Chromosomal Mutations Lesson: Chromosomal Mutations Lesson

Transcription

Chromosomal Mutations
Lesson: Chromosomal Mutations
Lesson Developer: Dr. Kiran Bala , Dr. Nidhi Garg
College/ Department: Deshbandhu College , Hindu College
University of Delhi
Institute of Life Long Learning, University of Delhi
Table of contents

Introduction

Deletion

Duplication

Inversion

Translocation

Aneuploidy

Polyploidy

Autopolyploidy

Allopolyploidy

Endopolyploidy

Summary

Questions

Glossary

References/Suggested Books

Useful weblinks
Introduction
Mutation is any hereditary alteration in the genetic constitution of an individual organism, virus,
or extra chromosomal genetic element. Mutations can result from unrepaired damage to DNA or
RNA genomes by exposure to radiation or chemicals, mismatch during the replication process,
or from the insertion, deletion, translocation, duplication and transversion of segments of DNA
by mobile genetic elements. A mutagen is an agent that induces mutation. Mutations may or
may not produce visible changes in the phenotypic forms of an organism. Mutations play a
significant role in the process of evolution, development of the immune system (increased
diversity of epitope region of antibody) and even in cancers. Inheritance of extra or less
number
of
chromosomes
is
known
as
chromosomal
anomaly,
abnormality
or
chromosomal aberrations. Such changes are either in the total number of chromosomes or
parts of chromosomes, in genes or their rearrangements and give rise to genetic disorders.
The study of chromosomal disorders is done using cytogenetic methods. Cytogenetic analysis is
used for diagnosing prenatal abnormalities, evaluation of patients with mental retardation,
multiple birth defects, and abnormal sexual development and in some cases of infertility or
multiple miscarriages. Cytogenetic analysis is also useful in the study and treatment of cancer
patients and individuals with hematological disorders.
Chromosomal aberrations are mostly caused as a consequence of DNA breakage. The breakage
happens at two different positions of two DNA strands followed by rejoining of the broken
regions to give different rearrangement of the gene (Figure 1), which is different from the
earlier organization. Chromosomal rearrangements can be introduced by an artificial break in
DNA double helices using a high energy ionizing radiation, specifically X-rays and gamma rays.
Chromosome contains a single, continuous and double-stranded DNA molecule. When the cell
(and hence the DNA) is exposed to ionizing radiation or natural/chemical mutagen, it results in
breaks in the two strands of DNA. Since such DNA breaks are deleterious. The repair machinery
of the cell is instrumental in deploying proteins which repair the damage and joins the broken
ends of DNA. As long as the two ends of the same DNA strand are rejoined, the
original DNA sequence is restored. However, if ends of two different strands are joined, then a
chromosomal rearrangement is produced.
DNA has one centromere and two telomeres to retain the ability of faithful division. If
a centromere is not present in the chromosome, then during the anaphase stage of mitosis and
meiosis the chromosome will not be pulled towards the pole and it will be lost from the progeny
nucleus.
Figure 1: Chromosomal rearrangements
Source: ILLL in house
A dicentric chromosome is one, which has two centromeres. Therefore, it will be simultaneously
pulled towards opposite poles at the anaphase, and will have an anaphase bridge. This
chromosome with an anaphase bridge will not be incorporated into the progeny cell. At the end
of each chromosome the DNA molecule is composed of a stretch of single-stranded repeat
sequences called telomeres. These telomeres form a cap at each end of the eukaryotic
chromosomes, which are required for the complete replication of the chromosomes, thus
broken (non-telomeric) ends cannot replicate properly.
In chromosomal rearrangements, a large fragment of DNA can be lost (deleted) or duplicated.
As a consequence of such gross changes, the gene balance will be affected. A phenotypic
abnormality depends on the length of a chromosome segment lost or duplicated, due to gene
imbalance. Crossing over is other important cause of chromosomal rearrangements between
the repetitive (duplicated) DNA fragments. This crossing over is also known as non-allelic
homologous recombination (NAHR). This type of crossing over can produce aberrant
chromosomes i.e., deletions, duplications, inversions and translocations (Figure 1).
Chromosome
structure
abnormalities
can
lead
to
either
balanced
or
