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433 Cards in this Set
- Front
- Back
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The neural plate forms during the....
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third week
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The neural plate forms when...
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Cells in the central region of the epiblast are induced to form neural cell precursors.
These cells become columnar in shape and form the neural plate |
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The neural tube forms when...
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As a result of the cellular shape changes to become more columnar, the neural plate starts to fold resulting in neural folds and the creation of the neural groove
Fusion of the neural folds forms the neural tube |
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Neurulation
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the formation of the neural plate and neural tube
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Neuropore formation happens b/c...
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Further fusion of the neural tube proceeds in cranial and caudal directions until it is open only at both ends
These openings are the rostral (anterior) and caudal (posterior) neuropore. |
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The cranial neuropore closes when?
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day 25
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The caudal neurpore closes when?
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day 27
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The wall of the neural tube thickens to form...
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the brain and the spinal cord
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Neural tube closure is complete when?
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By the end of 4 weeks
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Three primary brain vesicles:
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formed by the end of 4 weeks:
prosencephalon (forebrain) mesencephalon (midbrain) rhombencephalon (hindbrain) |
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The 3 part brain flexes:
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Midbrain flexure
Pontine flexure Hindbrain flexure |
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The three primary brain vesicles differentiate into....
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five vesicles as a 4.5-week embryo
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Forebrain consists of
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Telecephalon
Dienchephalon |
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Cerebral hemispheres form from...
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outpockets from the forebrain
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The telecephalon is made of:
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cerebral hemispheres (form as outpockets from the forebrain)
ventricles inside the hemispheres |
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Development of the cerebral hemispheres
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Cerebral hemispheres form from outpockets from the forebrain
Cerebral hemispheres grow rapidly and cover the rest of the brain. |
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Ventricle Development
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In each hemisphere is a ventricle filled with cerebrospinal fluid
These ventricles communicate through a foramen with the diencephalic third ventricle called the interventricular foramen of Monroe |
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Describe the ventricles of the brain:
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There are four ventricles in the brain:
-two lateral in the cerebral hemispheres -the third in the diencephalon -the fourth in the metencephalon. |
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Commissure Formation
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form during Week 16
are numerous connections between the two sides of the brain They are the corpus callosum (biggest), anterior (olfatory bulb),optic chiasma, hippocampal |
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Neural tube Zones:
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the Neural tube has 3 zones:
Ventricular Intermediate Marginal |
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Intermediate zone forms...
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the cortex:
forms the gray matter of brain made of neuronal cell bodies Axons of cells form white matter of brain Gray matter on the outside ; white matter on the inside |
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Cortex growth:
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At first, cortex is smooth
Cortex grows and forms gyri and sulci |
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Sulci
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grooves (furrows)
Lateral and Central sulci |
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Gyri
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are bumps or raised portions of cortex
Serves to increase surface area without increasing the size of the skull |
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Insula
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an inner lobe inside lateral sulcus formed when the cortex overgrows itself
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Choroid Plexus
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a collection of blood vessels in each ventricle that make cerebrospinal fluid (CSF)
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CSF
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made by the choroid plexuses in each of the brain vesicles
circulates from one vesicle to another |
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CSF circulation:
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from the lateral ventricles through the interventricular foramen of Monroe to the third ventricle
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CSF leaves the fourth ventricle through:
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two lateral openings (foramina of Luschka) and one midline opening (foramen of Magendie) in its roof
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arachnoid granulations
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reabsorb CSF
protrude into the dural sinuses and transfer CSF to the venous system. |
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The narrowest part of the CSF circulatory path is....
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in the cerebral aqueduct
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The diencephalon begins to differentiate into:
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the epithalmus
the thalamus the hypothalamus the pituitary gland the pineal gland |
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Epithalmus
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From lateral wall diencephalon
Goes away |
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Thalmus formation
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Develops on each side in the lateral of the diencephalon
Fuses to form a bridge across the 3rd ventricle; Interthalamic adhesion |
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Interthalamic adhesion
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bridge across the 3rd ventricle formed from fusion of the thalmus
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Hypothalamus
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Below thalamus in the lateral wall of diencephalon
Forms the mammillary bodies on the ventral surface of the hypothalamus |
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Pineal gland
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Forms from the roof of the diencephalon
Is cone shaped |
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Pituitary gland
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By 5 week it has a stalk formed from the floor of diencephalon
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Pituitary gland double origin forms...
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2 lobes
Anterior (glandular part) Forms a pars intermedia, pars anterior and pars tuberalis Posterior (neural part) Infundibulum: pars nervosa, median eminence and infundibular stem |
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The midbrain becomes the...
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mesencephalon
The mesencephalon does not split into 2 parts |
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The mesencephalon forms the...
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Forms the Tectum (roof)
Forms the Tementum (floor or carpet) |
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Tectum Components
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Superior and Inferior colliculi
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Tegentum components
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Substantia nigra
Cerebral peduncles |
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The hindbrain forms the:
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Metenchepalon
Myelencephalon |
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Metencephalon
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Pons - Contains cerebellar peduncles
Cerebellum |
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Cerebellum development
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Forms from the metencephalon
The cerebellum forms by 16 weeks |
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Cerebellum Lobes
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Flocculonodular-from archicerebellum
Vermis-from paleocerbellum Anterior lobe-form paleocerbellum Posterior lobe- |
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Cerebellum Central Nuclei
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1. Denate
2. Pontine 3. Vestibular 4. Sensory nuclei of the trigeminal nerve (CNV) |
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Myelencephalon
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Open part
Closed part- Medulla oblongata |
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Medulla oblongata
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Closed part of the myelencephalon
Looks like spinal cord Has alar and basal plates Alar –sensory Basal-motor |
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Alar plates
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Gracile nuclei/tract
Cuneate/tract Olivary nuclei |
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Basal plates of medulla
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pyramids
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Neural tube at 4 weeks
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The neural tube is closed, and neuroepithelial cells form a pseudostratified columnar epithelium.
Neural crest cells are just starting to migrate from the dorsal region of the neural tube. |
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Fiber tracts are organized....
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in the periphery of the spinal cord in a region called the marginal layer (white matter).
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Spinal Cord Nuclei are organized...
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closer to the lumen in a region called the mantle layer.
These nuclei form gray matter |
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SHH
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secreted by the notochord and floor plate regulates development of motor regions of the spinal cord.
Regulates Motor Areas |
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BMPs
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(bone morphogenic proteins), regulate development of sensory areas of the spinal cord.
Initiate the Signaling Cascade for Sensory Areas in the Spinal Cord |
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Neural Crest cells
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Neural crest cells along the spinal cord migrate out of the neural tube after it has closed.
These cells form many structures, including the dorsal root ganglia for spinal nerves. |
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In addition to forming spinal ganglia, crest cells form...
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cells of the adrenal medulla
all of the sympathetic and parasympathetic ganglia the enteric ganglia of the gut (remember hirschsprung’s disease) |
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Cranial nerve pattern is related to...
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segmentation of the rhombomeres.
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The hindbrain is segmented into...
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rhombomeres
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Rhombomeres produce
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neural crest cell populations
motor nuclei for cranial nerves. |
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Regulation of differentiation of the rhombomeres is by...
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HOX genes.
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Most Cranial Nerves Have Their Motor Neurons in...
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the Hindbrain in Specific Rhombomeres
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Sensory ganglia of cranial nerves are derived from
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ectodermal placodes and neural crest cells.
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Ectodermal placodes
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thickenings in the surface ectoderm
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Neural crest cells combine with the four epibranchial placodes to form...
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sensory ganglia for cranial nerves V, VII, IX, and X.
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A spinal nerve is the fusion of...
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a ventral (motor) and a dorsal (sensory) root
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Motor nerve fibers appear...
