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119 Cards in this Set
- Front
- Back
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If two monozygotic twins demonstrate 100% concordance what type of genetic inheritance is this?
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completely genetic
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If two dizygotic twins demonstrate 50% concordance, what type of genetic inheritance is this
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completely genetic
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If concordance is greater among monozygotic twins than dizygotic twins, what does this say about whether or not this is a genetic trait?
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there is a component of genetics with the trait
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If the concordance for MZ=DZ what type of genetic inheritance is this?
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totally environmental
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If pyloric stenosis shows concordance for MZ=22% and DZ=2%, is there a significant genetic component?
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yes… MZ>DZ genetic component
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Which of the following has a genetic component? Cleft lip & palate, pyloric stenosis, schizophrenia, insulin dependent diabetes melitus
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all
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What do multiple miscarriages and retardation suggest?
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chromosomal abnormalitites
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What do earlier age of onset and increasing severity with generation suggest? (anticipation… males)
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trinucleotide repeat disease
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What is a compound heterozygote?
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2 different mutant alleles at the same loci, from mom and dad
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If affected individuals are seen in every generation, what does this suggest?
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Dominant inheritance
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What is the probability of the child of an affected heterozygous parent having an effected child?
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50%
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What term does the following define? The range of phenotypic expression seen among family members carrying the same mutation.
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Variable expressivity
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What term does the following define? Individuals carry the disease gene but don not show clinical symptoms (all or none)
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Reduced penetrance
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What type of inheritance is demonstrated with Marfans?
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autosomal dominant with reduced penetrance
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What type of inheritance does Huntington's disease demonstrate?
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Autosomal dominance with age dependent penetrance
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If no male to male transmission occurs, what type of inheritance is suggested and the disease is rarely expressed in females? Why is there no male to male inheritance?
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X-linked recessive… because males get their X from their mothers… and females get two Xs
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What is the chance that the daughter of an affected male of an X-recessive inheritance will be a carrier?
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100%
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What are the odds that carrier females of an X-linked recessive disease will transmit an allele to their… a) son… b) daughter
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both are 50%
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If there is an affected in each generation, both males and females are affected, but there are no male to male transmissions and all of the daughters of an affected male are affected, what type of inheritance is suspected?
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X-linked dominance
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In X-linked dominant, who are more likely to be affected, males or females, why?
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Females are 2X as likely to be affected, because they receive an X from mom and an X from dad
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What is the probability that an affected male will have an affected… a) son… b) daughter
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a) son - zero… b) daughter 100%
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In X-linked dominance inheritance, which gender is more likely to be mildly affected, why?
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females, because they have X-inactivation (mosaic), while males can't switch to another X because they have only one X
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What is anticiaption and which gender is likely to produce this phenomenon?
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a)progressively earlier onset and increasing severity with sucessive generations… b) males
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For Huntington's what are the respective penetrance following CAG repeats? <27 CAG… 27-35 CAG… 36-39 CAG… > 39 CAG
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<27 CAG: Normal… 27-35 CAG: premutation… 36-39 CAG: reduced penetrance… > 39 CAG: complete penetrance
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What is a polymorphism as compared to a mutant allele?
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Polymorphism is an allele that exhibits many forms (at least two different types in the population), while a mutant differs from both wild-type and polymorphic alleles (can be used to indicate diseased gene)
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What does hemizygous mean?
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males having an X and a Y
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What is incomplete dominance?
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when an intermediate for a trait exists between homozygous and heterozygous phenotypes
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What is codomince?
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When the phenotype for both alleles is expressed
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In sickle cell anemia for a heterozyous individual, what type of inheritance is seen with respect to each allele?
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the normal allele is incompletely dominant… the abnormal allele is incompletely recessive… it manifests as a recessive trait
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With resect to inheritance, what is it called when half of the normal protein causes disese?
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haploinsufficient
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What is it called when the abnormal allele interferes with the function of the normal allele?
