Download X and Y Chromosomes

X and Y Chromosomes
Sex Chromosomes
• Sex determination is not a highly conserved trait in evolution: there
are lots of ways to do it. Sex chromosomes seem to have evolved
many times independently.
• Mammals (except monotremes) use a chromosomal method of
determining sex: XX is female and XY is male.
– The gene involved is the SRY gene
• Birds use a ZW system: ZZ is male and ZW is female.
– the evolutionary origin of mammalian and bird sex chromosomes is
different
– However, the Y and the W are both small chromosomes with few genes
on them.
• Some reptiles use developmental temperature to determine sex:
depends on the species, but hot is male and cold is female in some.
• Drosophila also use an X-Y system (i.e. male is XY and female is
XX), but the evolutionary origin and mode of action of Drosophila
sex chromosomes is different form mammalian.
The SRY Gene
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The SRY gene, located on the Y chromosome, is the primary
determinant of sexual development. Also called Testis
Determining Factor.
– That is, if a developing embryo has a functional SRY gene in its
cells, it will develop as a male. And, if there is no functional SRY,
the embryo develops as female.
– There is a homolog of SRY on the X: SOX3. It is highly diverged in
sequence from SRY.
– SRY makes a transcription factor that activates genes needed to
convert the indifferent gonad of the early embryo into testes.
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Although the SRY gene is usually on the Y chromosome, it
occasionally gets transferred to the X.
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People with this condition (46,XX testicular disorder of sexual development)
are male, but often with small testes and sometimes genital abnormalities.
Also, they are infertile.
Also, sometimes the SRY gene is inactivated by mutation.
– Leading to 46,XY females (Swyer syndrome)
– it is also possible to have a partially inactive SRY gene, leading to
ambiguous genitalia
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Amusing bit of history: Aristotle taught that gender was
determined by the state of the semen: hot semen produced a
male child and cold semen generated a female child.
X and Y Homology
The X is a large submetacentric chromosome with
many genes on it, most of which are unrelated to sex.
The Y is acrocentric and much smaller. Only 83 active
genes on the Y, most of which are related to sex
determination and spermatogenesis.
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About 1400 genes on the X
However, many homologues exist between the X and
the Y, with the Y gene often a pseudogene. This
suggests a common evolutionary origin.
The tips of the X and Y pair in meiosis, and undergo
crossing over. These areas are called the
pseudoautosomal regions (PARs).
There is another large region of homology between the
X and the Y, due to the translocation of a block of
Xp21 onto the Y.
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Occurred 3-4 million years ago, after the human-chimpanzee
divergence.
Very few genes here: it is mostly transposable elements and
other repeated sequences
No X-Y pairing or recombination here.
Pseudoautosomal Regions
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Unlike the rest of the X and Y chromosomes, the PARs pair with each other
in meiosis 1 and undergo crossing over.
Because of their behavior in meiosis, genes in these regions are inherited in
the same way as autosomal genes, and do not act like sex-linked genes:
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PAR1 is on the short arms of both X and Y. (Xp and Yp)
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About 2.6 Mbp (the Y is 58 Mbp total length)
Contains 24 genes, all of which are NOT inactivated in X chromosome inactivation
Successful meiosis and spermatogenesis in males requires a crossover between the PAR1
regions on the X and the Y
PAR2 is on the long arms of the X and Y. (Xq and Yq)
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Genes in the PARs are not hemizygous (present in only 1 copy) in males: 2 copies, one of the
X and one on the Y.
There is no difference in the offspring phenotypes from reciprocal crosses (switching the sexes
of the parental phenotypes).
Much shorter: 320 kb
Only 4 known genes: one of them (SYBL1) undergoes X chromosome inactivation
Crossing over can occur in meiosis, but is not required.
When different placental mammals are compared, all have pseudoautosomal
regions, but which genes are in them, and where the boundaries lie, are quite
variable.
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Marsupials don’t have PARs or any pairing between X and Y chromosomes
Genes in PARs
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During the pre-molecular era in the 20th century, several Y-linked traits were
proposed: hairy ears, porcupine man, etc. All have been disproven.
