lec 17 chromosomal changes

lec 17 chromosomal changes - Variation in chromosome...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Variation in chromosome number: variation in ploidy Euploidy: containing only complete sets of chromosomes (as opposed to aneuploidy) Diploidy (2n) : Monoploidy (n) : Variation in chromosome number: variation in ploidy Euploidy: containing only complete sets of chromosomes (as opposed to aneuploidy) Diploidy (2n) : Polyploidy: containing more than the normal diploid number Monoploidy (n) : Triploidy (3n) : Tetraploidy (4n) : Hexaploidy (6n), Octoploidy (8n), etc Chromosomes shown as seen at metaphase, hence there are two sister chromatids per chromosome Variation in chromosome number: variation in ploidy In animals, monoploidy and polyploidy are rare: monoploidy: some ants and bees: males are monoploid, derived from unfertilized eggs. They produce sperm through mitosis females are diploid, derived from normal fertilization, create eggs through meiosis polyploidy: hermaphroditic worms, goldfish, some amphibians possibly it is difficult to properly segregate multiple copies of X and Y chromosomes Variation in chromosome number: variation in ploidy In animals, monoploidy and polyploidy are rare: monoploidy: some ants and bees: males are monoploid, derived from unfertilized eggs. They produce sperm through mitosis females are diploid, derived from normal fertilization, create eggs through meiosis polyploidy: hermaphroditic worms, goldfish, some amphibians possibly it is difficult to properly segregate multiple copies of X and Y chromosomes In plants, polyploidy is common and monoploidy easily induced: polyploidy: makes larger cells, and more robust and larger plants monoploidy: can be artificially induced and is useful in plant breeding Variation in chromosome number: variation in ploidy In animals, monoploidy and polyploidy are rare: monoploidy: some ants and bees: males are monoploid, derived from unfertilized eggs. They produce sperm through mitosis females are diploid, derived from normal fertilization, create eggs through meiosis polyploidy: hermaphroditic worms, goldfish, some amphibians possibly it is difficult to properly segregate multiple copies of X and Y chromosomes In plants, polyploidy is common and monoploidy easily induced: polyploidy: makes larger cells, and more robust and larger plants monoploidy: can be artificially induced and is useful in plant breeding Polyploidy: odd numbers of basic chromosome set (3n, 5n, 7n, etc) : infertile even number of basic chromosome set (2n, 4n, 6n, 8n): fertile Basis for increase in ploidy number: Normal mitosis 2n interphase * S phase prophase mitosis 2n telophase Basis for increase in ploidy number: Normal mitosis 2n Normal mitosis interphase * 2n S phase interphase * S phase prophase mitosis 2n prophase Inhibition of mitosis * telophase 4n mitosis telophase * for example, by agents that inhibit spindle formation (cold, certain drugs (e.g. colchicine), pressure, etc) Basis for increase in ploidy number: Normal meiosis interphase (chromosomes shown condensed for clarity) 2n S phase only one of two products shown) prophase I (early,before chiasmata) only two of four products shown telophase I gametes n meiosis I meiosis II Basis for increase in ploidy number: Normal meiosis interphase (chromosomes shown condensed for clarity) 2n S phase Inhibition meiosis I S phase only one of two products shown) prophase I (early,before chiasmata) only two of four products shown telophase I gametes n meiosis I meiosis I meiosis II meiosis II 2n Basis for increase in ploidy number: Normal meiosis interphase (chromosomes shown condensed for clarity) 2n Inhibition meiosis II S phase S phase Inhibition meiosis I S phase gametes n meiosis I meiosis I meiosis II meiosis I meiosis II 2n meiosis II 2n only one of two products shown only two of four products shown telophase I only one of two products shown) only one of two products shown) prophase I (early,before chiasmata) Basis for increase in ploidy number: 2n mitosis 2n meiosis n Basis for increase in ploidy number: Diploid cells 2n faulty mitosis 2n mitosis 4n meiosis gamete 2n meiosis 2n n Basis for increase in ploidy number: Diploid cells 2n faulty mitosis mitosis 4n 2n 2n mitosis 2n faulty meiosis meiosis gamete 2n 2n meiosis 2n n Basis for increase in ploidy number: Diploid cells 2n faulty mitosis mitosis 2n 2n faulty meiosis meiosis 2n * fertilization zygote 2n mitosis 4n gamete 2n 4n meiosis 2n n * * 4n 2n * = indicates fertilized by similar gamete Basis for increase in ploidy number: Diploid cells 2n faulty mitosis mitosis 2n 2n faulty meiosis meiosis 2n 4n meiosis 2n n * * fertilization zygote 2n mitosis 4n gamete 2n 4n * 4n 2n * = indicates fertilized by similar gamete Basis for increase in ploidy number: Diploid cells 2n faulty mitosis mitosis 2n 2n faulty