Non-Mendelian Inheritance Flashcards
<p>define incomplete penetrance</p>
<p>mutations present in everyone, not everyone appears to have the diseaseE.g. familial breast cancergene modifier + environmental trigger = pathogenesis</p>
<p>sporadic cases occur due to</p>
<p>recurrent de novo mutation</p>
<p>imprinting occurs due to</p>
<p>inheritance of variant from appropriate parent genes expressed from only one chromosome expression is determined by the parent that contributed the gene
- i.e. what disease you get depends on which chromosome was doing the expressing</p>
<p>anticipation</p>
<p>triplet repeat expansion</p>
<p>mitochondrial disease occurs due to</p>
<p>maternal inheritance</p>
<p>multigenic inheritance occurs due to</p>
<p>multiple genes of modest risk</p>
<p>mitochondrial inheritance</p>
<p>- have their own genome
- smaller than nu genome
- 93% coding
- maternal inheritance
- polyploidy
- higher natural mutation rate</p>
<p>human mitochondrial DNA</p>
<p>circular shape rather than long and thin like nu DNA</p>
<p>maternal inheritance</p>
<p>- can only be passed on from the mum
- only get mitochondria from mother as they are present in the egg cell only
- if the mother has mutant mitochondrial DNA it is inevitable that her offspring will also inherit it
- however the affected son of the mother won't pass it on</p>
<p>heteroplasmy</p>
<p>Heteroplasmy is the presence of more than one type of organelle genome (mitochondrial DNA or plastid DNA) within a cell or individual.
It is an important factor in considering the severity of mitochondrial diseases.</p>
<p>polyploidy</p>
<p>Polyploidy is the state of a cell or organism having more than two paired (homologous) sets of chromosomes. homoplasmy
- all mitochondiral DNA is identical heteroplasmy
- mixture of 2 populations thresehold level of MtDNA mutants before disease</p>
<p>why is mitochondrial genome a mutational hotspot</p>
<p>- lacks efficient DNA repair system
- lack protective proteins
- associated with inner mitochondrial membrane
- production of oxygen radicals during oxidative phosphorylation</p>
<p>mitochondrial DNA mutations</p>
<p>affecting protein synth mutations in protein coding genes</p>
<p>mitochondrial protein synthesis mutations</p>
<p>single deletions (up to 5-9kb, one or more tRNA genes)
point mutations (rRNA/tRNA genes)
decreased MtDNA protein synth decrease respiratory chain complexes</p>
<p>examples of mitochondrial disease</p>
<p>LHONMELAS</p>
<p>LHON</p>
<p>leber hereditary optic neuropathyrapid, bilateral central vision lossoptic nerve damage onset 2nd/3rd decadetreatable</p>
<p>MELAS</p>
<p>lactic acid build up causes muscle weakness, pain, headaches, vomiting, hearing loss, heart and kidney problems, diabetes and hormonal imbalancestroke like episodes under 40, progressive brain damage</p>
<p>evidence for imprinting</p>
<p>nuclear transplantation studies uniparental diploidy in humans (two copies of the same gamete)
uniparental disomy (one chromosome is doubled up i.e. both are inherited from the same parent)</p>
<p>gynogenote</p>
<p>two maternal genomesrarely leads to the development of new organism normal embryo but doesn't grow properly due to poor membrane and placenta development mass of embyronic tissues, ovarian teratoma</p>
<p>androgenote</p>
<p>two parental genomesabnormal embryo but normal membrane and placenta development mass of placental structure, hydatidiform mole, miscarriage</p>
<p>human models of imprinted disease</p>
<p>angelman syndromePrader-Willi syndromeBeckwith-Weidemann syndrome</p>
<p>angelman syndrome</p>
<p>inappropriate laughterepilepsy awkward gaitsevere mental retardation</p>
<p>Prader-Willi syndrome</p>
<p>hypotonia at birth
- decreased muscle tone short statureinsatiable appetite (marked obesity)
mild-moderate mental retardation</p>
<p>Beckwith-Weidermann syndrome</p>
<p>complex behavioural phenotypescancer</p>
<p>genetic mechanisms in AS and PWS</p>
Deletion, uniparental disomy, imprinting, point mutations
Deletion: chromosome 15q11-13, about 70% of AS and PWS cases, deletion of maternal chromosome (AS), deletion of paternal chromosome (PWS)
Uniparental disomy: paternal UPD
- AS (lacking maternal chromosome 15, about 1-2% of cases), maternal UPD - PWS (lacking paternal chromosome 15, about 25-30% of cases)
Imprinting defect: AS - about 2-4% of cases, maternal chr has paternal imprint, maternal genes silenced. PWS - about 1-3% of cases, paternal chr has maternal imprint, paternal genes silenced
Point mutations: AS - UBE3A gene, ubiquitin ligase, expressed in brain (maternal chromosome only), about 10% of cases. PWS: not seen
molecular defects in PWS and AS
AS: maternal deletion - 70%
paternal UPD - 1-2%
imprinting defect - 2-4%
UBE3A mutation - 10%
PWS: paternal deletion - 70%
maternal UPD - 25-30%
Imprinting defect - 1-3%
two different syndromes but same chromosomal region
polygenic inheritance
common in common diseases
CVD, non-mendelian familial breast cancer and colon cancer
combination of multiple polymorphisms that individually have a small effect
Environmental contribution important
Risk to offspring «_space;mendelian disease
Application in screening and treatment risk Stratification coming
mechanism of genomic imprinting
- Precise mechanism is unclear- Involves multistep process
- First: Chromosome is marked, Parental origin, Occurs in the zygote prior to fusion of the 2 gametes
- Second: Parent of origin mark must be stably maintained
- Third: Parent of origin mark must be identified by transcriptional machinery, Monoallelic expression (somatic cells)
- Finally: Specific to germ cells, Mark must be erased and reset
DNMT and imprinting
- Given semiconservative replication of DNA
- Once DNA is methylated it stays methylated
Provides mechanism for stably maintaining an imprinted gene
methylation and its impact of transcription patterns
- Block expression directly: interfering with transcriptional activator complexes
- Block expression indirectly: recruiting factors that induce chromatin structures
Good model - H19/IGF2 locus
features of ICRs
- Regulate other imprinted genes in the same region
- Differential DNA methylation established in germline and maintained in somatic cells
- Differential histone modification Act as chromatin insulators
define penetrance
the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype).
