From Genotype To Phenotype PDF

# From Genotype To Phenotype ## Özden Hatırnaz Ng, Özlem Akgün Doğan, Yasemin Alanay **MED 111 2023 - 2024** ## Classical View of Genotype - Phenotype The diagram shows a classical view of genotype-phenotype. It depicts a series of DNA double helices, representing different genotypes, leading to...

# From Genotype To Phenotype ## Özden Hatırnaz Ng, Özlem Akgün Doğan, Yasemin Alanay **MED 111 2023 - 2024** ## Classical View of Genotype - Phenotype The diagram shows a classical view of genotype-phenotype. It depicts a series of DNA double helices, representing different genotypes, leading to different phenotypes: - **Monogenic phenotype**: Represented by a star shape. - **Polygenic phenotype**: Represented by a cloud shape. - **Pleiotropic phenotype**: Represented by a star shape. The arrows indicate the direction of the flow, with a **conformation** step between genotype and phenotype. Free Energy increases along the y-axis. ## Genotype To Signaling This diagram shows the relationship between genotype and signaling: * **Genotype**: Shown on the right side, with a series of chromosomes, genes, and altered genes. * **Genotypic modules**: Represented as a network of connected nodes, with red, yellow, and blue shapes indicating different components. * **Phenotype modules**: Represented as a more compact network. * **Molecular-level phenotype**: Shown as a matrix with green, purple, red, and blue colors, representing gene expression under different conditions. This information is conveyed through a curved arrow to the phenotype modules. * **Organism-level phenotype**: Shown as a group of stick figures, representing different individuals under different conditions: condition 1 and condition 2. ## Signaling - Communication Among The Cells This diagram shows the steps involved in cell signaling: 1. **Signal = Ligand**: A signal molecule, represented by a red circle, binds to a receptor. 2. **Receptor = Sensor**: The receptor protein, shown as a blue tube, initiates a signaling cascade. 3. **Signaling cascade**: This cascade involves multiple steps, represented by purple blocks, leading to the activation of targets. 4. **Targets**: The targets are: - **Metabolic enzyme**: Showing a blue rectangle, causing a change in metabolism - **Gene regulations**: Shown as a blue pentagon shape, leading to a change in gene expression - **Cytoskeletal protein**: Depicted as a blue parallelogram, causing a change in the cell shape ## What is a signal? * A signal is a **ligand**: A molecule with the capability to bind to another molecule and initiate signaling. Here are examples of signals: * **Peptides, proteins** - Growth factors * **Amino acid derivatives** - Epinephrine, Histamine * **Small molecules** - ATP * **Steroid, prostaglandines** * **Gases** - Nitric Oxide (NO) ## Commands Of The Cell Signaling This diagram depicts different commands of the cell signaling: - **Survive**: Blue circles, indicated by A, B, and C arrows, lead towards a cell with the word "SURVIVE". - **Divide**: Blue circles, indicated by A, B, C, D, and E arrows, lead towards two dividing blue circle cells with the word "DIVIDE" - **Differentiate**: Yellow circles, indicated by A, B, C, F, and G arrows, lead towards a green circle cell labeled "DIFFERENTIATE". - **Die**: A blue circle, indicated by a single arrow, leads towards a fragmented cell labeled "apoptotic cell" ## How The Cells Communicate The diagram shows four different types of cell communication: - **Contact-dependent**: A signaling cell, represented by a red shape, has a membrane-bound signal molecule that directly interacts with a target cell, shown as a blue circle. - **Paracrine**: A signaling cell, represented by a red shape, releases a local modulator that interacts with multiple target cells, also represented by blue circles. - **Synaptic**: A neuron releases a neurotransmitter, shown as a yellow shape, from its axon that travels across a synapse to a target cell. - **Endocrine**: An endocrine cell, represented by a red shape, releases hormones that travel through the bloodstream to reach a target cell, shown as a blue circle. ## Cell Surface Receptors The diagram shows three types of cell surface receptors: - **Ion-channel-linked receptors**: Two receptors are shown with signal molecules, represented by blue circles, binding to them. This opens ion channels, enabling the flow of ions. - **G-protein linked receptors**: Two receptors are aligned. A signal molecule, represented by a blue shape, binds to the receptor, activating a G-protein, shown as a green circle. This activated protein in turn activates an enzyme. - **Enzyme-linked receptors**: In the first scenario, a signal molecule, represented by a blue shape, binds to two receptors. This brings the receptors closer, activating the catalytic domain. In the second scenario, a signal molecule, represented by a red shape, directly binds to a single receptor and activates an enzyme. ## Receptor Tyrosine Kinases (RTKs) This diagram illustrates the activation of receptor tyrosine kinases: 1. Ligand binding: Two ligand molecules bind to two receptors. 2. Transmembrane domain: The two receptors move closer through their transmembrane domains. 3. Tyrosine kinase domain: Once the receptor tyrosine kinase domains are close to each other, the domains phosphorylate, activating the kinase. ## Dimerization This diagram shows different examples of dimerization, bringing together two receptors: **A: TrkA - Nerve growth factor** **B: KIT - Stem cell factor** **C: FGFR - Fibroblast growth factor** **D: ErbB - Epidermal growth factor** ## Activation is Via Cross Phosphorylation This diagram shows the process of activation through cross-phosphorylation: 1. **Receptor expression**: Several receptors are initially expressed, represented by a vertical line with color variations. 2. **Ligand binding**: A ligand molecule binds to two receptors. 3. **Hetero/homo dimerization**: The ligand binding brings the two receptors together, leading to a dimer. 4. **TK activation by transphosphorylation**: The kinase domains of the receptors cross-phosphorylate each other, activating the tyrosine kinase. The activated receptor tyrosine kinase then propagates the signal downstream, leading to transcription and ultimately leading to degradation or expression of the receptor. ## Different Receptor Tyrosine Kinases This diagram shows different types of receptor tyrosine kinases as vertical lines. - Each vertical line represents a different receptor. - Each vertical line is divided into segments representing: - Extracellular domain: Colored in various colors: yellow, green, black, blue etc. - Transmembrane domain: Red. - Intracellular domain: Blue. - The colored boxes at the bottom of the image represent different domains: - Tyrosine kinase domain - Cysteine-rich domain - Fibronectin type III domain - Leucine-rich domain - Cachein domain - Immunoglobulin domain - EGF domain - SAM domain - PDZ domain - Epidermal growth factor domain - WW domain - Proline-rich domain - YXXL protein - Acid box - Soma domain - Mam domain - Jorna domain ## G-protein Coupled Receptors (GPCRs) * The largest receptor group in eukaryotes. * They bind to ligands: Lights, peptides, lipids, sugars, and proteins. The diagram shows a schematic structure of a GPCR: - It has a single polypeptide chain crossing the membrane 7 times (transmembrane domain). - The extracellular domain is shown where the ligand binds. - The cytoplasmic domain is shown where the G-protein interacts. - N-terminal is marked as N - C-terminal is marked as C The diagram also includes a picture of **Robert J. Lefkowitz and Brian K. Kobilka,** the Nobel Prize winners in Chemistry in 2012 for their studies on G-protein coupled receptors. **More than half of the known drugs act via GPCR.** ## G-Proteins * Specialized proteins with the ability to bind the nucleotides: **Guanosine triphosphate (GTP)** and **Guanosine diphosphate (GDP)**. * Two types: - Heterotrimeric: Three subunits: **α, β, γ** - Small G-proteins The diagram shows a representation of a G-protein coupled receptor interacting with a G-protein. A neurotransmitter binds to the G-protein coupled receptor activating the complex. The activated G-protein detaches from the receptor and moves to interact with other pathways in the cell. - Extracellular side - Intracellular side - The G-protein has three subunits, alpha, beta, and gamma. ## Ras Monomeric Small G-protein * The **rat sarcoma virus (RAS)** was first discovered in **1960**. * It belongs to the **GTPase superfamily** of intracellular switch proteins. This diagram shows the RAS superfamily, which is divided into families: - **RAS family**: Includes KRAS, NRAS, and HRAS. - **RAB family** - **RHO family** - **ARF family** - **RAN family** Each family is further divided into subfamilies. There are 5 subfamilies within the RAS family: - **RAS:** This subfamily includes genes like ERAS, NRAS, HRAS, KRAS, and DIRAS. - **RAL:** This subfamily includes genes like RALA and RALB. - **RAP:** This subfamily includes genes like RAP1A, RAP1B, RAP2A, and RAP2C. - **RAD:** This subfamily includes genes like GEM and REM. - **RHEB:** This subfamily includes genes like RHES, RHEBL1, and RHEB. - **RIT:** This subfamily includes genes like MT1, RITZ, RIN, and RIC. ## Activated MAP Kinase Kinase Kinase This diagram depicts a series of activation steps leading to a change in transcription: 1. **Activated RAS**: Bound to GTP, it triggers a signaling cascade. 