meiosis meiosis 2n 4n meiosis 2n n * * fertilization zygote 2n mitosis 4n gamete 2n 4n * 4n 2n Fertilization can occur between gametes of the same species (autopolyploidy) or gametes from different species (allopolyploidy) = indicates fertilized by similar gamete * Basis for increase in ploidy number: Diploid cells 2n faulty mitosis mitosis 2n 2n faulty meiosis meiosis 2n 4n meiosis 2n n * * fertilization zygote 2n mitosis 4n gamete 2n 4n * 4n 3n 2n Fertilization can occur between gametes of the same species (autopolyploidy) or gametes from different species (allopolyploidy) = indicates fertilized by similar gamete * faulty mitosis mitosis 2n 2n faulty meiosis meiosis 2n 4n meiosis 2n n * * fertilization zygote 2n mitosis 4n gamete 2n 4n * 4n 3n 2n Infertile, but could turn into fertile hexaploid if chromosome number duplicates again (e.g. through faulty mitosis) Basis for increase in ploidy number: Diploid cells 2n Fertilization can occur between gametes of the same species (autopolyploidy) or gametes from different species (allopolyploidy) = indicates fertilized by similar gamete * Variation in chromosome number: variation in ploidy Chromosome segregation during meiosis in polyploid cells: Odd # (e.g. triploid) 3n Homologs aligned at metaphase I Anaphase I Meiosis II gametes Other chromosomes will also segregate at random, creating a genetic imbalance in gametes and zygotes Variation in chromosome number: variation in ploidy Chromosome segregation during meiosis in polyploid cells: Odd # (e.g. triploid) Even # (e.g. tetraploid) Even-numbered polyploids evolve mechanism so that 4n homologs are aligned in pairs. This is easier if the polyploid derives from the hybridization of different species (allopolyploid) than if from the same species (autopolyploid) 3n Homologs aligned at metaphase I Anaphase I Meiosis II gametes Other chromosomes will also segregate at random, creating a genetic imbalance in gametes and zygotes Genetic balance in gametes and zygotes fertile infertile Meiosis in a heterozygous tetraploid: AAaa A1 A2 a1 a2 Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 a1 a2 a2 a1 Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 a1 a2 a2 a1 A2 a2 a2 A2 Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 MI M II A1 a1 A2 a2 A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 MI M II And so on… A1 a1 A2 a2 A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 MI M II A1a1 A2a2 A1 a1 A2 a2 A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa What will fraction of gametes will be aa? Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 a1a2 A1a1 A2a2 MI M II A1a1 A2a2 A1 a1 A2 a2 A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa A1a2 A2a1 A1A2 a1a2 A1a2 A2a1 A1A2 What will fraction of gametes will be aa? 1/6 Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 a1a2 A1a1 A2a2 MI M II A1a1 A1 A2a2 a1 A2 a2 A1a2 A2a1 A1A2 a1a2 A1a2 A2a1 A1A2 What will fraction of gametes will be aa? 1/6 For AAaa x AAaa, what fraction of progeny will be wildtype? A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 a1a2 A1a1 A2a2 MI M II A1a1 A1 A2a2 a1 A2 a2 A1a2 A2a1 A1A2 a1a2 A1a2 A2a1 A1A2 What will fraction of gametes will be aa? 1/6 For AAaa x AAaa, what fraction of progeny will be wildtype? Expected aaaa = 1/6 x 1/6 = 1/36 A1 a1 A2 a2 2(A1a1) 2(A2a2) Aa Meiosis in a heterozygous tetraploid: AAaa A1 A2 A1 A2 A1 a1 A1 a1 A1 a2 A1 a2 a1 a2 a2 a1 A2 a2 a2 A2 A2 a1 a1 A2 a1a2 A1a1 A2a2 MI M II A1a1 A1 A2a2 a1 A2 a2 A1a2 A2a1 A1A2 a1a2 A1a2 A2a1 A1A2 What will fraction of gametes will be aa? 1/6 For AAaa x AAaa, what fraction of progeny will be wildtype? Expected aaaa = 1/6 x 1/6 = 1/36 A1 a1 A2 a2 If A is fully dominant, A_ _ _ progeny will be 1- (1/36) = 35/36 2(A1a1) 2(A2a2) Aa Variation in chromosome number: aneuploidy Euploidy: balanced (complete) set of chromosomes Aneuploidy: numerical change in the number of chromosomes, so that it is not an exact multiple of the basic set Variation in chromosome number: aneuploidy Euploidy: balanced (complete) set of chromosomes Aneuploidy: numerical change in the number of chromosomes, so that it is not an exact multiple of the basic set Monosomy: lack of one chromosome from diploid (2n - 1) Polysomy: additional chromosomes from diploid: trisomy : (2n + 1) tetrasomy : (2n + 2) Variation in chromosome number: aneuploidy Euploidy: balanced (complete) set of chromosomes Aneuploidy: numerical change in the number of chromosomes, so that it is not an exact multiple of the basic set Monosomy: lack of one chromosome from diploid (2n - 1) Polysomy: additional chromosomes from diploid: trisomy : (2n + 1) tetrasomy : (2n + 2) Monosomy/Polysomy usually results in more severe phenotypes than does polyploidy, caused by imbalance of number of copies of different genes. Variation in chromosome number: aneuploidy Euploidy: balanced (complete) set of chromosomes Aneuploidy: numerical change in the number of chromosomes, so that it is not an exact multiple of the basic set Monosomy: lack of one chromosome from diploid (2n - 1) Polysomy: additional chromosomes from diploid: trisomy : (2n + 1) tetrasomy : (2n + 2) Monosomy/Polysomy usually results in more severe phenotypes than does polyploidy, caused by imbalance of number of copies of different genes. Aneuploidy originally studied in plants, such as the Jimson weed Datura stramonium: 12 chromosomes; 12 syndromes affecting seed capsule morphology, each associated with a trisomy Distinguishing chromosomes: overall shape and size Metacentric: centromere near middle Acrocentric: centromere near end (those apparently at end, previously called “telocentric,” also have regions extending beyond the centromere) Distinguishing chromosomes: overall shape and size Metacentric: centromere near middle Acrocentric: centromere near end (those apparently at end, previously called “telocentric,” also have regions extending beyond the centromere) Banding patterns using DNA intercalating agents and dyes, reveals highly reproducible patterns corresponding to chromosomal regions of differential base composition and DNA packaging. Patterns serve to identify individual chromosomes and also to subdivide chromosomal regions Quinacrine Giemsa stain Q-bands (fluorescent banding) G-banding (most commonly used, 2000 G-bands in humans, ) R-banding (reverse of G-banding) (see Fig. 7.3 and 7.4 Snustad) C-banding (stains near centromeres) G-banding Distinguishing chromosomes: overall shape and size Metacentric: centromere near middle Acrocentric: centromere near end (those apparently at end, previously called “telocentric,” also have regions extending beyond the centromere) Banding patterns using DNA intercalating agents and dyes, reveals highly reproducible patterns corresponding to chromosomal regions of differential base composition and DNA packaging. Patterns serve to identify individual chromosomes and also to subdivide chromosomal regions Quinacrine Giemsa stain p (short) Q-bands (fluorescent banding) G-banding (most commonly used, 2000 G-bands in humans, ) R-banding (reverse of G-banding) (see Fig. 7.3 and 7.4 Snustad) C-banding (stains near centromeres) q (long) The p (short) and q (long) arms are subdivided into numbered regions starting at centromere G-banding Fig. 7.5 Snustad The human karyotype Karyotype: chromosomal constitution, arranged in order of length of chromosomes and position of the centromere. (Karyotyping: arranging chromosomes into karyotypes) G-banding R-banding Fig. 7.5 Snustad The human karyotype Karyotype: chromosomal constitution, arranged in order of length of chromosomes and position of the centromere. (Karyotyping: arranging chromosomes into karyotypes) G-banding R-banding Fig. 7.1.5 Snustad In humans, most common trisomy is Down syndrome (trisomy 21) (G-banding) Basis for aneuploidy: non disjunction Normal meiosis interphase (chromosomes shown condensed for clarity) 2n S phase prophase I meiosis I telophase I meiosis II gametes n n n n Basis for aneuploidy: non disjunction Normal meiosis interphase (chromosomes shown condensed for clarity) 2n Non-disjunction at meiosis I 2n S phase S phase prophase I non disjunction of acrocentric chromosome meiosis I telophase I meiosis I meiosis II gametes n meiosis II n n n n+1 n+1 n-1 n-1 Basis for aneuploidy: non disjunction normal meiosis interphase (chromosomes shown condensed for clarity) 2n S phase prophase I meiosis I telophase I meiosis II gametes n n n n Basis for aneuploidy: non disjunction normal meiosis interphase (chromosomes shown condensed for clarity) 2n Non-disjunction at meiosis II 2n S phase S phase prophase I meiosis I meiosis I telophase I non disjunction of acrocentric chromosome meiosis II gametes n meiosis II n n n n+1 n-1 n n Comparison of non-disjunction at meiosis I and meiosis II Non-disjunction at meiosis I interphase (chromosomes shown condensed for clarity) 2n Non-disjunction at meiosis II 2n S phase S phase prophase I (early,before chiasmata) non disjunction of acrocentric chromosome meiosis I telophase I gametes n+1 n+1 meiosis II n-1 meiosis I non disjunction of acrocentric chromosome meiosis II n-1 n+1 n-1 n n Comparison of non-disjunction at meiosis I and meiosis II Non-disjunction at meiosis I Non-disjunction at meiosis II interphase (chromosomes In the absence of shown condensed recombination for clarity) (e.g.between sex-specific 2n 2n regions of X and Y chromosomes), site of S phase S phase non-disjunction can be distinguished by meiotic prophase I products (early,before chiasmata) non disjunction of acrocentric chromosome meiosis I telophase I gametes n+1 n+1 meiosis II n-1 meiosis I non disjunction of acrocentric chromosome meiosis II n-1 n+1 n-1 n n Aneuploidy can also originate in