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A second practice problem set
(with answers)
is on the course website.
The review session for the second midterm
is on Thursday evening, April 10, from 7-9pm
in ROOM 141 GIANNINI HALL
mentioned GSD via a Maternal Effect system (for a blowfly)
Genotype of mother
determines (or at least influences) the
Phenotype of the progeny
m/m
mother: vs.
m/+
progeny: m/m, m/+, or +/+
progeny
phenotype
mutant
progeny: m/m, m/+, or +/+
progeny
phenotype
wildtype
Strict maternal effect (only mother can supply the needed + gene product)
mentioned GSD via a Maternal Effect system (for a blowfly)
Genotype of mother
determines (or at least influences)
influences the
Phenotype of the progeny
m/m
mother: vs.
m/+
progeny: m/m, m/+, or +/+
progeny
phenotype
mutant
progeny: m/m, m/+, or +/+
progeny
phenotype
wildtype
Strict maternal effect (only mother can supply the needed + gene product)
m/m
mother: vs.
m/+
m/m
progeny: or
m/+, or +/+
progeny: m/m, m/+, or +/+
progeny phenotype mutant
progeny phenotype wildtype
progeny
phenotype
wildtype
Rescuable maternal effect (either mother or progeny can supply + gene product)
X-chromosome dosage compensation in Drosophila:
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)
Among the genetic pathways that control development,
those controlling sexual development are perhaps the best understood.
Sxlnull is female-specific lethal
SxlConstitutive is male-specific lethal
Fig. 18.23 (p675)
also dosage
compensation
Sxl controls sex determination; dsx controls sexual dimorphism
What about worms? (C. elegans)
XX AA
hermaphrodites
(females that make sperm)
X AA
males
(1) both hermaphrodite X’s active
(like the fly)
(2) male X twice as active as each hermaph. X
(3) at the transcriptional level
(like the fly)
(like the fly)
(4) hermaph.-specific lethal genes encode protein complex
on hermaphrodite X’s that turns transcription down
fly male-specific lethal genes encode protein complex on male X that turns it up
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
Study of variations in “X inactivation strength” (in whole mice)
defined the
Xce (controlling element)
(determines chromosomal inactivation competativeness)
Study of T(X,A)s in mouse tissue-culture cells defined the
Xic (inactivation center)
(“source” of inactivation in cis)
almost all
genes in cis
shut off
c+
X
Xic = Xce
Xic = Xce
The source of a (number of) very odd RNA (s):
Xist
X-inactivation-specific-transcript:
…a non-coding RNA from the inactive X that coats
the inactive X chromosome in cis
X
X
X
X
X
X
one of the first examples of a regulatory RNA
Consequences of deleting Xic (source of Xist):
Xist RNA
X
X
Xist RNA
X
X
always the active X
Xist transgene (inducible) on autosome
will coat autsome with Xist and silence it
…but only during an early window of time