Non-Mendelian Inheritance Flashcards
What are the three types of nonmendelian inheritance?
- Mitochondrial
- Mosaicism
- Epigenetic (including imprinting)
What is the law of segregation?
Maternal allele contribution = paternal allele contribution
What is epigenetics? What induces it?
Study of heritable changes in gene expression, which occur without changing the nucleotide sequence. May be induced by environment, aging, or disease state
“change in phenotype without a change in genotype”
What are three ways in which epigenetic change can occur?
- DNA methylation
- Histone modification + other chromatin changes
- Repressor proteins which bind to silencer regions of DNA
Is the imprinted gene turned on or off? What percentage of the genome does this comprise? When does this happen?
Turned off, comprises 1% of genes. The tag is placed via methylation during spermatogenesis or oogenesis to modulate gene expression in developing embryo
What is the imprint erased and re-established? What determines the imprinting pattern?
Erased in germline cells, and re-established during gametogenesis for the next generation.
Imprinting pattern determined by sex of parent. So, a chromosome in a female which was previously paternally imprinted will become maternally imprinted in next generation
How do we know that maternal chromosomes must play a large role in the development of the fetus?
In Diandry trisomies, fetuses have severe intrauterine growth retardation and syndactyly (most common type of trisomy)
How do we know that paternal chromosomes must play a large role in the development of the placenta?
In Digyny trisomies, there is a small, underdeveloped placenta. Furthermore, in diandry trisomies, there is a “large, cystic placenta”
What causes Prader-Willi syndrome?
A deletion of 15q11-13 in a paternally imprinted chromosome. This causes the loss of maternally-imprinted gene expression
What characterizes Prader-Willi?
Hypotonia and poor feeding in infancy, followed by obesity with hyperphagia in childhood. Will also have hypogonadism and intellectual disability, with short stature
What causes Angelman syndrome?
A deletion of 15q11-13 in a maternally imprinted chromosome. This causes the lack of expression of paternally-imprinted genes.
What characterizes Angelman syndrome?
Intellectual disability, microcephaly, unusual/frequent laughter, ataxic movement, and seizures
How might uniparental disomy cause a problem in gene expression?
If the chromosome which is inherited from the parent has imprinted genes, certain genes will be lost or over-expressed depending on the parent who gives it
What is the usual cause for uniparental disomy? How often does this happen?
Trisomic rescue, when the embryo ejects a trisomic chromosome but that includes the only one from a parent (happens about 1/3 of time in trisomic rescue)
What are two other causes for uniparental disomy?
- Monosomic rescue - duplication of a single chromosome in a monosomic embryo
- Gamete complementation - a gamete from one parent was going to lead to a trisomy, whereas the other was going to lead to a monosomy.
These are VERY rare
What does maternal UPD for chromosome 15 cause?
Prader-Willi syndrome -> loss of maternally expressed. Same as a deletion on paternal 15
What does paternal UPD for chromosome 15 cause?
Angelman syndrome -> loss of paternally expressed. Same as a deletion on maternal 15
What causes segmental UPD?
A post-zygotic (somatic) recombination error
What is the best known example of segmental UPD? What are its features?
Beckwith-Wiedemann syndrome. This is caused by 11p paternal UPD.
Features: Overgrowth, hemihypertrophy, macroglossia (large tongue), abdominal wall defects + embryonal tumors. Basically, an overgrowth syndrome.
Other than imprinting disorders, what does UPD put you at a higher risk for?
Autosomal recessive disorders, since if the parent has the autosomal recessive disorder, giving both their chromosomes will definitively result in the disease.
How can a carrier of an autosomal recessive disorder cause the disorder with a non-carrier mate? What is heterodisomy?
Isodisomy UPD -> nondisjunction in meiosis 2. Sister chromatids are inherited.
Heterodisomy -> nondisjunction in meiosis 1 causes non-identical homologous chromosomes to be inherited.
