Review session for midterm Thursday April 5 2007 7 9 pm 101 Morgan Hall Sex understanding its biological significance appreciating how genetics was used to understand how it is determined ESD environmental sex determination GSD genotypic sex determination GSD via a Maternal Effect system for a blowfly Genotype of mother determines or at least influences the Phenotype of the progeny Male producing mothers f f X males f f f f sons Female producing mothers F f X males f f 1 1 sex ratio F f f f daughters A potential problem with many GSD systems including our own fruit flies honeybees XX AA XY AA female male PROBLEM AA female A male NO PROBLEM fact gene output is generally proportional to gene dose in metazoans fact 20 of all fly genes are on X few of these are on fly Y males are monosomic for 1 5 of their genome even 1 is rarely tolerated potentially genetically unbalanced males are monosomic haploid for entire genome not genetically unbalanced XX XY How eliminate the anticipated X linked gene expression difference between the sexes X chromosome dosage compensation 1 increase X linked gene expression 2x in males fruit flies the fly 2 decrease X linked gene expression in females by 1 2 2a reduce each X by 50 2b inactivate one X the worm us mammals Recall that Muller observed X linked gene dose effect within a sex but not between the sexes o wa wa darker more wildtype wa Df w or wa w o wa Y lighter less wildtype wa Y Dp wa YET wa wa same color as wa Y leaky hypomorphic mutant alleles twice as leaky in males vs females It must follow that wa Y Dp wa darker more wildtype wa wa Infer wildtype alleles twice as active in males vs females to achieve balance wildtype normal X linked alleles work twice as hard in males as they do in females XX XY X chromosome dosage compensation Are the male genes working twice as hard or instead are the female genes working half as hard is the glass half full or half empty Can actually answer the question But first Are the alleles on both the female s X chromosomes even working YES Muller knew white gene functioning is cell autonomous Gynandromorph w w w XXAA X AA Female Male a cell s phenotype reflects its genotype with respect to the particular gene w w eye is solid red not mosaic red and white alleles on both X s must be active Are male X linked genes turned UP or are female X linked genes turned DOWN Giant Polytene Salivary Gland Chromosomes measure rate of RNA precursor incorporation into nascent transcripts during interphase average transcription rates per unit DNA X chromosome 2800 genes X chromosome 2800 genes average transcription rates per unit DNA female X female autosomes male autosomes male X transcription rate for Male X linked genes are turned UP relative to autosomal or female X linked genes What phenotype would one expect for mutations that disrupted genes that encode the machinery for X chromosome dosage compensation Female XX no X hyperactivation Normal gene function needed only for hyper Male XY X hyperactivation Phenotypic consequences of loss by mutation male X A 0 5 specific lethal needed only to prevent hyper female X A 1 specific lethal That is how the relevant genes are recognized MSLs encode protein complex on male X How do we mammals dosage compensate XX AA females XY AA males One Barr Body No Barr Body First clue sex chromatin Barr Body rule BB X 1 XO AA Turner females XXY AA Kleinfelter males XXXX AA No Barr Body One Barr Body mentally retarded females Three Barr Bodies Another clue Odd behavior of an X linked mammalian gene G6PD G6PD heterozygote Individual blood cells are phenotypically either G6PD or G6PD only one or the other X linked allele seems to be active in any given blood cell not what we saw with the eye of the w w fly Geneticist Mary Lyon BarrBodies X 1 Observations mosaic expression of G6PD on X mosaic c expression when c on X translocation of autosomal coat color gene c to X Hypothesis 1 Barr Body inactivated X chromosome 2 Dosage compensation by inactivation of all but one X chromosome x Barr Body Xx AA females XY AA males Xxxx AA females X chromosome inactivation Xmaternal Xpaternal 1 initiated very early in development at 500 cell stage in humans 2 generally random in embryo proper paternal maternal often paternal in extra embryonic 3 once initiated stably inherited an epigenetic phenominon 4 reactivation of inactivated X occurs in germ cells during oogenesis 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 hair cell autonomous trait EDA EDAPHENOTYPIC MOSAICS Identical twins Patchiness signifies little skin cell mixing during development For X linked genes If a a mammals are functional mosaics of a a cells are all non functional X linked alleles a semi dominant dominance depends on how phenotype is operationally defined NO Need to know for gene a how is a phenotype related to a gene expression 1 perhaps not cell autonomous and 50 a function is sufficient for normal phenotype consider hemophilias 2 perhaps cell autonomous but deleterious early abnormal cells selected against they may be outcompeted by normal cells Most animals compensate well for cells lost during development the genetics of the X controlling element X1matX1pat 50 50 mat vs pat active X2matX2pat 50 50 mat vs pat active X1matX2pat 65 35 mat 1 vs pat 2 active X2matX1pat 35 65 mat 2 vs pat 1 active Mapping the source of the inactivation bias defined Xce Among the genetic pathways that control development those controlling sexual development are perhaps the best understood Fig 18 23 p675 transcriptional control control by pre mRNA splicing transcriptional control dosage compensation Sxl controls sex determination dsx controls sexual dimorphism
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