mitosis: through non disjunction (similar to that occurring in meiosis II) to generate disomies and monosomies or through chromosome loss to generate monosomies. If this occurs in a germ cell precursor, then the change can be transmitted to the next generation Aneuploidy can also originate in mitosis: through non disjunction (similar to that occurring in meiosis II) to generate disomies and monosomies or through chromosome loss to generate monosomies. If this occurs in a germ cell precursor, then the change can be transmitted to the next generation Sex chromosome abnormalities: aneuploidy of sex chromosomes Viable but with syndromes why viable?: Y carries few genes, and all but one X chromosome are inactivated little genetic imbalance why is there a syndrome then? Y does contain some genes, and some regions in the X chromosome escape inactivation Aneuploidy can also originate in mitosis: through non disjunction (similar to that occurring in meiosis II) to generate disomies and monosomies or through chromosome loss to generate monosomies. If this occurs in a germ cell precursor, then the change can be transmitted to the next generation Sex chromosome abnormalities: aneuploidy of sex chromosomes Viable but with syndromes why viable?: Y carries few genes, and all but one X chromosome are inactivated little genetic imbalance why is there a syndrome then? Y does contain some genes, and some regions in the X chromosome escape inactivation Reminder: in humans, sex determination depends on presence or absence of Y chromosome (presence of Y determines being male, absence of Y determines being female) XO, monosomy X = Turner syndrome: female, short stature, usually sterile, other defects XXX, trisomy X = Triplo X syndrome: female, normal but with reduced fertility, slightly increased frequency of mental retardation XXY, XXXY, XXXXY, etc, XXYY, Klinefelter syndrome: male, long limbs, abnormal sexual maturation XYY, double-Y syndrome: males, tend to be tall, slightly impaired mental function. Chromosome abnormalities per 100,000 recognized human pregnancies Some trisomies not Trisomy abnormal chromosomes found at all (probably abnormal chromosomes 1 0 0 resorbed very early in pregnancy) e.g. 1,5 2 159 0 3 53 0 4 95 0 5 0 0 6-12 561 0 13 128 17 (Patau syndrome) 14 275 0 15 318 0 16 1229 0 17 10 0 18 223 13 (Edwards syndrome) 19,20 52 0 21 350 113 (Down syndrome) 22 424 0 XYY 4 46 XXY 4 44 XO 1350 8 XXX 21 44 Triploid 1275 0 Tetraploid 450 0 Other 519 265 7500 550 (of 15,000 spontaneous abortions) (of 85,000 live births) Chromosome abnormalities per 100,000 recognized human pregnancies Some trisomies not Trisomy abnormal chromosomes found at all (probably abnormal chromosomes 1 0 0 resorbed very early in pregnancy) e.g. 1,5 2 159 0 3 53 0 Most trisomies do not 4 95 0 survive to live birth 5 0 0 e.g. 2, 3, 4, 6-12, etc 6-12 561 0 13 128 17 (Patau syndrome) 14 275 0 15 318 0 16 1229 0 17 10 0 18 223 13 (Edwards syndrome) 19,20 52 0 21 350 113 (Down syndrome) 22 424 0 XYY 4 46 XXY 4 44 XO 1350 8 XXX 21 44 Triploid 1275 0 Tetraploid 450 0 Other 519 265 7500 550 (of 15,000 spontaneous abortions) (of 85,000 live births) Chromosome abnormalities per 100,000 recognized human pregnancies Some trisomies not Trisomy abnormal chromosomes found at all (probably abnormal chromosomes 1 0 0 resorbed very early in pregnancy) e.g. 1,5 2 159 0 3 53 0 Most trisomies do not 4 95 0 survive to live birth 5 0 0 e.g. 2, 3, 4, 6-12, etc 6-12 561 0 13 128 17 (Patau syndrome) Trisomies 13,18 and 14 275 0 21 rarely survive to birth, 15 318 0 16 1229 0 17 10 0 18 223 13 (Edwards syndrome) 19,20 52 0 21 350 113 (Down syndrome) 22 424 0 XYY 4 46 XXY 4 44 XO 1350 8 XXX 21 44 Triploid 1275 0 Tetraploid 450 0 Other 519 265 7500 550 (of 15,000 spontaneous abortions) (of 85,000 live births) Chromosome abnormalities per 100,000 recognized human pregnancies Some trisomies not Trisomy abnormal chromosomes found at all (probably abnormal chromosomes 1 0 0 resorbed very early in pregnancy) e.g. 1,5 2 159 0 3 53 0 Most trisomies do not 4 95 0 survive to live births 5 0 0 e.g. 2, 3, 4, 6-12, etc 6-12 561 0 13 128 17 (Patau syndrome) Trisomies 13,18 and 14 275 0 21 rarely survive to birth 15 318 0 Trisomy 21 is 16 1229 0 affected by maternal 17 10 0 18 223 13 (Edwards syndrome) age, increasing in incidence 10-fold 19,20 52 0 every 10 years after 21 350 113 (Down syndrome) age 30 22 424 0 XYY 4 46 XXY 4 44 XO 1350 8 XXX 21 44 Triploid 1275 0 Tetraploid 450 0 Other 519 265 7500 550 (of 15,000 spontaneous abortions) (of 85,000 live births) Some trisomies not Chromosome abnormalities per 100,000 recognized human pregnancies found at all (probably Trisomy abnormal chromosomes abnormal chromosomes resorbed very early 1 0 0 in pregnancy) e.g. 1,5 2 159 0 3 53 0 Most trisomies do not 4 95 0 survive to live birth 5 0 0 e.g. 2, 3, 4, 6-12, etc 