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.

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