Lecture 32: Numerical Chromosomal Abnormalities and Nondisjunction. Meiosis I Meiosis II Centromere-linked markers
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1 Lecture 32: Numerical Chromosomal Abnormalities and Nondisjunction Meiosis I Meiosis II Centromere-linked markers
2 Female Male 46,XX 46,XY Human chromosomal abnormalities may be numerical or structural. Numerical Total # chromosomes / cell Trisomy = 3 copies of a single chromosome 47 Monosomy = 1 copy of a single chromosome 45 Triploidy = 3N 69 Tetraploidy = 4N 92 Structural Deletion Duplication Translocation (involves 2 chromosomes)
3 Chromosomal abnormalities manifest themselves in two ways: 1) Spontaneous abortions 50% of human pregnancies --> spontaneous abortion or miscarriage nearly all during first trimester of pregnancy, with many during the first month, when pregnancy is recognized only by hormonal assays 50% of spontaneously aborted embryos and fetuses have chromosomal abnormalities Therefore 25% of all human embryos have chromosomal abnormalities.
4 Breakdown of chromosomal abnormalities in spontaneous abortions: Trisomy 16 13, 18, 21 XXX, XXY, XYY All others Monosomy X (45,X or XO) Triploidy Tetraploidy Other 15% 9% 1% 27% 18% 17% 6% 7% Total 100%
5 Chromosomal abnormalities manifest themselves in two ways: 2) Defects in newborns: 0.5% aggregate frequency Among the most common: XXY XYY XO XXX Trisomy 13 Trisomy 18 Trisomy 21 Structural anomalies 1 / 1,000 males 1 / 1,100 males 1 / 7,500 females 1 / 1,200 females 1 / 15,000 1 / 11,000 1 / / 400
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8 Sex chromosomes SEX DETERMINING SIGNAL MALE FEMALE Fruitfly XY XX # of X ;s Mammals XY XX Y (+ or -) Nematodes XO XX # of X ;s hermaphrodite Birds ZZ ZW? Some Reptiles temperature
9 Trisomy 21 Down Syndrome Numerical chromosomal disorders are the result of nondisjunction = failure of chromosomes to separate normally during cell division Nondisjunction can occur during or meiosis (before fertilization) mitosis (after fertilization). How could you figure out whether nondisjunction for chromosome 21 had occurred during meiosis or mitosis?
10 SSR 21.1 A B C D SSR 21.2 What can you conclude? A B C D At least two things: 1. The presence in the affected child of two different maternal alleles for SSR 21.1 indicates that nondisjunction occurred before fertilization (in meiosis) in the mother. 2. There has been recombination between the two chromosome 21 s in the mother prior to nondisjunction.
11 Human Male Meiosis replication Meiosis I: separate homologs Meiosis II: separate sister chromatids Meiosis I Meiosis II Gametes
12 Human Female Meiosis replication Meiosis I 1st polar body Meiosis II 23 Gamete or 2nd polar body 23 Gamete or 2nd polar body
13 Normal chromosome 21 segregation: Meiosis I A B Meiosis II B A 23 AA 4 possible gametes 23 AB BA BB
14 Nondisjunction in female meiosis I leading to trisomy: A A Meiosis I B A 1st polar body 48 A B no Chr 21! 44 Meiosis II 24 AA or AB and BA or BB Gamete 24 what s left 2nd polar body
15 Nondisjunction in female meiosis II leading to trisomy: Meiosis I A B Meiosis II B A 1st polar body 24 AA and AB no Chr 21! gamete 22 2nd polar body
16 The key to distinguishing Meiosis I vs Meiosis II nondisjunction is the centromere-linked marker, which will segregate as follows: Proper disjunction A or B Meiosis I nondisjunction A and B Meiosis II nondisjunction (A and A) or (B and B)
17 Nondisjunction in female meiosis I leading to trisomy: Meiosis I B A A B Meiosis II 1st polar body no Chr 21! AA or AB and BA or BB Gamete 24 what s left 2nd polar body
18 The key to distinguishing Meiosis I vs Meiosis II nondisjunction is the centromere-linked marker, which will segregate as follows: Proper disjunction A or B Meiosis I nondisjunction A and B Meiosis II nondisjunction (A and A) or (B and B)
19 Nondisjunction in female meiosis II leading to trisomy: Meiosis I A B Meiosis II B A 1st polar body 24 AA and AB no Chr 21! gamete 22 2nd polar body
20 very close to centromere SSR 21.1 A B C D farther from centromere SSR 21.2 A B C D Interpretation: The data for SSR21.1, the centromeric marker, demonstrate that nondisjunction occurred in maternal meiosis I. Taken together, the SSR21.1 and SSR21.2 data demonstrate that recombination between the mother's two chromosome 21 s occurred prior to nondisjunction.
21 C D D D very close to centromere SSR 21.1 A B C D A B farther from centromere SSR 21.2 A B C D D D Interpretation: The data for SSR21.1, the centromeric marker, demonstrate that nondisjunction occurred in maternal meiosis I. Taken together, the SSR21.1 and SSR21.2 data demonstrate that recombination between the mother's two chromosome 21 s occurred prior to nondisjunction.
22 Studies of many individuals with trisomy 21 using centromere-linked markers have revealed following breakdown of cases: Nondisjunction in maternal meiosis: 88% Meiosis I: Meiosis II: 65% 23% Nondisjunction in paternal meiosis: 8% Meiosis I: Meiosis II: 3% 5% Post-zygotic mitosis: 3%
23 The risk of trisomy 21 rises dramatically with increasing maternal age: Age of Mother Incidence of trisomy per 1925 births 1 per 885 births 1 per 365 births 1 per 110 births 1 per 32 births 1 per 12 births Trisomy 21 provides the major rationale for advising pregnant women 35 years of age or older to undergo amniocentesis (examination of fetus' chromosomes by light microscopy). In human females, oocytes enter but arrest in prophase of meiosis I during fetal development. Each oocyte remains arrested in prophase of meiosis I until that individual oocyte is ovulated, as much as 50 years later! An oocyte proceeds through meiosis II only after (and if) it is fertilized.
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