unbalanced
rearrangements.
1. Balanced rearrangements refer to the transfer of genetic information in the same
amount, and therefore do not lead to phenotypic abnormalities. It is of two types i.e.
inversions and reciprocal translocation.
i. Inversion is a rearrangement in which the order of the genes in a section of a chromosome is
cut out, reversed by 180 degree, an inversion loop is formed and the inverted portion is
rejoined back.
ii. Reciprocal translocation is usually an exchange of material between two non-homologous
chromosomes. These are most frequent and are produced by single break in each of the two
non-homologous chromosomes (Figure 2).
Figure 2: Reciprocal translocation
Source: http://upload.wikimedia.org/wikipedia/commons/c/cb/Translocation-4-20.png
2. Unbalanced rearrangements involve deletions, duplications or both (Figure 3).
i.
Deletion of a chromosome segment leads to partial monosomy of that segment.
ii.
Duplication of a chromosome segments leads to partial trisomy of that segment which
lead to an abnormal phenotype.
Figure 3: Deletion and Duplication rearrangments
Source:
http://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Deletionvectorized.svg/300pxDeletionvectorized.svg.png
Deletions:
A deletion refers to missing of a part/ whole arm of the chromosome. It is simply the loss
of one or more than one gene from the chromosome arm. If the deleted fragment of a
chromosome lacks a centromere it will get detached and lost. Depending upon the length
of the lost DNA fragment, the number of genes lost, may vary. Deletion can be
interstitial/intragenic i.e. within a gene and multigenic deletion, where many genes
are missing. Intragenic deletion deactivates the gene and shows the same effect as null
mutations of that gene. Multigenic deletions have more dreadful consequences than
intragenic deletions.
Homozygous deletions generated through inbreeding can be lethal. Heterozygous
deletions may also be lethal because of chromosome imbalance or because recessive
deleterious alleles have chance to express themselves. Certain deletions can easily be
identified by examining dividing chromosomes under the microscope. During synapsis that
occurs between a chromosome with a large deficiency and a normal chromosome, the
unpaired region of the normal homolog would loop out of the synaptic complex into
a deletion loop or compensation loop (Figure 4a). Deletion loops have been detected
in the polytene chromosomes of Drosophila flies, in which the homologs are tightly paired
and aligned (Figure 4b).
Figure 4: Looped configurations in a Drosophila deletion
heterozygote
Source:http://zlgc.seu.edu.cn/jpkc/2010jpkc/jykc2/Content/jxzy/genetics/chapt13/photo
_library/text_photo_library/13_04.jpg
ILLL in house
Deletions of specific human chromosome regions cause unique syndromes of phenotypic
abnormalities. An example of this is the Cri du chat syndrome (French for “cat’s cry”). It
results from the deletion of a part of the short arm of chromosome 5 (also called 5psyndrome). The affected children have a high-pitched cry similar to the mewing of a cat at
the time of birth which gives this syndrome its name. The affected individual shows the
following characteristics1. Pinched facial features
2. Mental retardation
3. Karyotype analysis is used to determine whether a child will have only the cat-like cry
and perhaps poor weight gain, or will have all of the signs and symptoms, which
include low birth weight, poor muscle tone, a small head, and impaired language skills.
Another consequence of deletion is seen in organisms that are heterozygous for a
deficiency. A common example is the notch phenotype in Drosophila (Figure 5). In these
mutant flies the wings contain a notch on the lateral and the posterior margins.
Figure 5: Photograph of a wing from an animal of genotype N 264-39 / +. The thick vein and
serration is indicated by arrowheads.
Source: http://www.sanpatricio.co.uk/Innexins/inxpicviewer.php?thebigpic=35 written for
permission
The notch phenotype results from a dominant mutation on the X chromosome because
Drosophila females heterozygous for this mutation have notched wings and also transmit
the defected allele to their female progeny. This mutation results in lethality when present
in homozygous condition in females and heterozygous condition in males as such females
and males have never been recovered. Females with the notch phenotype are also
heterozygous for recessive mutation such as white-eye, facet eye or split bristle. Since
these mutations are recessive in nature the heterozygotes show the wild type phenotype.