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Dominant negative effect
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What is it called when the mutant allele is enhanced in one or more of its normal properties? Give two examples.
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simple gain of function… Huntington's and dwarfing condition achondroplasia
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Contrast the following 1) Allelic heterogeneity, 2) locus heterogeneity and, 3) genetic heterogeneity
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1) Allelic Heterogeneity is a different mutation at the same loci, 2) locus heterogeneity are mutations at different loci, 3) Genetic Allelic encompasses both heterogeneity and locus heterogeneity
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Give two examples of locus heterogeneity.
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1) Retinitis pigmentosa (x-linked, autosomal recessive and autosomal dominant forms… and sometimes with retardation) 2) Ehlers-Danlos syndrome [connective tissue collagen being fragile or too elastic] ( x-linked, autosomal recessive and autosomal dominant forms)
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T/F Allelic heterogeneity is defined by a mutation at a given locus that results in a clinically indistinguishable or similar disorders.
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True, but not completely true… these disorders can also be very different
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Give an example of allelic heterogeneity.
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Some mutations in the RET gene can cause Hirschsprung disease (colonic motility/severe constipation) or multiple endocrine neoplasia (dominantly inherited cancer) or both
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Lecture 9
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Which cell type can proliferate (self-renewal) and differentiate into various lineages?
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Stem cell
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a)Which comes first, the progenitor or a determined cell?… b) what is the difference?
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Progenitor --> determined… b) the progenitor has information for identity, but is not stable… the determined cell is now restricted to a cell type but does not yet express the phenotype
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Does a determined cell express its phenotype?
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no
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As cell lineages develop, when will it usually express terminal markers (phenotype)?
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as it differentiate to express terminal markers it will usually coordinate with withdrawl from the cell cycle… which restrict its fate (limit its potential)
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What is believed finally happens in differentiation?
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a one way street (terminal process) that ends in cell death.
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What is special about germ cells?
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the completely differentiate, but they retain some potency
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What mechanism explains stem cell potency?
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repression of differentiation
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What is a fate map?
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Brings understanding to embryology by tracing cell lineages of daughter cells from a progenitor
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How do researchers understand the state of commitment of cell (survive, divide, differentiate or die)?
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experimental Transformation, which reveals the processes of determination and induction
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What is induction?
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cell-to-cell communication (The first critical step in initiating differentiation) that directs cells to new developmental pathways
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What is differentiation?
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The process of commitment of cells to particular fates
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What is a master gene?
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these gene are key regulator transcription factors whose expression drive entire tissue and organ programs in development
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Are these master genes well conserved in animals?
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yes, thus we can look at worms, flies and frogs… and it can be seen in more than one area of the body
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What are the two major mechanisms by which cell identity is established (determination)?
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1. Asymmetric Division: Inheritance of cytoplasmic determinant, thus sister cells are born different 2. Symmetric division: sister cells become different due to influences acting on them
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Cells are primarily differentiated by which process?
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induction
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Why are inductive mechanism important?
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they are important because they ensure that cells and tissues deveop in the proper spatial arrangement, e.g., axis, limbs, etc.
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what is a morphogen
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A protein present in embryonic tissues in a concentration gradient that induces a developmental process over a distance… (e.g., the transplantation of a posterior limb bud can induce the new surrounding cells to differentiate with a new game plan)
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What is sonic hedgehog?
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a diffusible peptide morphogen
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How is the morphogen concentration relevant to development?
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different cell populations will respond differently with differential gene expression based on this gradient
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Do morphogens usually work via passive diffusion?
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No, inhibitor of the morphogen help shape the pattern
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What are/were hegehog, notch, TGFß, and Wnts considered?
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They're now considered inducing reagents… they were once considered peptide growth factors,,, or affectors of the signaling pathways that are regulated by growth factors
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what are the 2 types of stem cells?
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embryonic and adult
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Early in development, which cells layer retains potency and forms the embryo proper and adult tissues, the outer layer (trophecdtoderm) or inner layer (Inner cell mass… ICM) ?