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Motor nerve fibers arising from the ventro-lateral spinal cord appear at week 4
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The nerve fibers of the dorsal root nerve are formed by...
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axons dervived from neural crest cells.
These neural crest cells become dorsal root ganglia |
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The spinal nerve splits to become
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Dorsal primary rami
Ventral primary rami |
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Limb Plexus
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Ventral primary rami join at the limbs to form plexi
Dorsal divisions of the plexi supply extensor muscles Ventral divisions of the plexi supply flexor muscles |
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Sympathetic
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Neural crest cells migrate along each side of the spinal cord lateral to the vertebral bodies
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Parasympathetic Nervous System
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Arise from neurons in the brain stem and the sacral region of spinal cord
Cranial Sacral |
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Cranial PNS
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CN III- synapses cilliary ganglion
CN VII-synapses pterygopalantine and sub mandibular ganglion CN IX-synapses in otic ganglion CN X-peripheral ganglia in the body |
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Craniopharyngioma
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a type of brain tumor derived from pituitary gland embryonic tissue
arises from rests of odontogenic (tooth-forming) epithelium within the suprasellar/diencephalic region Can compress the optic chiasm |
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Hydrocephalus
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(fluid around the brain)
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Hydrocephalus treatment
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Shunts are inserted into one of the lateral ventricles, and excess fluid is carried by a tube under the skin to the peritoneal cavity or jugular vein.
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Myelomeningocele
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classified as a defect of the neural tube
(also called meningomyelocele), a complex congenital spinal anomaly that causes varying degrees of spinal cord malformation, or myelodysplasia. commonly referred to as spina bifida |
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Neural tube defects are the result of...
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a teratogenic process that causes failed closure and abnormal differentiation of the embryonic neural tube during the first 4 weeks of gestation.
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The most common neural tube defects are....
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anencephaly and myelomeningocele
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The initial event of eye formation is...
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formation of the optic vesicle as an outpocketing from the diencephalon
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The optic vesicle is clearly visible by...
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4 weeks of gestation.
it begins to form before the neural tube has closed |
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The lens placode invaginates until it forms...
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the lens vesicle
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The optic vesicle invaginates until it forms....
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the two-layered optic cup
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Once the optic vesicle reaches the surface ectoderm, it....
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induces the ectoderm to form the lens placode
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The optic stalk invaginates forming...
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the choroid fissure
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hyaloid artery
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grows in through the choroid fissure to supply the lens
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inner layer of the optic cup
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tall and columnar and will form the neural layer of the retina
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outer layer of the optic cup
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more cuboidal and will form the pigmented layer of the retina.
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Eye at 7 weeks
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Posterior cells in the lens vesicle lengthen and differentiate into lens fibers and begin to obliterate the lens cavity.
Eyelids start to form from ectoderm and mesoderm above and below the eye. The optic stalk has closed the choroid fissure and is differentiating into the optic nerve |
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the eyes are not sensitive to light until....
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28 weeks.
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The eye at 15 weeks
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The edges of the optic cup develop into the iris and ciliary body. (not ganglion)
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The edges of the optic cup develop into..
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the iris and ciliary body. (not ganglion)
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The sclera and cornea develop from...
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mesenchyme (most of which is derived from neural crest cells) surrounding the optic cup.
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The anterior chamber is formed between...
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the cornea and iris
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The posterior chamber forms between...
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the lens and ciliary body posteriorly and the iris anteriorly.
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The chambers of the eye are connected via...
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the scleral venous sinus (canal of Schlemm at the iridocorneal angle ).
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Fluid in the eye is produced by...
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the ciliary process in the ciliary body and circulates from the posterior to anterior chambers.
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iridopupillary membrane
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lies anterior to the lens and is a remnant of mesenchyme from formation of the anterior chamber
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Sphincter and dilator pupillary muscles develop from...
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ectoderm at the outer edges of the optic cup.
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Ciliary muscles develop from...
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mesenchyme adjacent to the ciliary body.
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The ciliary body contains...
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the ciliary process
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The ciliary body is connected to the lens by...
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zonula fibers.
Contraction of the ciliary muscles pulls on these fibers and regulates lens curvature |
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The lacrimal glands develop from...
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a number of solid buds in the ectoderm
Small at birth and do not function until 6 weeks after birth |
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The lacrimal glands begin to function at...
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6 weeks after birth
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Tears do not form until...
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1-3 months after birth
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PAX6
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the master gene for eye development and is expressed in the midpoint of the anterior neural ridge during the third week of development
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PAX2
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regulates development of the optic nerve.
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When are Eye Fields Established?
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Early in the 3rd Week with Appearance of the Anterior Neural Ridge in the Neural Plate
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Coloboma
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Colobomas arise when closure of the optic fissure is not completed
Usually only the iris is involved (coloboma iridis), but sometimes the defect extends into the optic stalk |
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Synophthalmia
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fused eyes
Causes for these defects include mutations in SHH, alcohol exposure, and altered cholesterol metabolism in the baby (Smith-Lemli-Opitz syndrome). |
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Otic placode formation
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Signals from the hindbrain during week 3 instruct adjacent ectoderm cells to thicken and form otic placodes
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The otic placodes invaginate to form...
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otic vesicles
These vesicles form dorsal to the 1st pharyngeal pouch and cleft. |
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The otic vesicle forms...
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the membranous labyrinth ( a hearing sac)
This sac becomes the saccule and utricle |
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The Saccule forms..
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the cochlear duct
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The Utricle forms...
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the semicircular canals
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Bony labyrinth formation
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As the membranous labyrinth forms, it induces the surrounding mesenchyme to form bone
This becomes the bony labyrinth |
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The semicircular canals differentiate from...
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the utricular portion of the otic vesicle
These canals are situated at right angles to each other and assist with balance and positioning of the head and body |
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The semicircular canals are innervated by...
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the vestibular ganglion of CN VIII
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Cochlear duct
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(organ of Corti)
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The membranous labyrinth is suspended in...
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fluid called perilymph
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The perilymph surrounding the cochlea is separated into...
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two chambers:
Scala vestibuli Scala tympani |
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The middle ear develops from....
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the first pharyngeal pouch which forms the tympanic cavity and auditory (eustachian) tube
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The ear ossicles are formed from...
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(Malleus, Incus and Stapes)
1st pharyngeal arch forms the malleus and incus 2nd pharyngeal arch forms the stapes |
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The malleus touches...
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the eardrum (tympanic membrane)
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The Incus is in between...
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the malleus and stapes and touches both
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The stapes touches...
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the window of the cochlea.
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Tensor tympani
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moves the malleus
Innervated by CN V3 |
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Stapedius muscles
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move the stapes
Innervated by CN VII |
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Vibrations caused by sound hitting the eardrum are...
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transferred to the ossicles and then to the cochlea.
they set up vibrations in the membranous labyrinth of the cochlea, which are perceived as sound and hearing. |
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The external ear develops from...
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the 1st and 2nd pharyngeal arches
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The external auditory meatus is a derivative of...
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the first pharyngeal cleft (groove)
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The auditory tube is a derivative of...
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the first pharyngeal pouch
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The eardrum forms from...
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the membrane separating the first pouch from the first groove
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The eardrum separates..
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the external acoustic meatus from the middle ear
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The tympanic membrane (eardrum) is covered by...
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ectoderm externally and endoderm internally with a thin layer of mesenchyme between the two layers
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The tympanic membrane is innervated by...
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CNVII (corda tympani n.) and CN IX (plexus leading to lesser petrosal n.)
