Genetics Topic 12 Flashcards

Transcription Factors

act by stabilizing the assembly of the basal transcription apparatus

• bind to consensus sequences (RE’s) in regulatory promoters and enhancers

• opposite of an enhancer sequences is a silencer DNA sequence

• result of a long series of events traceable to the origins of the organism as a single cell

Repressor proteins

bind to silencer DNA and inhibit transcription

Developmental Biologists

seek to trace these long chains of causality, identifying the signals and interactions that lead to the expression of specific sets of transcription factors in particular cell types

Morphogens

allow cells to determine where they are in the body

• synthesized locally and diffuse and act over long distances to induce cellular responses, establish body axis

• master regulators of segmentation genes that control the differentiation of the Drosophila embryo into individual segments

Hormones

steroids or small proteins

Growth Factors

small proteins that function like hormones but with more local effects

• binding causes receptor to change shape, triggering phosphorylation cascade that activates transcription factors

• bind to response element and cause transcription of cell devision-related genes and/or genes that drive cell growth and differentiation

EvoDevo

evolution often acts on regulatory mutations that change the amount of a signal produced or the ability of a cell type to read that signal so they “misread” where they are in the body or what they should be doing

Segmentation Genes

gradually refine the body structure, first into broad sections, then smaller sections, then finally into body segments using different classes of genes with increasingly narrow and specific patterns of expression. Broadly speaking, earlier-acting groups regulate later-acting groups in a sort of molecular domino effect

• control the differentiation of the Drosophila embryo into individual segments

Gap Genes

define regional sections of an embryo

Pair Rule Genes

define individual segments

Segment Polarity Genes

affect the orientation of segments

Hox Genes

turned on in specific places through regulation by segmentation genes and give each segment an identity, telling it what structures it should grow

• show how powerful a developmental gene can be, especially when it is a transcriptional activator that turns many target genes on or off to activate a particular genetic “program”

• each only expresses in the part of the body it controls and the genes the Hox protein controls have an RE only it binds to

• responsible for determining the identity of particular segments or structures of the body. When hox genes are inactivated or expressed in unusual location due to utations, they may cause body segments to take on new identities

• help determine the identity of individual segments by producing transcriptional activators that bind to DNA and activate other genes

• need to be carefully regulated to prevent homeotic mutations (ex. extra nipples)

• in vertebrates, these genes have been duplicated over evolutionary history and now exist as four similar gene clusters labeled A through D, genes of the different clusters work together to establish the identity of body segments along the head-tail axis. The genes toward the beginning of the cluster tend to specify structures at the head end of the organism and the genes toward the end of the cluster tend to specify structure near the tail end

• If the promoters have acquired mutations that allow the transcription factors to find the promoters more easily or bind better, then the gene may be more active. If the changes have made the promoter less likely to bind transcription factors then the gene may be less active. If that gene itself is the code for a transcription factor then its expression will alter the expression of other genes

BMP (bone morphogenetic protein)

growth factors- each binds to its own BMP receptor and triggers a different set of genes to turn on

cascade of gene regulation establishes the polarity and identity of individual segments. In development, successively smaller regions of the embryo are determined

Intracellular Receptors

found inside of the cell (in the cytoplasm or nueclues)

Cell Surface Receptors

found in the plasma membrane

Ligands of intracellular receptors

small, hydrophobic molecules able to cross the plasma membrane to reach their receptors

Hormones and Growth Factors

influence the functions of cells by binding to receptors whose shape and electrical charge interact with one particular hormone. Whena hormone binds to its receptor it causes a change in shape of the receptor that triggers changes in the cell.

