BSCI 222 St Leger Exam 3

Transcriptional Activator Proteins

bind to consensus sites (response elements) on DNA & stimulate transcription

morphogens

allow cell to determine where they are in the body

*synthesized locally

*act over long distances to induce cell responses

*establish body axis

*master regulators of segmentation genes

hormones

steroids or small proteins

growth factors

small proteins that function like hormones with local effects

EvoDevo

*evolution acts on regulatory mutations

*it changes the amount of signal produced / the ability of the cell to read a signal

*thus cells don't know where they are in the body or what they should be doing

segmentation genes

gradually sections body into segments with a molecular domino effect

gap genes

define regional sections of an embryo

pair rule genes

Define individual segments. Expressed in alternating segments

segment polarity genes

affect orientation of segments

hox (homeotic) genes

*regulated by segmentation genes

*gives each segment it's identity

*can act as a transcriptional activator that turns on target genes (genetic program)

*each gene has one specific RE it binds to

Order segmentation genes act

1) gap genes

2) pair rule genes

3) segment polarity genes

homeotic mutation

a mutation that causes a change in the placement of body parts, ie. fly's antenna to be replaced by a leg or extra nipples

HoxD13

mutation causes synpolydactyly: fingers/toes fused together

HoxC8

-Rib/Backbone development

-Nearly identical in several vertebrates

thrinaxodon

first animal to have distinct thoracic and lumbar regions of the vertebral column

BMP

bone morphogenetic protein

growth factors that each bind to its own receptor to turn on sets of genes

BMP2

digit (fingers, etc.) formation

*mutation can lead to brachydactyly, facial dysmorphosism

Intracellular Receptors

inside the cell (cytoplasm/nucleus)

*ligands typically small & hydrophobic to cross membrane

Cell Surface Receptors

in plasma membrane

*membrane anchored proteins

*ligand does not need to cross membrane

Protein Phosphorylation

protein kinase (it's KINd so it) gives a phosphate to a protein from an ATP making ADP

*adds negative charge to protein surface which changes it's shape

Protein Dephosphorylation

Phosphatases (TAkes back a phosphate) reverse phosphorylation turns ADP back to ATP

Steps of signal transduction pathway

1) reception

2) transduction

3) amplification

4) response

*at each step the signal is transduced to a new form/shape

differentiation

process in which cells become specialized in structure and function

*driven by cell division related genes

Fibrodysplasia Ossificans Progressiva (FOPS)

muscle & connective tissue gradually replaced by bone

*dominant mutation in BMP receptor kinase that triggers bone formation

*dominant mutation is 100% penetrant with variable expressivity

MyoD

a transcription factor that binds to enhancers of various target, produces transcription factor that binds to the promoters of genes that produce features of skeletal muscle cells

MyoD response element

CATCTG

*present in promoters of multiple genes specifically expressed in muscles

*produced in response to Pax3/growth factors in future muscle cells

Myostatin

repressor of MyoD

*inhibits activation of myoblasts (muscle stem cells)

*if knocked out, then massive muscles

*muscle hypertrophy

double muscling phenotype

Caused by disruption of the myostatin gene

*desirable in livestock

*Bully Whippet dog has mutation

Tissue specific enhancers

Aka: alternative promoters, silencers

*activate or repress the gene in a certain body part

reporter gene

gene with an easily identifiable phenotype that can be used to identify whether a regulatory sequence is active

Eve

expressed at the point where alternative segments will form under the control of a different alternative promoter

*even skipped pair rule

phenotype of stripes/bands like 6 pack muscles or ridges in a roly poly

LacZ

encodes B-galactosidase crucial for lactose metabolism

Oxytosin

OT

stimulates smooth muscle cell contraction, used to induce labor, ejaculation, milk ejection, social behavior

Vasopressin

VP

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

categories of love

Lust: testosterone, estrogen

Attraction: dopamine, norepinephrine, serotonin

Attachment: oxytocin, vasopressin

Vole

Prairie- monogamous, long microsatellites, inserts in promoters of endorphin receptor genes, causing receptors to be expressed in more parts of the brain

