04BIS1012012NDJLect4a

04BIS1012012NDJLect4a - BIS101-001 Genes and Gene...

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Unformatted text preview: BIS101-001: Genes and Gene Expression Dosage Compensation, Non-disjunction and Chromosome Abnormalities Lecture #4a Chapters, 3 and 4 March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 1 In this lecture Sex in Drosophila and human are determined by X and Y chromosomes. In humans, maleness is determined by the testes determining factor (TDF) on the Y and the androgen receptor gene on the X. Heterogametic sex requires dosage compensation. This is accomplished indifferent ways in man and flies. Chromatin exists in 3 states: euchromatin, heterochromatin and facultative heterochromatin. X inactivation in humans can create genetic mosaics. Non-disjunction is the failure of chromosomes to segregate during metaphase I or metaphase II of meiosis. Non-disjunction can create chromosome abnormalities that can be detrimental. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 2 Sex Determination "It is as if in the evolution of sex, a fragment at one time broke away from an X chromosome... and thereafter in relation to the other chromosomes, was helpless to prevent them from expressing themselves in the form of an incomplete female, the creature we call the male! It is largely to this original Xchromosome deficiency of the male that almost all the trouble to which the male falls heir may be traced." ..Ashley Montague in: The Natural Superiority of Women. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 3 Sex Chromosomes and Sex Determination Drosophila and humans use XY chromosomes to distinguish males (the heterogametic sex) from females (the homogametic sex). However, chromosome aberrations, which involve the presence or absence of extra Y or Xchromosomes, reveal some important differences between mammals and invertebrates like Drosophila. Chromosomes Drosophila Humans NV= not viable XX XY XXY XO XXX NV March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 4 Sex Chromosomes and Sex Determination In humans, femaleness is determined by genes on the X while in maleness is determined by the testis determining factor (TDF) gene on the Y chromosome. In the case of testicular feminization (androgen insensitivity syndrome), individuals are genetically male but look like normal females (except that they are sterile and have blind vaginas). These individuals carry an X-chromosome linked mutation in the gene for androgen receptors. Therefore, androgens (testosterone and androsterone) can not exert their affect on the target cell and tissues. The difference between Drosophila and humans is that in Drosophila, sex is determined by the ratio of X to the three autosomes -- A or, X:A. Therefore, 2X:2A = 1 = female whereas 1X:2A = 0.5 = male. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 5 Dosage Compensation The enzyme glucose-6-phosphate dehydrogenase (G6PD) catalyzes the oxidation from glucose-6-phosphate to produce the cyclic ester, phosphoglucono-1, 5-lactone, and NADPH. The locus for this gene is on the X chromosome in both Drosophila and humans. G6PD is X-linked so normal females carry 2 copies of this gene while normal males will carry 1 copy. One might expect the levels for this enzyme to be twice as high in females as males. However, when the enzyme is assayed in both males and females in Drosophila and humans, the levels of G6PD are the same. This is called " dosage compensation" and Drosophila and humans use two different mechanisms to achieve it. In Drosophila, the level of G6PD in the male is upregulated so that the ratio of enzyme levels between males and females is 1:1, not 0.5:1. Upregulation is believed to occur by decondensing the chromatin in the male X so that its genes are hypertranscribed (more mRNA produced than normal). March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 6 Nucleosome: Histone octomer + 200bp of DNA 40bp linker DNA 1.8 turns or 160bp DNA March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 7 Histone Acetylation Activates Transcription March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 8 Hypertranscription Chromatin remodeling Decondensation of male X chromatin may be achieved by acetylation of amino-terminal end of the histone H4 protein. The addition of an acetyl group to the positive charged amino acids, lysine (K) and arginine (R) at the end of H4 neutralizes electrostatic interactions (+ and charge) between the histones allowing chromatin to relax. Relaxed chromatin is more easily transcribed. A complex genetic mechanism prevents hypertranscription of the X chromosomes in the female. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 9 H4-Lys16 acetylation in chromatin accessibility Chromatin fibers 30 nm chromatin fiber 10 nm (beads) Hypoacetylated chromatin Deacetylated H4-Lys16 Hyperacetylated chromatin Acetylated H4-Lys16 NO transcription March 19, 2012 Transcription possible 10 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 Chromatin Structure (deacetylation and methylation) March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 11 Dosage Compensation:Chromatin Decondensation The Dosophilia gene sex lethal (sxl) inhibits the acetylation of chromatin and hence, inhibits chromatin decondensation. Decondensed chromatin is required for chromatin accessibility and hypertranscription. