Human Karyotype

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Human Karyotype
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Sex Chromosomes
Genes are located on chromosomes-- sort
independently initial evidence inheritance of
sex chromosomes determined sex males pass X
chromosomes to daughters, mothers to
sons autosomes all chromosomes other than sex
chromosomes X-linked a gene located on the X
chromosome will have different inheritance
patterns depending on reciprocal
cross hemophelia (lack of blood clotting) is
found on the X-chromosome several carriers and
sufferers existed in the House of Winsor but
is no longer found in the english royal family
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Sex Chromosomes
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Chromosome Abnormalities
In about 1/2 of spontaneous abortions, the fetus
has a major chromosomal abnormality--
medically very important monosomy individual is
missing a copy of an individual
chromosome monosomy, in general, is usually
lethal-- one copy just isn't enough
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Chromosome Abnormalities
trisomy a diploid organism having a third copy
of one chromosome Down Syndrome primarily
mental (but sometimes cardiac) defect caused
by trisomy of chromosome 21 VERY common
chromosome abnormality-- 1750 live births
even so, about 2/3 of trisomy 21 fetuses are
spontaneous abortions
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Chromosome Abnormalities
non-disjunction failure of a chromosome to
separate to separate poles of the mitotic
spindle non-disjunction of chromosome 21 can
occur in either division of meiosis leading
to trisomy 21
non-disjunction in meiosis II
non-disjunction in meiosis I
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Chromosome Abnormalities
Trisomy 21 is more common in the egg and much
more common in women over 45 (up to
6!) amniocentesis process of collecting cells
from the developing embryo in order to look
for genetic defects trisomy chromosomes
segregate abnormally-- either tri- or uni-
valently trivalent homologous pairing during
meiosis of 3 pairs of chromosomes univalent
unpaired chromosome of 3 possible ones during
meiosis
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Chromosome Abnormalities
euploidy condition where there are one or more
extra complete sets of chromosomes but where
the relative gene dosage is constant often
become further modified with chromosomes lost or
gained triploidy 3 complete sets of
chromosomes tetraploidy 4 complete sets of
chromosomes
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Chromosome Abnormalities
balanced translocation condition where
non-homologous chromosomes interchange parts,
but no genes are lost or duplicated unbalanced
translocation part of the genome is lost or
duplicated
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Chromosome Abnormalities
Sex chromosome trisomies are even more common
than trisomy 21 generally least severe because
the body already has to deal with having
either one too many or one too few X chromosomes,
and Y is small trisomy X XXX genotype most are
phenotypically normal double Y XYY males
essentially normal Kleinfelter and
Turner syndrome individuals are generally
sterile Kleinfelter may have mild mental
impairment
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Dosage Compensation
Women have twice the number of genes on the X
chromosome than men do Women are also lacking
any genes on the Y chromosome for the genes to
be relatively equally expressed, some mechanism
must exist for either male genes to increase
their level or females decrease dosage
compensation ability of cell to adjust gene
expression levels based on the number of
copies present X inactivation process of
shutting down all but 1 X chromosome once
inactivated, remains inactivated in all daughter
cells inactivates at different times in
different tissues
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Dosage Compensation
X inactivation center site on X chromosome
(Xq11.2 and Xq21.1) where chromosome
condensation is initiated Xist X inactivation
specific transcript RNA that coats X chromosome
and prevents transcription of most genes
Xist is one sequence that is transcribed from the
inactive X chromosome Xist coating leads to
increased methylation of cytosines in regulatory
regions, acetylation of histones, and
aggregation of DNA binding proteins all 3 are
associated with silencing gene transcription muta
tions that delete Xist fail to undergo gene
inactivation
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Dosage Compensation
Barr body inactive X chromosome found in nucleus
of interphase cells Xist colocalizes with the
Barr body
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Dosage Compensation
single active X principle all but one X
chromosome is inactivated question if 1 X
chromosome is always inactivated, why do
X-linked traits show up almost exclusively in
males? answer different cells randomly silence
