for educational purposes

1. HUMAN GENETICS
BMD 404
First Semester (2017/2018)
By
Desmond Omane Acheampong

2. Human Chromosomes
 Introduction
• Chromosomes are complex structures located in the
cell nucleus and composed of DNA, histone
proteins, RNA and polysaccharides, and carrying
genetic information in the form of genes.
•

3. Characterizing Human Chromosomes
• Metaphase is a stage of mitosis in the eukaryotic
cell cycle in which chromosomes are at their
second-most condensed and coiled stage (they are at
their most condensed in anaphase).
These chromosomes, carrying genetic information,
align in the equator of the cell before being
separated into each of the two daughter cells.
Metaphase accounts for approximately 4% of the
cell cycle's duration.

4.  These chromosomes, which are not of the same
length are called autosomes

5. • The 23rd pair are the sex chromosomes (different in
both male and female)
In females, both sex chromosomes are of the same
length and are designated X chromosomes
In males, the sex chromosomes consist of one X
chromosome and a smaller chromosome designated
as Y

8.  Staining and morphology of chromosomes
Human chromosome studies are generally carried
out with cells grown in tissue culture
These cells are blocked during metaphase by the
addition of chemical that inhibit spindle fiber
formation (Vinca alkaloids, Taxanes, Podophyllin)
After fixation, staining, and preparation of blocked
metaphase cells, the chromosomes are viewed LM.

10. The site of the centromere (primary constriction) is
a consistent feature of a metaphase chromosome.
The centromere divide each chromosome into two
components called arms. Rarely is the centromere
precisely in the middle.
In most chromosomes, this results in readily
identifiable short and long arms
The shorter arm is designated as the p(petite) arm
and the longer arm as q.

12. When the centromere is near the middle of a
chromosome, the chromosome is called metacentric.
When it is positioned some distance from a
chromosomal end, not at or near the centre, the
chromosome is submetacentric.
An acrocentric chromosome has its centromere located
near a chromosome end.
Telocentric is when the centromere is located at the
chromosome’s end

15. The ratio of the arm lengths (p/q), the centromere index
[p/(p/q) x 100], and the length of each chromosome
relative to the total length of a haploid set were used
initially to classify different chromosomes
By convention, the longest autosomal chromosome is
designated as chromosome 1, the next longest as
chromosome 2, and so on.
In some cases, the originally assigned chromosome
numbers do not reflect the actual chromosome length.
Eg it is now known that chromosome 22 is slightly
longer than chromosome 21.

16. Some of the chromosomes have distinguishing
features other than variations in the location of
centromere. Eg distinctive secondary constrictions
are present during metaphase on chromosomes 13,
14, 15, 21 and 22.

17. Relatively, chromosome length and other features
are not entirely satisfactory in identifying each
specific chromosome.
Eg chromosomes 8, 9, 10, and 11 have similar
lengths and centromere position.

18. This problem was resolved when various
cytochemical procedures were introduced to give
chromosome a distinctive staining pattern of light
and dark transverse bands.
A band is that part of a chromosome which is
clearly distinguishable from its adjacent segments
by appearing darker or lighter by one or more
banding techniques.
Eg when either a Giesma staining procedure or a
quinacrine stain is used, different sets of bands
called G-bands and Q-bands, respectively are
observed.

20. A band can be dark, pale, diffuse, thick, or thin.
But with any one technique, the characteristics of a
band are usually the same.
The bands may represent:
differences of DNA sequences along a
chromosome,
 the relative amount of condensed DNA in different
segments of a chromosome,
localized structural features such as DNA loop
formation within sectors of a chromosome,
the presence of specific proteins that bind to
designated sections of a chromosome.

21. The patterns in each arm allow each chromosome to
be identified and routinely recognize regions within
each arm.
The band numbering system was initially created
when about 400 bands for an entire haploid human
chromosome set were known.
To identify specific chromosome segments, the
chromosome arms were divided into regions.
 Consistent and distinct morphological features
(landmarks) were used to designate each
chromosome region.

23. With the 400-band staining procedure, a region
rarely had more than five bands.
Bands within each region are numbered in
succession from the centromere to the end of
each arm.
As the number of resolvable bands that could be
stained reliably increased from 400 to 500, and
then to 850, a number of the original bands were
found to made up of more than one band

24. A region is therefore defined as a segment of a
chromosome arm lying between the midpoint of two
landmarks.
Regions are denoted with arabic numerals starting
from the centromere and proceeding to the end
(terminus) of each chromosome arm.
Chromosome 1, the longest in the human
chromosome set, has three regions on its short (p)
arm and four on long (q) arm.