Both would need trisomic rescue to occur after fertilization.
What is an example of a single gene disorder which can cause Angelman syndrome differentially depending on who inherits it?
UBE3A gene on chromosome 15p11.2 is paternally imprinted. If inherited from father, everything is normal. If inherited from mother, gene is not silenced, and there will be no working copies of UBE3A in the offspring -> leads to 11% of Angelman syndrome.
What is the definition of a mitochondrial disease?
Group of disorders that arise from a dysfunction of mitochondrial respiratory chain, caused by a mutation in EITHER nuclear DNA or mitochondrial DNA
(only 10-15% is due to mtDNA dysfunction)
What tissues are most susceptible to mitochondrial disease? When can these diseases first appear?
Tissues highly dependent on oxidative metabolism.
Typically, eyes, heart, and CNS.
Mitochondrial disease can appear at any age.
What is the only respiratory complex which is encoded by exclusively nuclear proteins?
Complex II.
All others, including ATP synthase, have contributions from both mitochondrial and nuclear DNA
What is one uncommon role of mitochondria?
Calcium homeostasis
How many genes are encoded by mtDNA, and what do they do? How are they inherited?
37 genes. 13 are for ETC components, 24 are for translation components.
They are only inherited from mother to child
What is the primary explanation for the clinical variance in mitochondrial disease?
Heteroplasmy - each cell has 100s of mitochondria, and there are 2-10 circular copies of DNA per mitochondria. The mutant mtDNA is expressed to varying degrees in each person and each tissue, and must exceed a certain threshold to cause biochemical disease
What contributes to variance in the inheritance of mitochondrial disease?
the bottleneck effect -> if the fetus gets unlucky, and the mother’s ovum contains an unlucky proportion of mutant mitochondria, they will have much more severe disease than an egg with fewer copies of mutant mtDNA
What characterizes MELAS?
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
Stroke-like episode before the age of 40, encephalopathy characterized by seizures or dementia, lactic acidosis / red fibers, and at least two of the following: normal, early development, recurrent headaches, or recurrent vomiting.
What characterizes Kearns-Sayre syndrome?
Multisystem mtDNA disorder, affects skeletal muscle, CNS, and heart. Causes progressive external ophthalmoplegia (starting before age 20), pigmentary retinopathy, and heart block. Thus, eye paralysis and vision loss. Die in 3rd or 4th decade
What is MERRF? How is it pathologically identified?
Myoclonic Epilepsy associated with Ragged Red Fibers
Myoclonus, seizures, cerebellar ataxia, and ragged red fibers on muscle biopsy due to replication of mitochondria in an attempt to compensate (seen with Gomoroi stain)
Name the mtDNA disorder: Acute, unilateral central vision loss followed by loss of vision in the other eye within weeks
LHON: Leber Hereditary Optic Neuropathy
Reduced penetrance, with males 4-5 times more likely to be affected. Onset is 18-30 years.
What is the cause of most mitochondrial disease?
Autosomal recessive mutations inherited from either parents. Only 10-15% is caused by mtDNA
Where do you search for abberant mtDNA?
In skeletal muscle DNA, rather than blood. Need to have tissue which is rich in mitochondria
What are ways to diagnose mitochondrial diseases other than targeted mutation testing?
- Supportive biochemical features - blood or CSF lactate, acylcarnitine profile, or urine organic acids
- Look for multisystem involvement
- Muscle biopsy for ETC studies, as well as mtDNA extracted from muscle
- Molecular testing of panels of nuclear and mtDNA genes, which is now a MORE COMMON DIAGNOSTIC APPROACH
What is difficult about genetic testing for mitochondrial disease? Prenatally?
Often sporadic, single mitochondrial DNA deletions. Predisposition to form multiple mtDNA deletions can be inherited
Prenatally: Can be difficult because CVS sampling does not definitively correlate with amount of mtDNA mutated. If the mutation is known in the family, it is easier to screen prenatally.