SYBL1 is in PAR2, but it is subject to inactivation: only 1 copy is active in
both males and females.
– Y chromosome copy is inactive in males
– A particular allele, a G->C in an intron region that controls splicing, has a strong
statistical correlation with bipolar affective disorder
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People with bipolar disorder (also called manic depression) have periods of very elevated mood (happy
and energetic, often with poorly thought-out decisions) and periods of depression. It is caused by a
combination of genetic and environmental factors, but the genetic factors are poorly understood at
present.
– The protein product (called VAMP7) is a transmembrane protein involved in vesicle
docking of transport vesicles that are moving from endosomes to the lysosomes
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This may affect outgrowth of neurites (projections from the neurons)
SHOX (Short stature HOmeoboX-containing) is involved in bone
development.
– It is subject to haploinsufficiency: only one copy causes the short stature and
minor skeletal deformities on Turner syndrome, and 3 copies seems to cause
tallness in people with 3 sex chromosomes.
– Mutations in this genes have similar effects.
• The Y has a number of genes for sperm development. Mutation sin
these genes cause sterility.
Traits Once Thought to be Y-linked
• Hairy ears (OMIM entry 425500): long
hairs growing out of the outer edge of
the ear.
– A 2004 study by Lee et al. showed that a
group of men from southern India with hairy
ears had Y chromosomes from several
different haplogroups. Since the Y doesn’t
recombine (outside of PARs), this
observation would require several different
independent mutations. This seems unlikely.
• Porcupine Man (OMIM 146600: ichthyosis
hystrix gravior). The drawing is of Edward
Lambert, around 1731. Spiny scales covered
most of his body, and also affected 10 other
males in 3 generations of descendants.
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A 1958 study showed that several females in this family
also had the condition, implying that it wasn’t Y-linked.
Muller’s Ratchet
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An important result of sexual
reproduction is that mutations can
be eliminated by recombination.
Two individuals with deleterious
mutations in different genes can
produce offspring with neither
mutation.
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Or, to put it more precisely, the
heterozygous offspring of those two
individuals can produce gametes with
neither mutation.
Muller’s ratchet: in the absence of
recombination, mutations
accumulate: there is no easy way
to get rid of them.
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Predicts that strictly asexual species
won’t survive long unless they share
DNA by some other means (like
horizontal gene transfer).
Y Chromosome Evolution
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The X and Y started off as the same chromosome, but the Y has become
much smaller (both in size and number of genes) and lost the ability to
recombine with the X. Several factors are involved:
1. Loss of recombination is due to a series of inversions. Crossing over
between an inversion and a normal chromosome results in dead offspring.
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No crossing over led to an accumulation of mutations: Muller’s ratchet. The Y contains many
pseudogenes, versions of X chromosome genes that have become inactive due to mutation.
– The same phenomenon is seen with the Y in Drosophila and the W in birds.
– X-degenerate DNA
2. Genes necessary for spermatogenesis are protected from Muller’s ratchet by
having 2 copies present in palindromes, kept virtually identical by gene
conversions. (ampliconic DNA)
3. Large amounts of transposable elements and repeat sequences have
accumulated in certain regions. (heterochromatic DNA)
4. A large block of Xp21 has been transposed onto the Y (and still exists on the
X). (X-transposed DNA)
Inversion History
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The history of inversions of the Y can be traced by looking at synonymous
substitution rates between X and Y homologous genes.
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Synonymous substitutions are changes in the DNA of the codons that don’t affect the amino
acids (due to the degeneracy of the genetic code).
They should be selectively neutral, since the resulting proteins are the same.
Synonymous substitution rates vary in groups, which suggests blocks of
chromosome that became unable to share alleles between the X and Y.
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Before the inversions occurred, crossing over kept the X and Y copies identical.
Once crossing over became lethal (due to the inversions), synonymous substitutions
accumulated.
Ks vs. Position on Y Chromosome
Gene Conversion
• Gene conversion is an alternative
outcome of crossing over in
meiosis.
