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Chromosome Mutations Reading Tutorial
INTRODUCTION
The sperm and egg cells (gametes) required for sexual reproduction are produced by
meiotic cell division. Gametes are haploid cells. In humans, each gamete contains 23
chromosomes (22 are autosomes and 1 sex chromosome; either X or Y). In males, the
four haploid cells produced by meiosis all specialize and become sperm. In females, the
cytoplasm is divided unevenly to produce one large, haploid ovum (egg) and three small
haploid cells called polar bodies. The polar bodies are little more than discarded sets of
chromosomes and eventually disintegrate.
Animation of meiosis
http://www.sumanasinc.com/webcontent/animations/content/meiosis.html
WHAT ARE CHROMOSOME MUTATIONS?
Mutations that alter the number or structure of the chromosomes in the cells of an
organism are called chromosome mutations.
Changes in chromosome number involve the loss or gain of an entire chromosome.
Changes in chromosome structure involve alterations in the number of genes, type of
genes or sequence of genes on a chromosome.
HOW DO CHROMOSOME MUTATIONS ARISE?
Known causes of chromosome mutations including errors during DNA replication, errors
during meiosis, and exposure to DNA mutating factors. The cause for some chromosome
mutations is still unknown.
We will focus on the events during meiosis that lead to chromosome mutations.
Changes in chromosome structure can occur when there is an uneven exchange of genes
during crossing over in prophase I. Changes in chromosome number occur when
homologous chromosomes fail to separate properly during anaphase I.
Most faulty gametes are never fertilized or fail to develop when fertilized. A study
published by the NIH on first trimester miscarriages reveals 61% were due to
chromosomal abnormalities. (www.ncbi.nlm.nih.gov/pubmed/16232180)
If the faulty gamete is fertilized and develops, the fetus is born with a genetic syndrome.
Genetic syndromes are disorders characterized by a group of typical features or
symptoms caused by abnormal chromosomes.
http://ocw.tufts.edu/data/20/293257/292180_medium.jpg
PART I: MUTATIONS THAT CHANGE THE # OF CHROMOSOMES IN THE GAMETE CELL
The mutation that causes gametes to have one extra or missing chromosome is called
nondisjunction.
NONDISJUCTION
Nondisjunction is the failure of a homologous chromosome pair to separate during
meiosis. Two of the gametes receive an extra chromosome (both members of a
homologous pair). The other two are missing a chromosome (no members of a
homologous pair). The normal gamete should have one member of each homologous
chromosome pair.
1. Iupui.edu
2.
WHAT HAPPENS IF THE FAULTY GAMETE IS FERTILIZED?
If a gamete with both members of a homologous pair is fertilized, the embryo will have
TRISOMY (three copies of a chromosome). Two of the homologues came from the faulty
gamete and one homologue from the normal gamete that fertilized it.
If a gamete with no members of a homologous chromosome pair is fertilized, the
embryo will have MONOSOMY (one copy of a chromosome). The faulty gamete
contributed no homologues while the normal gamete that fertilized it contributed one
homologue.
Trisomy can occur to the autosomes or sex chromosomes.
View the following animation to review all of this material.
http://www.sumanasinc.com/webcontent/animations/content/mistakesmeiosis/mistak
esmeiosis.swf
AUTOSOMAL TRISOMIES (Three copies of a non-sex chromosome)
Autosomal trisomies were the most frequent chromosome mutation found in the
research study on first trimester miscarriages comprising 37% of the abnormal
karyotypes. Sixteen percent of the autosomal trisomies were to chromosome 16.
Despite their prevalence, only three autosomal trisomies are compatible with life. The
most common (and most viable) is Down Syndrome (Trisomy 21). Edwards Syndrome
(trisomy 18) and Patau Syndrome (trisomy 13) are rare and children with these
syndromes have a poor prognosis. The viability of Down Syndrome is due to how small
chromosome 21 is. This means fewer genes are being overexpressed compared to extra
copies of the larger chromosomes.
Down Syndrome
http://learn.genetics.utah.edu/content/disorders/chromosomal/down/
http://image.slidesharecdn.com/
THE SEX CHROMOSOMES
The 23rd pair of chromosomes in humans are the sex chromosomes. Females have an XX
chromosome combination and males have an XY chromosome combination. The X and Y
chromosome not truly homologous to one another. The X chromosome contains 800900 protein encoding genes while the Y contains 50-60. A small number of genes on
both ends of the X chromosome are still homologous to genes on the Y allowing them to
behave as a homologous pair during meiosis in males.
https://phylogenous.files.wordpress.com/2010/07/physical-picture-of-chromosomes.jpg
Homologous Regions
Unique to Y
Unique to X
To keep the number of “working” X chromosomes equal in males and females, one of
the two X chromosomes in every cell of the female body is inactivated at random early
on in development. This is known as Lyonization or Dosage Compensation. The inactive
X chromosome can be seen microscopically as a “Barr Body” on the edge of the nucleus.