6-12 561 0 13 128 17 (Patau syndrome) Trisomies 13,18 and 14 275 0 21 rarely survive to birth 15 318 0 Trisomy 21 is 16 1229 0 affected by maternal 17 10 0 age, increasing in 18 223 13 (Edwards syndrome) incidence 10-fold 19,20 52 0 every 10 years after 21 350 113 (Down syndrome) age 30 22 424 0 XYY 4 46 Among sex chromosome XXY 4 44 abnormalities, monosomy (XO, XO 1350 8 Turner’s syndrome) is most XXX 21 44 common. It also has lowest Triploid 1275 0 survival, at least in part Tetraploid 450 0 due the uncovering of lethals Other 519 265 present in only copy of X. 7500 550 (of 15,000 spontaneous abortions) (of 85,000 live births) Some trisomies not Chromosome abnormalities per 100,000 recognized human pregnancies found at all (probably Trisomy abnormal chromosomes abnormal chromosomes resorbed very early 1 0 0 in pregnancy) e.g. 1,5 2 159 0 3 53 0 Most trisomies do not 4 95 0 survive to live birth 5 0 0 e.g. 2, 3, 4, 6-12, etc 6-12 561 0 13 128 17 (Patau syndrome) Trisomies 13,18 and 14 275 0 21 rarely survive to birth 15 318 0 Trisomy 21 is 16 1229 0 affected by maternal 17 10 0 age, increasing in 18 223 13 (Edwards syndrome) incidence 10-fold 19,20 52 0 every 10 years after 21 350 113 (Down syndrome) age 30 22 424 0 XYY 4 46 Among sex chromosome XXY 4 44 abnormalities, monosomy (XO, XO 1350 8 Turner’s syndrome) is most XXX 21 44 common. It also has lowest Triploid 1275 0 survival, at least in part due Tetraploid 450 0 the uncovering of lethals Other 519 265 present in only copy of X 7500 550 Polyploidy is not (of 15,000 spontaneous abortions) (of 85,000 live births) tolerated in humans Chromosome 21 Smallest autosome (1.5% of the human genome, 350 genes) 350 genes , most on the long arm (43 million bp in length) Down syndrome - trisomy 21 90% from female nondisjunction, 10% from male NDJ Among female NDJ, 75% anaphase I Among female anaphase I NDJ, 50% lacked cross-over Mosaic Down syndrome (1% of total) Due to mitotic NDJ during development Usually less severe Familial Down syndrome due to translocations (2-3%) Variation in chromosome structure: Wild-type 1 2 3 4 5 6 7 8 9 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 5 6 7 7 8 8 9 10 9 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 Duplication 1 2 3 4 5 6 7 3 4 7 8 5 8 9 10 6 9 7 10 8 9 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 Duplication Inversion 1 2 1 3 5 4 4 5 7 3 3 6 8 4 2 7 5 6 8 9 10 6 7 9 7 8 10 8 9 9 10 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 Duplication 1 2 1 Inversion 3 5 4 4 5 6 7 3 3 7 9 8 4 2 5 8 10 6 6 9 7 7 8 10 8 9 9 10 Translocations (exchanges between non homologous chromosomes 21 22 23 24 1 2 3 4 1 2 23 24 21 22 3 4 5 6 7 8 9 10 5 6 7 8 9 10 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 Duplication 1 2 1 Inversion 3 5 4 4 5 6 7 3 3 7 9 8 4 2 5 8 10 6 6 9 7 7 8 10 8 9 9 10 Translocations (exchanges between non homologous chromosomes 21 22 23 24 1 2 3 4 1 2 23 24 21 22 3 4 5 6 7 8 9 10 5 6 7 8 9 10 Origin of chromosomal aberrations: - errors in replication - recombination at repeats - faulty meiotic or (induced mitotic) recombination - exposure to agents that cause double stranded DNA breaks (e.g. X-rays) 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletion 1 2 3 6 Duplication 1 2 1 Inversion 3 5 4 4 5 6 7 3 3 7 9 8 4 2 5 8 10 6 6 9 7 7 8 10 8 9 9 10 Translocations (exchanges between non homologous chromosomes 21 22 23 24 1 2 3 4 1 2 23 24 21 22 3 4 5 6 7 8 9 10 5 6 7 8 9 10 Origin of chromosomal aberrations: - errors in replication - recombination at repeats - faulty meiotic or (induced mitotic) recombination - exposure to agents that cause double stranded DNA breaks (e.g. X-rays) A chromosomal aberration may in addition disrupt a gene at each of its breakpoints 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletions 1 2 3 6 5 6 7 7 8 8 9 10 Deletions (or Deficiencies) usually delete several to hundreds of genes Del + often has effects due to genetic imbalance 9 10 Variation in chromosome structure: Wild-type 1 2 3 4 Deletions 1 2 3 6 5 6 7 7 8 8 9 9 10 10 Deletions (or Deficiencies) usually delete several to hundreds of genes Del + Del Del often has effects due to genetic imbalance or Del Y is most often lethal because essential genes are deleted Variation in chromosome structure: Wild-type 1 2 3 4 Deletions 1 2 3 5 6 6 7 7 9 8 8 9 10 10 Deletions (or Deficiencies) usually delete several to hundreds of genes Del + Del Del often has effects due to genetic imbalance or Del Y is most often lethal because essential genes are deleted Wild-type 1 2 3 4 5 6 Duplications 1 2 3 4 3 4 7 5 8 6 9 10 7 8 9 10 Duplications increase the number of copies of a particular chromosomal region. They are less likely to be detected than deletions, since most have no effect and can only be detected through cytology. Dup + can have phenotype due to genetic imbalance, but