– In a crossover, 2 homologues
break and rejoin opposite partners,
so genes outside the region of the
crossover are now connected
differently than in the original
chromosomes: they go from
parental to recombinant.
– In gene conversion, a small
region (1-2 kbp) at the site of
recombination becomes
homozygous, while the
homologous chromosomes stay in
the parental configuration.
– A result of the detailed molecular
mechanism of recombination.
The lines represent double stranded DNA
from the 2 homologues.
In the parents (parental configuration),
alleles D and F are on one chromosome,
while d and f are on the other (coupling
phase).
Following a crossover, (recombinant
configuration) D and f are on one
chromosome and d and F are on the other
(repulsion phase).
In gene conversion, a small region (1-2
kbp) at the site of recombination becomes
homozygous: both homologues end up with
the same allele (here, allele e). Note that D
and F , and d and f, are still in coupling: the
chromosomes are still in the parental
configuration.
Gene Conversion in Palindromes
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Gene conversion can also occur within a chromosome it there are
homologous regions on it.
– This is especially true of unpaired chromosomes like the X and Y in humans.
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On the Y are 8 large palindromic sequences (inverted repeats), from 9 kbp
to 1.45 Mbp. Each gene in this region is thus duplicated. Gene
conversions between these palindromes keeps the two copies almost
identical (>99.9% identical).
– This gets around Muller’s ratchet: if mutation inactivates one copy of the gene,
there is another good copy, and in some offspring both copies will be converted
to the good version. Offspring where both copies are bad will be sterile or die.
– Genes in these palindromes are all involved in spermatogenesis.
Dosage Compensation
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There are over 1000 genes in the
X chromosome. How can females
have 2 X’s and males only 1
without running into gene dosage
problems?
Lyon hypothesis (1961):
placental mammals randomly
inactivate all but 1 X at the 200400 cell embryo stage
(blastocyst). The inactivated X's
become Barr bodies: latereplicating condensed chromatin
sitting on the nuclear membrane
(heterochromatin).
– Number of Barr bodies is always 1
less than the number of X’s: Seen
in XXY, XXX, etc.
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why are females rarely colorblind?
Many retinal precursor cells
present at time of inactivation, so
get a fine-grained mosaicism-brain fills in colors
Glucose 6-Phosphate Dehydrogenase
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Early evidence for X-inactivation: glucose 6phosphate dehydrogenase (G6PD). Gene on the X,
with two alleles: normal and G6PD deficient. Red
blood cells from heterozygous females showed two
populations, with and without G6PD.
Cancerous tumors were shown to originate from a
single cell in a similar fashion: in heterozygous
females, only one G6PD allele was active in the entire
tumor.
G6PD is an enzyme active in red blood cells that
shunts glucose off from glycolysis and helps generate
NADPH. NADPH reduces glutathione, which converts
hydrogen peroxide into water.
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G6PD deficiency leads to a buildup of hydrogen
peroxide, which can destroy the red blood cells
(hemolysis).
One common allele found in the Mediterranean
region is especially susceptible after ingestion of fava
beans (favism). The beans contain a compound
(vicine) that results in peroxide formation. Mortality
rate in the absence of transfusions is about 10%.
Malaria parasites also induce peroxide formation, so
G6PD deficiency helps kill cells that are being
infected.
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The distribution of G6PD deficiency globally matches the
distribution of malaria. Very similar to sickle cell anemia.
Tortiseshell and Calico Cats
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A gene for coat color exists on the X
chromosome. It has 2 alleles, orange
fur and black fur.
Because only X chromosome is
active, an individual cell will express
either black or orange but not both.
Inactivation occurs early in
development, and the descendant
cells usually stay together to make a
patch on the skin
Leads to orange and black patches:
tortoiseshell.
Calico cats also have white patches,
due to another (autosomal) gene.
Although rare, Klinefelter syndrome
cats (XXY) exist: they are male
calicos and tortiseshells.
Mechanism of Inactivation
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X inactivation starts at a specific point on the
chromosome: Xq13.2. Chromosomes lacking
this XIC region do not become inactivated.