Meadow- promiscuous, short microsatellites

commitment phobia

homozygous in microsatellite in allele 334, increased marital problems, lower generosity, reduced maternal sensitivity

bonobos

use sex for social cohesion, less aggressive, longer microsatellites

Epigenetics

traits inherited independently of DNA sequence itself

active ncRNA

non-coding RNA, often via RNA mediated methylation

neo-lamarckian pattern of inheritance

traits acquired after birth can be passed to offspring

epigenome

collection of tags on DNA (methyls) that control DNA folding, it learns from it's experiences

*susceptible to environmental factors in prenatal and ages 6-9

histone code

100+ different posttranslational modifications of histone tails control activity of nearby genes

*adding phosphates, methyl, & acetyl

histone modification

more methyl= silences gene

more acetyl= increased gene expression

pioneer factors

first to bind regulatory molecules, facilitating binding of additional transcription factors ie. FoxP2

FoxP2

a gene that is important in language and speech production

histone acetyltransferases (HATs)

Enzymes that add acetyl groups to histones.

PRC 1 & 2

closes down DNA by folding it up by methylating histones

polycomb complex

*methyltransferase activity

*remodel chromatin to silence gene expression via tri-methylation of lysine 27 in histone 3 (H3K27 tri methylation) recruits histone deacetylases (HDAC)

CpG islands

a group of CG sequences that may be clustered near a promoter region of a gene. The methylation of the cytosine bases usually inhibits transcription.

missing heritability problem

genetic variations can't account for all the heritability of diseases, behaviors, and other phenotypes

endocrine disruptors

diethylstilbestrol

can result in inter/transgenerational inheritance of breast cancer

Agouti

turns mice yellow and obese with tumors if completely acetylated

nutrigenomics

the study of how genes & nutrition interact

*predict how body will react to certain nutrients

royal jelly

suppresses Dnmt3 (methylates DNA) leading to expression of genes that encode characteristics of the queen

Thrifty Phenotype

prenatal malnutrition in first 6 months of the womb, leading to persistent changes in methylation

high incidence of obesity, diabetes, heart disease, schizophrenia

*takes more than 2 generations to return to normal methylation

surgery induced weight loss

remodeling the sperm DNA methylation, so next generation is lean by controlling appetite not obese like father

bdnf

brain-derived neurotrophic factor, a neurotrophin similar to nerve growth factor

*exercise increases acetylation & decreases DNA methylation, enhancing bdnf, which is why exercise enhances memory

Twin studies

twins have same genes at birth, so by studying them we can see what changes the environment has, so as they get older the more different their genomes are

*fraternal twins share half their genes

ecological epigenetics

invasive species often lack genetic diversity (founders effect) but adapt quickly to new habitats in part through epigenetic diversity

behavioral epigenetics

non genetic, life experiences, especially early in life, have long-lasting effects on behavior

Epigenetic Changes (maternal)

behavior, reproduction, metabolism

*induced by maternal behavior

*more mom rat licks= decreased methylation of a glucocorticoid receptor promoter, lowers stress, less fear filled

*lick male more than fem, increasing rough & tumble play

GR gene

GR=glucocorticoid receptor

*higher levels of GR in hippocampus are better at detecting cortisol, therefore recover quicker from stress

Stress Circuit

HPA axis (hypothalamic-pituitary-adrenal axis), controls reactions to stress

Cortisol

freeing stored energy for flight/fight

*high levels over long time lead to heart disease, depression, infection susceptibility

Genomic imprinting

genes are active or not depending on whether inherited from mom or dad based on methylation at start of development

*through adolescence to adult, some regions of brain switch from maternal to paternal vice versa

Igf2

Insulin Growth Factor 2

*promotes sugar up take from mother's blood stream

*dad turns this factor on, mom keeps hers silent

genetic conflict hypothesis of genomic imprinting

imprinting is the result of "antagonistic alleles"

*conflict of interest between paternal and maternal derived genes

Igf2R

insulin growth factor 2 receptor

*inhibits fetal growth and maternally expressed so that IGF2 doesn't kill the mother by stealing all her resources