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ICM
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Which cells are totipotent?
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ICM
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What are totipotent (ICM) cells?
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Totipotent cells differentiate into embryonic stem cells, which can be used to generate different lineages
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Where do embryonic stem cells come from?
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ICM
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How can knock-out or knock-in mouse be made using Embryonic stem cells
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inject ES into the ICM of host blastocyte
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What is a chimeric mouse?
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a mouse that has both the characteristics of its own DNA and the DNA from the contributed embryonic stem cell
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What is a progenitor and precusor cells?
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intermediate cells after stem cell, but not terminally differentiated cells that retain some potency
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Characterize adult stem cells (progentor cell, e.g., myloid).
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They are stem cells associated with a particular tissue, like hematopoietic or neural cells
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Are adult stem cells identified morphologically?
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No, they are identified with cell marker using FACS, where a flourescent marker is added to surface receptor
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What is FACS?
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flourescence activated cell sorter
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What device would you purify a cell population to have only adult stem cells ?
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look for cell markers using FACS
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How are animal clones made… and why does this confound our understanding of differentiated cell lines?
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clones are made with adult differentiated cell nuclei… its confounding only in the sense that in vivo cell don't de-differentiate, but this is offset by the fact that these cells still have their entire genome
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What is somatic cell nuclear transfer (SCNT) aka, therapeutic cloning?
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an approached used to generate embryonic stem cells to be used to regenerate tissue
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How is SCNT accomplished
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by taking an embryo and emptying its DNA and replacing it with an adult nucleus --> leading to a nuclear transfer blastocyte… could be used for neuro-degenerative, hamatopoietic and heart disease
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T/F: it will not be possible to grow stem cells from adult tissues.
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False, it may be possible one day
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What is combinatorial control
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the use of a discrete number of transcription factor to control a greater number of gene expression
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What is the process for cloning an animal?
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1) remove the the DNA from the host egg cell…2) Cell fusion or nuclear injection… 3) Cell division… 4) cell division… 5) embryo 6) take this product and embed in the foster mother, or use as ES for therapeutic cloning
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How do you isolate a human embryonic stem cells?
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culture the cells derived from ICM on a feeder layer of irradiated fibroblasts
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What can mesenchymal stem cells be used for?
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Renewal: MSC can be induced to many different cell lines
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Lecture 10
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do hematopoietic stem cells retain potency?
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yes, they can generate all the blood cells including lymphoid and myeloid lineages
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What is the function of Stromal Cytokines?
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Stromal Cytokines activate expression of certain key transcription factors that control the proliferation and differentiation of blood cells.
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What is the major cytokine in blood cell expression?
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Erythropoietin
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What is the key transcriptional regulator for blood cells?
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GATA-1
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How can blood cell progenitor be distinguished from blood cells?
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using colony forming assays and by transplantation
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What often serves as stromal (support cells) for hematopoietic stem cells (HSC)?
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HSC
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How do you define an HSC?
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FACS (or other purification methods) combined with analyzing the long-term repopulation of lethally-irradiated host
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Besides FACS and long-term repopulation of lethally irradiated hosts, what approf quantifying progenitors?
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Colony forming assay (after the fact)
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What is the 3 step sequence of proliferation for multipotent myeloid prgenitor ( in a CFU-mix)
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Progenitor --> Burst forming (BFU-E) --> Colony forming unit (CFU-E) --> erythropoiesis
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What is the first commited erythroid unit?
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BFU-E
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T/F early prgenitors can be identified by morphology.
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False, but their descendant can be identified using culture assay
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Match the 3 key factors required for erythropoiesis to their "forming unit"?
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IL3 (myeloid progenitor) … IL3 + GM-CSF (BFU-E)… GM-CSF + Erythropoietin (CFU-E) … Erythropoetin for erythroid differentiation.
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What purpose does Epo serve in erythroid differentiation?
