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Chromosomal Polymorphism Polymorphism: a more than one version of a trait being actively present in a population, a heritable difference between individuals in the same species. For example: ABO blood groups Immunoglobulins Minor variants in chromosome structure DNA sequence polymorphism Exactly we should call these chromosome heteromorphism. variants Common positions & forms of chromosome heteromorphism Size of chromosome About 10% of clinically normal males have a longer or short Y. Satellite —presence or absence, size mainly on 13,14,15,21 and 22 Secondary constriction of chromosome 1, 9 and 16 Presence or absence, length Banding pattern polymorphism Fluorescence intensity of chromosome 3, 4 Chromosome heteromorphism Characteristics Having no remarkable heritable effect and cannot result in pathologic reaction According to Mendelian inheritance Often happening in constitutive heterochromatin regions Application Individual Identification Detecting the origin of extra chromosomes Detecting the origin of cells Gene mapping Gene mapping--Duffy blood group Donahue observed a peculiar microscopicallyvisible stretch of chromatin on his own largest chromosome (Chromosome #1). Ⅰ Ⅱ ab bb bb ab ab bb ab ab bb Ⅲ ab ab bb bb aa ab aa bb Ⅳ ab aa Presence of the heteromorphism on chromosome 1 a and b ab ab The Duffy blood group genotypes Sex Chromosomes Human males are the heterogametic sex with two different sex chromosomes, (XY). 22 pairs of auto 1 pair of sex chro. XX or XY Human females are the homogametic sex (XX). DNA content of human chromosomes Chromosome Amount of DNA (Mb) Chromosome Amount of DNA (Mb) 1 2 3 4 5 6 7 8 9 10 11 12 263 255 214 203 194 183 171 155 145 144 144 143 13 14 15 16 17 18 19 20 21 22 X Y 114 109 106 98 92 85 67 72 50 56 164 59 X chromosome dosage Sex Chromosomes: Genes on X: females XX, males XY females 2 , males 1 How to create equal amount of X chromosome gene products in males and females? Shouldn’t XX females produce twice the amount of X-linked gene products (proteins) as XY males? Dosage Compensation decrease X gene products by half in females (e.g. humans called X-inactivation) XX females “compensate” by inactivating one of their X chromosomes to make a single “dosage” of X-linked genes. X-inactivation reveals alleles in cats heterozygous for the fur color gene Genotype is Xyellow/Xblack Yellow patches: black allele is inactive Xyellow/Xblack Black patches: yellow allele is inactive Xyellow/Xblack The Lyon Hypothesis of X Inactivation In normal females, only one of the two X chromosomes is genetically active X chromosome inactivation occurs early in development (late blastocyst stage of embryogenesis, 32-64 cell stage). Proposed by Mary Lyon and Liane Russell (1961) X inactivation is random. The inactive X can either be maternal or paternal in origin and the choice is random in each cell and independent of the choice in other embryonic cells. X inactivation is irreversible in somatic cells - the inactive X in a particular cell remains inactive in all descendents of that cell. X-inactivation Barr Bodies Murray Barr (1949) chromatin (inactive X) appears as a dense object in the nucleus XX with one Barr body XY chromatin negative (no Barr body) Barr Bodies are Inactivated X Chromosomes in Females Normal male, Turner female Normal female, Klinefelter male 0 1 2 3 # Barr bodies= N-1 rule Inactive X chromosome is visible as Barr body XXX female XXXX female imprinted inactivation Reversed (early blastocyst) Extraembryonic tissue Inconsistencies between syndromes and X inactivation If normal XX female has one X inactivated, why is a X Turner female not normal? Similarly, if XXY male has one X inactivated, why does he have Klinefelter syndrome? Exceptions to Lyon hypothesis •although X inactivation is usually random, a structurally abnormal X, e.g., an X chromosome bearing a deletion, is preferentially inactivated; •in individuals with X-autosome translocations, it is usually the normal X chromosome that is preferentially inactivated; although X inactivation is extensive, it is not complete, some genes are known to escape inactivation; while x inactivation is permanent in most somatic cells, it must be reversible in the development of germ cells. Some