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SEX

SEX. “Despite the fact that women are significantly different from men, there is considerable reproductive evidence that they belong to the same species” British Medical Journal. SEX. What are the questions ? Why sex ? Virtually all metazoans have it But why two ? How is it determined ?

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SEX

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  1. SEX • “Despite the fact that women are significantly different from men, there is considerable reproductive evidence that they belong to the same species” • British Medical Journal

  2. SEX • What are the questions ? • Why sex ? • Virtually all metazoans have it • But why two ? • How is it determined ? • Humans are different from alligators and fruit flies

  3. X and Y chromosomes • The X is BIG (5-6% of genome) with lots of genes (mostly encoding somatic function) markers, and disease-associated mutations. • The Y is small (though variable in length)…but it does have some genes

  4. Y-chromosome genes

  5. Sex Determination

  6. Sex Determination • Humans are different from alligators and fruit flies • Klinefelter syndrome individuals( 47,XXY) have male phenotype • Study rare exceptions to the rule (Sex Reversal: • XX males, XY females) • Hypothesis: Y chromosome material translocated to X in XX males

  7. X and Y chromosomes at meiosis

  8. Sex-determining region Y -85% of XX-males have Y-derived sequences -Single gene, SRY, with conserved HMG DNA-binding domain -Sry confers male development in transgenic mice -20% of XY-females have deletions or point mutations in SRY (HMG domain) -SRY NECESSARY BUT NOT SUFFICIENT FOR SEX DETERMINATION

  9. Dosage compensation

  10. X-inactivation—the Lyon Hypothesis—in Somatic Cells • Early • Random…usually • Complete…mostly • Permanent and clonally propagated • Female is MOSAIC of cells, each cell is functionally HEMIZYGOUS

  11. X-inactivation

  12. Evidence for X-inactivation • Genetic • Cytologic • Biochemical

  13. Barr Body Number of sex chromatin (Barr bodies) bodies is equal to Xn-1

  14. G6PD

  15. Ornithine Transcarbamylase

  16. Implications of Lyonization • Greater variability of clinical manifestations in heterozygous females than in hemizygous males • Skewed X-inactivation

  17. X-inactivation • X-Inactivation Center (XIC) • XISTXInactive-Specific Transcript • Female-specific expression in karyotypically normal individuals • Amount of XIST transcript is proportional to number of X chromosomes minus one • Association with Barr body • Inactivation of Xist prevents inactivation • Counting, Establishment, Maintainance

  18. Klinefelter Syndrome • 1/1000 males • Post-pubertal testicular failure • Small testes, hyalinized tubules, azospermia • Infertility, variable hypogonadism • Social pathology • At least 2 X’s and one Y in at least some cells (usually 47,XXY) • Nondisjunction in PI or MI • Multiple X’s---MR

  19. Klinefelter syndrome

  20. 48,XXXY # of Barr bodies ?? Amount of XIST transcript ?

  21. Turner syndrome • 1/5,000 females • Gonadal dysgenesis, disappearance of eggs • Sexual immaturity • Amenorrhea • Infertility • Short stature • Somatic abnormalities • Something wrong with the second X in some cells

  22. Turner syndrome

  23. Turner syndrome

  24. 45,X ~50% chromatin-negative Nondisjunction 80% Paternal (99% of 45,X conceptuses spontaneously aborted) 46X,abnormalX ~15% chromatin-positive Mosaicism ~30% 45X/46XX or XY or X abnormal X, etc Mitotic nondisjunction XX line mollifies syndrome

  25. Why Turner Syndrome ? • Males don’t have Turner syndrome • Hypothesis: X-linked genes that • 1. escape inactivation • 2. have Y-chromosome homologs

  26. Fragile X Syndrome • Frequency: ~1/3500 males, ~1/6000 females • Phenotype • Facial abnormalities • Macroorchidism • Connective tissue abnormalities • Moderate mental retardation (mild in females) • (ADDH, autism) • Fragile site (FRAXA) at Xq27.3

  27. Fragile X syndrome

  28. FRAXA

  29. Inheritance of Fragile X Syndrome X-linked….but… • 20% of obligate carrier males are phenotypically and karyotypically normal---Normal Transmitting Males (NTM) • MR in females ONLY if mutation inherited from mother • Penetrance (MR) is a function of position in the pedigree and increases in successive generations—Sherman Paradox

  30. FMR1 Gene • 38 kb gene at Xq27.3 • Encodes a 614-AA RNA-binding protein (FMRP) • 5’-UTR contains a polymorphic CGG triplet repeat • Normal 6 to 52 repeats (mode 30) • Affected 100s to 1000s of repeats (>230) • Mitotically unstable

  31. FMR1 Gene

  32. FMR1/FMRP

  33. Premutation • 60 -- 200 CGG repeats • Normal Transmitting Males • Most carrier females • Unmethylated and transcribed • Unstable. Expands in female meiosis • Risk of expansion depends on repeat length <20% for n<70 >99% for n>90 • No full mutation from normal repeat

  34. Sherman Paradox

  35. Molecular Diagnosis of FRAX

  36. Size of premutation alleles

  37. Triplet Repeat Diseases

  38. And FISH !

  39. Down Syndrome • Growth retardation • Mental retardation—variable • Somatic abnormalities • Abnormal facies (flattened face and occiput, large tongue, small ears, epicanthal folds) • Congenital heart disease (40%)—AV canal • GI abnormalities (5%)—duodenal stenosis • Leukemia (10 to 20 x increased risk) • Ear infections • Thyroid problems • Premature aging (cataracts, Alzheimer Disease) • Pathogenesis: overexpression of genes on 21q

  40. Down syndrome

  41. Down syndrome--Cytogenetics • Trisomy 21 95% • Maternal nondisjunction in 95% • 80% of these are MI (maternal age effect) • Unbalanced translocation 4% • (9% <30 yo mothers; <2% >35 yo • 60% are 14q21q • 50% of these are de novo—50% areinherited ! • <40% are 21q isochromosome---nearly all de novo • Mosaicism (milder phenotype) <3% • Cytogenetic analysis is essential !

  42. Down syndrome—maternal age effect

  43. Down syndrome—recurrence risks • ~1% for Trisomy 21 • ~10 to 15 % for unbalanced translocation if mom is carrier; <5% if dad is carrier • Note: each first degree relative of a balanced translocation carrier has a 50% chance of being a balanced translocation carrier.

  44. Screening for Down syndrome risk • Maternal age • Second trimester screening • Low alpha-fetoprotein (AFP) • Low unconjugated estriol • High chorionic gonadotrophin (hCG) • First trimester screening • Nuchal translucency • High free beta-subunit of hCG • Low pregnancy-associated plasma protein A

  45. Prenatal diagnosis of Down syndrome • Amniocentesis • Chorionic villus sampling (CVS) • Standard cytogenetic analysis • FISH

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