To study the notch phenotype, the polytene chromosomes of females showing the notch
phenotype were examined. The researchers found a deficiency loop along the X
chromosome from band 3C2 through band 3C11 (Figure 6). These bands include the loci
for several genes including the white, facet and split genes. A deletion of this region in one
of the two X chromosomes has two consequences. First, it causes the notch phenotype.
Secondly, it creates a partly hemizygous condition by deleting the wild type genes for
white, facet and split phenotype, when their mutant alleles are present on the
corresponding homologous chromosome. Thus, as a result the mutant white, facet and
split alleles express themselves. The phenotypic expression of recessive alleles or genes in
association with a deletion is known as pseudodominance. Till date, several different types
of Notch phenotypes have been discovered and upon investigation all have revealed the
deletion of the band designated as 3C7.
Figure 6: Deficiency loop observed in the polytene chromosomes of
Drosophila showing the Notch phenotype. The deletion ranges from
bands designated as 3C2 to 3C11.
Duplication:
Duplicated genes are those, which are present in more than one copy in the haploid
genome. Duplications can be dispersed or tandem. Dispersed duplications are found in a
number of different locations while tandem duplications are found next to each other.
Tandem duplications play a major role in evolution, because it is easy to generate extra
copies of the duplicated genes through the process of unequal crossing over (Figure 7).
These extra copies can undergo mutations to take on altered roles in the cell, or they can
become pseudogenes, which are the inactive forms of the gene.
Unequal crossing over happens during the prophase of meiosis one. Homologous
chromosomes pair at this stage, and sometimes pairing occurs between the similar but not
identical copies of tandem repeats. If a crossover occurs within the misaligned copies, one
of the resulting gametes will have an extra copy of the duplicated gene and the other
gametes will not. In hemoglobin for example, in humans, the beta-globin gene cluster
contains 6 genes: epsilon (an embryonic form), gamma-G, gamma-A (the gammas are
fetal forms), pseudo-beta-one (an inactive pseudogene), delta (1% of adult beta-type
globin) and beta (99% of adult beta-type globin).
Gamma-G and gamma-A are very similar, differing by only one amino acid. If mispairing
in meiosis occurs, followed by a crossover between delta and beta, the hemoglobin variant
Hb-Lepore is formed. This is a gene that starts out delta and ends as beta. Since the gene
is controlled by DNA sequences upstream from the gene, Hb-Lepore is expressed as if it
were a delta. That is, it is expressed at about 1% of the level that beta is expressed. Since
normal beta globin is absent in Hb-Lepore, the person has severe anemia.
Figure 7: The origin of duplicated and deficient regions of
chromosomes as a result of unequal crossing over. The tetrad on the
left is mispaired during synapsis.
Gene Redundancy and Amplification—Ribosomal RNA Genes
Duplication of chromosomal segments has the potential to amplify the number of copies of
individual genes. This has clearly been the case with the gene encoding ribosomal RNA, which is
needed in large amounts to support protein synthesis. We might hypothesize that a single copy
of the gene encoding rRNA is inadequate in many cells that demonstrate intense metabolic
activity. Studies using the technique of molecular hybridization, which enable us to determine
the percentage of genome that codes for specific RNA sequences, show that our hypothesis is
correct. Indeed, multiple copies of genes code for rRNA. Such DNA is called rDNA, and the
general phenomenon is referred to as gene redundancy. For example, in the common
intestinal bacterium Escherichia coli (E. coli), about 0.7 percent of the haploid genome consists
of rDNA—the equivalent of seven copies of the gene. In Drosophila melanogaster, 0.3 percent
of the haploid genome, equivalent to 130 gene copies, consists of rDNA. Interestingly, in some
cells, particularly oocytes, even the normal redundancy of rDNA is insufficient to provide
adequate amounts of rRNA needed to form ribosomes. Oocytes store abundant nutrients,
including huge quantities of ribosomes, for use by the embryo during early stages of
development.
More ribosomes are included in oocytes than in any other cell type. By considering how the
amphibian Xenopus laevis acquires this abundance of ribosomes, we shall see a second way in
which the amount of rRNA is increased. This phenomenon is called gene amplification. The
