg cells

Question 6

Relevance of mitochondria that propel the sperm forward

Answer 6

These specific mitochondria rarely, if ever, contribute to the mitochondrial genomic complement of the conceptus

Question 7

Difference between nuclear and mitochondrial genome

Answer 7

Question 8

How many genes in mtDNA

What are their functions

Answer 8

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

Question 9

What genome encodes the mito. proteins

Answer 9

77 of the 90 mitochondrial respiratory chain proteins, and all other mitochondrial proteins, are encoded by the nuclear genome

Question 10

What are specific import sequences used for

Answer 10

Transporting proteins into the mitochondria

Question 11

Cause of most mitochondrial disorders

Answer 11

Caused by mutations of the nuclear genome and are inherited according to the classic mendelian rules of inheritance

Question 12

From whom does the offspring inherit its mitochondria

Answer 12

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

Question 13

How is the mitochondrial genome different from the nuclear genome

Answer 13

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

Question 14

Typical pedigree with mitochondrial inheritance of a disorder

Answer 14

Question 15

Define heteroplasmy

Answer 15

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

Question 16

Define homoplasmy

Answer 16

All mtDNA copies have the same sequence (e.g. all mtDNA copies contain a particular mutation)

Question 17

Name the 3 typical features of mitochondrial inheritance

Answer 17

1. Reduced penetrance
2. Variable expressivity
3. Pleitropy

Question 18

Define threshold effect

Answer 18

Whether a heteroplasmic mitochondrial mutation is actually expressed phenotypically depends on the proportion of the cells’ normal mtDNA to mutated mtDNA

Question 19

Is there a change in the proportion of normal and mutated mtDNA copies

Answer 19

It may vary considerably in different organs or in the course of successive cell divisions

Symptoms may change over time

Question 20

What do mitochondrial mutations affect

Answer 20

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

Question 21

What do mito. mutations affect in terms of metabolism

Answer 21

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

Question 22

What are the typical symptoms of mito. mutations

Answer 22

encephalopathy

ataxia

myopathy

cardiomyopathy

external ophthalmoplegia

retinal degeneration

renal tubular dysfunction

Question 23

What happens to affected individuals during light exercise

What would skeletal muscle histology show

Answer 23

have an insufficient oxidative phosphorylation capacity and suffer lactic acidosis

Shows ragged red fibres representing subsarcolemmal accumulation of mitochondria

Question 24

Heteroplasmy overview

Answer 24

Question 25

MELAS Syndrome (mitochondrially inherited disorder)

Answer 25

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 tRNA^Leu gene

Question 26

MERRF Syndrome

Answer 26

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 tRNA^Lys gene

Question 27

NARP Syndrome

Answer 27

Neuropathy

Ataxia

Retinitis Pigmentosa

Caused by m.8993T>G or T>C in the ATPase gene

Question 28

CPEO

Answer 28

Chronic Progressive External Ophthalmoplegia

Caused by large deletions of mtDNA

Question 29

Kearns-Sayre Syndrome

Answer 29

CPEO

Retinopathy

Ptosis

Deafness

Cardiac Arrythmias

Ataxia

Caused by large deletions of mtDNA

Question 30

Pearson Syndrome

Answer 30

Anaemia

Pancytopenia

Exocrine pancreatic function disorder

Hepatopathy

Failure to thrive

Caused by large deletions of mtDNA

Question 31

When should a mitochondrial disorder be considered

Answer 31

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)

Question 32

LHON

Answer 32

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

Question 33

Leigh Syndrome

Answer 33

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

Question 34

What substance is found in the blood, urine or CSF of those with Leigh Syndrome

Answer 34

Elevated lactic acid

Question 35

What is Leigh Syndrome characterised by

Answer 35

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

Question 36

Occurence of Leigh Syndrome

Answer 36

More common in certain populations

Question 37

How many genes can the mutation be in

Answer 37

> 75 genes => mito. disorder with the broadest clinical genetic heterogeneity

Question 38

What is the type of the majority of mutations associated with Leigh’s

What is the most common inheritance pattern

Answer 38

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)

Question 39

How can a small number of affected individuals (Leigh’s) inherit it

Answer 39

In an X-linked recessive pattern, including the majority of PDH complex deficiencies

Question 40

Define haplogroups

Answer 40

• 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

Question 41

What are the 2 types of haplogroups

What do they indicate

Answer 41

Paternally inherited Y-chromosome DNA (Y-DNA)

Maternally inherited mitochondrial DNA (mtDNA)

Indicate the agnatic (or patrilineal) and cognatic (or matrilineal) ancestry

Question 42

Why can Y-DNA and mtDNA be used to trace ancestry

Answer 42

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

Question 43

What can Y-DNA haplogroups determine

How is this done

Answer 43

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

Question 44

What is the mitochondrial most recent common ancestor of all living humans

Answer 44

mtMRCA

Question 45

What sort of DNA is mtDNA

Answer 45

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

Question 46

What are many mtDNA mutations associated with

Answer 46

Energy related conditions but also osteoporosis, Alzheimer’s disease and Parkinson’s disease