less frequently than deletions Variation in chromosome structure: Wild-type 1 2 3 4 Deletions 1 2 3 5 6 6 7 7 9 8 8 9 10 10 Deletions (or Deficiencies) usually delete several to hundreds of genes Del + Del Del often has effects due to genetic imbalance or Del Y is most often lethal because essential genes are deleted Wild-type 1 2 3 4 5 6 Duplications 1 2 3 4 3 4 7 5 8 6 9 10 7 8 9 10 Duplications increase the number of copies of a particular chromosomal region. They are less likely to be detected than deletions, since most have no effect and can only be detected through cytology. Dup + can have phenotype due to genetic imbalance, but less frequently than deletions Dup Dup can be viable if not too large and breakpoints do not disrupt an essential gene Variation in chromosome structure: How important is gene dosage (i.e. having other than two gene copies)? - for most genes, copy number is not too important Variation in chromosome structure: How important is gene dosage (i.e. having other than two gene copies)? - for most genes, copy number is not too important - for others it is extremely important e.g. Triplolethal (Tpl) in Drosophila is lethal if not present in exactly two copies Tpl+ Tpl+ normal (2 copies) Dl (Tpl) Tpl+ lethal Tpl+ Dp (Tpl) Tpl+ lethal (three copies) (one copy) Variation in chromosome structure: How important is gene dosage (i.e. having other than two gene copies)? - for most genes, copy number is not too important - for others it is extremely important e.g. Triplolethal (Tpl) in Drosophila is lethal if not present in exactly two copies Tpl+ Tpl+ normal (2 copies) Dl (Tpl) Tpl+ lethal (one copy) Tpl+ Dp (Tpl) lethal (three copies) Tpl+ - for others, altering copy number causes effects but allows viability e.g. Notch in Drosophila Notch+ Notch+ normal wings (2 copies) Dl (Notch) Notch+ wings with jagged (notched) edges (one copy) Notch+ Dp (Notch) Notch+ aberrant wing veins (three copies) Variation in chromosome structure: How important is gene dosage (i.e. having other than two gene copies)? - for most genes, copy number is not too important - for others it is extremely important e.g. Triplolethal (Tpl) in Drosophila is lethal if not present in exactly two copies Tpl+ Tpl+ normal (2 copies) Dl (Tpl) Tpl+ lethal (one copy) Tpl+ Dp (Tpl) lethal (three copies) Tpl+ - for others, altering copy number causes effects but allows viability e.g. Notch in Drosophila Notch+ Notch+ normal wings (2 copies) Dl (Notch) Notch+ wings with jagged (notched) edges (one copy) Notch+ Dp (Notch) aberrant wing veins (three copies) Notch+ As more genes become unbalanced there are greater phenotypic effects. e.g. in humans, heterozygous deletions for 3% of genome or duplications of 5% of genome are lethal Variation in chromosome structure: Wild-type 1 2 3 4 5 6 direct 1 2 3 2 3 4 5 6 inverted 1 2 3 3 2 4 5 6 3 4 5 2 3 6 Tandem duplications Dispersed (non-tandem) duplications 1 2 Detection of duplications Wild-type 1 Pairing during synapsis (each line represents two sister chromatids) Tandem inverted duplication 1 1 2 2 1 3 2 4 3 5 5 3 3 4 4 2 3 4 6 6 Complementary pairing in duplication loop 5 4 4 6 3 Homolog 1 5 6 Homolog 2 Variation in chromosome structure: Wild-type 1 2 3 4 5 6 direct 1 2 3 2 3 4 5 6 inverted 1 2 3 3 2 4 5 6 3 4 5 2 3 6 Tandem duplications Dispersed (non-tandem) duplications 1 2 Detection of duplications Wild-type 1 Pairing during synapsis (each line represents two sister chromatids) Tandem inverted duplication 1 1 2 2 1 3 2 4 3 5 5 3 3 4 4 2 6 3 5 4 4 6 4 1 6 1 Complementary pairing in duplication loop Homolog 1 3 2 2 5 3 3 6 4 Homolog 2 5 6 6 4 4 5 3 Duplication loops assume different configurations, which maximize pairing between homologs Variation in chromosome structure: Detection of deletions Wild-type 1 2 3 1 4 2 5 6 6 7 7 Deletion 4 3 Pairing during synapsis (each line represents two sister chromatids) 1 2 Deletion loop Deletions are useful to “uncover” genetic regions and for genetic mapping (see linkage and mapping lectures) 5 6 7 Homolog 1 1 2 6 7 Homolog 2 Variation in chromosome structure: Detection of deletions Wild-type 1 2 3 1 4 2 5 6 6 7 7 Deletion 4 3 Pairing during synapsis (each line represents two sister chromatids) 1 Deletion loop Deletions are useful to “uncover” genetic regions and for genetic mapping (see linkage and mapping lectures) 5 2 6 7 Homolog 1 1 2 Polytene salivary gland chromosomes in Drosophila 6 7 Homolog 2 Variation in chromosome structure: Detection of deletions Wild-type 1 2 3 1 4 2 5 6 6 7 7 Deletion 4 3 Pairing during synapsis in prophase of meiosis I (each line represents two sister chromatids) 1 Deletion loop Deletions are useful to “uncover” genetic regions and for genetic mapping (see linkage and mapping lectures) 5 2 6 7 Homolog 1 1 2 Polytene salivary gland chromosomes in Drosophila 6 7 Homolog 2 Polytene chromosomes