Transcript Chromosomal Inheritance

Chromosomal Basis of
Inheritance
Chromosome Theory
• Chromosome number is constant within
the species but varies among.
• Chromosome theory emerged right after
Mendel’s work by Sutton and Boveri
(1902).
http://flybase.bio.indiana.edu:82/
Sex Chromosomes in Humans
and Drosophila
– Females have two X, while
males have X and Y.
– Producing two kinds of
gametes, so males are
heterogametic.
– Producing one kind of
gamete, so females are
homogametic.
– Random fusion of gametes
produces an F1 that is ½
female (XX), and ½ (XY).
Fig. 11.3
Parental Cross
F1 x F 1
Males are hemizygous (w/Y) because
there is no homologous gene on the Y
chromosome.
Morgan’s student Calvin Bridges:
1.
Discovered 1/2000 are either white-eyed female or red-eyed
male.
2.
Hypothesized that X chromatids failed to separate in meiosis
resulting in non-disjunction.
3.
Possible outcomes (aneuploidy = chromosomes absent or present
in unusual number).
1. YO

die (no X chromosome)
2. XXX

die (extra X)
3. Xw+O

red-eyed sterile males (no X from mother)
4. XwXwY 
white-eyed females (two X from mother)
Fig. 11.5 Nondisjunction in meiosis involving the X chromosome
Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.
Aneuploidies
1.
2.
3.
4.
YO
XXX
Xw+O
X wX wY