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 sxl 12 Dosage Compensation by Upregulation in Drosophilia Adult III IV X X 2X:2A ratio =1 II III Adult II IV X(Decondensed) Y 1X:2A ratio=0.5 sxl female Sxl prevents decondensation of X and formation of transcription complex by binding msl2 (a component in the complex). No dosage compensation male no sxl In the absence of Sxl, decondensation of X occurs, transcription complex (mle, msl3, msl1, msl2) forms causing 2-fold hypertranscription and dosage compensation 13 March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 Dosage Compensation by Upregulation in Drosophilia Adult III IV X X 2X:2A ratio =1 II III Adult II IV X(Decondensed) Y 1X:2A ratio=0.5 sxl female No decondensation of X and no dosage compensation. Sxl prevents formation of a transcription complex that alters chromatin structure male no sxl Transcription complex (consisting of mle, msl3, msl1, msl2) forms to decondense chromatin (H4Ac) and hypertranscribe the X by 2-fold. female, sxl binds to msl2 to prevent complex formation. 14 March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 The X:A ratio regulates expression of the Sex lethal (sxl) gene. Key sex determination factors : q Denominator Elements: Helixloop-helix proteins encoded by genes on the autosomes Numerator Elements: Helixloop-helix proteins encoded by genes on the X chromosome Numerator elements monitor the X:A ratio through formation of homodimers or heterodimers sisterless-A and sisterless-B q March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 15 Dosage Compensation in Humans In humans, dosage compensation is accomplished by "Lyonization" or "X-inactivation." The Lyon Hypothesis states that: q q q q q X inactivation occurs early in embryonic development (16-64 cell stage) X inactivation is random, that is, either the paternal or maternal X chromosome may be inactivated With a few critical exceptions, X inactivation is nearly complete -- nearly all genes on the X chromosomes are silenced X chromosome inactivation persists in all subsequent mitotic divisions. X chromosome inactivation is clonally propagated (or replicated) throughout all subsequent cell divisions in the organism. Early in embryonic development, one of the two X chromosomes is condensed into an genetically inactive structure on the inside of the nucleus called a "Barr body." Somatic mosaicism in females occurs when different X chromosomes are inactivate during embryogenesis. BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 16. March 19, 2012 Inactivated X chromosomes are call Barr Bodies The number of Barr bodies in a nucleus is equal to X-1, where X equal the total number of X chromosomes in the cell. In this image, X=3. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 17 Early X inactivation results in somatic mosaicism Females heterozygous for AED showing mosaicism. Pattern is determined by chance and differs from one individual to the next. anhydrotic ectodermal dysplasia Female heterozygous cat for two alleles for coat color, O (orange) and o (black). Black and orange sectors are due to X chromosome inactivation. "White" is a third coat color gene not found in tortoiseshell cats. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 18 Sex chromosome aberrations in humans X-Chromosome Constitution XY XY Barr Bodies (max./cell) 0 0 Sex phenotype Syndrome male female normal male testicular feminization; sterile 1/65,000 male births metamale; aggressive behavior, above average height, 1/1000 births Turner 's; sterile gonadal dysgenesis,1/5000 female births normal female Klinefelter's; sterile, small testes, below normal intelligence, 1/1000 male births Triple X, tall, learning disabilities Triple X-Y, Klinefelter's syndrome Tetra X, tall, learning disabilities Tetra-X-Y, Klinefelter's syndrome Penta-X, tall, mental retardation XYY 0 male XO XX* XXY 0 1 1 female female male XXX XXXY XXXX XXXXY XXXXX 2 2 3 3 4 female male female male female March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 19 Non-disjunction Morgan used non-disjunction of the Drosophilia chromosomes to show that the gene for eye color is located on the X chromosome Many chromosome abnormalities result from "nondisjunction during metaphase 1 or metaphase 2 of meiosis. March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 20 Down's syndrome and non-disjunction Non-disjunction of chromosome 21. "ACOG Says All Pregnancies Should Be Evaluated for Down's" By Judith Groch, Senior Writer, MedPage Today March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 21 Review: Non-disjunction Human chromosome abnormalities (aneuploidy) resulting from nondisjunction in metaphase 1 of meiosis). No normal gametes. Non-Disjunction Move 1 March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 22 Review: Non-disjunction Human chromosome abnormalities (aneuploidy) resulting from nondisjunction in metaphase 2 of meiosis). Half the gametes are normal. Non-Disjunction Move 2 March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 23 Frequency of Down Syndrome (Trisomy 21) The frequency of Trisomy 21 (Down Syndrome) is relatively constant at 1/1,000 births for mothers below the age of 30. As the age of the mother increases above 30, the frequency of Trisomy 21 also increases to a frequency of 40 per 1000 live births (or 1/25 live births) for mothers 45 and older. There is a similar relationship between the mother's age and the frequency of other aneuploidy syndromes. The reason for this relationship is not clear. One explanation is the length of time the oogonium spends in the first division of meiosis. Another explanation is that a younger mother may be less tolerant of an aneuploid fetus through some unknown mechanism. 45 40 Down Syndrome Births/1000 Live Births 35 30 25 20 15 10 5 0 17 22 27 30 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Mother's Age March 19, 2012 BIS101001, Spring 2012--Genes and Gene Expression, R.L. Rodriguez 2012 24 ...
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