non-mendelian inheritance

Question 1

<p>define incomplete penetrance</p>

Answer 1

<p>mutations present in everyone, not everyone appears to have the disease
E.g. familial breast cancer

gene modifier + environmental trigger = pathogenesis</p>

Question 2

<p>sporadic cases occur due to</p>

Answer 2

<p>recurrent de novo mutation</p>

Question 3

<p>imprinting occurs due to</p>

Answer 3

<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>

Question 4

<p>anticipation</p>

Answer 4

<p>triplet repeat expansion</p>

Question 5

<p>mitochondrial disease occurs due to</p>

Answer 5

<p>maternal inheritance</p>

Question 6

<p>multigenic inheritance occurs due to</p>

Answer 6

<p>multiple genes of modest risk</p>

Question 7

<p>mitochondrial inheritance</p>

Answer 7

<p>- have their own genome

- smaller than nu genome
- 93% coding
- maternal inheritance
- polyploidy
- higher natural mutation rate</p>

Question 8

<p>human mitochondrial DNA</p>

Answer 8

<p>circular shape rather than long and thin like nu DNA</p>

Question 9

<p>maternal inheritance</p>

Answer 9

<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>

Question 10

<p>heteroplasmy</p>

Answer 10

<p>Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases.</p>

Question 11

<p>polyploidy</p>

Answer 11

<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>

Question 12

<p>why is mitochondrial genome a mutational hotspot</p>

Answer 12

<p>- lacks efficient DNA repair system

- lack protective proteins
- associated with inner mitochondrial membrane - production of oxygen radicals during oxidative phosphorylation</p>

Question 13

<p>mitochondrial DNA mutations</p>

Answer 13

<p>affecting protein synth

| mutations in protein coding genes</p>

Question 14

<p>mitochondrial protein synthesis mutations</p>

Answer 14

<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>

Question 15

<p>examples of mitochondrial disease</p>

Answer 15

<p>LHON

| MELAS</p>

Question 16

<p>LHON</p>

Answer 16

<p>leber hereditary optic neuropathy
rapid, bilateral central vision loss
optic nerve damage 
onset 2nd/3rd decade
treatable</p>

Question 17

<p>MELAS</p>

Answer 17

<p>lactic acid build up causes muscle weakness, pain, headaches, vomiting, hearing loss, heart and kidney problems, diabetes and hormonal imbalance
stroke like episodes under 40, progressive brain damage</p>

Question 18

<p>evidence for imprinting</p>

Answer 18

<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>

Question 19

<p>gynogenote</p>

Answer 19

<p>two maternal genomes
rarely 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>

Question 20

<p>androgenote</p>

Answer 20

<p>two parental genomes
abnormal embryo but normal membrane and placenta development

mass of placental structure, hydatidiform mole, miscarriage</p>

Question 21

<p>human models of imprinted disease</p>

Answer 21

<p>angelman syndrome
Prader-Willi syndrome
Beckwith-Weidemann syndrome</p>

Question 22

<p>angelman syndrome</p>

Answer 22

<p>inappropriate laughter
epilepsy
awkward gait
severe mental retardation</p>

Question 23

<p>Prader-Willi syndrome</p>

Answer 23

<p>hypotonia at birth - decreased muscle tone
short stature
insatiable appetite (marked obesity)
mild-moderate mental retardation</p>

Question 24

<p>Beckwith-Weidermann syndrome</p>

Answer 24

<p>complex behavioural phenotypes

| cancer</p>

Question 25

<p>genetic mechanisms in AS and PWS</p>

Answer 25

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

Question 26

molecular defects in PWS and AS

Answer 26

AS: 
maternal deletion - 70%
paternal UPD - 1-2%
imprinting defect - 2-4%
UBE3A mutation - 10%

PWS:
paternal deletion - 70%
maternal UPD - 25-30%
imprinting deect - 1-3%

two different syndromes but same chromosomal region

Question 27

polygenic inheritance

Answer 27

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 &laquo_space;mendelian disease
Application in screening and treatment risk
Stratification coming

Question 28

mechanism of genomic imprinting

Answer 28

• 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

Question 29

DNMT and imprinting

Answer 29

• Given semiconservative replication of DNA
• Once DNA is methylated it stays methylated
  Provides mechanism for stably maintaining an imprinted gene

Question 30

methylation and its impact of transcription patterns

Answer 30

• Block expression directly: interfering with transcriptional activator complexes
• Block expression indirectly: recruiting factors that induce chromatin structures
  Good model - H19/IGF2 locus

Question 31

features of ICRs

Answer 31

• 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

Question 32

define penetrance

Answer 32

the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype).