.Protein LYONIZATION. The process by which all X chromosomes in excess of one are made genetically inactive and heterochromatic.

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1 + Electrical field - LYONIZATION Colleen Jackson-Cook, Ph.D, FACMG Sanger Hall, Room 5-7 ccook@mcvh-vcu.edu The process by which all X chromosomes in excess of one are made genetically inactive and heterochromatic. Embryonic Timing X-inactivation is thought to occur during the blastocyst stage of embryogenesis. X-inactivation is a random process (5% maternal and 5% paternal) As a result of random inactivation females are a mix or mosaic of information inherited from their mother and father. In contrast, males have only X chromosome information inherited from their mother..protein A. Clonal Stability..Protein B Regions Having Inactivation =Escape from inactivation in only a subset of females tested =Escape from inactivation consistently seen in females tested Gd A Gd B X-inactivation center: Located at Xq3; a gene controlling inactivation is located at this site and acts in cis Original Cell Culture Clonal (established from a single cell) cultures Once an X chromosome is inactivated it remains inactivated. Thus, all daughter cells (following mitosis) maintain the same X chromosome inactivation pattern.

2 Exceptions to Random X-inactivation: Cases having structural abnormalities of X chromosome Klinefelter Syndrome (47,XXY)

3 Turner Syndrome (45,X) Short 4 th metacarpal Webbed Neck

4 Individuals having 4 or more sex chromosomes tend to have increased severity of symptoms, with growth and mental deficiencies (Examples: 48,XXXX; 48,XXXY; 49,XXXXX; 49,XXXXY; etc.) Sex determination The process(es) which determine what sex an embryo will become. Sexual Differentiation The cellular and morphogenetic changes that take place that distinguish one sex from another. Differentiation occurs after sex determination. Barr Body A dark area of stain seen in a nucleus that represents an inactive X chromosome. # Barr bodies = # X chromosomes - Examples of # of Barr Bodies Seen in Various Conditions Condition Normal male (XY) Normal female (XX) Turner syndrome (X) Klinefelter (XXY) XYY XXYY XXX XXXXY XXXXX # Barr Bodies # Y somes 2 2 Phenotypic Sex

5 SRY Gene Likely to be the sex determining region of the Y chromosome in humans. The SRY gene is thought to serve as the first switch in a cascade involving many genes that ultimately leads to a male phenotype. Possible Mechanism for XX s/xy s Erroneous recombination outside pseudoautosomal region results in genes typically found on the Y chromosome being relocated to the X (and vice versa) Appear normal with GTG-bands Need special molecular cyto or DNA based testing CONSORTIUM SEX CHROMOSOME MAP Y CHROMOSOME X CHROMOSOME Genes on Y chromosome involved in Sex Determination/Differentiation Map based on 3 woman years of data collection; map positions approximate Map based on 3 man years of data collection; map positions approximate -Pseudoautosomal region Shopping region (SALE) -Shoes -Cosmetics Communication -If you don t know I m not going to tell you (SAYYOUARESORRY) -You should know what I want -Reloading the dishwasher bonding region (TALK) -Phone (call when they say they will) -IM -eating out -Additional studies pending Love for flowers Asymmetry of Sex Differentiation Genes Known to Play Role in Sex Differentiation SOX9 (on 7q); Target for SRY and early factor in cascade (camptomelic dysplasia 46,XY females; bone & cartilage malformation) Camptomelic Dysplasia (SOX9 gene mutations) Chromosomal male; phenotypic female Rare, autosomal dominant condition Large head, short trunk, bowed limbs (especially femurs and tibias) Hip dislocations and abnormalities Chest bell-shaped; trachea narrowed (leads to respiratory distress) DAX (on Xp); Interacts with SRY and plays role in cascade (46,XY female) Genes on 9p and WT (p) also involved Thickened, dysmorphic long bones and bowing of tibias and femurs. (Images from MedPix; submitted by Joel McFarland

6 Asymmetry of Sex Differentiation Genes Known to Play Role in Sex Differentiation SOX9 (on 7q); Target for SRY and early factor in cascade (camptomelic dysplasia 46,XY females; bone & cartilage malformation) DAX (on Xp); Interacts with SRY and plays role in cascade (46,XY female) Genes on 9p and WT (p) also involved Androgen Insensitivity Syndrome (Testicular Feminization) Defect in androgen receptor leads to failure of response to testosterone. As a result, an XY individual develops externally as a female. Other findings include: absense of axillary hair; sparse pubic hair, blind vagina; no uterus or uterine tubes; testes are present (within the abdomen or inguinal canal [sometimes mistaken for hernia]) Gender assignment not an issue psychosexual development and sexual function are normal female (with infertility) Sexual differentiation conditions Many genes involved; therefore more common than sexual determination conditions