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Repositions the ears to their normal position:
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Growth of the mandibular component of the first arch posteriorly
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External pinna development:
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Six hillocks appear on the first and second arches
These hillocks then differentiate into all of the complex helices and bumps of the external pinna. |
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Pinna Parts
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Helix
Triangular Fossa Antihelix Tragus Antitragus Lobule Concha |
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Skin at 4 weeks:
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simple ectoderm epithelium over mesenchyme
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Skin at 1-3 months:
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ectoderm basal cell (germinative) division generates stratified epithelium
somite dermatome spreads out under the epithlium differentiates into connective tissue and blood vessels |
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Skin at 4 Months:
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basal cell proliferation generates folds in basement membrane
Embryonic connective tissue (mesoderm)-differentiates into dermis Ectoderm contributes to nails, hair follicles and glands |
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Skin at 5 Months:
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germinative cells of ectoderm form cords in the mammary region
They elongate to form mammary glands. |
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Mammary glands will complete development...
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in females at puberty
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Epidermis consists of...
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a single layer of ectodermal cells that give rise to an overlying periderm layer
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Epidermis becomes...
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3 layers:
Stratum basale Intermediate layer Periderm |
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Periderm
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Undergoes keratinization and desquamation
Continually replaced by cells from basal layer |
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Vernix Caseosa
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formed on the outside of fetus from desquamated cells along with sebum
Protects the fetus from constant exposure to aminotic fluid which has a high urine content |
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Later the 3 Epidermis layers become...
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5 layers:
Stratum basale Spinosum Granulosum Lucidum corneum |
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Melanoblasts (cytes) form from...
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neural crest cells (found in stratum basale)
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Langerhans cells form from...
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bone marrow
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Merkel cells associated with...
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nerve endings
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Epidermis
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Week 4-5 early skin is a single ectodermal layer, stratum germinativum basal layer
Week 11 forms intermediate layer Week 10 epidermal ridges are formed by proliferation |
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Fingerprints
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Lateral plate mesodermal in origin
Forms connective tissue Nerves influence dermal ridge formation |
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Dermis
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At first loosely aggregated mesodermal cells
Cells secrete extra cellular matrix of glycogen and hyaluronic acid Cells differentiate into fibroblasts Vessels and sensory nerves form Will form dermal papillae (Contains tactile Meissner corpuscles) |
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Hair Formation
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Week 12 cells from stratum basale grow into dermis and form hair follicle
Mesodermal cells in dermis form the dermal root shealth and arrector pili muscle Deepest part of follice is hair bulb |
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Hair bulbs invaginated by...
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mesoderm called hair papillae (has blood vessels and nerves)
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Hair shaft made from...
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germinal matrix in hair bulb
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Embryonic Hair Function
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important role in binding the skins waxy protective coating against our water environment
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Hair formation during puberty:
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endocrine regulation by sex hormones
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Nail development
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Develop from epidermis
First develop on digit tips then migrate to dorsal surface Nerves go with nail |
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Skin Glands:
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Mammary
Sweat Sebaceous |
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Mammary glands
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Develop form mammary ridge (ectoderm) into the dermis (mesoderm)
Canalization of the glands form alveloli and lactiferous ducts Lactiferous ducts form nipples |
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Sweat glands
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Develop from downgrowths of epidermis into the dermis
Secrete a watery fluid Have myoepithelial cells that differientiate from the ectodermal gland cells Distributed in axilla, pubic, and nipples |
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Sebaceous glands
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Develop from epithelial wall of hair follicle
elaborate sebum (oily substance) into the hair follicles Will mix with desquamted cells to form the Vernix caseosa |
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Tooth Development
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Develop from ectoderm and underlying neural crest cells
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Dental lamina develops from...
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oral epithelium and grows down into the neural crest cell layer
Dental lamina will make tooth buds which become enamel organs |
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Enamel organs make
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ameloblasts
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Dental sacs are formed by...
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condensations of neural crest cells that surrond the dental papillae
Will form cementoblasts (cementum) and Periodontal ligaments |
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Dental papillae are formed by..
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the neural crest cells
Odontoblasts (dentin) and pulp |
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Melanocytes are found in which layer of epidermis
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basale
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Screening Tests
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noninvasive
cheap, quick low risk to fetus offered to general population no definitive answers, but can ID candidates for diagnostic tests |
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Diagnostic Tests
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invasive
expensive, long time higher risk to fetus performed on high risk populations provide definitive diagnosis |
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The Holy Grail of Prenatal Testing
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Screening and diagnosis as early as possible
Procedures that are as non-invasive as possible Procedures that are as safe as possible for the fetus High sensitivity and specificity |
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Diagnostic sensitivity
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Compares the true positives and false negatives in a clinical test
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High sensitivity test:
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The number of false negatives is very low or non-existent
A negative result is a reliable way to rule out the presence of a disease or condition Negatives are more likely to be true negatives, not false negatives |
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SNOUT:
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“a highly SeNsitive test, when Negative, rules OUT”
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Diagnostic specificity
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Compares the true negatives and false positives in a clinical test
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High specificity test:
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The number of false positives is very low or non-existent
A positive result is a reliable way to confirm the presence of a disease or condition Positives are more likely to be true positives, not false positives |
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SPIN:
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“a highly SPecific test, when Positive, rules IN”
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Accepted Goals of Prenatal Testing
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Detection of birth defects and genetic abnormalities
Prenatal sex determination Identification of high-risk pregnancies Reassurance to high-risk families Information to make decisions Any or all of these can be questionable goals under various circumstances. |
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First trimester Testing
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Chorionic villus sampling (CVS)
First trimester screen (ultrasound, PAPP-A, and b-hCG) |
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Second trimester Testing
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Triple screen (MSAFP, b-hCG, and uE3)
Quad screen (Triple screen plus inhibin A) Penta screen (Quad screen plus h-hCG) Amniocentesis Cordocentesis |
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Third trimester Testing
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Biophysical profile (includes nonstress test and ultrasonography)
Fetal movement monitoring (kick counts, etc.) Contraction stress test Glucose challenge screening and glucose tolerance test Group B Strep test |
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Risk scores
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Represents the chance that the fetus has the disease or condition for which we are screening
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Most common risk threshold used to determine high risk pregnancy:
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1 in 270
Lower than 1 in 270 (e.g. 1 in 100): indicates further testing Higher than 1 in 270 (e.g. 1 in 500): indicates a low-risk pregnancy |
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ACOG Current Guidelines
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ALL pregnant women should be OFFERED screening for Down syndrome regardless of age
Ideally should be done before week 20 Indicates that the noninvasive screening tests are much more reliable than they once were |
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General risk factors for birth defects
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Maternal age at delivery > or = 35 years
Family or personal history of birth defects Previous child with birth defects Use of certain medicines in the early stages of pregnancy Diabetes, high blood pressure, lupus, asthma or allergy Use of illegal drugs or alcohol Multiple fetuses Obesity Ethnicity (Sickle-cell, CF, Tay-Sachs, etc.) |
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Ultrasonography
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Common because it is cheap, widely available, and safe throughout pregnancy
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Ultrasonography Information obtained includes:
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Placental and fetal size
Multiple births Placental abnormalities Abnormal presentations of the fetus Estimation of fetal age (critical for proper interpretation of most screening test results) |
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First Trimester Combined Screen
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Screening for nuchal translucency combined with blood tests for PAPP-A and beta-hCG levels
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Screening for nuchal translucency
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is useful in the late first trimester (weeks 10-12) for possible Down syndrome
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PAPP-A
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Pregnancy-associated plasma protein A
Secreted metalloproteinase that cleaves insulin-like growth factor binding proteins Measured in maternal serum during first trimester |
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Beta human chorionic gonadotrophin (b-hCG)
|
Produced by the syncytiotrophoblast and enters maternal bloodstream
Maintains the hormonal activity of the corpus luteum during pregnancy Basis of most pregnancy tests (shows up in serum by week 2, in urine by week 3) Used in both first trimester and second trimester screens |
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Very high b-hCG levels suggest...