genes that code for rRNA are located in an area of the chromosome known as the nucleolar
organizer region (NOR). The NOR is intimately associated with the nucleolus, which is a
processing center for ribosome production. Molecular hybridization analyses have shown that
each NOR in the frog, Xenopus, contains the equivalent of 400 redundant gene copies coding
for rRNA. Even this number of genes is apparently inadequate to synthesize the vast amount of
ribosomes that must accumulate in the amphibian oocyte to support development following
fertilization. To further amplify the number of rRNA genes, the rDNA is selectively replicated,
and each new set of genes is released from its template. Because each new copy is equivalent
to one NOR, multiple small nucleoli are formed in the oocyte. As many as 1500 “micronucleoli”
have been observed in a single Xenopus oocyte. If we multiply the number of micronucleoli
(1500) by the number of gene copies in each NOR (400), we see that amplification in Xenopus
oocytes can result in over half a million gene copies! If each copy is transcribed only 20 times
during the maturation of the oocyte, in theory, sufficient copies of rRNA are produced to result
in well over 12 million ribosomes.
The Bar Mutation in Drosophila
Duplications can cause phenotypic variation that might at first appear to be caused by a simple
gene mutation. The Bar-eye phenotype in Drosophila (Figure 8) is a classic example. Instead of
the normal oval-eye shape, Bar-eyed flies have narrow, slit-like eyes. This phenotype is
inherited in the same way as a dominant X-linked mutation. In the early 1920s, Alfred H.
Sturtevant and Thomas H. Morgan discovered and investigated this mutation. Normal wild-type
females (B+>B+) have about 800 facets in each eye. Heterozygous females (B>B+) have
about 350 facets, while homozygous females (B>B) average only about 70 facets. Females
were occasionally recovered with even fewer facets and were designated as double Bar
(BD>B+). About 10 years later, Calvin Bridges and Herman J. Muller compared the polytene X
chromosome banding pattern of the Bar fly with that of the wild-type fly. These chromosomes
contain specific banding patterns that have been well categorized into regions. Their studies
revealed that one copy of the region designated as 16A is present on both X-chromosomes of
wild-type flies but that this region was duplicated in Bar flies and triplicated in double Bar flies.
These observations provided evidence that the Bar phenotype is not the result of a simple
chemical change in the gene but is instead a result of duplication.
Figure 8: Bar-eye phenotypes in contrast to the wild-type eye in
Drosophila.
Source:
http://www.nature.com/scitable/content/25319/pierce_9_7_large_2.jpg
displayed with permission
Inversions
Inversion occurs due to flipping around of a part of a chromosome. The experimental
studies show that 5-10% of inversion leads to health problems, as they disrupt structural
genes. Some inversions are detected in fetal chromosomes, but the physicians are not
able to co-relate the symptoms associated with the inversion. If one of the
fetal
chromosomes has an inversion and even then they are healthy, then the child most likely
will not have any symptoms of the inversion. If parents don't have an inversion, then the
defective region must have arisen in a gamete and may depend on knowing which genes
are involved.
An adult can be heterozygous for an inversion and be healthy, but have reproductive
problems. It was reported that a woman had an inversion in the long arm of chromosome
15, due to which she had two spontaneous abortions, two stillbirths and two children with
multiple problems who died within days of birth. Later on, she did eventually give birth to
a healthy child. Inversion occurs when a chromosomal segment is removed and then
replaced backwards. The problem arises during meiosis, when a chromosome with an
inversion is heterozygous with a normal chromosome. Crossing over between the inverted
chromosome segment and non-inverted homolog leads to recombination. Loop formation
by inverted chromosome allows the genes to align. Due to crossing over within the loop,
in the resulting recombinant chromosomes, some regions are duplicated and some
deleted. Anomaly in chromosomes results from the chromatids that are crossed over
during inversion.
As the offspring carrying crossover gametes are not viable and not recovered, it seems
like the inversion suppresses crossing over. Actually in inversion heterozygotes, the
