Review session for midterm:Thursday, April 5, 20077-9 pm101 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)

Female-producing mothers

Male-producing mothers

F / f

f / f

F / f & f / f daughters

f / f sons 1:1sex ratio

Genotype of mother

determines (or at least influences) thePhenotype of the progeny

f / fX males

f / fX males

A potential problem with many GSD systems (including our own):

XXAA

XYAA

female male

fruit flies: honeybees:

AA A

female male

fact: 20% of all fly genes are on Xfew of these are on fly Y

males are monosomic for 1/5 of their genome

males are monosomic for entire genomehaploid

PROBLEM NO PROBLEM

(even 1% is rarely tolerated)

potentially genetically unbalancednot genetically unbalanced

fact: gene output is generally proportional to gene dose in metazoans

How 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 compensation

2a: reduce each X by 50%

2b: inactivate one X

fruit flies (“the fly”)

the worm

us mammals

XX XY

wa/wa = (same color as) wa/Y

YET:

Recall that Muller observed X-linked gene dose effect within a sex,but not between the sexes

wa/Y; Dp(wa)/+ > (darker, more “wildtype”) wa/wa

It 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. females

Infer: wildtype alleles twice as active in males vs. females to achieve balance

wildtype (normal) X-linked alleleswork twice as hard in males

as they do in females

= X-chromosome dosage compensationXX XY

Are 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?

YES

Can 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 gene

w+/w- eye is solid red,not mosaic red and white

(XXAA)

Female(X AA) Male

Gynandromorph:

w+/w- w-

…alleles on both X’s must be active

Are male X-linked genes turned UPor are

female X-linked genes turned DOWN?

Giant Polytene Salivary-Gland Chromosomes

X chromosome 2800 genes

measure 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 chromosome 2800 genes

average transcription rates (per unit DNA):

female X = female autosomes = male autosomes < male X

What phenotype would one expect for mutationsthat disrupted genes that encode the machinery

for X-chromosome dosage compensation?

needed (only) for hyper

needed (only) to prevent hyper

male (X:A=0.5)-specific lethal

female (X:A=1)-specific lethal

Normal gene function: Phenotypic consequencesof loss by mutation:

Female: XX Male: XY

no X hyperactivation X hyperactivation

That is how the relevant genes are recognized

(MSLs encode protein complex on male X)

How do we mammals dosage compensate?

OneBarr Body

NoBarr Body

XOAA Turner females

XXYAA

Kleinfelter males

XXXXAA (mentally retarded) females

No Barr Body

One Barr Body

Three Barr Bodies

XYAA

females males

XXAA

“sex chromatin”First clue:

#BB = #X-1

Barr Body rule:

Odd behavior of an X-linked mammalian gene:

Individual blood cells arephenotypically either

G6PD+ or G6PD-

only one or the other X-linked allele seems to be active

in any given blood cell

Another clue:

G6PD+/G6PD-:heterozygote

not what we saw with the eye of the w+/w- fly

Geneticist Mary Lyon:

#BarrBodies = #X-1

Observations:

Hypothesis:

(2) Dosage compensation by inactivation of all but one X chromosome

XYAA

malesfemales

XxAA

females

XxxxAA

(1) Barr Body = inactivated X chromosome

x

Barr Body

mosaic 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 oogenesis

Xmaternal 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/hair

EDA+/EDA-

PHENOTYPICMOSAICS

cell autonomous trait

Identical 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- cells

NO

(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 hemophilias

Most animals compensate well for cells lost during development

X2matX2pat 50:50 mat vs. pat active

X1matX2pat

X2matX1pat

Mapping the source of the inactivation bias defined Xce

the genetics of the X controlling element

X1matX1pat 50:50 mat vs. pat active

65:35 mat (1) vs. pat(2) active

35:65 mat (2) vs. pat(1) active

Fig. 18.23 (p675)

Among the genetic pathways that control development,those controlling sexual development are perhaps the best understood.

controlby pre-mRNAsplicing

Sxl controls sex determination; dsx controls sexual dimorphism

transcriptionalcontrol

dosagecompensation

transcriptionalcontrol