Download Female Male Human chromosomal abnormalities may be numerical

7.03 Lectures 33-34
12/05/01, 12/07/01
Humans usually have 46 chromosomes per cell, including 22 pairs of autosomes (44 autosomes
total) and one pair of sex chromosomes:
Female
Male
Human chromosomal abnormalities may be numerical or structural.
Numerical
Total # chromosomes / cell
Trisomy =
Monosomy =
Triploidy =
Tetraploidy =
Structural
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7.03 Lectures 33-34
12/05/01, 12/07/01
Chromosomal abnormalities manifest themselves in two ways:
1) Spontaneous abortions
of human pregnancies -->
nearly all during first trimester of pregnancy, with many
during the first month, when pregnancy is recognized only
by hormonal assays
of spontaneously aborted embryos and fetuses have
Therefore
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7.03 Lectures 33-34
12/05/01, 12/07/01
Breakdown of chromosomal abnormalities in spontaneous abortions:
Trisomy
XXX, XXY, XYY
All others
Monosomy X (45,X or XO)
Triploidy
Tetraploidy
Other
Total
100%
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7.03 Lectures 33-34
12/05/01, 12/07/01
Chromosomal abnormalities manifest themselves in two ways:
2) Defects in newborns:
Among the most common:
XXY
XYY
XO
XXX
Trisomy 13
Trisomy 18
Trisomy 21
Structural anomalies
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7.03 Lectures 33-34
12/05/01, 12/07/01
Let's now focus on Trisomy 21, also known as Down Syndrome:
phenotype: short stature, mental retardation, characteristic facial features, congenital heart defects
(in 40% of affected individuals), increased risk of leukemia (cancer of white blood cells), increased
risk of cataracts (clouding of lens of eye), premature aging.
For more information on all aspects of Down syndrome, see a fantastic web site maintained by a
pediatrician with a son with Down Syndrome: www.ds-health.com
Trisomy 21
Down Syndrome
Numerical chromosomal disorders are the result of
nondisjunction =
Nondisjunction can occur during
or
How could you figure out whether nondisjunction for
chromosome 21 had occurred during
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7.03 Lectures 33-34
12/05/01, 12/07/01
Consider the following results with two chromosome 21 SSRs in a child with Down syndrome and
his parents:
SSR 21.1
SSR 21.2
A
B
C
D
A’
B’
C’
D’










What can you conclude? At least two things:
1. The presence in the affected child of two different maternal alleles
for SSR 21.1 indicates that
2.
There has been
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7.03 Lectures 33-34
12/05/01, 12/07/01
But at exactly which stage of meiosis did nondisjunction occur?
Let's draw out meiosis as it normally occurs, illustrating just two of the 23 pairs of chromosomes in
a human cell, and exaggerating the size of the centromeres:
Human Male Meiosis
Meiosis I:
Meiosis II:
In men, each meiosis yields 4 gametes, or sperm.
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7.03 Lectures 33-34
12/05/01, 12/07/01
In women, however, only one gamete is produced from each meiosis. The other three haploid
equivalents are discarded in structures called the first and second polar bodies.
Human Female Meiosis
In human females:
•Meiosis I begins (prophase is entered) during embryogenesis and is not completed in any
particular egg until that egg is ovulated, sometime after puberty.
•Meiosis II does not occur until fertilization.
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7.03 Lectures 33-34
12/05/01, 12/07/01
Now we'll focus on chromosome 21 alone, add the genetic markers SSR21.1 and SSR21.2, and
figure out the details in this case of nondisjunction leading to trisomy 21. First we'll diagram how
chromosome 21 would normally segregate at meiosis:
Normal chromosome 21 segregation:
46
92
Meiosis I
46
46
Meiosis II
23
23
23
23
Recognize that, in female meiosis, only one of the 4 possible gametes will be formed. The other
three haploids will be found in 1st and 2nd polar bodies, but assignment to gamete or polar bodies
appears to be a random matter, so all 4 possible gametes are diagrammed above. Diagrams
below will return to convention of showing 1st and 2nd polar bodies.
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7.03 Lectures 33-34
12/05/01, 12/07/01
Nondisjunction in female meiosis I leading to trisomy:
A
B
46
A
A’
A
A’
A’
B’
B
B’
B
B’
92
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7.03 Lectures 33-34
12/05/01, 12/07/01
Nondisjunction in female meiosis II leading to trisomy:
A
B
A
A’
A
A’
A’
B’
46
B
B’
B
B’
92
Meiosis I
A
A’
46
46
A
1st polar body
B’
Meiosis II
B
A’
B
B’
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7.03 Lectures 33-34
12/05/01, 12/07/01
The key to distinguishing Meiosis I vs Meiosis II nondisjunction is
the centromere-linked marker, which will segregate as follows:
Proper disjunction
Meiosis I nondisjunction
Meiosis II nondisjunction
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7.03 Lectures 33-34
12/05/01, 12/07/01
We'll now reexamine our data:
SSR 21.1
SSR 21.2
Interpretation:
A
B
C
D
A’
B’
C’
D’










The data for SSR21.1, the centromeric marker,
demonstrate that nondisjunction occurred in
Taken together, the SSR21.1 and SSR21.2 data
demonstrate that
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7.03 Lectures 33-34
12/05/01, 12/07/01
Studies of many individuals with trisomy 21 using
centromere-linked markers have revealed following
breakdown of cases:
Nondisjunction in maternal meiosis:
Meiosis I:
Meiosis II:
Nondisjunction in paternal meiosis:
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7.03 Lectures 33-34
12/05/01, 12/07/01
The risk of trisomy 21 rises dramatically with increasing maternal age:
Age of Mother
Incidence of trisomy 21
20
30
35
40
45
50
Trisomy 21 provides the major rationale for advising pregnant
women 35 years of age or older to undergo amniocentesis
(examination of fetus' chromosomes by light microscopy).
In human females, oocytes enter but arrest in prophase of
Each oocyte remains arrested in prophase of meiosis I until that
individual oocyte is ovulated, as much as 50 years later!
Geneticists speculate but are uncertain whether the lengthy arrest in meiosis I contributes to the
increasing risk of nondisjunction as women age.
That trisomy 21 causes a marked phenotype suggests that having 3 rather than 2 copies of certain
genes can be harmful. Gene dosage matters!
In 2000, an international team of scientists reported the complete sequence of chromosome 21.
Based on electronic analysis of the sequence, they estimated that the chromosome contains only
about 225 genes. Which of these genes (and how many of these genes?) are responsible for the
Down syndrome phenotype? We do not know the answers to these questions, which are the
focus of intense research efforts today.
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