Transcript Complementation

Sex Linkage and Determination
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• In humans, fruit flies, XX = female; XY = male.
• Because there are genes on sex chromosomes,
inheritance of certain traits can be sex-linked.
• Early 1900s, Thomas Hunt Morgan was doing
classical genetics on fruit flies, looking for
mutants and checking out the patterns of
inheritance.
• He studied the white eye phenotype and
discovered something odd…
What Morgan saw
Reciprocal cross
produced a
different result:
Inheritance of
eye color
depended on
sex of the fly.
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Morgan and the F2 generation
When the all red eyed F1
heterozygotes were crossed, a
3:1 ratio was observed, but not
evenly divided between the
sexes.
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significance
• With regard to X linked traits, males have only
one allele, not two. They are said to be
hemizygous.
• Morgan’s work led to the understanding that
genes are located on chromosome’s because
inheritance of certain traits corresponded to
inheritance of a visibly different chromosome.
• Inheritance of X-linked traits results in typical
crisscross inheritance: mother to son.
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Crisscross inheritance
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Carrier mother passes allele to son who expresses it,
passes allele to daughter who carries it, etc.
Hemophilia & color blindness: examples in humans.
http://www.udl.es/usuaris/e4650869/docencia/segoncicle/genclin98/temes_teoria/imatge
s_temes_teoria/image3.gif
Sex determination
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• Different organisms have different
chromosomal mechanisms for determining sex.
– XX/XO: typically, the male has one copy.
• Nematodes, e.g. C. elegans
– XX/XY: as in humans, fruit flies, XX = female; XY =
male.
• Heterogametic sex is the one that produces a
mixture of gametes. Usually the male but:
– Female can be heterogametic in some species
– Designation is ZZ/ZW where female is ZW
More on sex determination
• Temperature affects sex determination in many
reptile species
– Females result from low, high, or extremes of
temperature.
– Hypothesis:
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History
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• Sex determination studies began in late 1800’s
• Work in humans started around 1912, but didn’t
get it right until 1956.
• Keys to understanding sex determination in
humans:
– Improved karyotype methods
– Study of aneuploidy of sex chromosomes
– Aneuploidy is the wrong number of a particular
chromosome.
– Aneuploidy results from non-disjunction
Abnormalities in chromosome number result
from non-disjunction
Homologues fail to separate during Meiosis I.
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Abnormalities in chromosome number result
from non-disjunction-2
Sister chromatids fail to separate during Meiosis II.
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Evidence for XX/XY
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• 47, XXY Klinefelter syndrome
– male in appearance, but some feminization; sterile.
– slow to learn, but not retarded.
– XXXY etc. similar, but more severe symptoms
• 45, XO Turner syndrome
– Monosomy, the only one occurring in humans
– female, sterile, short webbed neck, broad chest,
short.
– majority aren’t born
• If XXY is still male and XO is female
– Y must be determinant of maleness
Other sex chromosome aneuploidies
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• 47, XXX
– Some phenotypically normal
– Others, sterility, mental retardation
• 47, XYY
– 1965 study: higher number of inmates with XYY
– revisited: no real correlation with criminal behavior
• Controversial research, no clear answer.
– taller than average, slightly lower IQ on average.
About the Y
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• Y chromosome has been shrinking.
– Now missing many of genes that X has.
• Two regions: PAR and MSY
• PAR= pseudoautosomal region
– Regions near p telomere and q telomere are
homologous to X chromosome. Crossing over can
occur there during meiosis. Because of this, genes
in this location do not behave as sex-linked traits,
thus said to be pseudoautosomal because they
behave like genes on autosomes rather than sex
chromosomes.
Male specific region Y
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• X-transposed region
– 99% identical to X chromosome region, but only 2
genes; the rest are not expressed.
• X-degenerative region
– Contains DNA related to X chromosome regions
– Several functional genes
– Contains SRY that codes for testis-determining
factor, necessary for maleness during development.
• Ampliconic region
– Highly similar genes related to male development
and fertility.
Evidence for SRY
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• SRY contains gene for testis determining factor
• Crossing over in meiosis
– Males with two X chromosomes; SRY found on one
– Females with X and Y; SRY is missing from Y
• Transgenic mice
– Remove SRY from Y chromosome
– Mice are XY but are female
– Reciprocal experiment also done
Gene dosage
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• It matters how many copies of genes there are.
– Snapdragons: heterozygous flowers are pink.
– Multiple histone genes.
– Too many of some genes is deleterious.
• 3 copies of chromosome 21 = Down Syndrome
• What about sex chromosomes? XX vs. XY
– Y chromosomes are missing most of genes X has.
– So, if 1 set of genes on the X is good for males, is
two sets (2 X chromosomes) bad for females?
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Dosage compensation: Barr, Ohno, and Lyon
• Barr noticed that in the nucleus of females, but not
males, a darkly staining body is visible.
• Ohno hypothesized that this was an inactivated X
chromosome in females so that there would only be 1
functional copy of genes, as in males.
• Inactivated X is called a Barr body.
• Individuals with incorrect numbers of sex
chromosomes have appropriate number of Barr
bodies.
– E.g. XXX females have 2 Barr bodies
Lyon Hypothesis
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• X chromosome inactivation takes place early in
development.
• In placental mammals, it can be either X chromosome.
– All the descendents of that cell have the same X
chromosome inactivated.
– Results in a mosaic, patches of tissue with different
lineages.
• Human females: anhidrotic epidermal dysplasia,
no sweat glands; X linked gene, female has
patches of skin w/o sweat glands, cells
descended from a cell in which the X
chromosome with the normal gene was
inactivated.
• G6PD alleles; Patches of color blindness
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Descent of cells:
How mosaics are made.
Two homologous
chromosomes, blue & red.
Black indicates
inactivation = Barr
body
Formation of Barr bodies-2
Classic example: the calico cat.
One X chromosome codes for
orange fur, the other for black. Cat
shows characteristic mosaic patterns
caused by one or the other X
chromosome being inactivated.
White fur results from the effect of
another gene.
http://www.petstreetmall.com/merchant/Embroidery/Cat/CalicoCatBody.gif.jpe
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Molecular basis of Barr body formation
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• Xic is a region on the X near the centromere.
• Xic region includes a region called Xist (X inactivation
specific transcript)
– This area is transcribed, but RNA isn’t used to make
a protein; it binds to the DNA of the rest of the X
chromosome.
– This promotes molecular changes that inactivate
the chromosome including extensive methylation
(except for XIC) and condensation of DNA (into
smaller space).
• In the OTHER X chromosome, Xic region is
methylated so it will NOT be active.
Active and inactive regions
Red: active genes.
Black: inactive
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Human sexuality
•
http://info.med.yale.edu/therarad/summers/wgss255a%20lecture%2013.ppt#1
• Interesting powerpoints with more questions
than answers
– Caution: graphic images
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