Intracellular Receptors

found inside of the cell

• ligans are small, hydrophobic molecules able to cross plasma membrane to reach receptors

Cell Surface Receptors

found in plasma membrane

• membrane-anchored proteins that bind to ligands on the outside surface of the cell. In this type of signaling, the ligand does not need to cross the plasma membrane

Protein Phosphorylation and Dephosphorylation

life’s major mechanism for transferring energy between molecules and doing the work of life

Protein Kinases

transfer phosphates from ATP to protein (phosphorylation)

Phosphotases

flip proteins back into their non-phosphorylated state

Phosphorylation

adding a phosphate group attaches a big cluster of negative charge to the surface of the protein which attract or repel amino acids within the protein itself, changing its shape, conducting “work”

Phosphorylation Cascade

many relay molecules in signal transduction pathways are protein kinases

• molecules that relay a signal from receptor to response are mostly proteins

Signal Transduction Pathway

at each step, the signal is transduced into a different form, usually a shape change in a protein

• multistep pathways can amplify a signal: few molecules can produce large cellular response

• 1. signal is received

• signal is transduced

• signal is amplified

• cell responds

the binding of a signaling molecule to a cell surface receptor triggers the first step in a chain of molecular interactions

like falling dominoes, the receptor acitvates another protein, which activated another and so on, until the protein producing the response is activated

at each step, the signal is transduced into a different form, usually a shape change in a protein

Response

cell signaling leading to regulation of transcription or cytoplasmic activities

Fibrodysplasia Ossificans Progressiva (FOPS)

muscle tissue and connective tissue are gradually replaced by bone, caused by a dominant mutation in a CMP receptor kinas that triggers bone formation. Dominant mutation is 100% penetrant with variable expressivity

Hox and Pax Genes

turn on suite of genes that specify that tissue

MyoD

transcriptional factor/activator produced in response to pax3/growth factors in cells destined to become muscle cells. switches on genes with MyoD response element (CATCTG). response element is present in the promoters of multiple genes specifically expressed in muscles

Transcriptional Factor/Activator

master regulatory in response to morphogens, hormones, growth factors, and other regulators

Myostatin

binds to a cell-surface receptor setting of a phosphorylation cascade that activates a transcriptional repressor (itself produced by MyoD) which binds to a silencer

• cells need to be able to turn off a switch- repressor of myoD, myostatin binds to specific myostatin receptor that inhibits the activation of myoblasts (muscle stem cells)

• lack of myostatin gene or receptor, get massive muscles

• mutation associated with muscle hypertrophy in a child

Double-Muscling Phenotype

natural mutations in mysotatin gene generate agriculaturally desirable in livestock species

Tissue Specific Enhancers/Alternative promoters or silencers

activate or repress the gene in a certain body part, binding transcription factors that are made in that part of the body only

• mutations in these play a key role in evolution of body form because changing protein sequence inactivated gene everywhere in body, but mutation in enhancer will change expression pattern, leading to new feature without killing animal

Evolution more frequently about changes in regulation of genes rather than about genes themselves

Reporter Gene

to find out where regulatory sequence is active- show that pair-rule gene even-skipped (eve) is expressed at the point where alternative segments will form under the control of a different alternative promoter (aka tissue specific enhancer aka regulatory segment)

Reporter Gene Expression

Chimp versions of the enhancer missing in humans used to drive LacZ gene expression in mice embryos to show where they do their work

Vasopressin

regulation of fluid balance and blood pressure, memory, learning, social behavior

have own receptor

Oxytocin

uterine smooth muscle contraction during childbirth, ejaculation, milk ejection from the mammary glands, social behavior

have own receptor

Human (Mammal) Emotions

result from modifications of preexisting networks (oxytocin and vasopressin are ancient pleiotropic peptides along with their receptors have been coopted for many functions)

Multiple Tissue Specific Enhancers

function as alternative promoters express oxytocin and vasopressin receptors in the kidney (urination), breast (lactation), limbic (brain attachment, social intimacy)

• each enhancer has many response elements and so can response to signals mediated by transcriptional activators at different times or in different tissues)

Oxytocin and Vasopressin

different effects in cells with different proteins and pathways

• also cross-talk with other neuropeptides such as dopamine and serotonin

closely related hormones found in every mammal species but only associated with monogramy in some

Love

broken down into three categories: lust, attraction, and attachment. Each category characterized by its own set of hormones stemming from the brain

• lust and attraction are pretty much exclusive to romantic entanglements, attachment mediates friendships, parent-infant bonding, social cordiality, and many other intimacies as well