26. However most of the other chromosomes the entire
short arm and some instances the long arm were
designated as single region

27. The designation 14q21, when translated in reverse
order would represent the first band (---1) in the
second region (--2-) of the long arm (-q--) of
chromosome 14 (14---).

28. The nomenclature was expanded by retaining the
rule of sequential numbering from the centromere to
the terminus of a chromosome arm for new sub-
bands of an original band and by adding a decimal
point to distinguish an original band from sub-bands
revealed by higher resolution techniques.
Eg if a band 2 of region 1 (ie band 12) of
chromosome is subdivided into three bands with an
enhanced staining procedure, then the designation
becomes 12.1, 12.2 and 12.3.

31. Karyotype
With a photograph, the chromosomes from a
particular metaphase spread are cut out and arranged
into aligned pairs of the same length, the result is
called a karyotype

33.  Chromosome Abnormalities
• Whole Chromosome changes (Aneuploidy)
The mitotic and meiotic process are not error free
Although the distribution of chromosomes is efficient,
occasionally whole chromosome may be lost or gained
because of defects in spindle function.
The failure of chromosomes to segregate properly
during meiosis I or meiosis II can result in gametes
with an extra chromosome or the loss of a whole single
chromosome

34. A change in the chromosome number (aneuploidy)
of a dividing somatic cell can be perpetuated in
some instances, although often such cells lose
capacity to divide.
The occurrence of an extra autosome (trisomy) in
most cases prevents any significant development of
the embryo and leads to its loss.
There are very few known conditions in which a
whole single autosome of a pair (monosomy) can be
missing and still result in a live birth.

35. The presence of extra chromosome 21 (21/21/21 or
trisomy 21) in a zygote can lead, in some instances,
to the completion of development and birth.
A female with an extra chromosome 21is designated
with the code 47,XX,21. In a male the symbolization
is 47,XY,21.

36. Symptoms include some degree of mental
retardation, slowed growth, shortening of the bones,
and characteristic broad, flat face with a small nose
and distinctive eyefolds.
This condition has been designated medically as
Down syndrome (DS)

38. The frequency of DS is approximately 1 out of 800
live births and increases with the age of the mother,
that is by maternal age of 40 years, there is a 1%
chance that a child will have an extra chromosome
21
Trisomy 18 (Edwards syndrome) occurs
approximately once in 8000 live births. Approx. 5 %
of zygotes with trisomy 18 develop to term.

39. Infants with trisomy 18 have severe abnormalities,
including mental retardation and malformation of
the heart
Mostly, trisomy 18 fails to thrive although some can
live up to 20 years.

41. The incidence of trisomy 13 (Patau syndrome) is 1
out of 25,000 births.
This condition is associated with severe defects,
with most trisomy 13 infants dying within a month
of birth. Few survive beyond 12 months.
Central nervous system defects and cleft palates are
consistent features of Patau syndrome.

43. Trisomy 9 is quite rare, with most children dying
within their first year from multisystem
abnormalities affecting the eyes, nose, limbs and
various organ systems.
The presence of an extra sex chromosome has less
biological impact than an autosomal trisomy
The XXY constitution (47,XXY; Klinefelter
syndrome) occurs in 1 out 600 males.

44. o These men are generally incapable of producing
sperm (infertile), but in other respects, the condition
is quite variable.
o Some Klinefelter syndrome men tend to be tall,
with long arms and large hands and feet.
Occasionally, they have decreased mental
capabilities but may be sexually competent.

46. The only condition with just one sex chromosome,
the X chromosome, is Turner syndrome (45,X),
which occurs in 1 out of 10,000 females.
Women with Turner syndrome are short and
infertile, have distinctive physical features,
including a thick neck, and, in some cases, suffer
from kidney and cardiovascular abnormalities.

47. Intelligence is not impaired, although delicate motor
skills may be affected
A single Y chromosome constitution (45,Y) has
never been observed in a live birth.

50. Trisomy X (47,XXX) occurs in 1 out of 1000
females.
There is no consistent set of features accompanying
trisomy X, although many trisomy X women
experience major learning problems.
An extra Y chromosome (47,XYY) occur in 1 out
of 1000 males. No significant biological disabilities
are associated with XYY males. They are fertile,
with normal intelligence and tendency to be tall.