2. **Activated MAP kinase kinase kinase**: Phosphorylated by activated RAS, it activates the next kinase in the pathway. 3. **Activated MAP kinase kinase**: Phosphorylated by activated MAP kinase kinase, it activates the next kinase in the pathway. 4. **Activated MAP kinase**: Phosphorylated by activated MAP kinase kinase, it activates the final targets. 5. **Targets**: Protein X, Protein Y, transcription regulator A and transcription regulator B ## The RAS/MAP Kinase Pathway The diagram represents the pathway initiated by the activated receptor tyrosine kinase and the role of RAS in this pathway: 1. **Ras activated**: Exchange of GDP for GTP activates RAS. 2. **Active Ras recruits, binds, and activates Raf**: The active Ras then recruits, binds, and activates a kinase protein called Raf. 3. **GTP hydrolysis leads to dissociation of Ras from Raf**: The GTP is hydrolyzed, releasing RAS from Raf. 4. **Raf activates MEK**: The activated Raf then activates MEK. 5. **MEK activates MAPK**: The activated MEK activates MAPK. 6. **Active MAP kinase translocates to nucleus; activates many transcription factors**: The activated MAPK translocate to the nucleus, where it activates transcription factors, triggering changes in gene expression, cellular growth, and other cellular processes. ## Mutations In The RAS Genes Or Their Regulators Render RAS Proteins Persistently Active * **Somatic variations of RAS cause malignancies**. * **Germline variations cause Rasopathies**. ## RAS As An Oncogene * **3 main isoforms**: - **KRAS**: Sarcoma viral oncogene homolog. Located on chromosome 12. It has 4A and 4B splice variants. - **NRAS**: Neuroblastoma RAS viral (v-ras) oncogene homolog. Located on chromosome 1. - **HRAS**: Harvey rat sarcoma viral oncogene homolog. Located on chromosome 11. This diagram highlights different domains within the RAS protein: - **OTP binding** - **Effector binding domain** - **Switch I:** Interacts with GTPase activating proteins (GAPs) and effectors. - **Switch II:** Interacts with guanine nucleotide exchange factors (GEFs). - **Farnesylated cysteine'**: Plays a role in membrane association and signaling. - **Palmitoylated cysteine**: Plays a role in membrane association and signaling. The diagram also highlights the hypervariable region which differs between the three RAS isoforms (HRAS, NRAS, and KRAS). ## Somatic Mutations of RAS Pathway This table summarizes the percentage of RAS mutation for different cancers: | Cancer | Isoform | Percentage | |----------------------------------------------|---------|-------------| | Pancreatic ductal adenocarcinoma | K | 98 | | Colorectal adenocarcinoma | K | 52 | | Multiple myeloma | K, N | 43 | | Lung adenocarcinoma | K | 32 | | Skin cutaneous melanoma | N | 29 | | Uterine corpus endometrioldcarcinoma | K | 25 | | Uterine carcinosarcoma | K | 14 | | Thyroid carcinoma | N > H | 13 | | Acute myeloid leukemia | N > K > H | 11 | | Bladder urothellal carcinoma | H, K > N | 11 | | Gastric adenocarcinoma | K | 10 | | Cervical adenocarcinoma | K | 8 | | Head and neck squamous cell carcinoma | H | 6 | The pie charts show the percentage of mutations for different RAS isoforms. - **KRAS**: 83% mutations are in the KRAS gene. - **NRAS**: 63% mutations are in the NRAS gene. - **HRAS**: 27% mutations are in the HRAS gene. The diagram shows the three most common mutations: G12, G13, and Q61 ## Although Many Of the Activating Ras/MAPK Pathway Variations Are Similar To Somatic Mutations Associated With Cancer, They Tend To Not Be As Strongly Activating It is likely that the strongly activating oncogenic mutations cannot be tolerated in the germline or in early development. ## Germline Variations In RAS Pathway * It leads to **RASopathies**. * One of the largest know groups of malformation syndromes. * Affecting 1/1000 individuals.