inversion has the effect of suppressing the recovery of crossover products during the
occurrence of chromosomal exchange within the inverted region. While the crossing over
always takes place between a paracentric or pericentric inversion, 50 percent of the
gametes would be ineffective. The resulting viable zygote is then greatly diminished. In
addition, one-half of the viable gametes have the inverted chromosome, and the inversion
will be continued within the species. The cycle will be repeated consecutively for meiosis in
future generation.
Inversions are of two types based on the position of the centromere relative to the
inverted section.
1. Paracentric Inversions: When a chromosome containing paracentric inversion
crosses over with a normal chromosome, the resulting chromosomes are either acentric,
with no centromeres, or dicentric, with two centromeres. The acentric chromosome isn't
attached to the spindle, so it doesn't have any centromere and the dicentric is usually
pulled apart (broken) by the spindle pulling the two centromeres in opposite directions.
Both conditions are lethal (Figure 9).
Figure 9: Paracentric Inversions
2. Pericentric Inversions: Crossing over between chromosome containing pericentric
inversion and normal chromosome, results in chromosomes containing some genes
duplicated and some deleted, they do have one centromere each. The gametes produced
from these are aneuploid and do not survive. Thus, either kind of inversion leads to lethal
combination when it crosses over with a normal chromosome. The surviving offspring
didn't have a crossover. Thus, when you count the offspring you only see the noncrossovers, so it appears that crossing over has been suppressed (Figure 10).
Figure 10: Pericentric Inversions
Translocations:
In translocations, non-homologous chromosomes exchange or combine segments. There
are two major types of translocation: reciprocal translocations (no visual loss of
chromatin), and Robertsonian translocations (centromeres of two non-homologous
chromosomes fuse and chromosomal material of short arm is lost).
Reciprocal translocations: “The offspring having reciprocal translocation generally
shows no phenotypic effects due to the rearrangement except for possible reproductive
abnormalities including infertility, spontaneous abortions and abnormal offspring”.
The
relocated proto-oncogenes, due to translocation lead to disruption in the cell cycle and the
development of tumours or leukaemia.” Reciprocal translocations show basic segregation
patterns (Figure 11) i.e., alternate segregation- the alternate chromosomes of the ring go to
the same pole; the normal chromosome on one pole and the translocated chromosomes to
opposite pole. Therefore, all the gametes receive complete chromosomal set and are fully
viable.
Adjacent-1-segregation- In open ring configuration, if one normal and one translocated
chromosome reach one pole and one translocated and one normal chromosomes reach to the
other pole, it is called adjacent-1-segregation.
Adjacent-2-segregation- In open ring configuration the two homologous chromosomes (one
normal and other translocated i.e., 1-1’) go to one pole and other two homologous 2-2’ go to
the other pole. This is called Adjacent-2-segregation.
Figure 11: Reciprocal translocation
As a result of the equality between the adjacent and alternate segregations, 50 percent of
gametes are unable to contribute to the next generation, a condition known as semisterility
or half sterility. The semisterility condition is a major diagnostic for reciprocal translocations
in heterozygotes. However, semisterility condition is defined differently for plants and animals.
In plants, 50 percent unbalanced meiotic products generally die at the gametic stage from the
adjacent-1 segregation. But in case of animals, the duplication and deletion product is viable as
gametes but lethal to zygote. The semisterility condition affects the reproductive fitness of
organisms and therefore it plays an important role in evolution. In addition, such unbalanced
condition in human leads to partial monosomy or trisomy, and causes a variety of birth defects.
Value addition: Video
Heading
text:
Understanding
Chromosomal
Translocation
-
Reciprocal Translocation
Body
text:
Click
the
link
and
learn
about
Robertsonian
translocation:
https://www.youtube.com/watch?v=MLDCJ2gUC84
Source: YouTube
Robertsonian translocations or Centric fusion: The resulting derivative chromosome from
Robertsonian translocation can be monocentric/dicentric depending on the position of the
breaks and exchange of chromatin segments. “No physical defects are shown until reproduction
