Robbins and Cotran 9th Edition Questions

Chapter 1

How much of the human genome is coding and what does it code?
Of the 3.2b basepairs, there are 20,000 genes that comprise about 1.5% of the genome that code for proteins (enzymes, structural components, and signaling molecules used to assemble and maintain all the cells in the body

What do we think that the rest of the genome does?
80% of the genome binds proteins, implying that it is involved in regulating gene expression, related to the regulation of gene expression, often in a cell-type specific fashion.

List the major classes of functional non-protein-coding sequences found in the human genome.
1. Promoter & enhancer, 2. Chromatin binding site structures, 3. non-coding regulatory RNAs, 4. Mobile genetic elements (transposons), 5. telomeres, 6. centromers.

What are the two most common forms of DNA variation in the human genome?
1) Single nucleotide polymorphisms (SNPs), 2) copy number variations (CNVs)

What are the possible implications of SNPs.
1) regulatory = alters gene expression, 2) Correlation with disease states when in close proximity with altered genes, 3) association used to define linkage disequilibrium,?

Define epigenetics.
Heritable changes in gene expression which are not caused by alterations in DNA sequence.

List the 6 types of epigenetic changes.
1) Histone & histone modifying factors (Histones organize chromatin into heterochromatin and euchromatin, 2) histone methylation, 3) histone acteylation, 4)histone phosphorylation, 5) DNA methylation, 6) Chromatin organizing factors.

What is the function of micro-RNA (mi-RNA)?
It does not encode protein, instead they function primarily to modulate the translation of target mRNAs into their corresponding proteins, and are responsible for post-transcriptional silencing of gene expression.

What is knockdown technology?
[[The use of synthetic si-RNA (short RNA sequences) introduced into cells that serve as substrates for Dicer and interact with the RISC complex in a manner analogous to endogenous miRNAs, and are used to study gene function, and are being developed as therapeutic agents to silence pathogenic genes, e.g. oncogenic in neoplasms.]]

What is long non coding RNA?
Lnc-RNA modulate gene expression by binding to regions of chromatin, restricting RNA polymerase access to coding genes within the region, and may exceed the number of mRNA's by 10-20 fold.

What is XIST?
[[XIST is a lnc-RNA which is transcribed from the X-chromosome and plays an essential role in physiologic X chromosome inactivation, though not inactivated itself, it forms a repressive cloak on the X chromosome from which it is transcribed resulting in gene silencing.]]

What are the cellular housekeeping functions?
1) protection from the environment, 2) nutrient acquisition, 3) communication, 4) movement, 5) renewal of senescent molecules, 6) molecular catabolism, 7) energy generation.

List the cellular compartments and the role in the cell.

[[1) cytosol = metabolism, transport, protein translation, 2) Mitochondria = energy generation, apoptosis, 3) Rough ER = synthesis of membrane and secreted proteins, 4) Smooth ER / Golgi = protein modification, sorting, catabolism, 5)Nucleus = cell regulation, proliferation, DNA transcription, 6) Endosomes = intracellular transport and export, ingestion of extracellular substances, 7) Lysosomes = cellular catabolism, 8) peroxisomes = very long-chain fatty acid metabolism]]

Describe the basic structure and functions of the cell membrane.
[[ The plasma membrane is composed of a lipid bilayer of phospholipids studded with a variety of proteins and glycoproteins involved in ion and metabolite transport, fluid phase and receptor-mediated uptake of macromolecules, cell-ligand/cell matrix/cell-cell interactions.]]

How are the large complexes in the plasma membrane formed?
They aggregate under the control of chaperone molecules in the RER or by lateral diffusion in the plasma membrane followed by complex formation in situ.]]

What are aquaporins?
Special integral membrane proteins which augment passive water transport in tissues where water is transported in large volumes.

How are channel and carrier proteins different?
Channel proteins created hydrophilic pores, permit rapid movement of solutes, restricted by size and charge, where Carrier proteins bind to their specific solutes and undergo a series of conformational changes to transfer the ligand across the membrane, relatively slow transport.]]

What is the "multidrug resistance (MDR) protein"?
A type of transporter ATPases which pumps polar compounds (e.g. chemo drugs) out of cells which may render cancer cells resistant to treatment.

What are the two fundamental mechanisms of fluid or macromolecules by the cell (endocytosis)?
1)Caveolae -invaginations of the plasma membrane, 2) Pinocytosis/receptor mediated endocytosis - macromolecules bind to receptor and membranes invaginate around it.

What is exocytosis?
It is the opposite process of pinocytosis, where the receptor bound macromolecule is move to the cell surface and released.

Describe the difference between phagocytosis and transcytosis.
[[In phagocytosis microbes are ingested forming phagosomes, which fuse with lysosomes and become phagylosomes, releasing undigested residual material when fusing again with the external membrane, in contrast transcytosis the materials are carried across the cell membrane unaltered.]]

