Sex understanding its biological significance Review session for midterm Thursday April 5 2007 7 9 pm 101 Morgan Hall appreciating how genetics was used to understand how it is determined GSD via a Maternal Effect system for a blowfly ESD environmental sex determination Genotype of mother determines or at least influences the Phenotype of the progeny GSD genotypic sex determination Male producing mothers f f X males f f f f sons Female producing mothers F f 1 1 sex ratio X males f f 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 fact 20 of all fly genes are on X few of these are on fly Y even 1 is rarely tolerated potentially genetically unbalanced XY How eliminate the anticipated X linked gene expression difference between the sexes X chromosome dosage compensation NO PROBLEM fact gene output is generally proportional to gene dose in metazoans males are monosomic for 1 5 of their genome XX 1 increase X linked gene expression 2x in males fruit flies the fly 2 decrease X linked gene expression in females by 1 2 males are monosomic haploid for entire genome not genetically unbalanced 2a reduce each X by 50 2b inactivate one X the worm us mammals 1 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 wildtype normal X linked alleles work twice as hard in males as they do in females XY XX 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 wa wa same color as wa Y Can actually answer the question leaky hypomorphic mutant alleles twice as leaky in males vs females It must follow that wa Y Dp wa darker more wildtype wa wa But first Are the alleles on both the female s X chromosomes even working YES Infer wildtype alleles twice as active in males vs females to achieve balance 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 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 not mosaic red and white alleles on both X s must be active X chromosome 2800 genes What phenotype would one expect for mutations that disrupted genes that encode the machinery for X chromosome dosage compensation X chromosome 2800 genes Female XX Male XY no X hyperactivation X hyperactivation average transcription rates per unit DNA female X female autosomes male autosomes male X Phenotypic consequences of loss by mutation Normal gene function needed only for hyper transcription rate for Male X linked genes are turned UP relative to autosomal or female X linked genes 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 2 How do we mammals dosage compensate 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 Another clue XX AA females 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 No Barr Body One Barr Body not what we saw with the eye of the w w fly mentally retarded females Three Barr Bodies Geneticist Mary Lyon X chromosome inactivation Xmaternal Xpaternal BarrBodies X 1 1 initiated very early in development mosaic expression of G6PD on X Observations at 500 cell stage in humans mosaic c expression when c on X 2 generally random in embryo proper translocation of autosomal coat color gene c to X Hypothesis 1 Barr Body inactivated X chromosome paternal maternal often paternal in extra embryonic 3 once initiated stably inherited an epigenetic phenominon 2 Dosage compensation by inactivation of all but one X chromosome Xx AA females x Barr Body XY AA males Striking human example of X inactivation in action For X linked genes If a a mammals are functional mosaics of a a cells Anhidrotic Ectodermal Dysplasia EDA hemizygous males EDA Y homozygous females are all non functional X linked alleles a semi dominant EDA EDA no sweat glands incl breasts missing abnormal teeth hair cell autonomous trait EDA EDAPHENOTYPIC MOSAICS 4 reactivation of inactivated X occurs in germ cells during oogenesis Xxxx AA females 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 Identical twins 2 perhaps cell autonomous but deleterious early abnormal cells selected against they may be outcompeted by normal cells Patchiness signifies little skin cell mixing during development Most animals compensate well for cells lost during development 3 Among the genetic pathways that control development those controlling sexual development are perhaps the best understood 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 Fig 18 23 p675 transcriptional control control by pre mRNA splicing transcriptional control dosage compensation Sxl controls sex determination dsx controls sexual dimorphism 4
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