Factoids Flashcards
How does methylation of cytosine repress genes?
The carbon at the 5th position in the pyrimidine is methylated. The methylated CpG dinucleotide recruits methyl-CpG-binding proteins (ex: MECP2), which recruit chromatin remodeling enzymes to silence transcription.
How can methylation activate gene expression?
3’ CpG methylation confers cell- and tissue-specific gene expression.
Is methylation a stable marker?
Yes, it can be transmitted through cell division, though may cancers show altered methylation states.
What is epigenetics?
mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence.
Reversible, post-translational modifications of histones and DNA methylation are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.
When are methylation markers established?
Methylation is established in the gamete and stably maintained in the somatic cells
Is DNA methylation irreversible?
No, it can be reset during gametogenesis to transmit the appropriate sex-specific imprint to progeny.
How do newly synthesized strands of DNA get methylated?
Maintenance Methyltransferase
What mechanisms can cause PWS?
Deletion of paternal 15q11-13
Disomy of maternal 15
Imprinting center mutation on paternal allele
What mechanisms can cause AS?
Deletion of maternal 15q11-13
Paternal uniparental disomy
Imprinting center mutation on maternal allele
Mutation of UBE3A on maternal allele
What causes deletion in 15q11-13?
Breakpoints occur in the vicinity of low copy repeats of the HERC2 gene, which may be involved in inter- and intrachromosomal misalignment and homologous recombination.
What do defects in the beta-globin gene cause?
Hemoglobin disorders
What do defects in the BRCA1 gene cause?
Breast and ovarian cancers
What do defects in the beta-myosin heavy chain (MYH7) gene cause?
Inherited hypertrophic cardiomyopathy
Which chromosome(s) is(are) gene rich?
chromosome 19
Which chromosome(s) is(are) gene poor?
chromosomes 13, 18, 21 (viable trisomies)
What are some unstable regions of the genome that cause disease?
SMA (5q13), DiGeorge Syndrome (chr22q), 12 diseases associated with 1q21.1
What were the two human genome project approaches?
- Construct clone map and select for clones, then generate several thousand sequence reads per clone and assemble.
- Generate tens of millions of sequence reads then assemble.
Large tandem repeats of a specific pentanucleotide sequence exist on the inert regions of which chromosomes?
1, 9, 16, and make up more than half of the Y chromosome
Where is the alpha-satellite family found and how long is the repeated unit?
centromere of each human chromosome and 171 bp. May be important for chromosome segregation in meiosis and mitosis
What is the Alu family?
It is a 300 bp dispersed repeat in the genome with ~500,000 copies in the genome, accounting for ~10% (SINE: Short INterspersed repetitive Elements)
What is the LINE (Long INterspersed nuclear Element or L1) family?
It is a 6 kb dispersed repeat in the genome with ~100,000 copies.
What are the medical implications of Alu and L1 families?
- They can retrotranspose, causing insertional inactivation
2. They can cause non-allelic homologous recombination, leading to microdeletions or microduplications
Name and describe the two types of indels
- Minisatellites: tandemly repeated 10-100 bp units. VNTRs
2. Microsatellites: 2-4 bp repeats. 5x10^4 per genome
How do you test for CNVs?
Array Comparative Genome Hybridization (Array CGH)
What is a gene family?
Genes that have high sequence similarity and similar but distinct function. Gene families arise from duplication.
What is genome “structural variation”?
Any change in the genome not due to a singly nucleotide substitution
What is important about DUF1220 amplication on 1q21?
This shows the greatest human-specific copy number expansion of any protein. Can also be linked to increased role in disease.
What is the synaptonemal complex
A ribbon-like proteinacious structure that holds together the paired homologues (bivalents). Crossovers occur at this stage, creating physical links (chiasmata) between homologs. Synaptonemal complex disassembles at the end of prophase 1, leaving the chiasmata as the only homolog link
Which is the most error prone step of meiotic division?
Homolog segregation in Meiosis 1
Name and describe the types of Ploidy
Haploid: 1 set of chromosomes
Diploid: 2 sets of chromosomes
Polyploidy: more than 2 sets of chromosomes
Euploidy: correct number of chromosomes
Aneuploidy: Incorrect #- trisomy of monosomy
Which aneuploidies allow conception to occur?
45, X ; trisomy 16, trisomy 21, 22
Which aneuploidies allow live birth to occur?
Trisomy 13, 18, 21 and gain or loss of sex chromosome
What causes polyploidy?
- Triploidy can occur at conception if two sperm/1 oocyte, diploid egg/1 sperm, 1 egg/diploid sperm. ~1-3% of conceptions. 69 chromosomes.