|
a molar pregnancy (genetic problem with the fertilized egg usually)
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High levels b-hCG are associated with...
|
multiple pregnancies
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Very low b-hCG levels are associated with...
|
miscarriage or ectopic pregnancy
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High or low b-hCG levels can both indicate...
|
a miscalculation of gestational age
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Detection of fetal cells in maternal bloodstream
|
Can be detected as early as 8 weeks
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Screening for nuchal translucency
|
is useful in the late first trimester (weeks 10-12) for possible Down syndrome
|
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PAPP-A
|
Pregnancy-associated plasma protein A
Secreted metalloproteinase that cleaves insulin-like growth factor binding proteins Measured in maternal serum during first trimester |
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High PAPP-A levels are associated with...
|
LGA babies
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Low PAPP-A levels are associated with...
|
trisomies 13, 18, and 21, as well as SGA or stillbirth
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Beta human chorionic gonadotrophin (b-hCG)
|
Produced by the syncytiotrophoblast and enters maternal bloodstream
Maintains the hormonal activity of the corpus luteum during pregnancy Basis of most pregnancy tests (shows up in serum by week 2, in urine by week 3) Used in both first trimester and second trimester screens |
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Very high b-hCG levels suggest...
|
a molar pregnancy (genetic problem with the fertilized egg usually)
|
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High levels b-hCG are associated with...
|
multiple pregnancies
|
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Very low b-hCG levels are associated with...
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miscarriage or ectopic pregnancy
|
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High or low b-hCG levels can both indicate...
|
a miscalculation of gestational age
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Detection of fetal cells in maternal bloodstream
|
Can be detected as early as 8 weeks
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Types of fetal cells present in maternal blood include:
|
trophoblasts
lymphocytes granulocytes stem cells nucleated erythrocytes |
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Fetal cell type preferred for testing purposes:
|
Nucleated erythrocytes
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ID of fetal cells in maternal bloodstream by...
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various cell-sorting techniques (immunocytological and FISH)
As few as 1 in 1000 of the cells obtained may be of fetal origin 4-5 fetal cells is enough for most diagnostic procedures |
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Aids to detection of fetal cells in maternal bloodstream...
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Presence of a Y chromosome
Presence of the rhesus D gene (if mother is Rh negative) Presence of embryonic or fetal hemoglobin |
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Kleihauer-Betke (KB) test
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Detects fetal-maternal hemorrhage
Usually used to determine correct amounts of Rhogam needed in cases of erythroblastosis fetalis Blood smears are subjected to an acid bath and then stained Helpful in diagnosis of fetal death, especially involving some kind of trauma |
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Fetal hemoglobin appears/stains...
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is resistant to acid and cells stain rose-pink
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Maternal hemoglobin appears/stains....
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is not resistant to acid and cells appear as “ghosts
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Chorionic villus sampling (CVS)
|
Earliest invasive method of obtaining fetal cells, usually for karyotype analysis
Performed from 10th to 12th weeks Risk of miscarriage is about 1 in 100 (About 1% greater than with amniocentesis) |
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Triple Screen
|
Optimally performed around the 16th week (second trimester)
Interpretation relies heavily on correct gestational age – levels fluctuate significantly |
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Triple Screen measures...
|
Three molecules are measured:
MSAFP (maternal serum alpha-fetoprotein) uE3 (unconjugated estriol) b-hCG (free beta human chorionic gonadotrophin) |
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MSAFP
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Maternal serum alpha-fetoprotein
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Fetal AFP levels
|
Fetal serum: high concentrations, with a peak around 14 weeks
Amniotic fluid: low concentrations normally (High concentrations can indicate NTDs or AWDs) |
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High MSAFP levels can mean:
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Gestational age of the fetus is wrong
More than one fetus is present NTDs AWD Fetus is not alive |
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Low MSAFP levels can mean:
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Gestational age of the fetus is wrong
Trisomy 21 or trisomy 18 Female is not pregnant |
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Higher AFP levels will be seen in:
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African-American women
Diabetic women Obese women |
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Lowest AFP levels in
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Asian women
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AFP as a precursor measurement
|
MSAFP is checked first as part of the Triple Screen, and then fetal AFP levels can be checked as part of amniocentesis (if warranted)
Added benefit: can determine if there is any acetylcholinesterase (AChE) in the aminotic fluid – it should NOT be present normally Correlate AFAFP and AChE levels to detect NTDs and AWD |
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Biochemistry of AFP
|
Appears to be the fetal counterpart of adult serum albumin
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AFP Functions
|
Transport of unidentified small ligands
Immunosuppression Intracellular transport of unsaturated fatty acids Estrogen transport Retinoic acid binding |
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AFP Expression in normal adult cells
|
low to undetectable
p53 binds to the AFP gene and prevents expression Mutations in p53 lead to AFP synthesis |
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High levels of AFP in a non-pregnant adult are usually predictive for...
|
hepatocellular carcinoma
High levels in non-pregnant adults are also associated with cancer of the testes or ovaries, liver disease in general (cirrhosis and hepatitis), or alcohol abuse |
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Unconjugated estriol (uE3)
|
Part of the Triple Screen
Produced in significant amounts only during pregnancy DHEA is made by fetal adrenal glands and metabolized in the placenta to estriol, which crosses into the mother’s circulation and can be detected in blood and urine |
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Low uE3 levels are associated with...
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chromosomal abnormalities (trisomy 21, trisomy 18)
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uE3 levels in the third trimester:
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Normally increase throughout the third trimester
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uE3 levels that drop suddenly suggest...
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a threatened fetus and emergency delivery may be considered
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NTD Triple Screen
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MSAFP high
uE3 Normal b-HCG Normal |
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Trisomy 21 Triple Screen
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MSAFP low
uE3 low b-HCG high |
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Trisomy 18 Triple Screen
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MSAFP low
uE3 low b-HCG low |
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Molar Pregnancy Triple Screen
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MSAFP low
uE3 low b-HCG very high |
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Multiple Fetuses Triple Screen
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MSAFP high
uE3 normal b-HCG high |
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Fetal Death Triple Screen
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MSAFP high
uE3 low b-HCG low |
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Quadruple Screen
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Triple Screen plus Inhibin-A measurement
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Inhibin-A
|
Secreted by placenta and corpus luteum
Downregulates FSH synthesis and inhibits its secretion by the anterior pituitary gland Measured in maternal serum Higher levels are associated with increased risk for trisomy 21 or for preterm delivery |
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Penta Screen
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Quad Screen plus hyperglycosylated hCG (h-hCG)
Improves screening sensitivity over the Triple Screen or Quad Screen but there are large variations in readings Also a useful marker for preeclampsia and other hypertensive disorders in the 2nd and 3rd trimesters |
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h-hCG also known as...
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Invasive Trophoblast Antigen (ITA)
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Elevated levels of h-hCG are associated with...
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trisomy 21 pregnancies
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Amniocentesis
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Second trimester (range 16-20 weeks)
Needle inserted into amniotic cavity and 15-20 mL of amniotic fluid is removed Amniocytes in fluid are cultured for up to 7 days to increase their numbers |
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Amniocentesis Risks:
|
Can be done as early as 11 weeks but this is not generally advised
Higher rates of miscarriage Some evidence of fetal respiratory effects Miscarriage (about 1 in 200) Maternal Rh sensitization |
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Amniocentesis Analysis
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Biochemical assays
DNA-based diagnosis (PCR) Chromosome analysis Karyotyping (slower) FISH (quicker) |
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Cordocentesis
|
Percutaneous umbilical blood sampling (PUBS)
Preferred method to access fetal blood Can be as early as 12 weeks Generally performed after 16 weeks Easiest at 20 weeks and beyond Target is the umbilical vein near the placenta |
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Cordocentesis
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Slightly higher fetal loss rate than either CVS or amniocentesis
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Cordocentesis Use
|
Used for rapid diagnosis of blood diseases (anemia, etc.)
