Genetics of Development Flashcards
What is Pierre Robin Sequence?
Patient presents with cleft lip, cleft palate, and small/receding lower jaw.
History of oligohydramnios (low amniotic fluid)
Physical exam will show airway obstruction. Recurrence risk is low and prognosis is pt may need more surgery
What is Treacher-Collins Syndrome?
Mutation in treacle protein
Recurrence risk is high
Family history of similar anomalies and imaging shows multiple craniofacial abnormalities and airway obstruction
What are the genetics in early development?
Regulative phase occurs until end of week 2
Loss of a cell is either compensated or embryo or aborted - all or nothing
Genome is maximally unmethylated at implantation - epigenetic programming starts
How is the primitive streak formed in a developing embryo?
Emergence of primitive streak ends the regulative phase (day 15) - formation of mesoderm
Primitive streak will become notochord and mark anterior/posterior axis
At anterior end of primitive streak is the node
Nodal gene is required for formation of the primitive streak - nodal protein is secreted protein of the TGF-beta family and nodal protein inds to serine kinase receptors in plasma membrane
What is the nodal protein considered?
A morphogen which is a diffusable substance that exerts control over morphogenesis by forming a concentration gradient
How is the dorsal/ventral and left/right axis formed?
Dorsal development is induced by two morphogens secreted from the node: noggin and chrodin
Left/Right asymmetry is supported by cilia that generate a unidirectional current and Asymmetric expression of sonic hedgehog (Shh)
Left/Right asymmetry defects occur rarely
How are patterns formed after axis are developed?
Determined by the Hox genes.
Hox genes encode homeobox binding transcription factors
Each tissue expresses a different combination of Hox genes
Tissue development depends on which set of Hox genes is expressed
Hox code provides positional information - ex. distance from the anterior pole of the anterior/posterior axis
What is epigenetic regulation during development and differentiation?
Developmental methylation
Environmentally induced methylation
Parent of origin specific imprinting
What is developmental methylation in relation to epigenetic regulation?
At time of implantation of embryo, genome is maximally unmethylated. As cell lineages differentiate, even more genomic regions are inactivated
What is environmentally induced methylation in relation to epigenetic regulation?
DNA methylation in response to starvation or stress in first trimester
What is parent of origin specific imprinting in relation to epigenetic regulation?
occurs ar about 200 loci during gametogenesis, chromosomes in egg/sperm have different imprints, some genes turned off in sperm, others turned off in egg, zygote has just one active copy of these genes (parent of origin specific monoallelic expression)
What is parent of origin methylation?
De novo DNA methylation occurs all through development to permanently change gene expression pattern. In first trimester to adapt to environmental influences. During gametogenesis to mark the parental origin of a chromosome (imprinting)
DNA methylation patterns are erased before implantation (erase old developmental pattern) and early in gametogenesis (erase old parent of origin imprint)
What is X chromosome inactivation?
Occurs inindividuals with two or more X chromosomes - 46, XX or 47,XXX or 47, XXY
All but one of the X chromosomes are inactivated
Mediateed by transcript of the XIST gene
DNA is methylated and histones deacetylated
Not complete - some regions escape inactivation
What is the process of X chromosome inactivation?
- In X chromosome inactivating center (gene in XIC on X chromosome designated XIST)
- On the X chromosome to be inactivated, the XIST gene is transcribed
- XIST RNA associates closely with the X chromosome and mediates the inactivation of the most of the chromosome by histone and DNA methylation (some regions escape inactivation and remain active)
What are the cycle of methylation/demethylation of events that occur during development?
- At fertilization, zygote obtains one set of chromosomes with a paternal and maternal imprint. Both chromosomes have their DNA methylation pattern
- Developmental DNA methylation is erased after fertilization and at time of implantation, erasure of developmental DNA methylation is complete but parent of origin imprint remains
- After implantation, new developmental DNA methylation is established
- During gametogenesis, parent of origin specific imprint is erased
- Following sex determination, a new parent of origin imprint is established and depending on the sex of the individual, both chromosome sets have either a male or female imprint. Meiosis produces gametes that have developmental and parent of origin DNA methylation patterns
How is the cause of a defect described?
Described by terms malformation, deformation, dysplasia, and disruption
How is the mechanism by which one defect causes multiple abnormalities?
Described by terms sequence and syndrome
What are malformations and examples?
Malformations result from intrinsic abnormality in the developmental process
Example: Polydactyly often results from errors in HOX signaling during patterning - intrinsic abnormality
What are deformations and examples?
Deformations result from an extrinsic influence on development
Example: Lack of amniotic fluid prevents extension of limbs and impairs development
What is dysplasia and examples?
Dysplasia results from an abnormal organization of cells within a tissue
Example: Hypochondroplasia results from premature ossification of cartilage (similar to achondroplasia)
What are disruptions and examples?
Disruptions result from the destruction of developing tissue
Example: Strings of amniotic tissue can form amniotic bands. Amniotic bands can wrap around limbs, amputate by cutting blood supply
What are syndromes and examples?
Syndromes are caused by a single defect that simultaneously affects the development of different systems
Example: Down Syndrome
What are sequences and examples?
Sequences are caused by a single defect that starts a cascade of events
Example: Pierre Robin Sequence
What are the extents of damage during different developmental stages?
During the first 1-4 weeks (blastogenesis): Multiple major abnormalities in entire embryonic regions
From week 5 - 8: Organogenesis. Abnormalities in specific organs, single major anomalies
After week 9: After organ formation. Mild effects
What is an association?
Group of birth defects that for unknown reasons often occur together
What does VACTERL stand for?
Vertebral defects
Anal atresia
Cardiac abnormalities
Tracheo-Esophageal fistula
Renal abnormalities
Limb abnormalities
What is VACTERL?
An association
very few patients present with all the defects in VACTERL and diagnosis is made when 3 of the abnormalities are found
Defects are thought to occur in the blastogenesis phase of development
Known risk factor: Maternal Diabetes
What are the most common birth defects?
Heart defects
Pyloric stenosis
Neural tube defects
Orofacial clefts
Clubfoot
How is growth regulated?
Development is very tightly regulated
One extra round of cell division early in development is likely fatal
An extra cell division late in developmental can lead to segmental overgrowth
Describe the robustness of development.
Development is a robust process.
Disturbances to the normal developmental process occur regularly and these disturbances can be countered by regulatory mechanisms
Examples: Genetically identical mice with formin mutation, raised under identical conditions. 20% develop bilateral renal aplasia, 80% do not. Renal development depends to a certain extent but not entirely on formin. Formin mutation has reduced penetrance (20%) - not explained by environment and can only be understood if one assumes formin mutation does not cause renal aplaisa, but increases the probability and things like chance are tied into it