Lyonization is NOT complete. The genes on the ends of the X chromosome that are
homologous to genes on the Y escape deactivation.
As you learn about different sex chromosome trisomy and monosomy syndromes,
you will notice their symptoms are relatively mild despite the gain or loss of an
entire sex chromosome. Extra X chromosomes (in a female or a male) will be
deactivated so there is always a single working X in the cell. In a female missing an
X chromosomes, the remaining X will be left on in all her cells.
The symptoms that do occur when there are extra or missing X chromosomes are
because of the small areas along the ends of the X chromosome that escape
deactivation. Normal females should have two active copies of these genes.
Normal males should have one active copy of these genes. Additional X
chromosomes increase the number of working copies of these genes. A missing X
chromosome Females missing an X chromosome will have only one copy of these
genes.
SEX CHROMOSOME TRISOMIES
Trisomy of the sex chromosomes include XXX, XXY and XYY.
1. Trisomy X (XXX) is a female with three X chromosomes. This condition occurs in
1 in every 1000 females. Most trisomy X females have no detectable defects
except above average height and below normal intelligence. In these females, two
of their three X chromosomes are deactivated.
2. XYY (Jacob Syndrome) is a male with one X and two Y chromosomes. Since the
Y chromosome only carries 50-60 protein encoding genes, the traits displayed by
XYY males are relatively mild. XYY males have higher levels of testosterone. They
often have severe acne, are taller than normal, and score slightly lower on IQ tests
than their XY counterparts.
3. Klinefelter Syndrome (XXY)
http://learn.genetics.utah.edu/content/disorders/chromosomal/klinefelter/
Klinefelter males will deactivate one of their two X chromosomes as a normal
female would.
AUTOSOMAL MONOSOMY
There are no cases of autosomal monosomy. Humans require both members of
each homologous pair of autosomes to survive. This is because of a phenomenon
known as genetic imprinting. Normal individuals contain two copies of each gene
(one from mom and one from dad). During embryonic development, certain
genes from each parent are silenced leaving the gene inherited from the other
parent as the single working copy. An autosomal monosomy could leave an
individual with no working copies of such imprinted genes.
www.learngenetics.utah.edu
An example of a genetically imprinted gene is IGF2. This gene is located on
chromosome 11. The material copy of this gene is silenced so all proteins
produced by this gene are transcribed from the paternal copy.
SEX CHROMOSOME MONOSOMY
Turner Syndrome (XO) occurs when a female has only one X chromosome in her
somatic cells. (The O represents a missing X chromosome.) This is the only type of
monosomy in humans. Females with Turner Syndrome do not deactivate their
only X chromosome.
Turner Syndrome
http://learn.genetics.utah.edu/content/disorders/chromosomal/turner/
PART II: MUTATIONS THAT CHANGE THE STRUCTURE OF THE CHROMOSOME
(ALTER THE NUMBER, TYPE OR ORDER OF THE GENES)
DELETION
A deletion is caused by the loss of one or more genes from a chromosome.
Region B could be a group of several hundred genes.
TYPES OF DELETIONS
A terminal deletion results in the loss of genes from one end of the chromosome.
An interstitial deletion occurs when an internal section of the chromosome is lost
and the remaining fragments are joined together.
Animation of Terminal and Interstitial Deletions (scroll down to Missing Pieces on
the linked page)
http://learn.genetics.utah.edu/content/chromosomes/diagnose/
Large deletions are easy to locate on a karyotype because one of the homologues
will be considerably smaller than the other. Smaller deletions require close
scrutiny.
CAUSE OF DELETIONS
Deletions usually arise from errors during crossing over in meiosis. As homologous
sister chromatids within a tetrad prepare to swap genes, they fail to align properly
and the switch is unequal. One sister ends losing a section of genes (a deletion)
while the other sister ends up with copies of its own genes and the complement
genes from its homologous sister (a duplication).
IMPACT OF DELETIONS
If both homologs carry the same deletion, the combination is usually lethal
suggesting that most regions of chromosomes are necessary for viability.
Generally the only viable deletions are small ones to ONLY one of the two
homologs.
Cri du Chat
http://learn.genetics.utah.edu/content/disorders/whataregd/cdc/index.html
DUPLICATIONS
A duplication occurs when multiple copies of a gene or group of genes is present.
The duplicated regions can be located adjacent to one another on the same
chromosome, on different areas of the same chromosome, or on entirely different
chromosomes.