Fetal transfusion can be performed around 20-22 weeks if necessary to get to viability (~24 weeks) Helps distinguish between true fetal mosaicism and false mosaicism |
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Karyotyping
|
Collection of tissue cells and culturing for a preset time (48-72 hours is common although it can be longer)
Treat with colchicine or colcemid to create metaphase arrest Rupture cells using hypotonic saline Stain with appropriate nuclear stain and visualize chromosomes (digitally) |
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FISH
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Fluorescent in situ hybridization
Can be performed on any fetal cell, including cells from 3-day-old embryos (preimplantation genetic diagnosis) Takes about 2 days and detects problems in up to 9 of the 23 chromosome pairs Fluorescently-labeled ssDNA probes bind to denatured chromosomes – visualization via fluorescence microscopy |
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Advantages of FISH over karyotyping
|
Can be used on interphase chromosomes – don’t have to wait for long cell cultures
Able to detect small deletions, insertions, and chromosomal rearrangements (resolution is around 1 Mb) – this is generally not possible in karyotyping |
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Biophysical Profile
|
Third trimester – generally performed after 24-26 weeks
Combines nonstress test and ultrasonography Five fetal attributes are scored; 2 points for each one; 0 if the attribute is not present or inadequate |
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Target Biophysical Profile
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8 or 10 is the target
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Chromosome Abnormalities
|
Important cause of morbidity and mortality
Occur in 1 in 150 live births Leading known cause of: mental retardation pregnancy loss (spontaneous abortions) |
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Spontaneous abortion stats
|
50% in first trimester
20% in second trimeste |
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Cordocentesis
|
Slightly higher fetal loss rate than either CVS or amniocentesis
|
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Cordocentesis Use
|
Used for rapid diagnosis of blood diseases (anemia, etc.)
Fetal transfusion can be performed around 20-22 weeks if necessary to get to viability (~24 weeks) Helps distinguish between true fetal mosaicism and false mosaicism |
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Karyotyping
|
Collection of tissue cells and culturing for a preset time (48-72 hours is common although it can be longer)
Treat with colchicine or colcemid to create metaphase arrest Rupture cells using hypotonic saline Stain with appropriate nuclear stain and visualize chromosomes (digitally) |
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FISH
|
Fluorescent in situ hybridization
Can be performed on any fetal cell, including cells from 3-day-old embryos (preimplantation genetic diagnosis) Takes about 2 days and detects problems in up to 9 of the 23 chromosome pairs Fluorescently-labeled ssDNA probes bind to denatured chromosomes – visualization via fluorescence microscopy |
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Advantages of FISH over karyotyping
|
Can be used on interphase chromosomes – don’t have to wait for long cell cultures
Able to detect small deletions, insertions, and chromosomal rearrangements (resolution is around 1 Mb) – this is generally not possible in karyotyping |
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Biophysical Profile
|
Third trimester – generally performed after 24-26 weeks
Combines nonstress test and ultrasonography Five fetal attributes are scored; 2 points for each one; 0 if the attribute is not present or inadequate |
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Target Biophysical Profile
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8 or 10 is the target
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4 or less Biophysical Profile
|
immediate delivery
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Chromosome Abnormalities
|
Important cause of morbidity and mortality
Occur in 1 in 150 live births Leading known cause of: mental retardation pregnancy loss (spontaneous abortions) |
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Spontaneous abortion stats
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50% in first trimester
20% in second trimeste |
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Eaxmples of Abnormalities in chromosome number
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Trisomies
Monosomies Nondisjunction events |
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Examples of Abnormalities in chromosome structure
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Translocations
Deletions Improper chromosome recombination |
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“Q bands” Banding Technique
|
Quinacrine banding
Requires fluorescence microscopy No longer widely used |
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“G bands” Banding Technique
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Giemsa banding
More commonly used Gives similar results to Q bands |
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“R bands” Banding Technique
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Reverse banding
Helpful for staining the distal ends of chromosomes |
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“C bands” Banding Technique
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Stains constitutive heterochromatin
Localized near the centromere |
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NOR stains Banding Technique
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Highlights Nucleolar Organizing Regions
Targets the stalks and satellites of acrocentric chromosomes |
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Highest concentration of genes in a chromosome is..
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generally toward the telomere
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Less active DNA in a chromosome is...
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generally towards the centromere
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“14q32” =
|
second band in the third region of the long arm of chromosome 14
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Unbalanced Structural abnormalities
|
Causes a gain or loss of genetic material
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Balanced Structural abnormalities
|
No gain or loss of genetic material in the chromosome rearrangement
Usually do not cause problems in the carrier of the abnormality – but may be inherited by offspring and cause serious problems |
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Why do chromosomes suffer structural abnormalities?
|
Improper synapsis and unequal crossing over during Prophase I of Meiosis
Chromosome breakage and rejoining (Areas of increased flexibility and fragility in DNA |
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Clastogens
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physical or chemical agents that increase the rate of chromosome breakage, ie:
Ionizing radiation Benzene, ethylene oxide, arsenic |
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Chromosome rearrangements that occur in meiosis...
|
will be observed in every cell of the individual
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Chromosome rearrangements that occur in mitosis....
|
potentially lead to a mosaic individual
Chromosome rearrangements are rarely seen in mosaic form, so this suggests meiosis, BUT.... |
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ascertainment bias
|
Mosaic individuals typically have a milder phenotype compared to non-mosaic individuals
Mosaicism can be extremely subtle (Limited to one tissue or group of tissues) |
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Translocations
|
Exchange of genetic material between two non-homologous chromosomes
Balanced translocations are among the most common chromosomal abnormalities (as high as 1 in 500) |
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Reciprocal translocations
|
Breaks occur in two different chromosomes and there is a mutual exchange
Leads to derivative (der) chromosomes The carrier of the translocation is usually normal |
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Robertsonian translocations
|
The short arms of two nonhomologous chromosomes are lost
The remaining long arms fuse to form a single new chromosome Occurs only in the acrocentric chromosomes (13, 14, 15, 21, and 22) Carriers of the translocation are normal but their karyotype has 45 chromosomes |
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Familial Down syndrome
|
Accounts for up to 5% of all Down syndrome cases
Robertsonian translocation of 14q and 21q No correlation with increased maternal age The presence of a Robertsonian translocation in one parent does correlate to the risk of Down syndrome in a Mendelian fashion |
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45, XY, der(14;21) (q10,q10)
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Typical carrier karyotype of Familial Down Syndrome
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Deletions
|
Chromosome breaks with loss of genetic material
|
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Terminal deletion
|
includes tip of chromosome
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|
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Interstitial deletion
|
two internal breaks that join with a loss of material in between
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|
|
The most common group of clinically significant chromosome structural abnormalities are...