List the three major classes of 3 cytoskeleton proteins.
1) Actin, 2)Intermediate filaments, 3)Microtubules

Describe actin.
Actin - 5 to 9nm diam fibrils, G-actin polymerized into F-actin, the form double strands helices, which interact with myosin (filamentous protein).

List the various intermediate filaments, which are 10nm in diameter.
1) Lamin A, B, and C (nuclear lamins of all cells, 2) Vimentin (mesenchymal), 3)Desmin (scaffold for actin/myosin), 4) Neurofilaments (axons of neurons), 5) Glial filament protein (glial cells), 6)Cytokeratins (acid and basic and vary based on cell type).

Describe microtubules.
[[ Microtubules are 25nm diam fibrils of dimers of a and b tubulin, with a negative end embedded in the centrosome near the nucleus, the + end grows or shrinks as needed. There are kinesins and dyneins motors that move stuff around the cell, also found in cilia and flagella.]]

What is clatharin?
A molecule found in the cell membrane that when the cell membrane invaginates forming a basket like structure.

List and describe the 3 main classifications of cell junctions.
[[1) Tight /occluding junctions - form a high resistance barrier to solute movement, and allows the cell to maintain polarity, 2) anchoring junctions / desmosomes - mechanically attach the cell and their cytoskeleton to other cells and the ECM (hemidesmosome), 3)communicating/gap junctions - mediate the passage of chemical or electrical signals from one cell to another.]]

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Chapter 5

MC cause of spontaneous abortion is ?
A demonstrable chromosomal abnormality.

1% of all newborn infants possess a gross chromosomal abnormality and 5% of people <25y present with
a genetic disease.

Mutation
permanent change in the DNA, if affect germ cells are transmitted to the progeny

List and describe 4 broad categories of human genetic disorders:

[[Disorders related to mutation sin single genes with large effects i. Usually follow classic Mendelian pattern of inheritance ii. Often highly penetrant (large proportion of pop with gene has disease) b. Chromosomal disorders i. Structural or numerical alterations in autosomes and sex chromosomes ii. Uncommon, high penetrance c. Complex multigenic disorders i. Interactions between multiple variant forms of genes and environmental factors (polymorphisms), poly genic means disease when many polymorphism present d. Single gene disorders with nonclassic patterns of inheritance (not mendelian) i. Disorders resulting from triplet repeat mutations ii. Mutations in mitochondrial DNA iii. Those influenced by genomic imprinting iv. Those influenced by gonadal mosaicism]]

List and describe the possible outcomes of a point mutation in a coding region?
[[a. Missense mutation – pt mutation changes amino acid code, conservative when the amino acid is preserved, non conservative when replaced with another amino acid, b. Nonsense mutation – makes a stop codon ]]

List and describe the possible outcomes of point mutation or deletion in a non-coding region.
[[a. Promoters/enhancers – interfere with binding of transcription factors, marker reduction or total lack of transcription, b. Introns – defective splicing > failure to make mature RNA > no translation]]

List and describe the possible outcomes of deletions and insertions.
[[a.Small coding: not multiple of three = frameshift, if multiple of 3 than add or del amino acids accordingly, often premature stop codon i. Tay Sachs disease: 4 base pair insertion in Hexosaminidase A gene ]]

List and describe the possible outcomes of trinucleotide repeat mutations.
[[a. Usually G&C, dynamic and increase during gametogenesis, “RNA stutters”,b. Fragile X – CGG 250-4000, Huntinton’s Disease ]]

List and describe three examples of inheritance of single gene mutations

[[a. AD – manifested in the heterologous state, one parent of index case is usually affected, males and females affected and both can transmit conditioni. De novo cases may not have affected parentii. Penetrance = fraction of people with gene who have the traitiii. Variable expressivity = those with mutant gene have variety of phenotypesiv. Often age of onset is delayed so can reproduce before die from diseasev. Biochem mechanisms1. Reduced production of a protein or dysfunctional/inactive protein2. Involved in regulation of complex metabolic pathyway subject to feedback inhibition3. Key structural proteins (collagen and cytoskeleton of RBC)a. May be a dominant negative , e.g. osteogenesis imperfecta4. Gain of function are rare, 2 formsa. Increased in proteins normal function (excess enzyme activity)b. Huntinton’s diseas (abn protein accumulates, toxic to neurons)b. ARi. Largest category – both alleles at a locus are mutated1. Expression is uniform, complete penetrance common, early onset, unaffected carrier family members, mostly enzymesc. X Linkedi. All sex linked, and almost all are recessive , if Y Chromosome affected usually infertile males > no progenyii. Male expression b/c hemizygous, daughter carriers with variable phenotype because of lionization of 2nd X e.g G6DPiii. Dominant . vitamin D resistant rickets]]

Stopped at P142