derive from DNA replication without cell division and side-by-side arrangement of the many resulting chromatids. They allow detecting chromosome rearrangements difficult to observe during mitosis/meiosis. Variation in chromosome structure 4 3 Pairing during synapsis (each line represents two sister chromatids) 1 2 Deletion loop 5 6 7 Homolog 1 1 2 6 7 Homolog 2 There is no recombination within deleted region (there is no homologous material corresponding to deletion loop (3-5 in figure) to recombine with) In deletion heterozygous (or homozygous) individuals, there are less recombination events centered on the deleted region Map distances between markers flanking deletions (e.g. 2 and 6), calculated in these individuals, are less than normal, i.e. markers flanking deletions appear closer than they actually are Deletion mapping m Wild-type (complementation) + m mutant (no complementation) Mutation m is known to map to a particular genetic region. It can then be tested against deficiencies near that region to localize genes with cytological or other physical (i.e. molecular markers) landmarks Cytological landmarks (e.g. bands) m within a chromosome chromosome with mutant allele in trans (i.e.. m / Df) to wild-type wild-type mutant wild-type wild-type Duplication mapping (hemizygous, could be in trans to a large deletion, or the Y chromosome if X-linked m mutant m ( i.e. m / Df(m) ; Dp or, for an X-linked gene mutant Duplication that does not cover gene m m/Y ; Dp ) m wild-type Duplication that covers gene m Mutation m can then be tested against deficiencies near that region m Cytological landmarks (e.g. bands) within a chromosome mutant chromosome in trans to mutant mutant wild-type wild-type mutant mutant Inversions Pericentric (includes centromere) Wild-type Pericentric inversions can result in a new position of the centromere 1 2 7 1 2 3 6 4 5 5 4 6 3 8 9 10 7 8 9 10 Inversions Pericentric (includes centromere) Pericentric inversions can result in a new position of the centromere 1 2 7 6 5 Wild-type 1 2 3 4 5 Paracentric (excludes centromere) 1 5 4 3 2 4 3 8 9 10 6 7 8 9 10 6 7 8 9 10 Inversions 2 7 Wild-type 1 2 3 4 5 Paracentric (excludes centromere) 1 5 4 3 2 Pairing of a paracentric inversion creates inversion loops 1 6 5 4 3 8 9 10 6 7 8 9 10 6 7 8 9 10 Inversion loop in polytene salivary gland Chromosomes in Drosophila Pericentric (includes centromere) Pericentric inversions can result in a new position of the centromere 1. Chromosomal cell content in a heterozygote for a paracentric inversion A B a C e D d E c 2. Synapsis at C C meiosis I F b c BB f A B C D dd EE ee bb F F F f f f b B Acentric fragment (lost) 4. At the end of meiosis, each gamete contains one of the following chromatids: C c D E d e E c A A a a 3. Homologous centromeres migrate to separate poles at anaphase I A D D Dicentric chromatid: breaks at random positions during anaphase I I e d c b B C D E F A B c d a e Broken chromatids with deleted regions a e d c b F II a a A f 5. Gametes with chromatids that underwent recombination do not produce viable offspring. III IV Paracentric inversions reduce the number of recombinant progeny: “crossover suppressors”. f Balancer chromosomes: contain multiple inversions throughout their lengths, so that they effectively suppress recombination within the homologous (non-balancer) chromosome. abc abc x Multiple inversion balancer, abc Bal, D with a dominant marker D Balancers can be used to keep with wild-type a+ b+ c+ alleles allelic combinations intact through generations abc abc Chromosome transmitted intact, without recombination abc TM3, Sb Phenotype: Most balancers contain a lethal mutation, so that homozygotes for the balancer are not viable abc lethal Bal, D a+ b+ c+ x lethal Bal, D lethal lethal lethal Bal, D Bal, D Bal, D dies lives dies Balancers allow to maintain lethal mutations in a stable stock, and in their intact chromosomal environment Balancers can also be used to determine which chromosome a mutation is in (dominant marker in balancer will segregate randomly from mutation if in a different chromosome, away from mutation if in same chromosome (S&S fig. 9.5) Translocations (exchanges between non homologous chromosomes Reciprocal translocation: parts of two non-homologous chromosomes trade places, without a net gain or loss of chromosomal material 21 22 23 24 1 2 3 4 1 2 23 24 21 22 3 4 5 6 7 8 9 10 5 6 7 8 9 10 Translocations (exchanges between non homologous chromosomes Reciprocal translocation: parts of two non-homologous chromosomes trade places, without a net gain or loss of chromosomal material 21 22 23 24 1 2 3 4 1 2 23 24 21 22 3 4 5 6 7 8 9 10 5 6 7 8 9 10 Robertsonian translocation: reciprocal translocation resulting from breaks at or near the centromeres of two acrocentric chromosomes 21 22 23 24 11 21 22 23 24 11 12 12 Robertsonian