|
Autosomal deletion syndromes
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|
|
Cri-du-chat syndrome
|
Also known as 5p deletion syndrome
Distinctive cry in infants – becomes less obvious after 2 years of age Deletion of the distal short arm of chromosome 5 – length of the deletion can vary Frequency is 1 in 50,000 live births Phenotype: mental retardation, microcephaly, and characteristic facial appearance |
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TERT
|
(telomerase reverse transcriptase)
Involved in regulation and replacement of the ends of chromosomes (telomeres) |
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|
Wolf-Hirschhorn syndrome
|
4p deletion syndrome
Microcephaly Micrognathia Short philtrum Ocular hypertelorism Growth and mental retardation |
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DeGrouchy syndrome type 1
|
18p deletion syndrome (Only part of the short arm of 18 is deleted)
Growth and mental retardation Slower development of language skills Varying degrees of holoprosencephaly, as well as eye and ear problems |
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|
DeGrouchy syndrome type 2
|
18q deletion syndrome
|
|
|
Hereditary Retinoblastoma
|
13q deletion syndrome
Growth and mental retardation Retinoblastoma |
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|
Microdeletion syndromes
|
Detectable with FISH and CGH
|
|
|
Prader-Willi
|
microdeletions in 15q
Typically a consistent 4 Mb deletion Determined by low-copy repeat sequences at the boundaries of the deletion Repeat sequences promote unequal crossing-over, which leads to the deletion |
|
|
Contiguous gene syndrome
|
microdeletion syndrome
results from deletion of adjacent genes on a chromosome, each causing a different facet of the syndrome |
|
|
WAGR syndrome
|
Wilms’ tumor
Aniridia Genitourinary abnormalities Mental Retardation |
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|
Ring chromosomes
|
Deletions at both ends of a chromosome, with fusion at the ends to form a ring
If the centromere is still present, the ring chromosome can still participate in cell division Ring chromosomes are often lost, leading to monosomy |
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|
Subtelomeric rearrangements
|
Regions near telomeres tend to have a high density of genes
At least 5% of unexplained cases of mental retardation may be due to subtelomeric rearrangements |
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|
1p36 (monosomy 1p36 syndrome)
|
Subtelomeric rearrangement
Moderate to severe intellectual disability Delayed growth Hypotonia Seizures Hearing and vision impairment |
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|
Duplications
|
Caused by unequal crossing-over
Results in a partial trisomy Typically not as serious as translocations or deletions, but it depends on the size of the duplication and the exact genes that are duplicated Thought to be an important engine of evolution |
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Inversions
|
Caused by two breaks in the chromosome but the intervening region simply reverses position
ABCDEFG becomes ABEDCFG |
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|
Pericentric Inversion
|
includes centromere
|
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Paracentric Inversion
|
does not include centromere
|
|
|
Isochromosomes
|
Duplicated chromosomes divide abnormally and create chromosomes with two long arms or two short arms
Isochromosomes of most autosomes are lethal conditions Exception: small acrocentric chromosomes |
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Most isochromosomes observed in live births are...
|
of the X chromosome – resemble Turner syndrome in phenotype
|
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Isochromosomes of 18q resemble...
|
Edwards syndrome
|
|
|
Isochromosomes of 21q resemble..
|
Down syndrome
|
|
|
Generalizations of chromosomal structural abnormalities
|
Most result in developmental delay or mental retardation (As many as 1/3 of all human genes play some role in CNS development)
Most involve alterations of facial morphogenesis that produce characteristic facial features Most produce growth delays Most exhibit accompanying congenital malformations (pleiotropic effects) |
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|
Principle of segregation
|
Sexually-reproducing organisms possess genes that occur in pairs (alleles) and the alleles segregate equally among all the gametes produced by these organisms
|
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Principle of independent assortment
|
Genes at different loci are transmitted independently of each other
Takes into consideration two or more genes, but they must be on two different chromosomes or very far apart on the same chromosome |
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|
Pedigrees
|
Graphical representations of family relationships and the occurrence of a particular disease in the family members
Recurrence risk |
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|
Proband
|
Also known as the propositus or the index case
First person in whom the disease is observed Indicated by an arrow |
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Autosomal dominant conditions
|
Only one dominant allele is required to have the disease
Most affected individuals are heterozygotes Usually seen in every generation Males and females are affected in equal proportions If one parent is affected, then up to 50% of the children may be affected If neither parent is affected, the children have NO chance of being affected |
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|
Autosomal recessive conditions
|
Typically rare in populations but the proportion of carrier individuals can be high (Autosomal dominant diseases typically do not have a carrier state)
Affected individuals must have two parents that are both carriers Usually skips one or more generations Males and females are affected in equal proportions Consanguinity is more often implicated |
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|
Autosomal recessive conditions Recurrence risk If both parents are carriers:
|
25%
|
|
|
Autosomal recessive conditions Recurrence risk If one parent is a carrier and the other is affected:
|
50%
At this point it resembles an autosomal dominant condition – quasidominant inheritance |
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|
Complete dominance
|
Mendel’s idea that the dominant allele could completely mask the effects of the recessive allele if it was present
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Factors that affect expression of disease-causing genes
|
De novo mutation (new mutation)
Variable expression Germline Mosaicism Reduced Penetrance Age-Dependent Penetrance Variable Expression Locus Heterogeneity |
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|
Age-dependent penetrance
|
Delay in the onset of a genetic disease, often into adulthood
Huntington disease (onset typically after age 30) CAG repeats – number of repeats correlates to the age of onset Age of onset tends to be earlier if the father transmits the disease allele |
|
|
Reduced penetrance
|
If 10% of the individuals known to be carriers from pedigree analysis do not exhibit the disease, the penetrance is 90%
Example: retinoblastoma (autosomal dominant) |
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|
Penetrance
|
the proportion of individuals in a population who carry the disease allele AND exhibit the disease phenotype
|
|
|
De novo mutation
|
(new mutation)
Disease has not been previously detected in the family |
|
|
Germline mosaicism
|
Two or more offspring present with a disease not previously detected in the family
One parent has suffered a mutation in some germline cells but not in somatic cells PCR can be used to detect differences in DNA from gametes and somatic cells that would normally express the disease phenotype |
|
|
Variable expression
|
Refers to the degree of severity of the disease phenotype
Parent may have a mild phenotype and the offspring may have a severe phenotype Often related to environmental factors or other genes that influence the expression of the disease allele |
|
|
Locus heterogeneity
|
A single disease phenotype caused by mutations at different loci in different families
Usually due to the presence of two or more gene products that have to interact to produce the normal phenotype Examples: Adult polycystic kidney disease (APKD) Osteogenesis imperfecta |
|
|
Pleiotropy
|
Genes that have more than one discernible effect on the body
Example: Marfan syndrome |
|
|
Consanguinity
|
Relatively common in non-Western populations
Includes uncle-niece and first cousin marriages Relatives more often share disease alleles and are more likely to have offspring affected by autosomal recessive disorders Percentage of shared genes is determined by the coefficient of relationship |
|
|
T/F: Males and females produce essentially the same amount of protein products from the X chromosome
|
True
|
|
|
Dosage compensation
|
Also known as the Lyon hypothesis
One X chromosome (randomly chosen) in each somatic cell of a female is inactivated early in embryonic development All descendents of a particular cell will have the same X chromosome inactivated Females are mosaic with respect to the X chromosome |
|
|
Phenotypic evidence of Dosage compensation
|
Calico cats
X-linked ocular albinism in humans |
|
|
Biochemical evidence of Dosage compensation
|
Alternate versions of enzymes in different cells/tissues
|
|
|
Cytogenetic evidence of Dosage compensation
|
Barr bodies
|
|
|
X Inactivation occurs....
|
7-10 days after fertilization
|
|
|
X Inactivation Begins at...
