Genetics Ch 22 & 23 Developmental Genetics & Cancer Genetics

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Blind Cave Fish

Some populations of Mexican tetras are blind after 10,000 yrs of living in caves
-lost sight bc there is no need for it bc they live in complete darkness
-result of increased expression of 2 genes (started the loss of sight)
-sonic hedgehog (shh) and tigg

Developmental Genetics

Totipotent: the ability to develop into all cells types including extra-embryonic tissue such as the placenta in mammals (ability to give rise to a complete embryo)
-every cell in a very early embryo is totipotent
-plant and fungal cells often remain toti

Totipotent

The ability to develop into all cells types including extra-embryonic tissue such as the placenta in mammals (ability to give rise to a complete embryo)
-every cell in a very early embryo is totipotent
-plant and fungal cells often remain totipotent

Pluripotent

Develop into any tissue, but could not develop into an embryo
-animal cells become committed to developing into a specific cell type

Determination

A process that often occurs after the 1st few cell divisions of the embryo (also called cell differentiation)
-once cell starts to differentiate that process is irreversible

Cloning of Animals

Cloning experiments w/ frogs date back to the 1950-1960s
-cloning of a mammal was not considered possible since highly differentiate cell could not be "reprogrammed" to fxn as a single-celled embryo
-Dolly the sheep (1997) showed that a terminally differe

How do you build a fruit fly?

How do you go from a single celled, fertilized egg to a highly differentiated, multicellular organism?
-not altering the genome/changing DNA sequences
-but instead changing gene expression

Drosophila Development

3 larval stages-pupal-adult

Initial Stages of Development

Syncytium: results from 9 nuclear divisions w/out cell division
-about 6,000 cells surround the outer surface of the embryo
-pole cells become the germline cells

Different set of genes for each stage of development

Orientation and 3 of body segments and the identity of each individual segment is established by the time the embryo is 10 hrs old
-2 hr embryo: egg polarity genes
-transcripts for egg polarity genes are present in the egg prior to fertilization= maternal

maternal effect genes

Transcripts for egg polarity genes are present in the egg prior to fertilization

Development in Drosophila

A cascade of genes fxn to direct the polarity of body formation and the structures associated w/ individual segment
-many of these genes code for morphogens (proteins), whose concentration gradients affect development of the surrounding regions
-concentra

Morphogens

A cascade of genes fxn to direct the polarity of body formation and the structures associated w/ individual segment
-many of these genes code for this (proteins), whose concentration gradients affect development of the surrounding regions
-concentration c

Establishing Dorsal Ventral Axis

Dorsal protein is distributed (uniformly) thru out cytoplasm in egg prior to fertilization (maternal effect gene)
-after fertilization, dorsal protein is absorbed into the nuclei on ventral side
-dorsal protein is a morphogen that fxns as a transcriptiona

Anterior Posterior Establishment

Bicoid mRNA is in the egg w/ 3' end anchored to the anterior end of the egg
-bicoid protein forms a gradient across the embryo
-high conc. of bicoid protein activates the expression of hunchback gene
-hunchback protein needed for development of head and t

Segmentation Genes

Expression of ~25 segmentation genes is controlled by the conc. gradients for the bicoid and nanos proteins
Mutant larva:
-gap genes= Kruppel
-pair-rule genes= even-skipped
-segment-polarity genes= gooseberry

Gap Genes

Fxn to establish the segmentation pattern
-mutant larva= Kruppel
-mutation of Kruppel causes the elimination of anterior segments

Pair Rule Genes

Fxn in development of pairs of segments
-mutations in fushi tarazu gene cause absence of
odd-numbered segments
-mutant larva= even-skipped
-mutation of even-skipped causes the deletion of
even-numbered segments

Segment Polarity Genes

Fxn in development of each individual segment
-there's a polarity in symmetry to each of the segments and these are being controlled by the segment-polarity genes
-mutant larva= gooseberry
-mutation of gooseberry causes the posterior half of each segment

Homeotic Genes

Fxn to define structures w/in individual segments
-mutations in these genes lead to development of structures in the wrong segment
(makes up the wings, legs, eyes, etc in embryo development)
-expression of these genes are controlled by the conc. gradients

Antennapedia Genes

Mutations in these genes lead to formation legs where the antennae should develop

Bithorax Genes

Mutations in these genes lead to the formation of the 2nd pair of wings, which are usually nonfunctional

Homeobox

Homeotic genes fxn to define structures w/in individual segments
-each gene contains a conserved sequence called this
-180 nucleotide (not) sequence that encodes for 60 amino acids
-forms a helix-turn-helix domain, common in DNA binding proteins
-used to

HOX Genes

Found conserved sequences in all animals that have been examined (1st found in a mouse)
-including nematodes, beetles, sea urchins, frogs, birds, mammals
-even found in plants and fungi
-transcription factors
suggest that these genes arose early in the ev

Homology Btw Homeotic Genes and Mammalian HOX Genes

Mammalian HOX gene homologs occur in the same order along the chromosome as Drosophila homeotic genes
-genes shown in the same color are homologous
-mammalian: there are 4 clusters of Hox genes in mammals, each cluster containing from 9 to 11 genes
-mamma