genes on X are not inactivated. Genes in pseudo-autosomal regions PAR1 and PAR2. XIST(X-inactive specific transcript ), active only on the Inactive X. Many Genes Escape X-Inactivation In a survey of 224 human X-linked genes, 34 (15%) escaped X inactivation. The genes escaping X-inactivation occur primarily on Xp. From: Carrel et al. Proc. Natl. Acad. Sci. 96(1999)14440-14444. Nonrandom X Chromosome Inactivation The cells with deleted X: The cells carry X-autosomal translocation Nonrandom X Chromosome Inactivation Normal X Deleted X Nonrandom X Chromosome Inactivation Normal X from X from auto Possible Mechanism autosomally-encoded 'blocking factor' which binds to the X chromosome and prevents its inactivation Sequences at the X inactivation center (XIC), binding to the “blocking factor”, control the silencing of the X chromosome Xist & Tsix Application Research on cancer Patient Tumor cells Normal cells cell culcure G6PD G6PD Sex Chromatin X-chromatin Origin Inactivated X Feature Facultative Heterochromatin Number =No. of X -1 Y-chromatin Long arm of Y Constitutive Heterochromatin =No. of Y Sex Determination What determines gender? XX (female) Sex Chromosomes XY (male) Number of X chromosomes, or presence of Y chromosome? What determines gender? Individuals with unusual chromosome combinations provide a clue: XO XXY female male => Y chromosome determines gender Y Chromosome mostly inert, very few genes, mostly repeat sequence DNA (high and middle). PAR: pseudo-autosomal regions on tips of X and Y: homologous, contain some genes. PAR1 has a required cross over for successful sperm development. Genes on the Y chromosome There are three classes of genes on the Y. Genes shared with X chromosome define the pseudoautosomal regions (PAR) Genes similar to X chromosome genes are X-Y homologs Genes unique to the Y including SRY gene Mapping the gene responsible for maleness Experimental paradigm: sex-reversed individuals XY females (missing critical bit of Y) XX males (possessing critical bit of Y) Deletion mapping of Y coupled with analysis of sex-reversed individuals and “chromosome walking” to get new sequences Mapping the gene responsible for maleness In 1990, Sinclair and colleagues narrowed the region to a 35,000 base-pair domain of the small arm of the Y chromosome. Sex-determining region Y Sex determining region Y Gene symbol : SRY Location : Yp11.3 SRY encodes a 223 amino acid zinc finger transcription factor that is a member of the high mobility group (HMG)box family of DNA binding proteins. The protein is expressed during testis development for only 2 days. Sequencing revealed a conserved motif that could have DNA-binding function SRY = TDF XY sex-reversed females have deletions or mutations of SRY transgenic mouse model - XX + Sry leads to testis development SRY expressed in gonad, but only transiently, at the onset of differentiation SRY gene on the Y chromosome was identified as the gene that codes for TDF: SRY is translocated to X in rare XX males SRY is absent from Y in rare XY females The “home run” experiment by Koopman et al. used transgenic mice. Genotypically Female Mice Transgenic for SRY are Phenotypically Male XY male XX male Anne McLaren. What makes a man a man? Nature. 1990,19;346(6281):216-7. Sexual development At the beginning of human development either male or female development is possible. Unspecialized gonads and two sets of reproductive ducts exist until week 6. An embryo develops as a male or female using information from the Y chromosome. Effect of Y Chromosome appearance of structures that will give rise to external genitalia appearance of “uncommitted” duct system of embryo at 7 weeks 7 weeks Y present Y absent Y present Y absent testes ovaries 10 weeks ovary birth approaching testis Other sex determination genes Puzzling XY sex-reversed females without detectable mutation in SRY SRY gene acts as a repressor or inhibitor of another gene, “Z”, that is involved in female development ? Other sex determination genes DAX1 - on X, exerting its effects early on in development, can suppress testis-formation in a dosage-sensitive manner SOX9 - on 17q, required with SRY for normal testis formation. Mutations in this gene cause campomelic dysplasia, which occurs in many sex reversed males The End