|
the X inactivation center (1 Mb region) and spreads
Intense DNA methylation and histone deacetylation X inactivation is permanent in somatic cells but must be reversed in germline cells |
|
|
Turner syndrome Genotype:
|
XO
|
|
|
Klinefelter syndrome Genotype:
|
XXY
|
|
|
T/F: X inactivation is incomplete
|
True
Some regions (about 15%) of the X chromosome remain active in ALL copies so they must be present for normal development |
|
|
Sex-linked inheritance
|
Mostly X-linked
X-linked recessive X-linked dominant Y-linked inheritance |
|
|
X-linked recessive inheritance
|
Examples: hemophilia A, Duchenne muscular dystrophy, red-green colorblindness
More commonly seen in males, but females can be affected |
|
|
Issues with X-linked diseases
|
Carrier females can exhibit the disease phenotype, if X inactivation is “lopsided”:
Manifesting heterozygotes Usually mildly affected Females with Turner syndrome (XO) can be affected with X-linked recessive diseases automatically (similar to males) |
|
|
X-linked dominant inheritance
|
Example: hypophosphatemic rickets
Sometimes only observed in heterozygous females Males often suffer from a lethal situation because they are hemizygous |
|
|
X-linked recessive inheritance
|
Never passes from father to son
Affected fathers pass the disease allele to ALL daughters, who become carriers Carrier mothers pass the disease allele to about 50% of sons, who are affected |
|
|
X-linked dominant inheritance
|
Females tend to be twice as commonly affected as males
Affected fathers cannot transmit the disease to sons Affected fathers will transmit the disease to ALL daughters Affected mothers have a 50% chance of transmitting the disease to both sons and daughters |
|
|
Y-linked inheritance
|
Questionable
The Y chromosome does not contain many genes Holandric genes/traits Passed from father to son exclusively |
|
|
Sex-limited traits
|
Occurs in only one sex, usually due to anatomical differences
|
|
|
Sex-influenced traits
|
Occurs in both sexes but more commonly in one
Usually due to sex differences in hormone levels Example: male pattern baldness |
|
|
Mitochondrial inheritance
|
Several copies of mtDNA per organelle
~17 kb, circular dsDNA Inherited exclusively through the maternal line Very high mutation rate (Lack of DNA repair mechanisms, High levels of oxidative damage, Leads to heteroplasmy) mtDNA mutations affect mitochondrial function, which in turn affects tissues and organs that rely on large amounts of ATP production |
|
|
LHON
|
(Leber hereditary optic neuropathy)
Mitochondrial inheritance |
|
|
Euploidy
|
“good set”
Chromosome number is a multiple of 23 (in humans) Haploid gametes and diploid somatic cells are both euploid |
|
|
Polyploidy
|
The individual has a complete extra set of chromosomes (can be any number of sets)
|
|
|
Polyploidy in plants...
|
seedless fruits
|
|
|
Triploidy
|
= 69 chromosomes
Probably accounts for 15% of chromosome abnormalities occurring at conception Generally results in spontaneous abortion |
|
|
Triploidy Caused by:
|
Dispermy (most common cause)
Fusion of an ovum and a polar body Meiotic failure |
|
|
Tetraploidy
|
= 92 chromosomes
Very rare (has been recorded in only a few live births) |
|
|
Aneuploidy
|
Cell contains extra individual chromosomes or lacks them
Total chromosome number is NOT a multiple of 23 eg Monosomy, Trisomy |
|
|
Monosomy
|
one of the chromosome pairs is present in only ONE copy
|
|
|
Trisomy
|
one of the chromosome pairs is present in THREE copies
|
|
|
Autosomal monosomies are...
|
almost always incompatible with life
|
|
|
Autosomal trisomies are...
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also problematic but can be compatible with life (21, 18, 13)
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Most common cause of aneuploidy is...
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nondisjunction during meiosis
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Trisomy 21
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(Down syndrome)
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Trisomy 21 Males vs. Females
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Males are usually sterile; females can reproduce but 40% fail to ovulate
Females have a 50% risk of producing trisomic offspring but risk of spontaneous abortion is the same as in other females |
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95% of Trisomy 21 cases are caused by....
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nondisjunction, usually in the mother
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Most Trisomy 21 cases are regarded as...
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de novo mutations
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Mosaicism in Trisomy 21:
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possible – the extra chromosome 21 can be lost from some cells during mitosis
Often results in a milder phenotype Mosaicism can be widespread or limited to certain tissues/organs |
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Which genes contribute to the trisomy 21 phenotype?
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40% of the genes on 21 have no known purpose
Important region seems to be 21q21 to 21q22.3 |
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DYRK1A
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candidate gene for mental retardation
Causes learning and memory problems in mice when it is overexpressed |
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DSCR1
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overexpressed in the brains of Down syndrome fetuses; plays a role in CNS development
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APP
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amyloid beta precursor protein
associated with some cases of Alzheimer’s disease and Trisomy 21 |
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Trisomy 18
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(Edwards syndrome)
Karyotype: 47, XY, +18 Second most common autosomal trisomy (1 in 6000 live births) BUT more common than Down syndrome at conception 50% of infants die within the first several weeks of life 5% survive to 1 year old More severe developmental difficulties than children with Down syndrome, including an inability to walk independently Significant maternal age effect |
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Trisomy 18 (Edwards syndrome)
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SGA (due to prenatal growth deficiency)
Characteristic facial features Distinctive hand abnormality Small ears and mouth Short sternum Short first toes Congenital heart defects (especially VSDs) Omphalocele Diaphragmatic hernia |
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In most Trisomy 18, cases the extra 18 comes from....
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the mother
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Trisomy 13
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(Patau syndrome)
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Nondisjunction and maternal age
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Two hypotheses:
1.Trisomic pregnancies occur in all females but cannot be as easily detected and spontaneously aborted in older mothers 2. There is an increase in nondisjunction in older mothers due to the age of their oocytes (oocytes are formed during embryonic development) Direct examination of sperm and eggs show that the second hypothesis is probably correct but the exact cause is not known |
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Aneuploidy of sex chromosomes
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Frequencies:
1 in 400 males 1 in 650 females X inactivation tends to make these less severe than autosomal aneuploidies |
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Turner syndrome
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Monosomy of the X chromosome (45, X)
Usually normal intelligence Height can be somewhat improved by growth hormone administration Normal ovaries absent No secondary sexual characteristics Usually infertile, but a small number of Turner syndrome individuals have borne children Extreme phenotypic variation Mosaicism (30-40% show 45, X/46, XX or 45, X/46, XY) Some have Xp deletions (some or all of the p arm) 60-80% of individuals lack the paternal X chromosome 99% do not survive to term |
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Turner syndrome
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Short stature
Ovarian dysgenesis Triangle-shaped face Broad, webbed neck Broad chest Lymphedema of hands and feet at birth Congenital heart and kidney defects |
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Genes involved in Turner syndrome phenotypes:
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A number of candidate genes being examined
SHOX: Encodes a transcription factor expressed in embryonic limbs Found at the distal tip of the X chromosome |
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Klinefelter syndrome
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Karyotype is 47, XXY
Frequency: 1 in 500 to 1000 live births Very mild phenotype in general Often not diagnosed until after puberty or in fertility clinics (adulthood) 48, XXXY and 49, XXXXY have been observed (Still a basic male phenotype; Mental and physical problems increase with each extra X chromosome) Testosterone therapy can be helpful |
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Klinefelter syndrome
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Very mild phenotype in general:
Taller than average males, disproportionately long arms and legs Small testes (usually sterile) Gynecomastia in 1/3 of individuals Intelligence in normal range but associated with learning disabilities |
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Trisomy X
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Karyotype: 47, XXX
Frequency: 1 in 1000 females Mild phenotypic effects (Sterility, Menstrual irregularity, Mild mental retardation) Often first identified in fertility clinics |
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Most Trisomy X cases are caused by....