Voles

monogamous prairie voles have receptors for oxytocin and vasopressin in different brain regions than their promiscuous relatives, meadow voles

The “Love” Instinct”

Monogamous mammlas have inserts (often microsattelites) in promoters of endorphin (oxtocin and vasopressin) receptor genes that cause receptors to be expressed in more parts of brain then polygamous species, particularly in areas associated with social interactions in the ventral forebrain (ventral pallidum region). When voles have sex, vasopressin and oxytocin are released and picked up by these receptors which in turn trigger a neural “reward system” so they associate pleasure with the vole they have just mated with

• short microsatellites selected for because they lead to promiscuity

• long microsatellites selected for because they lead to monogamy

Paternity tests (DNA fingerprinting) on prairie voles found that up to a quarter of the litters had not been fathered by the life partner. So they are socially monogamous but not genetically monogamous

• distinction between prairie voles and other monogamous rodents, dissociation of social and sexual fidelity, leads us to suggest that prairie voles are even better models of human attachment than has been appreciated

• individual prairie voles show differences in microsatellite length and distribution of the vasopressin receptors. This influences social bonding producing a spectrum of behaviors from monogamy to polygamy, each of which may be advantageous to different ecological circumstances

• Chimpanzees and bonobos have different promoter inserts than us and each other. Bonobos use sex for social cohesion and are much less aggressive and dominance oriented than chimpanzees

Influence of Genetic Polymorphisms on Gene Expression Levels, brain activation, and social behavior

Microsatellite length in human vasopressin receptor predicts receptor levels in the hippocampus and longer alleles are also correlated with higher levels of amygdala activation during a face-viewing task

within prairie voles, microsatellite length variation in the vasopressin gene promoter is associated with difference in V1a receptor expression patterns and behavior

Human Microsattelite and Receptors

human males homozygous for the microsatellite in allele 334 are more likely to exhibit “commitment phobia” with increased marital problems and lower generosity. Entrepreneurship and sexual opportunism maybe higher. Females have reduced maternal sensitivity, but a different allele associated with “extre pair matings”

Epigenetics

traits inherited independently of DNA sequence itself

-epigenetic regulation of pair-bonding-mating in prairie voles increases histone acetylation at the vasopressin and oxytocin promoters

Active ncRNA

often via RNA mediated methylation

• DNA molecules with epigenetic mark made by methylation, folding up enabling a neo-Lamarckian pattern of inheritance for some generations

Epigenome

collection of tags on the DNA (such as methyl groups) that control DNA folding (it learns from its experiences)

• important ways in which epigenetic inheritance can differ from traditional genetic inheritance with important consequences for evolution are

• rates of epimutation can be much faster than rates of mutation

• the epimutations are more easily reversible

Drosophila Model

development of fruit fly

• determination of dorsal-ventral axis

• determination of anterior-posterior axis

• segementation genes

• hox (homeotic genes)

• epigenetic changes in development

Early Epigenetics

soon after conception most methyl groups are stripped of DNA- the transposons are then remethylated. As development proceeds, additional tissue specific patterns of methylation

• early in development genes are “poised” like runners in the starting block, ready to jump into action

• in a differentiated cell, only 10-20% of the fenes are active. Different sets if active genes make a skin cell different than a brain cell

• environmental signals such as diet and stress in gene expression. Epigenetic flexibility is also important for forming new memories

Epigenetic Modifications

can involve histones or the DNA directly-in either case methylation suppresses gene expression by increasing the folding of DNA

• epigenetic tags give the cell a way to “remember” long term what its genes should be doing

• epigenetic modification alters which genes are on or off

“The Histone Code”

more than 100 different posttranslational modifications of histone tails control activity of nearby genes. Modifications include addition of phosphates, methyl groups, acetyl groups

Histone Modification

addition of methyl groups to the histone tails silences genes

addition of acetyl groups to histone tails increases gene expression

Pioneer Factors

opening up folded DNA. Transcriptional Actiavtor FoxP2 bind to condensed chromatin and recruit histone acetyltransferases (HATs) and other histone modification enzymes that increase gene expression