translocation 13 13 14 14 15 15 (lost) Chromosomal constitution Segregation in a heterozygous for a reciprocal translocation A B C a b T1 c T U P Q R d N1 D e f p q T2 r E F s N2 S t u Pairing at Metaphase I Chromosomal constitution Segregation in a heterozygous for a reciprocal translocation A B C a b T1 c D T U P Q R d e f p q T2 r entry into meiosis N1 U A B C a b c u T T1 t D E F s t u N2 N2 s e E f F r q p S d N1 S R Q P T2 Pairing at Metaphase I U A B C a b c u T T1 t D s e E f F r q p S d N1 N2 R Q P T2 Segregation at AnaphaseI Pairing at Metaphase I T1 A B C a b c N1 Alternate U u T t D d e E f F N2 s r q p S R Q P T2 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c u T t D T1 + T2 a b c p q r A B C P Q R d e f s t u D T U S E F e E F r q p S f Alternate N2 s d N1 N1 + N2 Telophase I U T1 R Q P T2 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t Alternate T1 + T2 p q r A B C P Q R d e f s t u D T U S E F a b c p q r d e f s t u A B C P Q R D T U S E F balanced a b c N2 s e E F r q p S d f balanced Telophase I u D N1 N1 + N2 gamete U T1 R Q P T2 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t Alternate p q r A B C P Q R d e f s t u D T U S E F p q r d e f s t u A B C P Q R D T U S E F balanced a b c a b c e E F r q p S d Adjacent-1 T1 + T2 N2 s f balanced Telophase I u D N1 N1 + N2 gamete U T1 R Q P T2 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t e r q p S d Alternate N2 s R Q P E f F T2 Adjacent-1 T1 + T2 T1 + N2 N1 + T2 p q r A B C P Q R A B C p q r a b c P Q R d e f s t u D T U S E F D T U s t u d e f S E F a b c p q r d e f s t u A B C P Q R D T U S E F balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t N2 s e r q p S d R Q P E f F Alternate T2 Adjacent-1 T1 + T2 T1 + N2 N1 + T2 P Q R A B C p q r a b c P Q R d e f s t u D T U S E F D T U s t u d e f S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F not balanced A B C not balanced p q r balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t N2 s e r q p S d R Q P E f F Alternate T2 Adjacent-2 (less frequent) Adjacent-1 T1 + T2 T1 + N2 N1 + T2 P Q R A B C p q r a b c P Q R d e f s t u D T U S E F D T U s t u d e f S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F not balanced A B C not balanced p q r balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t N2 s e r q p S d R Q P E f F Alternate T2 Adjacent-2 (less frequent) Adjacent-1 T1 + T2 T1 + N2 N1 + T2 N1 + T1 N2 + T2 P Q R A B C p q r a b c P Q R a b c A B C p q r P Q R d e f s t u D T U S E F D T U s t u d e f S E F d e f D T U s t u S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F not balanced A B C not balanced p q r balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t N2 s e r q p S d R Q P E f F Alternate T2 Adjacent-2 (less frequent) Adjacent-1 T1 + T2 T1 + N2 N1 + T2 N1 + T1 N2 + T2 p q r a b c P Q R a b c A B C p q r P Q R d e f s t u D T U S E F D T U s t u d e f S E F d e f D T U s t u S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F a b c A B C d e f D T U p q r P Q R s t u S E F not balanced A B C not balanced P Q R not balanced A B C not balanced p q r balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c T t N2 s e r q p S d R Q P E f Segregation pattern results in semisterility F Alternate T2 Adjacent-2 (less frequent) Adjacent-1 T1 + T2 T1 + N2 N1 + T2 N1 + T1 N2 + T2 p q r a b c P Q R a b c A B C p q r P Q R d e f s t u D T U S E F D T U s t u d e f S E F d e f D T U s t u S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F a b c A B C d e f D T U p q r P Q R s t u S E F not balanced A B C not balanced P Q R not balanced A B C not balanced p q r balanced a b c balanced Telophase I u D N1 N1 + N2 gamete U T1 Pairing at Metaphase I Segregation at AnaphaseI A B C a b c t D N2 In Robertsonian translocations, T1 contains all regions in N1 and N2, and there is no T2. s e q p R Q P E f r S d N1 Segregation pattern results in semisterility F Alternate T2 Adjacent-2 (less frequent) Adjacent-1 T1 + T2 T1 + N2 N1 + T2 N1 + T1 N2 + T2 p q r a b c P Q R a b c A B C p q r P Q R d e f s t u D T U S E F D T U s t u d e f S E F d e f D T U s t u S E F a b c p q r d e f s t u A B C P Q R D T U S E F A B C p q r D T U s t u a b c P Q R d e f S E F a b c A B C d e f D T U p q r P Q R s t u S E F not balanced A B C not balanced P Q R not balanced A B C not balanced p q r balanced a b c balanced Telophase I u T T1 N1 + N2 gamete U Familial Down syndrome – Robertsonian translocation 2-3% of Down syndrome incidence All translocations of long arm (q) 60% translocated to acrocentric ch 13, 14 or 15 half are inherited (remainder meiotic events) 50% chance that a carrier’s unaffected sib or offspring is a carrier 30% are 21q21q translocation virtually all newly arisen in parent’s germline only viable offspring would be Down syndrome ...
View Full Document

Ask a homework question - tutors are online