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nondisjunction in the mother (maternal age contributes)
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47, XYY syndrome
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Frequency: 1 in 1000 males
Tend to be taller than average males with slight reduction in IQ Increased risk of ADHD and learning disabilities Normal testosterone levels Normal sexual development and fertility Violent criminal behavior hypothesis Further research discredited this hypothesis |
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Imprinting
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plays a role in as many as 200 human genes
unless a trait is sex-linked, it makes no difference in the offspring whether an allele is inherited from the father or the mother In many human genes, one allele of the pair is transcriptionally inactive in one parent; normal offspring therefore have only one functional copy of that gene Some similarities with X inactivation |
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Imprinting
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Heavy methylation, especially at the 5’ end
Histone hypoacetylation Inhibition of transcription factors and other proteins important for transcription initiation |
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Prader-Willi and Angelman syndromes
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Caused by a 4 Mb deletion of 15q (15q11-13)
Deletion inherited from father = PWS Deletion inherited from mother = AS |
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Prader-Willi syndrome
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Short stature
Hypotonia Small hands and feet Obesity Mild to moderate mental retardation Hypogonadism Compulsive behavior (skin picking) |
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Angelman syndrome
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Severe mental retardation
Seizures Ataxic gait (“puppet children”) |
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Genetics of
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gene responsible encodes a protein involved in ubiquitin-mediated protein degradation during brain development (Results in mental retardation and ataxia)
This gene is active only on the maternal chromosome in brain tissue; when the chromosome deletion comes from the mother, there is no functional gene remaining |
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Genetics of Prader-Willi syndrome
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A variety of genes involved
OCA2: protein associated with skin and hair pigmentation SNRPN: small nuclear riboprotein complex; important for RNA splicing NDN: encodes nectin; affects growth of neurons and interacts with a number of other gene products snoRNAs: small nucleolar RNAs; important for modifications of other RNA molecules All these genes are active only on the paternal copy of chromosome 15 |
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Beckwith-Wiedemann syndrome
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Imprinting involving chromosome 11
(Can be a deletion or uniparental disomy) “overgrowth” condition LGA, Neonatal hypoglycemia, EMG triad: Exomphalos (omphalocele) Macroglossia (large tongue) gigantism Asymmetrical growth of limbs on one side Tumors (Wilms tumor, hepatoblastoma) |
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Beckwith-Wiedemann syndrome
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Deleted region includes IGF2 (insulin-like growth factor 2)
Normally active in only one copy (paternal is the active copy) Paternal uniparental disomy produces two active copies of the gene, resulting in increased IGF2 levels during development and overgrowth Another region of 11 contains growth inhibitor genes; if they are lost or silenced, they can cause overgrowth indirectly |
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Anticipation
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Genetic diseases can exhibit earlier age of onset and/or more severe expression as they progress through generations
Formerly thought to be an artifact resulting from better and earlier diagnosis Now believed to be a genetic mechanism |
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Myotonic dystrophy
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Autosomal dominant
Progressive muscle deterioration and myotonia Most common muscular dystrophy that affects adults |
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Myotonic dystrophy
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Most cases are caused by mutations in DMPK, a protein kinase encoded on chromosome 19
CTG trinucleotide repeat in the 3’ untranslated portion of the gene 5-37 copies of the repeat = normal 50-100 copies of the repeat = mildly affected Over 100 copies (up to thousands) = full-blown myotonic dystrophy Repeats cause DMPK mRNA to remain abnormally in the nucleus; interferes with proper splicing of other mRNA molecules (pleiotropic effect) |
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Repeat expansion
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Females tend to produce rapid (occurring in one generation) large expansions of the repeat sequences in myotonic dystrophy
Earlier age of onset and increased severity occur with each repeat expansion Repeat expansions are now linked to at least 20 different genetic diseases (including Huntington disease and Fragile X syndrome) Related to anticipation but they can be completely separate phenomena |
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Fragile X syndrome
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Mental retardation
Distinctive facial appearance (Long face, Large ears) Hypermobile joints Macroorchidism in postpubertal males More prevalent in males than females Breaks in the X chromosome when cells are cultured in folic acid-deficient medium |
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Fragile X syndrome
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Disease gene: FMR1 (Fragile X mental retardation 1)
5’ untranslated region contains a CGG repeat 6-50 copies in normal individuals 50-200 copies in “normal transmitting males” (premutation) 200-1000 copies in individuals with fragile X syndrome (full mutation) Female offspring of normal transmitting males can engage in repeat expansion |
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Fragile X syndrome
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Pathology is essentially the same as myotonic dystrophy
Highest levels of FMR1 mRNA expression are in the brain Mutated mRNA accumulates in the nucleus and produces toxic effects In full mutation, FMR1 gene expression can be shut down completely; gene becomes heavily methylated and this correlates to the severity of the disease |
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Gene mapping
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Using crossover information to determine distances between genes
Helpful in estimating rate of recurrence for various diseases |
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Physical mapping
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Various methods to determine the actual physical locations of genes on chromosomes
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Linkage
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Genes in the same region of a chromosome do not follow the principle of independent assortment
Genes are not completely independent particles as envisioned by Mendel; they are inherited as parts of chromosomes |
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Crossing-over occurs during...
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Prophase I of Meiosis
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Recombination frequency
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Measured in centimorgans (cM)
1 cM = 1% recombination = 1 Mb |
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Syntenic loci
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Located on the same chromosome; less than 50 cM apart
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Crossovers are more common during...
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Crossovers are 1.5 times more common during oogenesis than spermatogenesis
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Crossovers are more common near...
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the ends of chromosomes and much less common near the centromere
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LOD scores
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LOD = logarithm of the odds
Helps determine whether a linkage result is due solely to chance Comparison of: Likelihood that two loci are linked at a given recombination frequency Likelihood that two loci are not linked (recombination frequency is 50%) |
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Characteristics of a useful marker
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Codominant
Homozygotes can be distinguished from heterozygotes Numerous Get as close to the disease-causing gene as possible Highly polymorphic Many different alleles of the marker are found in the population |
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Association
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A statistical relationship between two traits in the general population
The two traits occur together in an individual more often than would be expected by chance |
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hereditary hemochromatosis
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association example
Autosomal recessive 78% of patients have the A3 allele of the HLA-A locus 27% of unaffected control subjects have the A3 allele |
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ankylosing spondylitis
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association example
HLA-B27 allele is found in 90% of European-Americans with this disease, but in only 5-10% of the general population Incidence is very low so most people who have the allele do not develop the disease BUT if an individual has the allele, he or she is 90 times more likely to develop the disease than an individual who does not have the allele Tests for diagnosing ankylosing spondylitis can include tests for the presence of HLA-B27 |
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GWAS
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Genome-wide association studies
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Average Distance between SNPs...
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is 3 kb on average
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GWAS Uses
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Useful for looking for genes related to common diseases (diabetes, heart disease, cancer)
Traditional linkage analysis is ineffective in these situations Don’t have to choose which genes to study Don’t have to focus on particular families |
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GWAS Drawbacks
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Spurious associations possible
Have to correct for age, sex, or ethnicity Imprecise definition of the disease state Inadequate sample sizes Other statistical issues |
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Chromosome morphology
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method of physical mapping
Showing that the disease is consistently associated with a cytogenetic abnormality: Heteromorphism |
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Deletion
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Different deletions associated with the same disease
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Translocation Chromosome Morphology
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Interruption of a gene that results in a disease – breakpoints of the translocation can serve to locate the gene
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Dosage mapping Chromosome Morphology
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Deletions and duplications
Reduce gene product to 50% of normal (deletions) or to 150% of normal (duplications) Detection of the gene product (enzymes, proteins, etc.) |
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Somatic cell hybridization
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physical mapping
Cultured mouse and human cells are induced to fuse using Sendai virus or polyethylene glycol Mouse cells are deficient in metabolic enzymes that are provided by genes on human chromosomes Cells begin to randomly delete human chromosomes as they divide Presence or activity of the gene product is correlated with the presence of the human chromosome on which the gene resides Hybridization studies can further pinpoint the location of the gene on one of the chromosomes |
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Positional cloning
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physical mapping
Start with an approximate location of a gene on a chromosome (associated with a marker) Analyze the region of DNA around the location of the marker Difficult because such a region may contain several Mb Cloning and sequencing of the region Human genome project information to help identify possible genes |
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Northern blot analysis
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physical mapping
Looking for mRNA from the gene in tissues associated with the disease phenotype |