51. Multiple sex chromosomes such as XXYY, XXXY
and other combinations of X and Y chromosomes
occur very rarely.
The affected individuals usually have more
pronounced mental retardation and infertility than
those with single sex chromosome abnormalities.
Chromosome trisomies and other chromosome
abnormalities do not always occur in all the cells of
an individual. That is, cell populations of various
organs are mixtures.

52. Some cells have normal chromosome complements,
whereas others carry chromosome abnormalities.
The occurrence of these kinds of mixtures is called
mosaicism.
Although distribution and frequency of cells with
chromosome abnormalities is important biologically,
mosaicism generally leads to longer survival times
and less severe symptoms in comparison to
individuals with a chromosome aberration in all of
their cells.

53.  Chromosome Structure Changes
Chromosome structural changes occur when the
DNA of a chromosome break is rejoined to another
broken piece of chromosome DNA, forming an
unusual rearrangement.
Most of these alterations occur during S phase and
involve faulty repair of DNA molecules or
mistakes during DNA replication.

54. Environmental agents, such as X rays or
chemicals, also induce chromosome breaks.
Chromosome structural alterations can affect a
single chromosome and lead to a loss of material
from the end of an arm (terminal deletion).

55. This can also lead to loss of material within a
chromosomal arm (interstitial deletion).
It can also lead to the addition of chromosomal
material into chromosomal arm (insertion).

56. When these changes are large enough,
chromosome banding patterns can be used to
define the limits and nature of the alteration.
A nomenclature (International system for Human
Cytogenetic Nomenclature, ISCN) provides a
shorthand description of chromosome
abnormalities that result from structural alterations.

57. Eg 46,XY,del(5)(p13) indicates that in a male (XY)
with 46 chromosomes, by count, the short arm (p)
of chromosome 5 has been deleted (del) from its end
to band p13.
Any terminal deletion of 5p that includes band p15
is associated with the cri-du-chat (‘‘cry of the cat’’)
syndrome.

58. Infants with this condition make sounds similar to a
cat’s mewing and have abnormally small heads
(microcephaly), a very wide space between the eyes
(ocular hypertelorism), small lower jaws
(micrognathia), extreme mental retardation, and
other physical abnormalities.

60. chromosomes, with short
arm of chromosome 4 being
deleted from its end
(terminal) to band 16.3
46,XY, del(1)(q11q21) A male with 46
chromosomes, with deletion
on the long arm between
band 11 and 21 (interstitial
deletion) of chromosome 1
46,XX, add(19)(p13)

61. In some instances, parts of two non-homologous
chromosomes are interchanged without any apparent
loss of chromosomal material (reciprocal
translocation/balanced translocation).
A translocation is abbreviated as t in the ISCN
system.
Eg t(7;19)(q22;q13.1) denotes a translocation
between chromosome 7 at band q22 and
chromosome 19 at band q13.1.
Overall, reciprocal translocations occurs about once
in 800 newborns.

63. Most translocations are family-specific, although
t(11;22)(q23;q11.2) has been observed in more than
100 unrelated families.
Because all chromosome material is retained,
despite some material in alien locations, reciprocal
translocations in most cases have no significant
impact on physical and mental capabilities.
However, there are some examples of disease-
specific chromosome rearrangements.

64. Many of these are found in somatic cells that have
become cancerous.
Eg the chromosomal rearrangement
t(9,22)(q34;q11) is present in about 90% to 95% of
cases of chronic myeloid leukemia (CML), a
cancer that causes an overabundance of certain types
of white blood cells called granular leukocytes

65. Balanced reciprocal translocations have important
genetic consequences.
During the meiotic process, when a reciprocal
translocation is present, synapsis will join the two
translocated chromosomes with the two normal
chromosomes to form a unique structure called a
quadrivalent, consisting of four duplicated
chromosomes.
During segregation at meiosis I, different
combinations of chromosomes of a quadrivalent
will go to the spindle poles.

66.  After meiosis II, some gametes will have a normal
complement of genetic information, whereas others,
after fertilization will produce zygotes with one or
three copies of the same chromosome segments
instead of the required two.

67. Eg the cells entering the meiotic process of a person
with t(7:19)(q22;q13.1) would have intact, normal
versions of chromosomes 7(7) and 19(19) as well as
the translocated chromosomes 19[der (19) and
7[der (7)].
The designation ‘‘der’’ denotes a derivative
chromosome and is used here to represent a
chromosome with a translocation.
As a consequence of meiosis, gametes with four
chromosome combination: [7, 19]; [7, der(19)];
[der(7), 19] and [der(7), der(19)] will be produced.

69. Chromosome Structure Changes