1 X chromosome a woman will have some cells
expressing 1 X chromosome, some other genetic
mosaic individual that contains cells of
multiple genotypes alleles on different
chromosomes, if mutant, can be expressed
differently individual isolated cells from women
will express 1 gene or another
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Dosage Compensation
Calico cats are visible examples of
X-inactivation 2 alleles, 1 orange, 1
black each allele is expressed in
patches (white is on an autosome and results
in spotting) males are always orange or black
spotted, never both X inactivation is not always
random-- marsupials always inactivate the X
chromosome from the male
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Dosage Compensation
Y chromosome slowly lost the function of various
genes over time some genes that are not
inactivated on X have homologs on Y tips of long
and short arms of X and Y chromosomes retain
homologous genes that escape
inactivation regions of homology are essential
for synapsis in spermatogenesis pseudoautosomal
regions region of X-Y homology at termini of p
and q because the homology regions are in both X
and Y, undergoes inheritance just like
autosomes alleles in pseudoautosomal regions can
migrate back and forth between X and Y
chromosomes
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Sex Chromosome Evolution
initially, X and Y chromosomes were most likely
normal autosomes near pseudoautosomal region at
Yp11.3 lies sry gene sry master sex
determination gene, testes determining factor
transcription factor regulating male embryonic
development transcription factor protein that
regulates transcription of a gene usually a
DNA binding protein or part of a protein
complex as Y and X chromosomes diverged,
deleterious mutations increased in Y X
chromosomes in women could still segregate and
recombine normally essential X-linked genes will
be preserved through dosage compensation genes
tended to be lost from Y chromosome in chunks
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(No Transcript)
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Sex Chromosome Evolution
synonymous same position in a gene homolog or
allele sequence based on nucleotide
sequence based on other chromosomes and other
organisms, the rate of mutation at synonymous
sites is known genes that are more recently
separated from their homologous gene region
are able to accumulate more mutations (ie. no
crossing over is allowed once genes move
because synapsis cannot occur) clusters of genes
with similar levels of accumulated mutations
suggest regions of genes migrated in evolution
in several different stages there are more
differences in gene sequence than large blocks of
recombination can account for-- other smaller
rearrangements occur
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Pedigree Analysis
For some organisms (particularly humans), its
not really feasible to perform controlled matings
as developed by Mendel requires a lot of
offspring to obtain enough data to find the
pattern alternatively, can look at several
generations of related individuals pedigree--
diagram showing the phenotypes of individuals
from several generations squares
males circles females solid individuals
showing a phenotype lines connected related
individuals
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Pedigree Analysis
siblings or sibs offspring of 2
parents carrier individual who does not show a
phenotype but who passes a mutation to their
offspring (always heterozygotes and always
a recessive gene)
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Pedigree Analysis
for dominant genes, there can be no carriers,
only affected individuals
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DNA Analysis
electrophoresis separation of molecules in an
electric field DNA moves toward the positive
electrode in an electric field due to the huge
number of phosphate groups in the DNA backbone
DNA fragments migrate through the gel
proportional to their size small pieces quickly,
large pieces slowly for agarose gels, bands are
usually visualized with ethidium bromide the
percentage of agarose determines what size DNA is
separated well
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DNA Analysis
normal agarose gels separate tens to
thousands of base pairs pulsed field gels can
separate thousands to 106 base pair range
by regularly changing the direction of the
electric field net direction is always toward
end acrylamide gels separate DNA down to
the level of a single base
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Regulation of Phenotype
many non-genetic factors can regulate gene
expression environment- temperature
decides male or female in some species
epistasis- one gene affects expression of another
gene compensation- another gene can take
over function of a defective one
phenocopy when an environmental condition
mimics a mutation ie. Vitamin D deficiency
mimics the genetic disease Rickets