– Pieces of the X translocated to other chromosomes
don’t get inactivated: only DNA physically
connected to XIC get inactivated.
– inactivation is necessary for life: cells (or embryos)
with more than one active X (due to mutations in
the inactivation mechanism) do not survive.
– XIC is also involved in the counting mechanism by
which all but 1 X is inactivated.
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The XIC region on the inactive X expresses one
important gene: XIST (X Inactive Specific
Transcript).
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The XIST RNA is about 18 Kb.
It is not translated, but it is spliced and poly-adenylated.
It is composed largely of repeated sequences.
The inactive X seems to be coated with XIST RNA, which
forms the Barr body.
If XIST is inactivated during the life of a cell, the X
stays inactivated: XIST is needed to initiate
inactivation, but not to maintain it.
XIST RNA in
Various Genotypes
• The amount of XIST
RNA is proportional to
the number of X
chromosomes minus 1.
More Inactivation Mechanism
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Other events happen after XIST is active:
– XIST RNA recruits “silencing protein complexes” to complete the inactivation.
– Histones on the inactive X are under-acetylated; histone acetylation is found near active
genes.
– the 5’ end of the XIST gene on the active X is heavily methylated, but the 5’ end of XIST
on the inactive X is not methylated.
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The other strand of the XIST gene is also transcribed, called TSIX. TSIX is thus
antisense to the XIST RNA, and TSIX RNA represses XIST expression. TSIX is
not expressed by the inactive X, but is expressed by the active X.
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It has recently been shown that the XIC regions of different X’s pair up transiently
at the time of inactivation, suggesting that the choice of which X stays active
depends on a cis-acting mechanism.
More X Chromosome Inactivation
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the X from the sperm is inactivated in the
zygote and very early embryo (a case of
imprinting).
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It remains inactive in the extra-embryonic
tissues: only the maternal X is active here.
The imprinting is removed in the morula
stage, so both X’s have an equal chance of
being inactivated in the developing embryo.
also reactivation in the oogonia: cells that
will undergo meiosis in the female.
In marsupial mammals, the paternal X is
always inactivated. Only the maternal X is
used during development.
There is also some reactivation of the X
during aging.
Some genes on the X escape inactivation,
especially genes that have functional
homologues on the Y. Thus, 2 copies of
these genes are active in all cells.
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Most, but not all, of these genes are in the
pseudoautosomal regions.
They account for the Turner and Klinefelter
syndrome phenotypes.
Human Sexual Development
Early Gonad Development
• Before 6-7 weeks of
development, the gonad is
indifferent: neither male
nor female.
• It develops from the same
tissue as the kidneys and
adrenal glands.
• Also developing by this
time: 2 sets of ducts that
will eventually lead to the
outside world.
– Wolffian ducts =
male
– Mullerian ducts =
female
Gonad Differentiation
• If SRY is present in the
indifferent gonad at 6
weeks, it gets activated.
This in turn activates
other genes, and the
indifferent gonad is
converted to a testes.
• In the absence of SRY, a
different set of genes is
activated, and the
indifferent gonad
becomes an ovary.
• The germ cells, which
actually become sperm
or eggs, migrate into the
gonad about this time.
Development of Phenotypic Sex
• The cells of the newly formed testes start
secreting the steroid hormone testosterone.
– Testosterone secretion peaks about week 16,
with levels similar to those found in adult males.
After this, the testosterone level drops to about
the same level as female fetuses.
– The testes also secrete another hormone:
Mullerian inhibiting substance (MIS) (aka antiMullerian hormone, AMH). (a glycoprotein
hormone)
• Another important process in the developing
male: during the last trimester of pre-natal life,
the testes migrate (“descend”) from the kidney
region into the scrotum.
• The developing ovary secretes estrogen, which
is important after birth, but estrogen from the
mother completely swamps it out before birth.
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Internal Ducts
In the early embryo, two duct systems form. After the gonad differentiates
into a testis or ovary, one set of ducts develops further while the other set
degenerates.
