PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Review session for midterm:Thursday, April 5, 20077-9 pm101 Morgan HallSex:--- understanding its biological significance-- appreciating how genetics was used to understand how it is determined.ESD: environmental sex determinationGSD: genotypic sex determinationGSD via a Maternal Effect system:(for a blowfly)Female-producing mothersMale-producing mothersF / ff / fF / f & f / f daughtersf / f sons1:1sex ratioGenotype of motherdetermines (or at least influences) thePhenotype of the progenyf / fX malesf / fX malesA potential problem with many GSD systems (including our own):XXAAXYAAfemalemalefruit flies:honeybees:AA Afemalemalefact: 20% of all fly genes are on Xfew of these are on fly Ymales are monosomic for 1/5 of their genomemales are monosomic for entire genomehaploidPROBLEMNO PROBLEM(even 1% is rarely tolerated)potentially genetically unbalancednot genetically unbalancedfact: gene output is generally proportional to gene dose in metazoansHow eliminate the anticipated X-linked gene expressiondifference between the sexes?(1) increase X-linked gene expression 2x in males (2) decrease X-linked gene expression in females by 1/2= X-chromosome dosage compensation2a: reduce each X by 50%2b: inactivate one X fruit flies (“the fly”) the worm us mammalsXX XYwa/wa = (same color as) wa/YYET:Recall that Muller observed X-linked gene dose effect within a sex,but not between the sexeswa/Y; Dp(wa)/+> (darker, more “wildtype”)wa/waIt must follow that:wa/wa > (darker, more “wildtype”) wa/Df(w)(or wa/w-)>o+wa/Y < (lighter, less “wildtype”) wa/Y; Dp(wa)/+o“leaky” (hypomorphic) mutant alleles twice as leaky in males vs. femalesInfer: wildtype alleles twice as active in males vs. females to achieve balancewildtype (normal) X-linked alleleswork twice as hard in malesas they do in females= X-chromosome dosage compensationXXXYAre the male genes working twice as hard, or instead are thefemale genes working half as hard? (is the glass half full or half empty)Are the alleles on both the female’s X chromosomes even working?YESCan actually answer the question.But first:Muller knew: white gene functioning is“cell autonomous”:a cell’s phenotype reflectsits genotype with respect to the particular genew+/w-eye is solid red,not mosaic red and white(XXAA)Female(X AA) MaleGynandromorph:w+/w-w-…alleles on both X’s must be activeAre male X-linked genes turned UPor arefemale X-linked genes turned DOWN?Giant Polytene Salivary-Gland Chromosomes X chromosome2800 genesmeasure rate of RNA precursor incorporationinto “nascent” transcripts (during interphase)…average transcription rates (per unit DNA)transcription rate for Male X-linked genes are turned UPrelative to autosomal or female X-linked genes X chromosome2800 genesaverage transcription rates (per unit DNA):female X = female autosomes = male autosomes < male XWhat phenotype would one expect for mutationsthat disrupted genes that encode the machineryfor X-chromosome dosage compensation?needed (only) for hyperneeded (only) to prevent hypermale (X:A=0.5)-specific lethalfemale (X:A=1)-specific lethalNormal gene function:Phenotypic consequencesof loss by mutation:Female: XX Male: XYno X hyperactivation X hyperactivationThat is how the relevant genes are recognized(MSLs encode protein complex on male X)How do we mammals dosage compensate?OneBarr BodyNoBarr BodyXOAATurner femalesXXYAAKleinfelter malesXXXXAA(mentally retarded) femalesNo Barr BodyOne Barr BodyThree Barr BodiesXYAAfemales malesXXAA“sex chromatin”First clue:#BB = #X-1Barr Body rule:Odd behavior of an X-linked mammalian gene:Individual blood cells arephenotypically eitherG6PD+ or G6PD-only one or the other X-linked allele seems to be active in any given blood cellAnother clue:G6PD+/G6PD-:heterozygotenot what we saw with the eye of the w+/w- flyGeneticist Mary Lyon:#BarrBodies = #X-1Observations:Hypothesis:(2) Dosage compensation by inactivation of all but one X chromosomeXYAAmalesfemalesXxAAfemalesXxxxAA(1) Barr Body = inactivated X chromosomexBarr Bodymosaic expression of G6PD+ (on X)mosaic c+ expression when c+ on X(translocation of autosomal coat color gene c to X)X-chromosome inactivation:(1) initiated very early in development(2) generally random in embryo proper (paternal = maternal)(3) once initiated, stably inherited(4) reactivation of inactivated X occurs in germ cells during oogenesisXmaternal Xpaternal(often paternal in extra-embryonic)an epigenetic phenominon(at ~500 cell stage in humans)Striking human example of X inactivation in action:Anhidrotic Ectodermal Dysplasia (EDA):hemizygous males (EDA-/Y) & homozygous females (EDA-/EDA-)no sweat glands (incl. breasts)missing & abnormal teeth/hairEDA+/EDA-PHENOTYPICMOSAICScell autonomous traitIdentical twins:little skin cell mixing during developmentPatchiness signifies…are all non-functional X-linked alleles (a-) semi-dominant?For X-linked genes: If a+/a- mammals are functional mosaics of a+ & a- cellsNO(1) perhaps not cell autonomous (and 50% a+ function is sufficient for normal phenotype)(2) perhaps cell autonomous, but deleterious early--- abnormal cells selected against (they may be outcompeted by normal cells) how is a phenotype related to a+ gene expression?Need to know for gene a:(dominance depends on how phenotype is operationally defined)consider hemophiliasMost animals compensate well for cells lost during developmentX2matX2pat 50:50 mat vs. pat activeX1matX2patX2matX1patMapping the source of the inactivation bias defined Xcethe genetics of the X controlling elementX1matX1pat50:50 mat vs. pat active65:35 mat (1) vs. pat(2) active35:65 mat (2) vs. pat(1) activeFig. 18.23 (p675)Among the genetic pathways that control development,those controlling sexual development are perhaps the best understood.controlby pre-mRNAsplicingSxl controls sex determination; dsx controls sexual
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