Region B might contain several hundred genes.
The cells of the organism have more than two copies of each of the genes within
the duplicated region.
CAUSE OF DUPLICATIONS
As with deletions, duplications are caused by errors during crossing over in
meiosis. As homologous sister chromatids within a tetrad prepare to swap genes,
they fail to align properly and the switch is unequal and one sister ends up with
copies of its own genes and the complement genes from the homologous sister.
The other sister loses that section of genes (deletion).
GENE DUPLICATION AND EVOLUTION
New gene duplications are rarely seen in individuals, but the human genome
carries evidence of past duplication events. The extra copies of genes produced by
gene duplication may retain their original function allowing the organism to
increase the synthesis of the gene product. The genes that code for rRNA and
tRNA have duplicates allowing the cell to increase their production. (Large
amounts of tRNA and rRNA are needed for protein synthesis.)The number of
duplicates is proportional to the size of the genome. E. coli bacteria have 300
duplicates of the tRNA gene and 7 duplicates of the rRNA gene. Humans have
1,300 duplicates of the tRNA gene and 300 of the rRNA gene.
INVERSIONS
An inversion changes the order of genes on a chromosome. This occurs when two
breaks occur on the chromosome and the region between the breaks rotates 180
degrees before rejoining with the two end fragments.
TYPES OF INVERSIONS
A paracentric inversion does not involve the centromere.
A pericentric inversion involves the centromere.
The karyotype below shows an inversion on chromosome 16.
slh.wisc.edu
http://home.comcast.net/~dmgt350/cytogenetics/invert3.htm
IMPACT OF INVERSIONS
2% of the human population carries an inversion in one of their chromosomes
without knowing it. This is because all of the genes are still present and in the
correct amount. Inversions reduce fertility. Problems arise as homologous
chromosomes attempt to cross over during prophase I of meiosis because the
chromosomes are no longer homologous. The order of genes is not the same.
Within the tetrad, an inversion loop forms so that complementary genes can be
aligned. The resulting products of meiosis include chromosomes with duplications,
deletions and inversions.
http://www.google.com/search?q=inversion+loops
Animation of Crossing Over with a Chromosome Inversion
http://highered.mcgraw-hill.com/olc/dl/120083/bio33.swf
TRANSLOCATION
A translocation occurs when chromosomes pieces are transferred between
nonhomologous chromosomes. Scientists do not fully understand why this
happens. The chromosomes that are affected by translocations contain regions
with genes that code for antibodies. These genes normally get cut and spliced in
different orders to increase the variation in the types of antibodies individuals can
produce. One hypothesis is the enzymes responsible for the splicing and
rearrangement of antibody genes create translocations when the cut and splice
chromosome pieces near the antibody genes by accident.
RECIPROCAL TRANSLOCATIONS
In a reciprocal translocation, there is an even swap made between two nonhomologous chromosomes (meaning each chromosome loses some of its own
genes and gains those from the other).
NONRECIPROCAL TRANSLOCATIONS
In a nonreciprocal translocation, genes from one chromosome break off and
attach to a non-homologous chromosome (one chromosome is losing a section of
genes and the other chromosome is gaining that section of genes).
Philadelphia chromosome is the result of a nonreciprocal translocation. As you can
see in the karyotype below, a portion of chromosome 22 and a portion of
chromosome 8 have been translocated to chromosome 9. (Chromosome 9 is now
referred to as Philadelphia chromosome.)
ROBERTSONIAN TRANSLOCATIONS
A Robertsonian translocation occurs when the long arms of two acrocentric
chromosomes (where the centromere very is off center) fuse at the centromere
and the two short arms are partially or completely lost. Robertsonian
translocations are confined to chromosomes 13, 14, 15, 21, and 22. The short arm
of each of these acrocentric chromosomes does not carry any essential
information. Robertsonian translocations change the chromosome number in the
individual’s diploid cells from 46 to 45.
The karyotype belong shows a Robertsonian translocation between chromosome
13 and 14. The long arms of 13 and 14 fused to form one chromosome (the large
number 13). The short arms were lost resulting in only one copy of chromosome
14.
Animation of Translocations (scroll down to translocations on the linked page)
http://learn.genetics.utah.edu/content/chromosomes/diagnose/
IMPACT OF TRANSLOCATIONS
Individuals that carry translocations may appear perfectly normal. They still have
all of the genetic information in the correct amount. As with other chromosome
mutations, they are often sterile or paritally sterile because the translocated
chromosomes cannot pair and exchange genes properly during prophase I of
meiosis. Resulting gamete cells carry duplications and deletions of genes and are
often inviable.