Testosterone causes the Wolffian ducts to develop into male structures:
epididymus, vas deferens, seminal vesicles.
– In the absence of testosterone, the Wolffian ducts disappear (except a bit
becomes the adrenal glands in both sexes)
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Mullerian inhibiting substance causes the Mullerian ducts to disappear.
– In the absence of MIS, the Mullerian ducts develop into the Fallopian
tubes, uterus, and upper vagina.
Another Duct Picture
Development of the External Genitalia
• This process is controlled by the presence or
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absence of dihydrotestosterone (DHT).
Testosterone gets converted into DHT by the
enzyme 5-alpha reductase, which is found in the
testes and the skin.
Both sexes start out with the same structures, which
develop along different lines under the influence of
testosterone and DHT.
The default condition in female: in the absence of
DHT, the external genital structures develop along
female lines.
DHT also causes hair loss: male pattern baldness.
Testosterone is converted to DHT locally. Rogaine
(the trademark name for minoxidil, a hair-restoring
drug) works by blocking 5-alpha reductase
External Development
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In the absence of DHT, the
genital swellings form the
labia majora; the genital
folds remain unfused and
form the labia minora; the
genital tubercle forms the
clitoris and the urogenital
sinus forms the lower part
of the vagina.
With DHT present, the
genital swellings migrate
and become the scrotum;
the urogenital folds enlarge
and enclose the penile
urethra and become the
shaft of the penis; the
genital tubercle becomes
the glans penis; and the
urogenital sinus forms the
prostate gland
Variant Conditions
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The large majority of people develop as either
completely male or completely female. However,
1% or more of the population has some variant
condition.
A few important terms:
– Gynecomastia: development of breasts in a male
– Hypospadia: the urethra exits the male body at the
base of the penis instead of at the tip, due to failure of
the urethra to become enclosed by the urogenital
folds.
– Intersex: a person whose genitalia are ambiguous or
a mixture of male and female
• Used to be called hermaphrodites, a term still used in
describing animals and plants with both male and female
sex organs
– a true hermaphrodite has both testicular and
ovarian tissue. Very rare, associated with
chimeras and mosaics.
– Ovotestes are gonads with both male and
female tissue in the same organ.
– Ambiguous genitalia can be quantified on the Prader
scale.
Chromosomal Variants
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Meiosis, the form of cell division that generates the
sperm and eggs, carefully puts exactly 1 copy of
each chromosome pair into each cell.
Sometimes meiosis goes wrong and puts 0 or 2
copies of some chromosome into a sperm or egg
cell.
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the best example of this: Down syndrome, which starts
with a sperm or egg with 2 copies of chromosome 21.
Maternal age effect: more frequent in older mothers
The sex chromosomes are quite tolerant of variants.
Most common types involve 45 or 47 chromosomes
There are many other, rarer types, with 48 or even
49 chromosomes, such as 49,XXXXY. Such
conditions almost always lead to serious mental
deficiencies.
The general rule: if the Y is present, the person is
internally and externally male.
Klinefelter Syndrome: 47,XXY
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Occurs about 1 per 500 male births. It is the
most common type of sex chromosome variant.
The presence of the Y chromosome causes a
47,XXY person to be male, both externally and
internally, because the testes are formed.
Root symptom: small testes, leading to low
testosterone levels. Most, but not all, are
sterile.
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At puberty, reduced facial and body hair,
broader hips, breast development.
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47,XXY children tend to be taller, less
physically strong and coordinated, and more
quiet and shyer than their peers. Some
language and learning problems are common:
often slow to learn to speak and read.
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Testosterone replacement therapy helps with
some of the physical symptoms. Speech
therapy and educational services also help.
46,XX males, with the SRY
gene on the X, have the
Klinefelter appearance.
Turner Syndrome: 45,X
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Only one X chromosome, sometimes called XO.
Since there is no Y chromosome, the primary
gonad is the ovary, and 45,X people are female.
About 1 in 2500 live female births.