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Epo is a survival cue (not an instructive signal) and results in massive expansion of CFU-E to reticulocytes and eventually mature erythrocytes that are continuously renewed.
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From which organ is erythropoietin derived?
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kidney
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How does erythropoietin regulate erythropoiesis?
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It activate a specific signal transduction pathway via the Epo receptor expressed on erthroid progenitor cells
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What is the lifespan of a RBC
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100-120 days
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Name a common signaling pathway in blood cell differentiation.
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JAK-STAT
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a) If cytokines share signaling subunits, how is specificity maintained? B) And where do stromal cells enter into this picture?
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a) these pathways appear to play a major role in survival rather than specific differentiation programs, b) Stromal cells signal survival cues (without which the cells will die)
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How were cell autonomous regulators of hematopoiesis (which are often DNA-binding transcription factors that activate cell-specific programs of gene expression) discovered?
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The genes encoding regulatory proteins were discovered in two ways: 1) genetically as leukemia translocation breakpoint and 2) biochemically as a DNA-Binding activity.
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Give an example of a leukemia translocation breakpoint gene that encodes hematopoietic regulatory proteins.
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SCL (Stem Cell Leukemia) gene, which is required for all hematopoiesis
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Give 3 examples of DNA-Binding activity that encodes for hematopoietic regulatory proteins
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GATA-1, which is required for erythropoiesis… and GATA-2, which is required for progenitor cell proliferation… and EKLF, which is required in the final stages of erythropoiesis
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What does SCL (proto-oncogene)
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At what stage is the hematopoietic regulator protein EKLF critical?
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the latest stages of erythropoiesis
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What phenotype is absent in KO mice that don't express the SCL regulatory protein ?
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no blood (expressi n stem cells and red cells)
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What phenotype is absent in KO mice that don't express EKLF DNA-binding protein?
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No adult globin (expressed red cells)
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What phenotype is absent in KO mice that don't express GATA-2 DNA binding protein?
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Almost no blood (expressed progenitors)
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What phenotype is absent in KO mice that don't express GATA-1 DNA binding protein?
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no red cells or megas (expressed red cells and megas)
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What do you end up with if you block GATA-1
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arrested at the pro-erythroblast stage, followed by apoptosis
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What transcription factor is needed for the expression of specific globin genes
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GATA-1
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Is GATA-1 sufficient for erythropoiesis?
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No. While it is needed for the expression of globin in the different developmental stages, it does not determine which globin genes are transcribed.
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In hematopoiesis, what do stromal environmental changes affect?
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during development, these stromal changes result in gene expression
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1) Where does GATA-1 bind? 2) Which of these 3 sites is required for regulating chromatin structure of the locus and is involved in the timely switch from embryonic, to fetal to adult gene expression?
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promoters, enhancers, and Locus control regions (LCR)
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How could globin gene switching help with ß-thalassemia?
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by reactivating the fetal or embryonic globin gene
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Can HSC convert into liver cells?
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yes, perhaps muscle heart and brain as well… however, issues of function and efficency are not completely characterized
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What are 3 current problems with using HSCs as a cell replacement therapy?
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1) not practical because it limited to a rare donor-derived cells… 2) donor cells may fuse to host cells so that transdifferentiation is only apparent… 3) trans-differentiation may require injury to the host cell to get stem cell activity
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What is a consequence of progenitor or blast cells blood cell not being properly regulated?
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Leukemia
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What is CML?
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Chronic myeloid leukaemia, where too many white cells are produced
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what is a common cause of CML?
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chromosomal translocation which fuses the Bcr gene with the c-Abl proto-oncogene (a kinase)… which results in the PHILADELPHIA CHROMOSOME (Ph+) and more importantly deregulation of the cell proliferation pathway
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How does Gleevec work on CML?
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Gleevec binds the ATP pocket of the Abl kinase and inhibits its activity and shuttling off the leukemic fusion protein
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What is a granulocyte?
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A type of white blood cell that fights bacterial infection. Neutrophils, eosinophils, and basophils are granulocytes
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