- Tetraploidy if DNA replicates, but the cell does not divide
What produces mosaicism?
Mitotic non-disjunction, often in early embryologic development. Phenotype depends on developmental stage, tissue type, chromosome involved.
Which type of meiotic segregation of derivative (reciprocal translocated) chromosomes in a quadrivalent leads to a balanced gamete?
Alternative
At what stage is the quadrivalent formed?
The zygotene stage of phrophase (meiosis 1), when partner homologs arrange themselves to maximize sequence pairing
When do homologs separate?
Metaphase
What happens in alternate segregation?
Centromeres of homologues go to opposite poles.
What happens in adjacent 1 segregation?
adjacent, nonhomologous centromeres go to the same pole
What is a Robertsonian Translocation?
Two acrocentric (13, 14, 15, 21, 22) chromosomes fuse together at the centromere, losing the satellite p arms and some rRNA encoding genes. Can be homologous or nonhomologous. May cause aneuploidy in offspring
Which are the most common types of Robertsonian Translocations
13;14 = ~75%
14;21
21;21
What phenotype is generally present with inversion?
Usually normal. Most inversions are familial. Present in ~1% of the population.
Describe the two types of inversion
- Pericentric: Inversion includes the centromere
2. Paracentric: Excludes the centromere
Name some benign pericentric inversions in the population
Constitutive heterochromatin inv: 19qh, 16qh, 1 qh, Yqh
Pericentric G-positive bands: 19p12 or q12
Pericentric region of 3
Pericentric region of 2
Does not lead to increased SABs, infertility, or recombinant offspring
How can pericentric inversions cause issues with crossover during meiosis?
A loop forms in order for the homologs to have maximal sequence pairing. Recombination crossover gives rise to two complementary recombinants:
One with a duplication of long arm, deletion of short arm flanking segments
One with a deletion of long arm, duplication of short arm flanking segments
What are the recombination products of paracentric inversions during meiosis?
They can be balanced, dicentric, or acentric. The latter 2 are unstable
What is Genetic testing
Testing body fluid or tissue for biochemical, chromosomal, or genetic markers that indicate the presence or absence of genetic disease
Chromosomal analysis indications and limitations
Can find aneuploidies, deletions, duplications, and insertions >3-5 Mb, and rearrangements
Cannot diagnose single gene deletion, point mutation, small deletions, insertions, and duplications, triplet repeats, and methylation
Name a disease that exemplifies incomplete penetrance
Type 1 diabetes
Name an example of a phenocopy
Thalidomide induced limb malformation shows similar phenotype to Roberts syndrome
Odds Ratio definition
Risk of carrying a disease with specific genetic variant/risk of carrying the disease without
How do you measure linkage disequilibrium?
1% recombination=1cM. Two Loci>50 cM apart are considered unlinked. LOD must be greater than 3 to show proof of linkage/gene localization
What does CYP3A metabolize and what inhibits/induces metabolism?
Metabolizes cyclosporine and felodipine. It is inhibited by Ketoconazole and grapefruit juice. It is induced by Rifampin
What are substrates of CYP2D6 and what inhibits metabolism?
Substrates: Codeine and tricyclic antidepressants
Inhibitors: Fluoxetine, Quinidine, Paroxetine
What does CYP2C9 metabolize?
Warfarin
What does NAT metabolize?
Isoniazid- used in tuberculosis treatment
What does TPMT metabolize?
6-mercaptopurine and 6-thioguanine. It can be fatal if given to children with ALL due to immunosuppression
What does GP6D metabolize?
sulfonamide and dapsone. It is an X-linked enzyme and can lead to hemolytic anemia in individuals who are GP6D deficient
What does VKORC1 metabolize?
Warfarin
Describe the 2 phases associated with pharmacokinetics
Phase 1: A polar group is attached to the compound to make it more soluble
Phase 2: A sugar/acetyl group is attached to detoxify the drug and make it easier to excrete
Where are CYP450 enzymes active?
Liver and intestinal epithelium
Hardy -Weinberg principle assumptions
- Large population with random mating
- No appreciable mutation rate
- no immigration/emigration of groups with different allele frequencies
- all genotypes are equally fit
Formulas for mutation rates
Autosomal Dominant: 1/2F(1-f)
Autosomal Recessive: F(f-1)
X-linked: 1/3F(f-1)
Which genes are associated with the formation of wolffian ducts?
SRY, SOX9, FGF9, SF1, NR5A1
Which genes are associated with the formation of Muellerian ducts?
WNT4, DHH, RSPO1
