Molecular/quantitative Genetics Review

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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?

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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

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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)

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-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

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-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)