PHLDA2

gene with alleles RS 1 & 2

RS1- higher birthweight

RS2- more common, powerful promoter, growth suppressor, only in humans, for mother's survival

obstetrical dilemma

increasing brain size, and narrowing the pelvis to be able to walk upright

Prader-Willi syndrome

deletion of a portion of father's chromosome 15

*mild mental disability, impaired satiety, compulsive behavior (mother's genes imprinted)

Angelman Syndrome

deletion of a potion of mother's chromosome 15

*severe mental disability, ataxia (lack of muscle control), frequent laughter

Turner's syndrome

born with only 1 X chromosome

*girls who inherit from mother have more social dysfunction than if inherited from father

Mest / Peg 1-3 genes

govern mouse's reproductive behavior

*only paternal genes active

*females lacking active paternal Peg 1= fewer oxytocin receptors= severe lack of maternal care

Grb10

Father- only active in Central Nervous System (CNS), social behavior in adults, without=more domineering

Mother- fetal growth, metabolism, fat storage

How does methyltransferase conduct selective epigenetic marking

1) TFs (DAX1/FoxP2) recruit enzymes that add/remove epigenetic tags

2) RNA-mediated methylation

RNA mediated methylation

regulatory RNA molecule binds to the DNA to be methylated, so methylation happens at a sequence-selected location

long non-coding RNAs (lncRNAs)

DNA stretches with instructions for RNA molecules, that don't code for proteins

*around 37,600 have been identified

*more than 200 base pairs

*conserved in sequence between vertebrates, but not in regulation

*tether proteins together like a rope

HOTAIR

links PRC2 & LSD1 to regukate histone de/methylation of Hox genes

PRC2

polycomb repressive complex 2

*adds methyls

LSD1

Lysine specific demethylase 1

*removes methyls

RdDM

RNA-directed DNA methylation

*RNA binds to specific DNA to guide methyltransferase to add methyl groups to DNA

Beckwith-Wiedemann syndrome

deletion of LncKCNQ1OT1

*expression of alleles from both parents

*Overgrowth, ear creases, macroglossia (large toungue), umbilical hernia

Xist gene

a gene on the X chromosome of mammals that results in the formation of a Barr body.

*the XIST gene inactivates the X chromosome by producing a lncRNA that blankets the chromosome triggering methylation that starts with LINE-1 that saturate the X chromosome

antisense RNA

a single stranded RNA which is a mirror image of the nucleotide bases of another RNA strand

*if bound to mRNA, mRNA con't be translated and no protein made

Tsix

antisense lncRNA

*expressed from the future active chromosome

*binds Xist during X chromosome inactivation

RNAi

RNA interference

*silencing of individual genes by very small RNAs (micro RNAs (miRNA) or short interfering RNA (siRNA) both produced from double stranded RNAs)

Dicer

recognizes double stranded RNA, then dices it into siRNA or miRNA

RISC

RNA induced silencing complex

*one strand as template to identify/destroy complementary RNAs

miR-1-1

developing heart & embryonic structures give rise to muscle

*negatively regulates Hand 2 (master regulator of venticle heart muscle)

*bind to 3' UTR

RITS

RNA-induced transcriptional silencing complex

*recruits methyltransferase to methylate DNA/histones

piRNAs

Piwi-interacting RNAs

*involved in RNA directed histone/DNA methylation (RNA silencing)

26-31 nucleotides long repetitive DNA in transposons

*organized into heterochromatin

*operate in germline cells to combat transposons

*if knocked out in gametes, the genomes are shredded

ApoB siRNAs

encapsulated into lipids creates stable lipid particles (SNALPS)

*injected into monkeys lowering ApoB with RNAi reduced serum cholesterol

Importance of Mutations

source of all genetic variation

*raw material for evolution

*source of diseases & disorders

*useful for probing fundamental biological processes

Missense Mutation

different amino acid

Nonsense Mutation

stop codon

Silent Mutation

same protein different codon

Neutral Mutation

changes amino acid sequence, without changing protein function

Lethal Mutation

causes premature death

Somatic Mutation

body cells

*passed to descendants by mitosis