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29 Cards in this Set
- Front
- Back
Isolated lethal X-linked recessive- chance that mother is a carrier
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2/3 of the time the mother is a carrier; 1/3 of the time the mutation is de novo
Exception: OTC deficiency, 90% time mother is carrier due to high mutation rate in paternal germline |
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Chromosomes important for imprinting?
What's more common, maternal or paternal UPD? |
6, 7, 11, 14, 15
Maternal more common- think trisomic rescue and non-disjunction more common in female germline. |
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Hardy-Weinberg assumptions
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-Large population, random mating
-Allele frequencies remain constant: 1) No appreciable new mutation rate 2) Individuals of all genotype capable of reproduction (no selection) 3) No significant migration between populations with different allele frequencies |
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Which would disrupt Hardy-Weinberg equilibrium more- non-random mating or selection/new mutations?
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-Non-random mating can substantially upset Hardy-Weinberg equilibrium
-Changes in allele frequency due to selection or new mutations have little effect on equilibrium -As long as random mating, recessive diseases can be considered in Hardy-Weinberg equilibrium, despite selection against homozygotes -Selection may be more obvious for dominant traits |
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Splice site mutations
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-At 5’ end = 9 nucleotide sequence, including the dinucelotide GT located in the intron immediately adjacent to splice site
-At 3’ end = 12 nucelotide sequence, include the AG located immediately 5’ intron-exon boundary Cryptic splice sites = intron base substitutions creating alternative donor/acceptor sites (cryptic splice sites), compete with normal splice sites, only a portion of mRNA may be improperly spliced |
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Initiator codon
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AUG (methionine)
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Stop codons
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UGA
UAA UAG |
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CpG hotspot mutations
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-Methylation at of C at 5’CpG3’
-Spontaneous deamination, methylated C>T -Results in C>T or G>A (opposite strand) |
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Conditions associated with advanced paternal age
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Achondroplasia
Craniosynostoses (Apert, Pfeiffer, Crouson) MEN2A Hemophilia B |
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Conditions associated with advanced maternal age
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Trisomies
Deletions in DMD |
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Which chromosomes are acrocentric?
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13, 14, 15, 21, 22
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Resolution karyotype v. oligoarray v. SNP array
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-Chromosome analysis = 5-10Mb resoluation
-Array CGH <5Mb Oligonucleotide arrays • 44K = 35kB apart • 105K = 9-17 kB -SNP arrays • <1 kB spacing • Detects LOH/UPD |
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Complete molar pregnancy
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Complete = no fetus and cystic placenta
-Usually diploid with 46,XX karyotype, all chromosomes are of paternal origin and usually all loci are homozygous -Sperm fertilizes an ovum that lacks a nucleus and it’s chromosomes then double -Choriocarcinoma = malignant neoplasm of fetal tissue, 50% develop from hydatidiform moles |
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Partial molar pregnancy
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Partial = remnants of placenta, small atrophic fetus
-Usually triploid, 2/3 of the time and extra set of paternal chromosomes are present -Extra paternal chromosomes result in abundant trophoblast but poor embryonic development -Extra maternal chromosomes result in severe retardation of embryonic growth with a small, fibrotic placenta |
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Ovarian teratoma
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benign tumors that arise from 46,XX cells containing only Maternal chromosomes (no paternal contribution), no placental development, may have differentiated masses
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Cat-eye syndrome
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4 copies of 22q11
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Smith-Magenis
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17p11.2 deletion
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Miller-Dieker syndrome
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17p13.3 deletion
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Wolf-Hischhorn
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4p16 deletion
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Williams syndrome
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7p11.23 deletion
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Trichorhinophlangeal syndrome
aka Langer-Giedion syndrome |
8q24 deletion
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Balanced translocations
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-Risk for unbalanced offspring 1-20% depending on rearrangement
-Possibility that break will disrupt gene (x-autosome translocation) Meiosis -Alternative: most common; 1 normal gamete, 1 balanced gamete -Adjacent 1: homologous centromeres go to separate daughter cells > unbalanced -Adjacent 2: rare, homologues chromosomes go to same daughter cell > unbalanced -3:1 segregation, gamete with 22 or 24 chromosomes |
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Translocation nomenclatures
Ex: der(3)t(3;11)(q12;p15.4) |
-Deletion of 3q12 to 3qter and duplication of 11p15.4 to 11pter
*Remember: Der represents chromosome centromere (so part of that chromosome is deleted) |
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Paracentric inversions
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-does not include centromere
-unbalanced chromosomes typically acentric or dicentric, not viable |
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Pericentric inversions
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- includes centromere
- unbalanced chromosomes have duplicated and deleted regions distal to inversion -risk for unbalanced offspring generally 5-10% -large pericentric inversions are more likely to lead to viable unbalanced offspring (THINK: small inversions would lead to a greater amount of duplicated/deleted material, therefore more likely to not be viable) |
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Pericentric inversion nomenclatures
Ex: 46,XY,rec(6)dup(6p)inv(6) (p22.2q25.2)mat |
-This is an pericentric inversion; unbalanced offspring has dup of 6p and del of 6q
-Mother = 56,XX,inv(6)(p22.2q25.2), balanced |
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X-chromosome inactivation
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-XIST = Xq13, noncoding RNA that is master regulator of x-inactivation
-15% of genes escape x-inactivation, another 10% show variable X inactivation -Most of the genes that escape X-inactivation are on distal Xp -Imbalances of genes on Xp may have more clinical significance than Xq |
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Non-random X-inactivation
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Unbalanced structural abnormalities = abnormal chromosome always inactive (THINK: selection bias
X-autosome translocation 1. Balanced = normal X chromosome inactive (THINK: both parts of translocation need to remain active) 2. Unbalanced = Translocation product carrying XIST is present and inactivated, leaving normal X active *Note: X-autosome translocations can cause break points, disrupting genes leading to X-linked disease (normal X inactivated) |
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Linkage analysis
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Theta = recombination frequency
-The smaller the recombination frequency, the closer the two loci -Theta = 0 = tightly linked (Linkage disequilibrium = inherited together) -Theta = .5 = unlinked, independent assortment (at least 1 crossover occurs every meiosis) LOD score = statistical method for measuring reliability of theta -LOD score of +3 or greater is considered definitive evidence that two loci are linked (strong evidence that theta differs from 0.5) |