– 10% of all spontaneous abortions (miscarriages)
are due to Turner syndrome; about 98% of all
Turner’s embryos die before birth
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Ovaries completely non-functional, so 45,X
women are sterile, with no production of sex
hormones and development of secondary sexual
characteristics at puberty.
Some characteristic physical abnormalities: short
stature, low hairline, webbed skin at neck.
Kidney and circulatory system problems
Often have problems with spatial reasoning and
mathematics. Also social difficulties: inability to
understand others’ emotions.
Can be treated with growth hormone and
estrogen.
You need 2 X chromosomes fo
proper ovarian development.
46,XY females (non-functional
SRYgene) resemble Turner’s
47,XYY
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About 1 in 1000 live male births. Most XYY’s are never
detected: a very mild condition.
– since 1960, newly discovered chromosome variants aren’t
given the discoverer’s name
It was once thought to create hyper-aggressive males with a
tendency towards criminal behavior.
– Richard Speck, the killer of eight student nurses in 1966,
pretended (falsely) to be an XYY to obtain leniency.
– A 1968 letter to the Lancet claimed that XYY men were in
prison at a rate "25-60 times as high as the prevalence in
the general population”, based on finding 2 XYY’s.
– the plot of Aliens 3 involves a prison planet for XYY’s.
XYY’s are generally normal in appearance, but with average
height about 7 cm above expected and normal build. Perhaps
acne is more common than average, but this is disputed.
They are often more physically active, somewhat delayed in
emotional maturity, and have a slight increase in learning and
speech problems.
Fertile, normal sex drive, normal testosterone elvels, very
rarely pass 2 Y’s to sons.
1970’s British TV series:
He had an extra Y, which
made him a macho , yet
patriotic, criminal!
47,XXX
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About 1 in 1000 live female births. So mild
as to be only rarely detected. Also called
triplo-X.
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Originally called “superfemale” (early
1960’s). <rolls eyes>
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Widely varying symptoms, including none at
all. Most are never diagnosed.
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Early onset menopause is more frequent
than in XX women.
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Slightly more passive and quiet as babies,
less assertive, delayed motor and linguistic
skills. Delayed emotional maturity and social
skills. Some have slightly decreased
intelligence and learning difficulties.
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Lower back problems are common. Fertility
normal, don’t generally pass 2 X’s to
children.
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Both terms refer to people who have 2 different chromosome
sets in different cells. For example, a 46,XX/47,XXY person
has some cells with 46 chromosomes and other cells with 47.
A mosaic starts out with a single fertilized egg. During an
early cell division in the embryo, one cell gained or lost a
chromosome. (This is non-disjunction, the same event that
happens in meiosis to generate Klinefelter’s, etc.)
A chimera starts out with two separate fertilized eggs,
fraternal twins. The two embryos fuse together to form a
single individual.
– It is not uncommon to have fraternal twins sharing some
blood cells, a “blood chimera”
– fused embryo chimeras are very rare: there are about
30-40 known XX/XY chimeras (and undoubtedly an
equal number same sex chimeras). “tetragametic
chimera”
– Chimerism is probably the way most true
hermaphrodites, who have both ovarian and testicular
tissue, are formed. However, actual XX/XY chimeras
have been everything from normal male, through various
degrees of ambiguous genitalia, to normal female.
Sexual development can be quite variable in such people,
because the characteristics depend on which cells have which
chromosome complement.
Mosaics and
Chimeras
Gene Mutations
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The variants up to now all involve whole chromosomes, which have lots
of genes on them. The effects of changing the dosage of many genes
tend to be widespread but mild. (or completely lethal, as with most nonsex chromosomes).
Now we are going to look at several gene mutations. In these cases,
only one gene is affected, but it is completely knocked out. This can
lead to large effects, but limited to a few subsystems in the body.
Rates are different: for chromosome changes, about 1 in 1000 births is
a typical frequency. For gene mutations, each parent needs to
contribute a mutated copy of the gene, so rates are usually 1 in 10,000
births or less.