by a carrier of a Robertsonian translocation” (Figure 12). The chromosomal pairing at
pachytene stage involves both the normal and the chromosome with translocation. The unequal
segregation during anaphase from the trivalent, leads to the formation of either normal, or
trisomies or monosomies, when fertilized by a normal gamete. “Trisomy for chromosomes 13
and 21 are compatible with life, whereas, trisomy for the other acrocentric’s (i.e. 14, 15 and
22) will virtually all be lost as spontaneous abortions. All the conceptions with monosomies will
also be lost prenatally.”
Figure 12: Robertsonian translocation
An important example of Robertsonian translocation is the familial Down syndrome. Down
syndrome in over 95 percent of cases is due to trisomy 21, which results from the
nondisjunction of chromosomes during meiosis in one of the parent. Therefore, there are
fewer chances of the same parents producing a second affected child. In the remaining
cases the frequency of occurrence of Down syndrome in a child, is very high over several
generations—therefore it is said that it “runs in families.”
The cytogenetic studies of the familial Down syndrome have revealed the actual cause to
be the 14/21, D/G translocation in one of the parents (Figure 13). This simply means that
in one of the parent the G-group chromosome 21 has translocated to one end of the
chromosome 14 belonging to D group. Such an individual is known as a balanced
translocation carrier and appears phenotypically normal, although he or she has only 45
chromosomes. In such an individual, during meiosis the gametes formed contains either
a) One copy of chromosome 21 and 14
b)
A normal 14 chromosome only and the 21 chromosome is missing
c)
A normal 14 chromosome and a translocated 21 chromosome
d)
The translocated chromosome 21 to chromosome 14
When these gametes are fertilized by a standard haploid gamete, four different situations
can arise.
a)
Although the zygote has 46 chromosomes but it exhibits Down syndrome because of
the presence of three copies of chromosome 21.
b)
One of the zygote has the normal complement of chromosomes and thus survives
normally.
c)
The third possibility is the translocation carrier just like the parent which will be a
normal individual.
d)
In the fourth case the individual produced is monosomic, which results in lethality.
These findings have led to the identification of an inherited trisomic phenotype where the
individual
apparently
has
diploid
number
of
chromosomes.
The
carrier
has
45
chromosomes but not the complete diploid amount of genetic material because a small
region is lost from both the 14 and 21 chromosome during the process of translocation.
The lost regions of chromosomes contain multiple copies of the rRNA genes. Although
there is a loss of about 20 percent of these genes, the carrier remains unaffected.
Figure 13: Familial Down Syndrome
Value addition: Video
Heading
text:
Understanding
Chromosomal
Translocation
-
Robertsonian Translocation
Body
text:
Click
the
link
and
learn
about
Robertsonian
https://www.youtube.com/watch?v=vbGw4VanNjk
Source: YouTube
translocation:
Chromosomal Translocations are a hallmark of Leukemia:
Changes in the chromosome structure or number, cause cancer. But the correlation
between many such alterations in chromosomes structure or number and the growth of
cancer is still not understood. For example, if an individual has an extra copy of 21
chromosome, there is a twenty fold increased risk of leukemia, when compared with
general population. How extra copy of chromosome can increase the risk of leukemia is
unknown. Chromosomal translocations are mutual in many types of cancer but their
relationship to cancer growth is still not deciphered. But in other cases, the relationship
between the chromosome mutation and the growth or maintenance of cancer is
recognized. Such a relationship is clearly seen in table 1.
Table 1: Specific chromosome alterations and cancer
Chromosome Alteration
Cancer
t(4;11)
Acute lymphocytic leukemia
t(8;21)
Acute myelogenous leukemia
t(15;17)
Acute promyelocytic leukemia
t(9;12)
Acute myelogenous leukemia
del(10q)
Prostate cancer
del(13q)
Retinoblastoma
T(X;18)
Synovial Sarcoma
inv(12p)
Testicular cancer
Del(11p)
Wilms tumor
t=translocation; del=deletion; inv=inversion
The best studied example is between 9 and 22 chromosomes, and is related with chronic
myelogenous leukemia (CML) (Figure 14). Earlier this translocation was reported in
abnormal chromosome 21, and was known as Philadelphia chromosome (as this was
discovered in that city). Janet Rowley in later studies confirmed that the Philadelphia