die (no X chromosome)
die (extra X)
red-eyed sterile males (no X from mother)
white-eyed females (two X from mother)
X-linked recessive: hemophilia A
• Lacks a clotting factor
• Queen Victoria either a carrier or a mutation
occurred in germ cells.
– If father to son inheritance, not X-linked recessive
– Many more males (females have 2 doses of X)
– Homozygous mutant mother, all sons inherit the
trait
– Carier mothers lead to 1:1 ratio
– Carrier female x normal male  all daughters
normal; half sons have trait
– Homozygous normal female x affected male  all
normal
Sex Determination in
Drosophila
• An X-chromosome-autosome balance
system is used.
• Drosophila has 3 pairs of autosomes,
and one pair of sex chromosomes.
– XX is female.
– XY is male.
– However, Y does not determine sex.
XXY fly is female, XO is male.
• The sex of the fly results from the ratio of the
number of X chromosomes (X) to the number
sets of autosomes (A):
– In a normal diploid male Drosophila:
• A=2
• X=1
• X:A ratio = 0.5
– In a normal diploid female Drosophila:
• A=2
• X=2
• X:A ratio = 1
Aneuploidy
• When X:A ratio is  1, the fly is female.
• When X:A ratio is  0.5, the fly is male.
• A ratio between 0.5 and 1 results in a sterile
intersex fly with male and female traits.
• Dosage compensation in Drosophila results
in doubling of expression of X-linked genes in
males, so the level of transcription equalized.
Sex Determination in
Drosophila
• The Sxl gene is turned on in females,
while it remains off in males.
• The presence of Sxl protein induces
productive splicing of mRNAs from
transformer (tra).
• Tra protein expressed from the female
tra mRNAs together with Tra2 (which is
expressed in both sexes) activate the
female splicing of mRNAs from the
gene doublesex (dsx).
• The Dsxf protein represses the
transcription of genes required for male
development and activates those
required for female development.
What happens when Sxl is
absent?
• tra mRNA is spliced in a
nonproductive pattern, which
includes exon sequences
containing a stop codon.
• No Tra protein is expressed
from the male tra.
• as a consequence dsxm
RNA is spliced in the male
pattern. The Dsxm protein
translated from this mRNA
represses female
development and promotes
male.
X
X
Dosage Compensation in
Drosophila
• In Drosophila, Sxl regulates dosage
compensation in two ways.
– Indirect: in females Sxl represses the translation of a
gene called male-specific lethal-2 (msl-2) which is
required to hyperactivate expression of X-linked
genes in males.
– Direct: Sxl directly regulates expression of some Xlinked genes. Because the processes of sex
determination and dosage compensation are coupled
in Drosophila, changes in chromosome number also
cause sex specific lethality rather than just sexual
transformation.
Hermaphrodites
• C. elegans can be either a male or a
"hermaphrodite," producing both sperm
and eggs.
• Although hermaphrodites can mate with
males, they can also self-fertilize.
Sexual Dimorphism
• Hermaphrodites are essentially female
animals that produce sperm during larval
development and oocytes during adulthood.
• They have sex-specific set of neurons and
muscles that control egg laying.
• Male worms are slimmer and have tails
equipped with structures that allow the male
to detect and inseminate an appropriate
mate.
If hermaphrodites can
reproduce themselves, then
why bother to have males?
• when the environment is unstable
• when the species is subject to stress
• new combinations of genes are introduced
into the population.
• Normally hermaphrodites spawn other
hermaphrodites. But when hermaphrodites
are stressed (e.g, warm environment, they
produce males).
• And they do it by dropping an X chromosome.
Sex Determination in Worms
• Genetically determined.
• Instead of having an X and a Y, worms have
only an X to work with.
• The ratio of X chromosomes to sets of
autosomes causes XX animals to become
hermaphrodites and XO animals to become
males.
• When hermaphrodites self-fertilize, they
produce other hermaphrodites.
• Stress may lead to males: an X gets lost in
the genetic shuffle, a male is born.
How does a worm count how
many Xs he or she has?
• xol-1, the master switch gene that controls sex
determination in the worm. When xol-1 is
active, it produces XOL-1 protein, which
initiates male development; when the gene is
switched off, and XOL-1 is absent, a
hermaphrodite develops.
Is there a problem with gene
dosage?
• Because hermaphrodites have two Xs, they also
have a double dose of every gene on the X,
even the ones that have nothing to do with sex.
• Genes make proteins, so hermaphrodites stand
to produce twice as much X-encoded protein as
males.
• Such genetic imbalance can be harmful in any
organism: Down's syndrome in humans is
caused by having an extra copy of chromosome
21. For worms, the extra X can be lethal.
Dosage Compensation
• To equalize their X proteins,
hermaphrodites turn down the activity of
all the genes on the X chromosome at
once by 50%.
• In Drosophila instead of reducing the
gene activity in the XX female, flies
double the activity of all the genes
expressed on the male's single X.
Once upon a time
• There was a perfectly normal pair of
chromosomes; X and Y diverged about
300 million years ago.
What did these ancestral
chromosomes look like?
• Although the Y houses a handful of genes
that make a male, about half the genes that
reside on this chromosome are also found on
the X.
• They encode proteins that take care of
general housekeeping and cellular
maintenance tasks, to be shared by both
sexes.
• Now these genes are recognized as living
fossils, representatives of the genes that were
present on the pair of identical chromosomes
from which X and Y sprang.
X and Y chromosomes
Evolution of X and Y
• Y acquired SRY, or a gene that performed a
similar role in sex determination.
• At some point, X and Y lost the ability to
recombine.
• The two Xs can still partner with one another
and exchange DNA.
• But with no proper partner, the Y began to
unravel, losing many of its genes. Such
genetic decay would explain why the Y
chromosome has only 50 or so genes while
the X supports about 1500.
Y chromosome is more than a
rotting X?
• It harbors genes that are male specific.
• Some of these genes, it appears, used to be
located on various autosomes; they relocated
to their home on the Y some 30 to 50 million
years ago.
• This genetic migration may represent an
opportunistic move—perhaps the Y provided
a safe haven for genes that benefit males but
are inconsequential or even somehow
harmful to females.
Dosage Compensation for Xlinked Genes in Mammals
• Gene dosage: how much of a gene is
produced per cell/organism.
• It varies between sexes in mammals
because:
– Females have 2 Xs and males have only 1
X.
Barr Body
• It is a condensed and mostly inactivated
X chromosome. Lyonization of one
chromosome leaves one
transcriptionally active X, equalizing the
dose between sexes.
• An X is randomly chosen in each cell for
inactivation early in development (in
humans, 16 days postfertilization).
Genetic Mosaics
• Descendants of that cell will have the same X
inactivated, making female mammals genetic
mosaics. Examples are:
– Calico cats, in which differing descendant cells
produce patches of different color in the animal.
– Women heterozygous for an X-linked allele
responsible for sweat glands, who have a mosaic
of normal skin and patches lacking sweat glands
(anhidrotic ectodermal displasia).
Lyonization
• After Mary Lyon (1961). It allows extra sex
chromosomes to be tolerated well. No such
mechanism exists for autosomes, and so an
extra chromosome is usually lethal.
• The number of Barr bodies is the number of X
chromosomes minus 1.
• Cis-acting factors (acting on the same
chromosome) encoded by the X must be
important in this process. Likewise,
transacting factors (acting on different
chromosomes) encoded by chromosomes
other than the X or Y were presumed to be
equally important.
In germ cells
• The inactivation is reversed during germ
cell formation so that all haploid oocytes
contain an active X chromosome and
can express X-linked gene products.
X-inactivation
• It involves three steps:
– Chromosome counting (determining the
number of Xs in the cell).
– Selection of an X for inactivation.
– Inactivation itself.
Counting chromosomes
• Involves the X-inactivation center (XIC in
humans, and Xic in mice). Experiments in
transgenic mice show that:
– Inactivation requires the presence of at least two
Xic sequences, one on each X chromosome.
– Autosomes with an Xic inserted are randomly
inactivated, showing that Xic is sufficient for
chromosome counting and initiation of lyonization.
Selection of X
• Selection of an X for inactivation is
made by the X-controlling element (Xce)
in the Xic region. There are different
alleles of Xce, and each allele has a
different probability that the X
chromosome carrying it will be
inactivated.
Inactivation
• Xist is required. It is expressed from the
inactive X.
– The Xist gene transcript is 17-kb. Although
it has no ORFs, it receives splicing and a
poly(A) tail.
– During X inactivation, this RNA coats the
chromosome to be inactivated and silences
most of its genes.
Sex Determination in
Mammals
• In placental mammals, cells with a Y
chromosome uniquely produce testisdetermining factor, which sets the switch to
male development.
– Testis-determining factor causes formation of
testes instead of ovaries.
– All other sex differences result from the specific
gonads (either ovaries or testes) and so testis
formation governs development of maleness.
Sex Determination in Humans
• In humans male and female embryos are
identical until the seventh week of
development.
• Sexual differentiation begins when a sexdetermining gene on the Y chromosome
directs the bipotential gonad to turn into
testes rather than ovaries.
• In the absence of a Y chromosome, the
embryo will develop female structures.
SRY (sex-determining region Y)
• SRY gene is in that region of the Y
chromosome that is deleted, and has
many of the expected properties:
– It is expressed only in the gonadal ridges
of the embryo just before testes form.
– Microinjection of the Sry gene into XX
mouse cells produced normal males.
What is SRY?
• The SRY/Sry gene product is likely a
transcription factor, regulating the
expression of other genes involved in
testis determination.
Genotypic sex determination
Evidence for the Y chromosome mechanism:
1.
2.
Y chromosome confers maleness and determines sex.
Verified by studies of non-disjunction aneuploidy:
XO




