Numerical ChromosomalAbnormalities andNondisjunction Lecture 32: ? Meiosis I? Meiosis II? Centromere -linked markers Female Male 46,XX46,XY Human chromosomal abnormalities may b e numerical or structural. Numerical Trisomy = 3 copies of a single chromosome 47 Monosomy = 1 c opy of a s ingle chromosome 45 Triploidy = 3N 69 Tetraploidy = 4N 92 Structural DeletionDuplicationTranslocation (involves 2 chromosomes) Total # chromosomes / cell Chromosomal abnormalities manifest themselves in two ways: 1) Spontaneous abortions of human pregnancies --> spontaneous abortion or miscarriage of spontaneously aborted embryos and fetuses have chromosomal abnormalities nearly all during first trimester of pregnancy, with many during the first month, when pregnancy is recognized only by hormonal assays 25% of all human embryos have chromosomal abnormalities . 50%50% Therefore Trisomy XXX, XXY, XYY All others Monosomy X (45,X o r XO) TriploidyTetraploidyOtherTotal 15% 9% 1% 27%18%17% 6% 7% Breakdown of chromosomal abnormalities in spontaneous abortions: 100% 16 21 18, 13, 2) Defects in newborns: 0.5% aggregate frequency Among the m ost c ommon: XXYXYYXOXXXTrisomy 13 Trisomy 18 Trisomy 21 Structural anomalies 1 / 1,000 males 1 / 1,100 males 1 / 7,500 females 1 / 1,200 females 1 / 15,0001 / 11,0001 / 9001 / 400 Chromosomal abnormalities manifest themselves in two ways: Fruitfly X Y X X # of X ’ ; s Sex chromosomes SEX DETERMINING SIGNAL MALE FEMALE Mammals X Y X X Y ( + o r - ) Nematodes XO X X # of X ’ ;s hermaphrodite Birds Z Z ZW ? Some Reptiles temperature Numerical chromosomal disorders are the result of Trisomy 21 Down Syndrome nondisjunction = failure o f c hromosomes to separate normally during cell division Nondisjunction can occur during How could you figure out whether nondisjunction for chromosome 21 had occurred during meiosis or mitosis? or meiosis (before fertilization) mitosis (after fertilization). g1g1 g1g1g1 g1g1 g1 g1g1 ABCD SSR 21.1 A’B’C’D’ SSR 21.2 What can you conclude? At least two t hings: 1. The presence in the affected child of two different maternal alleles for SSR 21.1 indicates that recombination between the two chromosome 21 ’ s in the mother prior to nondisjunction . nondisjunction occurred before fertilization (in meiosis) in the mother. 2. There has been replication Meiosis I Meiosis II Gametes 46 92 46 46 23 23 23 23 Meiosis I: Meiosis II: separate homologs separate s ister chromatids Human Male Meiosis Human Female Meiosis Gamete or2nd polar body 1st polar body Gamete or2nd polar body replication 46 92 Meiosis I Meiosis II 46 46 23 23 Normal chromosome 21 segregation: Meiosis II 4 possible gametes 46 46 46 Meiosis I 23 23 23 23 92 A A’ B B’ A A’ A A’ B B’ B B’ AA A’B’ B B’ B A’ AA ’ AB ’ BA ’ BB ’ Nondisjunction i n f emale meiosis I leading to trisomy: Meiosis I Meiosis II Gamete 46 92 48 24 24 AA ’ BB ’ AA ’ AA ’ BB ’ BB ’ A B’ A A ’ or AB ’ what ’ s left no Chr 21! 2nd polar body B B’ B A’ B A ’ or BB ’ and 1st polar body 44 A’ A Nondisjunction i n f emale meiosis II leading to trisomy: Meiosis I Meiosis II gamete 46 92 46 46 22 24 AA ’ BB ’ AA ’ AA ’ BB ’ BB ’ AA A’B’ BB ’ BA ’ A A ’ and AB ’ no Chr 21! 1st polar body 2nd polar body The key to distinguishing Meiosis I v s Meiosis II nondisjunction is the centromere-linked marker, which will segregate as follows: Proper disjunction Meiosis I nondisjunction Meiosis II nondisjunction A or BA and B(A and A) or (B and B) Nondisjunction i n f emale meiosis I leading to trisomy: Meiosis I Meiosis II Gamete 46 92 48 44 24 24 AA ’ BB ’ AA ’ AA ’ BB ’ BB ’ A B’ A A ’ or AB ’ what ’ s left no Chr 21! 2nd polar body B B’ B A ’ or BB ’ and 1st polar body A A’ B A’ The key to distinguishing Meiosis I v s Meiosis II nondisjunction is the centromere-linked marker, which will segregate as follows: Proper disjunction Meiosis I nondisjunction Meiosis II nondisjunction A or BA and B(A and A) or (B and B) Nondisjunction i n f emale meiosis II leading to trisomy: Meiosis I Meiosis II gamete 46 92 46 46 22 24 AA ’ BB ’ AA ’ AA ’ BB ’ BB ’ AA A’B’ BB ’ BA ’ A A ’ and AB ’ no Chr 21! 1st polar body 2nd polar body ABCD A’B’C’D’ g1g1 g1g1g1 g1g1 g1 g1g1 SSR 21.1 SSR 21.2 Interpretation: The data f or SSR21.1, the c entromeric m arker, demonstrate that nondisjunction occurred i n maternal meiosis I. Taken together, the SSR21.1 and SSR21.2 data demonstrate t hat recombination between the mother's two chromosome 21 ’ s occurred prior to nondisjunction . very close to centromere farther from centromere ABCD A’B’C’D’ g1g1 g1g1g1 g1g1 g1 g1g1 SSR 21.1 SSR 21.2 Interpretation: The data f or SSR21.1, the c entromeric m arker, demonstrate that nondisjunction occurred i n maternal meiosis I. Taken together, the SSR21.1 and SSR21.2 data demonstrate t hat recombination between the mother's two chromosome 21 ’ s occurred prior to nondisjunction . very close to centromere farther from centromere A A’ B B’ AB ’ B B’ D D’ C D’ D D’ Studies of many individuals with trisomy 21 using centromere -linked markers have revealed following breakdown o f c ases: Nondisjunction in maternal meiosis: Nondisjunction in paternal meiosis: 88% 8% Meiosis I: Meiosis II: 65%23% Post-zygotic mitosis: 3% Meiosis I: Meiosis II: 3%5% The risk of trisomy 21 rises dramatically with increasing maternal age: Age of Mother 203035404550 Incidence of trisomy 21 1 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 o f meiosis I during fetal development. Each oocyte remains arrested i n p rophase o f m eiosis I until that individual oocyte is ovulated, as much as 50 years later! An oocyte proceeds through meiosis II only after ( and if) i t i s fertilized.