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Sex Determination

Sex Determination. The Advantages of Sex Are Not Obvious (to Biologists). Sex is Expensive: -Energy and risk costs of mating -Two-fold cost of making males -Two-fold cost of meiosis (only passing on half your genes at a time)

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Sex Determination

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  1. Sex Determination

  2. The Advantages of Sex Are Not Obvious (to Biologists) Sex is Expensive: -Energy and risk costs of mating -Two-fold cost of making males -Two-fold cost of meiosis (only passing on half your genes at a time) Even species where both mating types can reproduce pay a price for sex Hypothesis: Benefit of increased genetic variation overcomes cost of sex (Weismann, 1904) BUT, recombination can separate favorable (co-adapted) allele combinations just as easily as it can assemble favorable combinations Is sex (exchange of genetic material) advantageous? Evidence from Nature: Asexual species are few in number and, though constantly arising, appear short-lived Experimental Data: not easy to generate

  3. Only 74 of approx. 42,300 vertebrate species are asexual (Vrijenhoek, 1989) Most existing asexual species have evolved recently from sexual ancestors i.e. they are evolutionarily short-lived

  4. Exceptions exist: some asexual species are stable Asexual Champions: bdelloid rotifers are thought to have been asexual for 100 my -380 morphological species in 20 genera -molecular evidence supports the evolution of rotifer species from common ancestors

  5. Sex is Not Always BinarySexual Phenotypes in Plainfin Midshipman Fish(Porichthys notatus) Type I Male: -Large body size -Vocalize (“hum”) to attract mate and defend territory -Excavate and defend nest -Cares for eggs and hatchlings -Mates by courting and attracting females Type II Male Two mating strategies: ”sneak spawning”--enters nest of Type I male and fertilizes eggs “satellite spawning”--ejaculate just outside nest and fan sperm into nest Type II Male: -Small body size -Only short vocalizations -No nesting or care of young -Huge testis Female Type I Male Hatchlings Female: -Small body size -Only short vocalizations -No nesting or care of young Type II Male -Lays eggs in nests of Type I males

  6. Sex is Not Forever Naturally occuring sex reversal: e.g. clownfish -sex is determined by social context (not genetic) -largest fish becomes fertile female -next largest becomes fertile male -others arrested as juveniles If dominant female removed, fertile male becomes fertile female A juvenile matures into fertile male

  7. Female to Male Switching in the wrasse Thalassoma duperrey Female Switching Male

  8. How is Sex Determination Initiated?What is a Sex Determination Switch?

  9. Karyotype vs. Phenotype in Drosophila KaryotypePhenotype X/A XX Female 1.0 XY Male 0.5 XO Male 0.5 XXY Female 1.0 X:A Female 1.0 XXX:AAA Female 1.0 XXXX:AAAA Female 1.0 XX:AAA Intersex 0.66 Therefore sex is determined by X:A ratio in Drosophila

  10. The Sxl Promoter Interprets the X:A Ratio

  11. Alternative RNA Splicing Controls Sex Determination

  12. Alternative RNA Splicing Controls Sex Determination

  13. Alternative RNA Splicing Controls Sex Determination

  14. XX XY ON OFF Sex lethal Drosophila Sex Determination ON OFF transformer tra 2 doublesex (Appearance and Behavior) DSXF DSXM fruitless (Behavior)

  15. Karyotype vs. Phenotype in Humans KaryotypePhenotypeSyndrome, associated phenotypes XX Female wt XY Male wt XO Female (1:2500) Turner’s syndrome (Short stature, infertile, many spontaneously abort) XXX Female (1:1000) Pretty normal, extra Barr Body XXXX Female Pretty normal, extra Barr Bodies XXXXX Female Pretty normal, extra Barr Bodies (Some mental retardation with extra X chormosomes) XXY Male (1:700) Klinefelter’s Syndrome, Barr Body XXXY Male Klinefelter’s Syndrome, Barr Bodies XXXXY Male Klinefelter’s Syndrome, Barr Bodies (Mental retardation and hypogonadism/infertility, increases with X chromosome dose, 60% spontaneously abort) XYY Male Pretty normal (mental retardation) XYYY Male Pretty normal (mental retardation) XYYYY Male Few reports Therefore sex is determined by Y chromosome Hypothesize a “Testis Determining Factor” (TDF)

  16. Mapping the Testis Determining Factor (TDF) XY w / Y Deletions Some Female XX w/ Y DNA translocated to autosome Some Male

  17. SRY is TDF SRY (Sex-determining region of the Y) -Contained within Y chromosome critical region -HMG box containing transcription factor -Expressed in primitive gonad -Sry transgene can transform XX mouse into male XY Sry+ XX Sry+ XY Sry+ XX Sry+ Koopman et. al. 1991

  18. Gonad Sexual Dimorphism WNT4a FGF9 DMRT’s Foxl2 Rspondin WNT4a Ovary Bipotential Gonad SRY SOX9 Testis FGF9

  19. SRY thought to account for only 20% of human XY sex reversal Sox9 -Sox9-/+ Campomelic Dysplasia 75% of XY individuals phenotypically female -Duplication including Sox9 XX individual phenotypically male (no SRY present) -Sox9 expression sufficient for testis development in XX mouse Genetics of Primary Sex Determination in Humans Deletion 9p -DMRT 1 and 2 deleted in 9p human XY sex reversals -Related to fly doublesex and worm mab-3 Foxl2 -premature ovarian failure (heterozygous truncations—could be dom neg) -ovarian tumors Wnt4 -female to male sex reversal Various chromosomal regions associated with sex reversal

  20. Primary Sex Determination Switches Y Chromosome Mammals X:A Ratio Flies and Worms Temperature Some reptiles ZZ vs. ZW Birds

  21. Temperature is “read out” in the gonads 26°C (Male) 33°C (Female) Cultured Gonads Intact Embryos Sox9Expression Sea Turtle Lepidochelys olivacia 2001 Temperature-dependent Sex Determination

  22. Sox100B is a Drosophila Sox 9 Homolog Expressed in a Male-specific Pattern in the Gonad Sox100B VASA St 17 Male Sox100B VASA Female DeFalco (2003) Developmental Cell, 5;205 DeFalco (2008) Developmental Cell, 14;275

  23. Sox100B is Required for Testis Development Sox100B gonad phenotype Testes Accessory gland Sox100B-/- pharate adult Wild type adult In Collaboration with Steven Russell, University of Cambridge

  24. Mammals Flies Birds Reptiles Creating Sexual Dimorphism Mammals Flies Birds Reptiles

  25. XX XY ON OFF Sex lethal Drosophila Sex Determination ON OFF transformer tra 2 doublesex (Appearance and Behavior) DSXF DSXM fruitless (Behavior)

  26. Evolution of Sex Determination Pathways in Insects PMID: 20877001

  27. Doublesex/Mab3 Related Transcription Factors (DMRTs) Conserved Regulators of Sexual Dimorphism

  28. Molecular Mechanisms Fly Human dsx DMRTs Sox100BSox9 Conserved Mechanisms for Gonad Sexual Dimorphism Mammals Flies Birds Reptiles

  29. How does a sex determination switch control sexual dimorphism?

  30. Primary vs. Secondary Sex Determination Primary sex determination: (cell autonomous) a cell or tissue directly assesses its sex based on the sex determination switch Secondary sex determination: (non-cell autonomous) a cell or tissue receives information about sexual identity from another tissue

  31. Cell Autonomous Sex Determination “Every cell decides for itself” (In Drosophila) “the chromosomal composition of each somatic cell determines its sexual development.” L. Wolpert, Principles of Development, 3rd Edition, 2007 J Szabad www.insectcompany.com underwatertimes.com

  32. XY Gonadectomy Female Mammals Mostly Undergo Secondary Sex Determination XX XY Female Male Jost, 1940’s

  33. Non-Autonomous Sex Determination in Mammals Sry Sertoli Cells Leydig Cells Mullerian Duct Regression Mesonephric Cell Migration Germ Cells Testosterone

  34. Non-autonomous Events Fgf9 Tgf-ß?? Dhh? Brennan and Capel, 2004 Early Events in Mouse Gonad Sexual Dimorphism Only Sertoli Cells Are Thought to Autonomously Require Sry