Inheritance is also a factor here: most chromosomal variants are
spontaneous events and don’t run in families. Gene mutations are
usually inherited variants: there is often a family/community history of
the variant type.
– New mutations do occur spontaneously, but it’s rare. Most gene variants
are inherited from the parents.
5-alpha Reductase Deficiency (5-ARD)
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5-alpha reductase is the enzyme that converts
testosterone into DHT. If both copies of the gene that
makes this enzyme are defective, the person has 5-ARD.
– Recall that DHT is responsible for the development of
male external genitalia
At birth, people with 5-ARD have undescended testes and
male ducts (with no female ducts), but genitalia that appear
somewhere between female and ambiguous, including a
very small penis with hypospadias (which appears to be an
enlarged clitoris), and a short vagina. Often raised as girls
At puberty, the increase in testosterone is large enough
that some DHT gets made, and they develop a male
appearance: the testes descend, the penis enlarges, facial
hair appears, the voice deepens, muscles develop.
Large group in the Dominican Republic: maybe 1 in 90
men. Called Guevedoces, a corruption of “huevos a los
doce” (eggs--testicles- at age 12). Raised as girls, they
easily switch to the male role.
– Other groups found in Malta, Jordan, Pakistan, New
Guinea
Guevodoces Case
Androgen Insensitivity
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The testes secrete testosterone, but the cells lack a receptor for
it. No receptor = no response to the hormone. Complete
androgen insensitivity, CAIS.
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46,XY with normal (undescended) testes
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Used to be called “testicular feminization”.
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Incidence about 1 in 20,000 births
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As a result, the male ducts (vas deferens, epididymus, seminal
vesicles) are not present. However, the testes secrete MIS,
which causes the female ducts (uterus, fallopian tubes, upper
vagina) to degenerate.
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CAIS people develop female external genitalia, including the
lower 2/3 of the vagina.
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External genitalia develop as male if DHT is present, but testosterone
and DHT use the same receptor.
At puberty, the testes again secrete testosterone. The enzyme
aromatase converts some of it into estradiol. Thus, female
secondary sexual characteristics develop. Often “voluptuously
feminine”. No menstruation of course: no ovaries and no uterus.
Pubic and armpit hair is usually scant or absent.
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Occasionally, the undescended testes can become cancerous, so
they are often surgically removed after puberty is complete (so as to
get normal female development).
Partial Androgen Insensitivity
•
Sometimes, the testosterone receptors work
inefficiently, due to less drastic mutations than in
CAIS. In these cases, the body cells respond in a
variable manner to testosterone, leading a a wide
variety of ambiguous genitalia. PAIS = partial
androgen insensitivity. Also called Reifenstein
syndrome.
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there is also mild androgen insensitivity (MAIS),
which leads to completely male appearance
internally and externally, but with some impairment
of masculinization at puberty.
Variable symptoms: can be predominantly male
(with hypospadia, abnormal scrotum, small
penis), predominantly female (with enlarged
clitoris, fused labia, separate vaginal and urethral
openings), or ambiguous genitalia (microphallus-less than 1 cm long), labia-like scrotum,
hypospadia, gynecomastia.
Similar variability in male internal ducts; females
ducts are usually absent due to MIS secretion.
Sometimes people with PAIS change gender
identity after puberty, in either direction.
Congenital Adrenal Hyperplasia
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•
•
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Also called 21-hydroxylase deficiency.
The adrenal glands sit on top of the kidneys and secrete a
variety of steroid hormones, including cortisone (stress
response), aldosterone (salt balance) and androgens (male
sex hormones).
Steroid hormones are made from cholesterol through a series
of biochemical steps. Any one of these steps can be
inactivated by mutation. However, about 95% of CAH cases
involve defects in the enzyme 21-hydroxylase.
21-hydroxylase is needed to make cortisol and aldosterone
(but not androgens). Cortisol is secreted in response to the
pituitary hormone ACTH, in a feedback loop. So, if there isn’t
enough cortisol being made, more ACTH is made, and this
causes the adrenal gland to grow larger (hyperplasia).