Apoptosis

Programmed cell death
-most cells have a genetic program for cell death
-a series of proteins called caspases cleave other proteins at specific sites
-eventually, cleavage of an inactive DNAse leads to activation and degradation of the nuclear genome foll

Caspases

A series of proteins that cleave other proteins at specific sites
-eventually, cleavage of an inactive DNAse leads to activation and degradation of the nuclear genome followed by cell death

Apoptosis in Development and Disease

(important in) Some stages in development require the removal of excess cells by apoptosis
-drosophila embryos w/ mutations in genes that trigger capsases and therefore do not have apoptosis die during embryogenesis
-some diseases are affected by excessiv

Eyeless Gene in Drosophila

Mutation was originally discovered in 1915
-recessive mutation causing formation of a small eye
-1993, Walter Gehring showed that the eyeless gene encodes a transcription factor
-engineered a transgene to be expressed in tissue where the gene is normally

Shared Development Pathways

Evo-Devo": is the study of evolution thru developmental pathways
Eyeless gene has counterparts in both the mouse and humans
-in mouse, the gene is called small eye
-in humans, it is the aniridia gene
-once thought that the eyes of insects and mammals evo

Antibody Diversity

Immune system can respond to nearly any antigen encountered
-estimated that mammalian immune system can produce ~10^15 diff antibodies
-how is this achieved w/ no more than 25,000 or so genes in the entire human genome?
-*how can this diversity of antibod

Somatic Recombination

Gene encoding the individual chains of the antibody is composed of segments coding the Variable (V), Joining (J), and Constant (C)
-pre-mRNA has 1 V region, several J regions, and 1 C region
-processing leads to each B-cell producing a unique kappa light

Cancer Genetics

Basically a genetic disease that is not inherited (cancer is a genetic disease)
Most, if not all cancers, result from DNA mutations
-many DNA damaging agents are also carcinogens
-certain cancers are consistently associated a particular chromosomal abnorm

Cancer are multiple hit events

Cancer is the result of a process involving 2/more genetic mutations
-individual may inherit one of the mutations, thus making them more susceptible since fewer additional events are required
-this is why certain cancers appear to plague certain families

Most cancers arise from spontaneous mutations

Cancer affects most individuals later in life since it usually results from random mutations accumulated over a lifetime
-exposure to environmental carcinogens increases the frequency of those random mutations
-increases the probability that the gene, whe

Clonal Evolution of Tumors

A single cell undergoes a mutation that allows abnormal rates of cell division (a clonal event/expansion of cells)
-overtime, cells develop additional mutations that allows them to be even more aggressive and proliferative
-defects in DNA repair pathways

Oncogenes

(cancer causing genes) Cell division is controlled by regulatory processes that both stimulate and inhibit cell division
-dominant mutations that stimulate cell divisions are these
-gain of fxn mutations
-normal genes expressed inappropriately
-proto-onco

Tumor Suppressor Genes

Recessive mutations that inactivate genes that inhibit cell division
-opposite of oncogenes
-loss of fxn mutations
-involved in cancer
-Rb-1= is a tumor suppressor gene (cell cycle checkpoint/control gene)
-the Rb-1 protein fxns to prevent cells from prog

Retinoblastoma

Is a rare childhood disease that is inherited as an autosomal dominant trait
-cells from these patients always show both Rb-1 alleles are mutated
-recessive mutation at the molecular level
-if you inherit a mutation in the Rb-1 gene, there is a 100% chanc

Retina Cells

Retina has ~10^8 cells
-effectively a 100% chance that you have a spontaneous mutation in the Rb-1 gene in at least one retinal cell
-if you inherit a mutated Rb-1 gene, you will have one retinal cell w/ 2 mutant alleles
-the single cell expands to form t

Other Contributions to Cancer

Includes:
-defects in DNA repair genes increase the overall rate of genetic mutations
-mutations affecting chromosome segregation
-mutations affecting DNA methylation, which influences gene expression
-affects on vascularization and metastasis

MicroRNAs and Cancer

Regulate gene expression by degrading specific mRNAs or interfering w/ their translation
-many tumors show a wide range of inhibition of microRNA activity
-may allow oncogenes to be expressed at even higher levels

Chromosomal Mutations

Some cancers are associated w/ specific chromosome mutations
-chronic myelogenous leukemia often involves a reciprocal translocation btw chromosomes 22 and 9
-fuses the BCR gene from chromosome 22 to portion of c-ABL (normal gene)
-fusion protein is more

Viruses

Associated w/ some cancers
-are clearly associated w/ a fairly small 3 of human cancers
-thought to be main source of cancers
-instead they are a minority of cancers
-can mutate and rearrange proto-oncogenes to create oncogenes
-they can also alter expres

Epigenetic Changes in Cancer

Finding changes in DNA methylation and chromatin structure associated w/ many cancer types
-methylation affects gene expression and cancer cells often have abnormal methylation patterns
-hyper-methylation= may repress expression of tumor suppressor genes

hyper methylation

May repress expression of tumor suppressor genes

hypo methylation

Has been shown to affect chromosome stability

Colorectal Cancer

Arises thru a series of mutations in specific genes
-loss of normal tumor suppressor gene APC (recessive mutation)
1. a polyp (small growth) forms on the colon wall
2. a benign, precancerous tumor grows
-activation of oncogene ras (dominant mutation)
3. a