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Developmental Genetics and Pharmacogenetics'


Describe how transcription factors, signaling molecules and ... X. laevis (African clawed frog) D. rerio (zebrafish) C. elegans (nematode), G. gallus (chicken) ... – PowerPoint PPT presentation

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Title: Developmental Genetics and Pharmacogenetics'

Developmental Genetics and Pharmacogenetics.
  • SF 33 Genetics 5
  • R. Daniel Gietz Ph.D.
  • Dept or Biochemistry and Medical Genetics

Learning objectives
  • After this lecture the student should be able to
  • Define the basic concepts of Pattern formation.
  • Describe how transcription factors, signaling
    molecules and Growth factor receptors influence
    human development.
  • Give an example of a birth defect caused by
    disruption of pattern formation.
  • List the 5 data types used in the field of
  • Give an example of a genetic condition that shows
    variability in genotype and drug sensitivity.

Developmental Genetics
  • Birth defects are the most common cause of infant
    death in the USA.
  • 100,000 children born in the USA each year with
    a birth defect.
  • defined as an isolated abnormality or they can be
    one of the more than 2000 genetic syndromes.
  • etiology is unknown however it is estimated that
    a large portion of the caused by mutations in
    genes that control normal development.

Basic Concepts
  • model systems
  • D. melanogaster (fruit fly)
  • X. laevis (African clawed frog)
  • D. rerio (zebrafish)
  • C. elegans (nematode),
  • G. gallus (chicken),
  • M. musculus (mouse),
  • P. hamadryas (baboon).

Model Systems
Model systems are useful for experimentation Muta
genesis screens can be carried out and a large
number of offspring can be analyzed for
abnormalities in embryonic development. Genes
can be mapped and cloned. Many of the genes
identified are evolutionarily conserved. Many of
the genes identified in Drosophila melanogaster
are utilized through out the animal kingdom to
establish the body plan during development.
Concepts in Modern Developmental Biology
  • Morphogenesis ..process of changes in cell shape,
    adhesion, movement, proliferation or cell death
    to give a 3 dimensional structure.
  • Differentiation is the process by which one or
    more clles acquire a specific pattern of gene and
    protein expression characterized by a cell type
    or tissue.

Concepts in Modern Developmental Biology
  • Fate is the quality of a specific region of an
    embryo that will develop the same or similar
  • Different regions of the embryo are described as
    a fate map.
  • The process by which a cell achieves its fate is
    called a developmental program.

Concepts in Modern Developmental Biology
  • A region of an embryo is said to be pluripotent
    if it can give raise to multiple structures.
  • During embryonic development embryonic regions
    become committed to their fate in a two stage
    process of specification followed by
  • Specification is labile determination is not

Concepts in Modern Developmental Biology
  • A cell lineage are the progeny of a particular
    cell. Cells that remain physically adjacent are
    referred to as clones.
  • Cells can have either lineage or position
    dependent development or in other terms cell
    autonomous (not affected by position) or cell
    nonautonomous (affected by position) development.

Concepts in Modern Developmental Biology
  • Embryonic induction is the process that
    determines the fate of one embryonic region after
    receiving a signal from another region.
  • Regulative development is defined by the
    compensation for removal of certain embryonic
    structures by others.
  • Mosaic development describes the process of
    development of different regions that are
    independent of each other.. Embryonic
    development goes from regulative to mosaic.

Figure 17-1
Genes involved in Development
  • The genes required for normal development encode
    many different types of products. These include
    signal transduction molecules such as growth
    factors and their receptors, DNA transcription
    factors, components of the extracellular matrix,
    enzymes, transport systems and other proteins.
    Some examples are given in Table 17-1.

Human developmental abnormalities
Homologue of Drosophila developmental control
Early Development
  • Early development is well understood
  • Due to experiments on mice
  • First cells to differentiate are those that give
    rise to extraembryonic tissues required for
    implantation and formation of the placenta
  • See figure 17-3

Fig 17-3
Early mammalian development
  • Early development is regulative.
  • a portion of the embryo can be lost or removed
    and is still able to develop normally
  • Any cell from the ICM can be removed in the first
    2 weeks via biopsy due to regulative development.
    Low risk of birth defects in first two weeks.