  35. Autonomous and Non-Autonomous Sex Determination Are Not Mutually Exclusive

  36. Pigment Cell Precursors Nonautonomous Sex Determination Hub Cells Autonomous Sex Determination msSGPs Nonautonomous Sex Determination DSX is expressed in the SGPs and hub cells DSXM dsx in situ BDGP Hempel and Oliver(2007) BMC Developmental Biology, 7:113 dsx both autonomously and nonautonomously to control sexual dimorphism male female DeFalco, Camara, Le Bras, & Van Doren(2008) Dev Cell 14(2): 275-86

  37. 2) Not all cells even know their sex: dsx and fru expression is highly tissue-specific New Ideas About Creating Sexual Dimorphism in Drosophila Not all cells decide their own sex: Cell-cell signaing is critical for regulating sexual dimorphism Sex is DANGEROUS: Ectopic expression of dsx is lethal Jursnich and Burtis, 1993

  38. “Knowing” Your Sex Chromosome Constitution vs. “Knowing” Your Sex Drosophila Mouse # X’s # X’s Y Sxl SRY Dosage Compensation (All Cells) Dosage Compensation (All Cells) tra Primary Sex Determination (Tissue Specific) dsx, fru Primary Sex Determination (Tissue Specific) Secondary Sex Determination (Signaling) Secondary Sex Determination (Signaling)

  39. How does a sex determination switch control sexual dimorphism?The Germ Cells

  40. Germline Sex Determination in the Mouse Germ CellSomatic GonadGerm Cell Behavior XXXXEnter Meiosis XYXYMitotic Arrest XYXXEnter Meiosis XXXYMitotic Arrest Therefore, the sex of the soma determines the initial sex of the germline. However, an XX germ cell cannot form sperm in a testis and XY germ cells form few oocytes in an ovary. Therefore, BOTH somatic signals and germ cell autonomous factors regulate germline sexual development.

  41. Karyotype vs. Phenotype in Humans KaryotypePhenotypeSyndrome, associated phenotypes XX Female wt XY Male wt XO Female (1:2500) Turner’s syndrome (Short stature, infertile, many spontaneously abort) XXX Female (1:1000) Pretty normal, extra Barr Body XXXX Female Pretty normal, extra Barr Bodies XXXXX Female Pretty normal, extra Barr Bodies (Some mental retardation with extra X chormosomes) XXY Male (1:700) Klinefelter’s Syndrome, Barr Body XXXY Male Klinefelter’s Syndrome, Barr Bodies XXXXY Male Klinefelter’s Syndrome, Barr Bodies (Mental retardation and hypogonadism/infertility, increases with X chromosome dose, 60% spontaneously abort) Turner’s Females and Klinefelter’s Males May Be Infertile Due to a Sexual Incompatibility Between Soma and Germline

  42. Loss of Cyp26b1 leads to induction of meiotic markers in male gonads RA levels are higher in female gonad Could JH play a similar role in Drosophila? F M JH epoxide hydrolase 2 Contol of Germline Sexual Behavior by Retinoic Acid Cyp26b1 is expressed in male but not female somatic gonad

  43. Somatic Signals and Germ Cell Autonomous Cues Also Regulate Germline Sex Determination in Drosophila

  44. How does a sex determination switch control sexual dimorphism?Other reproductive structures

  45. The Mouse Internal Reproductive Tract Develops From Either the Mullerian or Wolffian Ducts

  46. Anti-Mullerian Hormone (AMH, MIS) Testosterone Estrogen oviducts, uterus, cervix, upper vagina epididymis vas deferens Regulated by non-cell autonomous signals

  47. The External Genitalia Develops From a Common Bipotential Tissue Dihydrotestosterone (DHT) Regulated by non-cell autonomous signals

  48. Development of the Genital Disc in Drosophila Female genital primordium only develops in females to make female internal and external structures (analogous to Mullerian Duct) Male genital primordium only develops in males to make male internal and external structures (analogous to Wolffian Duct) Anal primordium develops along male or female pathway to make external structures (analogous to mammalian external genitalia) Not hormonally controled, but some non-cell autonomous signals involved

  49. Gonad Sexual Dimorphism WNT4a FGF9 DMRT’s

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