“Turner Syndrome”
Female
Sterile
1/10,000 (most XO fetuses die before birth).
Survivors show below average height, poorly developed
breasts, and immature sexual organs
XXY “Klinefelter Syndrome”
 Male
 1/1000
 Above average height, under-developed testes, and breast
development in ~50%
XYY-Male with above average height, fertility problems.
XXX-Female, normal though sometimes less fertile.
Studies of Sex Reversal
• In XX males, a small fragment of Y is
translocated to an X.
• Some XY females have a deletion of the
same region of Y.
XY females
• In the 1960s, the International Olympic
Committee (IOC) instituted genderverification tests to rule out the
possibility of males passing as females
in Olympic competition. Subsequently,
some female athletes were disqualified
from competition because of the results
of these tests.
XY individuals are
phenotypically female
• XY females are sex-reversed individuals, but they
are usually unaware of their genotype. Hormone
levels and muscle mass are typically female.
• The embryo proceeded down the path to becoming
female because the male sex-determining factor
might have been absent.
– SRY could have been deleted from the Y chromosome.
– Another possibility is that SRY was present and
functional, but cells were unable to respond to the onset
of male hormones (androgen insensitivity).
– XY females have been raised as females.
Tests for XY
• An early gender-verification test examined
the inactivated X chromosome (known as the
Barr body).
• The next step in testing was karyotyping.
• Later tests looked for the presence of the
SRY gene.
• What is the validity of using these tests to
determine athletic eligibility?
• Would an XY female necessarily have an
advantage over an XX female?
Is it discrimination?
• In June 1999 the IOC decided to
discontinue the gender-verification
practice on a trial basis for the 2000
Olympics in Sydney.
Birds, butterflies, moths, and
some fish
• Male is the homogametic sex (ZZ),
whereas the female is heterogametic
(ZW). Z-linked genes behave like Xlinked genes in mammals, but the sexes
are reversed.
Plants
• The arrangement of sex organs varies:
– Dioecious species (e.g., gingko) have plants of
separate sexes, one with male parts, the other
with female.
– Monoecious species have male and female parts
on the same plant.
• Perfect flowers (e.g., rose, buttercup) have both types of
parts in the same flower.
• Imperfect flowers (e.g., corn) have male and female parts
in different flowers on the same plant.
Environmental Sex
Determination
• A few species use environmental sex
determination systems, in which
environmental factors affect the sex of
progeny.
• Some types of turtles are an example.
– Eggs incubated above 32 C develop into
females, whole those below 28 become
males. Eggs between these temperatures
produce a mix.