Early Mammalian development
  • Mosaic development refers to when the fate of a
    cell is specified independently from its
  • If something is removed or destroyed what remains
    does not compensate
  • Teratogenic damage during this form of
    development causes harmful effects to fetal
  • Gastrulation is a critical part of development
    marks the beginning of the period when the embryo
    cannot easily compensate for losses or damage.
  • Several organ primordia are allocated from small
    numbers of cells organogenesis is sensitive to

Gene expression and Development
  • How do cells that are identical genetically form
    complex adult organisms composed of many
    different cell types and tissues?
  • What controls the fate of a single cell, making a
    cell differentiate into a brain or liver cell?
  • How do cells organize into discrete tissues?
  • How is the body plan of the organism determined?

Gene expression development
  • Most genes are house keeping genes
  • Some are specialty genes that define unique
    features of different cells.
  • Its the different combinations of genes that
    define each cell type.
  • Many single gene defects have pleiotropic effects
    due to the many different processes they are
    involved with.

Genetic Mediators of Development
  • CBP or Creb Binding protein is an important
    protein for transcription regulation.
  • Is a molecular bridge or co-activator in several
    types of tissues. See Figure 17-4A.
  • Loss of function causes a Dominant mutation

Fig 17-4A
Pleiotropic mutation
  • Rubenstein-Taybi syndrome
  • Caused by loss of function of the CBP or Creb
    Binding Protein causes a dominant mutation.
  • Phenotype is mental retardation with broad thumbs
    and toes accompanies by hirsutism, cyptorchidism,
    congentical heart defect and characteristic
    facial features with down slanting palpebral
    fissures and hypoplastic maxilla and a prominent
    nose see Fig 17-4B.

Fig 17-4B
Cell lineage
  • Once differentiated the phenotype of a cell is
    usually stable thru subsequent divisions
    establishing a cell line.
  • Certain cell lineages require replacement such as
    erythrocytes and platelets and depend on stem
  • Stem cells are said to be pluripotent
  • See Figure 17-5

Figure 17-5
Cell Fate
  • What are the genetic mechanisms that account for
    progressive specification and determination of
    cell fate during development?
  • Not fully understood
  • Models indicate that tissue specific
    transcription factors act in a hierarchical and
    combinatorial networks to specify cell fates
  • Waardenburg syndrome (PAX3) Figure 17-6.

Fig 17-6 A
Fig 17-6B
HOX Genes
  • Hox genes were discovered in D. melanogaster
  • Homeodomain proteins that bind DNA
  • Organized in gene clusters
  • See Figure 17-7

Figure 17-7
HOX mutations
  • Hox gene mutations in mice have been shown to
    produce homeotic transformation of vertebral or
    spinal segments.
  • HOX13 mutations cause synpolydactyly
  • Semidominant causing interphalangeal webbing and
    extra digits in hands and feet.
  • Figure 17-8

Figure 17-8
Paracrine Factors in Development
  • Work in a cell non autonomous fashion
  • Are secreted from cells and elecit a simple on or
    off switch or multiple responses due to the
    concentration gradient.
  • Paracrine Signalling Molecules (Morphogens)
  • 1.Fibroblast growth factors family (FGF FGFRs)
    19 different FGFs,.
  • 2.Hedgehog family (First discovered in the Fly)
  • 3.Wingless (Wnt) family (also discovered in the
  • 4.Transforming Growth Factor B family (TGF-?)

Genetic Mediators of Development
Genetic Mediators of Development
  • Hedgehog family
  • D. melanogaster, vertebrates have Sonic hedgehog,
    (Shh). Receptor is patched
  • Shh binds to patched suppresses transcription of
    the TGF-? and Wnt genes causing cell growth
  • Mutation is the human homologue PATCHED (PTC)
    causes Gorlin syndrome,
  • rib defects, cysts of the jaw and basal cell

Figure 17-10
Genetic Mediators of Development
  • Wnt family
  • D. melanogaster with homologues in vertebrates
  • glycoproteins
  • polarity of the limb for the dorso/vental axis.
    The participate in brain, muscle, gonads and
    kidney development.