And, all of those steroid molecules that were destined to
become cortisol and aldosterone get diverted into male sex
hormones (androstendione and testosterone), which don’t
need the 21-hydroxylase.
Very little effect on male fetus, which is already making
testosterone, except that after birth the lack of salt regulation
can lead to death from excess salt secretion (salt-wasting).
21-Hydroxylase Deficiency
•
Female (XX) fetuses with 21-hydroxlase deficiency
have some problems due to the flood of androgens
released by the adrenal gland. The ovaries are
normal, and the female (Mullerian) ducts are also
normal (since no MIS is made).
•
Main effects are on the external genitalia: enlarged
clitoris, sometimes with an enclosed urethra (i.e. like
the penis), labia can fuse and become scrotum-like,
vaginal opening can be partly or completely closed.
•
Appearance at birth varies a lot. Some appear to be
normal male with undescended (because nonexistent) testes. However, the chromosomes are XX,
the gonads are ovaries, and the uterus and fallopian
tubes are usually intact.
•
Normally, very little androgen is made in childhood.
But, CAH causes excess androgens throughout life,
leading to rapid growth, but an early closure of the
bone growth plates: a very short adult. Also: early
puberty, with menstrual problems (and poor sperm
production in males).
•
The other hormones, aldosterone and cortisol, need
to be replaced. The cortisol replacement calms the
ACTH activity, leading to less androgen production.
CAH in
females
CAH is the most frequent cause
of non-standard genitals in
genetically female (XX) children.
Some Environmental Causes
•
Progestin-induced virilization. Progestin was used to
prevent miscarriages in the 1950’s and 60’s. Related to
this is the use of androgens to treat endometriosis during
that time period, and occasional accidental use of
androgens. 160 known cases.
– XX fetuses develop as normal females with functioning
ovaries, but they may develop some male secondary
characteristics and often have enlarged clitorises. Effects
are very similar to CAH.
•
Freemartin: usually seen in cattle: female and male
twins, with testosterone from male leaking over to the
female due to a shared placenta. Normal female
appearance, but undeveloped ovaries and masculinized
behavior. Rare or unknown in humans.
– Aldous Huxley’s book Brave New World has human
freemartins created by hormone treatment of fetuses.
Maybe We Will Do The
Following
Y Chromosome Adam
•
Most of our Y chromosome lineages can be
traced to a man who lived about 84,000 years
ago.
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This man is our Y-chromosomal most recent common
ancestor (Y-MRCA).
Or, relating to the Biblical story of the first man, YAdam. This is a strictly metaphorical relationship,
implying no scientific basis for any part of the Biblical
story!
However, as more mitochondrial DNAs are
sequenced, especially from Africa (or
descended from there), more unusual lineages
have been found.
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Haplogroup A, found mostly among the San people in
central Africa, contains lineages that don’t converge
with everyone else’s until about 200,000 years ago.
(2013 data)
Haplogroup A00, found in an African-American, and
then among a few of his relatives in the Mbo tribe in
Cameroon, has an estimated divergence about 338,000
years ago. This is well before the appearance of the first
anatomically modern human fossils.
Methods and Rationale
• Method: The Y chromosome doesn’t recombine (outside of the
PARs). It is much bigger than mitochondrial DNA (60 Mbp vs.
16,000 bp), and the Y mutation rate is lower.
• A mutation occurs, and is then shared with all male-line (patrilineal)
descendants. Compare humans and chimpanzees, and find groups
that share mutations.
• Molecular clock: average rate of mutation stays constant
• Calibrate with know archeological events: peopling of Americas
(about 12,000 YBP) and Australia (50,000 YBP).
• Haplogroup A is the most diverged lineage (most basal in the
phylogenetic tree). Found primarily among the San, but also
scattered throughout Africa.
– who are hunter-gatherers in southern Africa, also known as Bushmen, featured
in The Gods Must Be Crazy movie, one sub-tribe is the !Kung.
– They also have the oldest mitochondrial DNA lineages
• Haplogroup BT is found in most Africans and nearly everyone else
outside of Africa. Many subgroups.