What is bi-allelic expression?
Genes are expressed from both gene copies
Majority of genes show bi-allelic expression
What is aneuploidy?
When does it occur?
Unbalanced number of chromosomes
Due to excess or deficiency of individual chromosomes
Most often arises via non-disjunction of two homologous chromosomes or sister chromatids during cell division
Which full term trisomies and monosomies may appear?
Trisomy: 13, 18, 21, XXY, XXXY, XYY
Monosomy: XO, but no autosomal
What is the major cause of intellectual disability and congenital heart disease?
Trisomy 21: Down Syndrome
What is Edwards syndrome?
Overlapping fingers, club foot, heart defects, developmental disability
How can phenotypes of various severity arise from a trisomy?
May have full trisomy, partial trisomy, or mosaicism, all producing phenotypes of varying severity
Having only one normal copy of a gene is not sufficient to support normal cell function
(e.g. in autosomal dominant inheritance)
What is mono-allelic expression?
Gene must be expressed from only one copy for normal cell function and development
How does monoallelic gene expression occur?
One of the copies is inactivated
X chromosome inactivation: epigenetic modification
Genomic imprinting: epigenetic and genetic modification
What is epigenetics?
Change in gene expression/repression with no chnage in DNA sequence
RNA mediated gene silencing
Are epigenetic changes passed on through cell division?
Cellular 'memory' encoded in chromatin
Why does X chromosome inactivation occur in females?
Gene dosage mechanism
One X chromosome inactivated to ensure the level of expression of X-linked genes is equal in males and females
When does X-chromosome inactivation occur?
Cells of the early embryo
Somewhere between 8-100 cell stage
Describe how X-chromosome inactivation occurs?
Non-coding RNA acting in cis (expressed by X and acts to create a wave of inactivation on the same X)
Is the same X chromosome inactivated in every cell in females?
Females are mosaic (average 50/50)
Is the pattern of X chromosome inactivation hertiable?
What is the inactive X chromosome referred to as?
If X chromosome inactivation occurs, is monosomy X sufficient for normal development?
Turner syndrome (45,X)
Infertility (absent or immature gonadal development)
Absence of secondary sexual development
Imapired neuro function
Are all genes on the second X chromsome inactivated?
Some genes excape X inactivation
Cluster around pseudo-autosomal regiion, and line up well with Y chromosome
What is genomic imprinting?
The process whereby the parental origin of a particular gene is marked by a reversible epigenetic mechanism
Expression of certain genes depends on whether they are inherited from the maternal or paternal gamete
When does genomic imprinting occur?
Uniform pattern in somatic cells of all individuals >
Imprints erased during gametogenesis >
Imprints re-established in mature gametes, maintained during embryogenesis (depending on the sex of the individual)
Approximately how may imprinted genes exist in the human genome?
1-2% protein coding genes
Define parthenogenetic and androgenetic?
Parthenogenetic: all 46 chromosomes from mother
Androgenetic: all 46 chromosomes from father
Describe the outcome of parthenogenetic and androgenetic embryos?
Parthenogenetic: typically non-viable, ovarian teratomas
Androgenetic: Hydatiform moles > malignant choriocarcinoma
Why are parthenogenetic and androgeneitc embryos typically non-viable?
Gene dosage of imprinted genes is disrupted
Are imprinted genes expressed in the same way in every cell?
No, some imprinted genes show differences in tissue and developmental regulation
(e.g. IGF2 is imprinted in many tissues but biallelic expression brain, adult liver and chondrocytes)
Describe the parental conflict hypothesis?
Maternally expressed genes tend to limit foetal growth (resource conservation)
Paternally expressed genes tend to promote foetal growth (resource extraction)
Give three examples of imprinting birth defects?
List four mechanisms by which imprinting disorders may arise?
1) Loss of heterozygosity (large deletions or duplications of regions that contain imprinted genes)
2) Uniparental disomy
3) Epimutation (alteration in epigenetic marks at imprinted loci without alteration in DNA sequence)
4) DNA mutations in genes that are usually imprinted or in imprinting control centres
What is loss of heterozygosity?
Large deletions or duplications of chromosome regions that contain imprinted genes
What is uniparental disomy?
Both copies of a chromosome inherited from the same parent
How can uniparental disomy arise?
1) Meiotic non-disjunction in both gametes
2) Meiotic non-disjunction in one gamete followed by duplication in zygote
3) Loss of one chromosome in zygote and duplication of other chromosome
4) Meiotic non-disjunction in one gamete followed by loss of chromosome in zygote
Descrinbe how loss of imprinting may occur?
Describe the incidence of Beckwith-Wiedemann syndrome?
Which chromosome os affected?
1 in 15000
Chromosome 11 (11p15.5)
Describe the imprinting errors that cause Beckwith-Wiedemann syndrome?
60% epimutation on maternal allele
10% mutation in maternal allele of CDKN1C
1-2% cytogenetically visible depletion or duplication
When is a pregnancy at greater risk of developing Beckwith-Wiedemann syndrome?
If assisted reproductive technologies are used
Which chromsomes are associated with Prader-Willi syndrome and Angelman syndrome?
How does Prader-Willi syndrome arise?
Deletions of paternal 15q11-13 > deficiency of paternally-expressed genes
Maternal UPD > deficiency of paternally-expressed genes
How does Angelman syndrome arise?
Deletions of maternal 15q11-13 > deficiency of maternally-expressed genes
Paternal UPD > deficiency of maternally-expressed genes
Describe the inheritance of mutations in imprinted genes for active paternal or inactive maternal genes?
Carrier males and affected males can have affected children but not carrier children (gene always expressed)
Carrier females and affected females cannot have affected children but can have carrier children (gene never expressed)
Describe the inheritance of mutations in imprinted genes for active maternal or inactive paternal genes?
Carrier females and affected females can have affected children but not carrier children (gene is always expressed)
Carrier males and affected males cannot have affected children but can have carrier children (gene is never expressed)