Genetic Mediators of Development
  • TGF-? family
  • large group of genes that produce proteins that
    form homo and heterodimers.
  • act in bone formation pathway as well other
    morphogenetic pathways.
  • Mutations in CDMP1 (cartilage-derived
    morphogenetic protein 1) cause various skeletal

Extracellular Matrix proteins
  • serve as scaffolding for all tissues and organs.
  • collagens, Fibrillins, proteoglycans, and large
    glycoproteins such as fibronectin, laminin, and
  • fibrillin-1 - Marfan syndrome
  • elastin supravalvular aortic stenoisis,

One Size Doesnt Fit All
What is it?
  • It is well known everyone does not respond to
    medication the same way
  • Environment, diet, state of health influence
  • Genes also play a critical role
  • Pharmacogenetics is the study of how genes affect
    the way people respond to medication
  • Goal is to tailor medicines to peoples unique
    genetic make ups.

  • the process would include genetic profiling of
    each patient by their physician
  • "personalize" their medicine to treat medical
    problems that may effect them in the future
  • The potential benefits of this are decreased
    adverse reaction to particular drugs.

Glossary of Pharmacogenetic Terms
Pharmacodynamics study of the relationship
between drug concentration and it site of action
and magnitude of effect Pharmacokinetics study
of bodily adsorption, distribution metabolism,
and drug excretion. Drug Chemical or biological
substance used in diagnosis, treatment or
prevention of a disease of phenotype. Molecular
Assay a test which measures a characteristic of
a molecule. Cellular Assay a test which
measures characteristics of a cell. Genotype The
genetic makeup of an individual. Phenotype
Observable characteristics of an individual.
Data important for the field of Pharmacogenetics
1.Clinical outcome variable response to drugs
can cause measureable differences in clinical
endpoints cure, morbidity side effects and
death. 2.Pharmacodynamic and drug response
Genetic variation in drug Targets can cause
measurable response to a drug. Data in this
category document biological and physiological
response. Variation is measured at the whole
organism level. 3.Pharmacokinetics genetic
variation in absorption, distribution
and Metabolism or elimination results in changes
in drug availability. Looks for genetic
variation that leads to variation in drug
Data important for the field of Pharmacogenetics
4.Molecular and cellular Functional Assays
genetic variation can alter these tests and this
may correlate with the organisms variation
in drug response. 5.Genotype Collection of
alleles carried by the organism.
168 variant genes, 417 drugs, 35 pathways, 333
diseases 108 phenotypes.
Some examples Breast cancer therapy some
individuals with a specific genetic Variation in
an enzyme called CYP2D6 do to respond well to
Tamoxifen a common breast cancer drug. Blood
Thinner Dosing differences in the gene VKORC1
Influence how much warfarin is optimal for each
person. This has Lead to faster and more precise
Glucose 6-phosphate dehydrogenase (G6PD)
  • clinical expression of G6PD variants encompasses
    a spectrum of hemolytic syndromes
  • Affected patients are usually asymptomatic,
  • patients have episodic anemia
  • severe hemolysis after exposure to drugs
    (including the antimalarial drug primaquine and
    certain sulfa drugs) or to fava beans

Malignant Hyperthermia
  • is a lifethreatening, acute pharmacogenetic
    disorder, developing during or after a general
  • Chloroform, Ether, Halothane, Enflurane,
    Isoflurane, Sevoflurane, Deflurane
  • Some MH families showed a defect on chromosome
    19, in the ryanodinereceptor

  • disorder in which the body produces too much of
    the chemical porphyrin.
  • cause chest pain, abdominal pain, muscle cramps,
    weakness, hallucinations, seizures,
    purple-red-colored urine, or mental disorders
    like depression, anxiety, and paranoia
  • Attacks of the disease can be triggered by drugs
    (barbiturates, tranquilizers, birth control
    pills, sedatives), chemicals, certain foods, and
    exposure to the sun.

  • Research into Pharmacogenetics will make the drug
    a physcian prescribes more effective and safer.
  • The HGP will aid in the identification of human
    genetic variation involved in variable drug