chromosome actually is the product of the translocations between chromosomes 9 and 22.
Hence, chronic myelogenous leukemia may derive from a single cell containing this
translocated chromosome.
By studying a large number of Philadelphia chromosomes, the proper position of the
breakpoints on the chromosomes 9 and 22 were founded. Through recombinant DNA
technology, the genetic mapping studies demonstrated that the C-ABL proto-oncogene
maps to the breakpoint region on chromosome 29 and the BCR gene maps close to the
breakpoint of chromosome 22. The c-abl protein is a kinase and bcr protein activates
phosphorylation reaction which catalyzed by kinase. In the translocation effect, entirely or
nearly of the C-ABL gene is translocated to a region within the BCR gene and giving a
hybrid BCR/ABL oncogene. The fusion of two normal genes produced the oncogene which
is transcriptionally active and expressing the 200 kDa protein product. This protein
product is then responsible for the generation of chronic myelogenous leukemia (CML).
Figure 14: Philadelphia Chromosome formation.
In Burkitt Lymphoma, both cytogenetic and molecular techniques are used for studying
the effect of translocation having chromosome 8 [these include t(8;14), t(8:22) and
t(2;8)]. The chromosome 8 with breakpoint in all of this translocation is same; the c-myc
proto-oncogene has been mapped at this locus. The loci at the breakpoints on the other
chromosome involved in this series of translocations all have immunoglobulin genes
located at the breakpoints. The act of changing the location of c-myc gene to a position
close to these immunoglobulin genes leads to over expression of the lymphoid cells.
Other leukemias and lymphomas show characteristic translocation breakpoints. In such
cases, as in CML, the translocation causes an oncogene formed by the fusion of two
normal genes and generation of hybrid protein that induces the cells to undergo malignant
transformation. As scientist identify hybrid gene products at translocation sites, and
abnormal gene product can be inactivated by developing the therapeutic strategies, and
this is found only in cancerous cells.
In the case of CML, a drug Gleevec
TM
has been designed. The first task in this progress is
to find out the structure of the hybrid BCR/ABL gene product. Once the information was
known, it was possible to formulate an effective drug which adhere and inactivate the
hybrid gene, which is produced only in CML-associated cancerous white blood cells. The
success of this exercise has developed interest in preparing drugs for other diseases
associated with hybrid gene.
Aneuploidy
Aneuploidy is the addition or the loss of one or more chromosomes from the complete
diploid chromosome set of an organism. The organisms with such chromosome are known
as aneuploids, which means “not a good set” and it is due to imperfect meiosis in a
parent cell. A complete chromosome set is euploidy, which means “good set”. Most
autosomal aneuploids are found in spontaneous abortions and it makes clear the
chromosomal mutation. The surviving individuals have specific syndromes and symptoms
depending on which chromosomes are missing or extra. Sex chromosome aneuploidy
usually produces less severe syndromes.
Number of abnormalities is produced but few of them survive to birth for example,
trisomies of chromosome 2, 16, and 22 are comparatively common in fetus but they do
not survive to birth. Aneuploids results from non-disjunction or some other abnormal
chromosomal separation at the time of meiosis/mitosis. Failure of chromosomal pair to
separate at anaphase of either the first or second meiotic division results in nondisjunction (Figure 15).
Figure 15: Extra and missing chromosomes-aneuploidy
This produces some gametes with two copies of one chromosomes and other gametes
have one less chromosome. During the fertilization when such gametes fuse, the zygote
has either 45 or 47 chromosomes, instead of the normal chromosome number 46.
Different trisomies are consistently caused by non-disjunction in offspring, at meiosis I or
II.
Numerical Abnormalities (Aneuploidy) in Autosomes: Most autosomal
aneuploids are not frequently observed in live births, due to the deadliness of large
imbalance of genetic material.
Value addition: Did you know?
Heading text: Comparing and contrasting Trisomies 13, 18, and 21
Body text: The descriptions of most common autosomal aneuploids among live births are
summarized in the table
Percent of Conceptions
Types of Trisomy
Incidence at Birth
That
Survive
1
Year
After Birth
13 (Patau)
1/12,500-1/21,700
<5%
18 (Edward)
1/6,000-1/10,000
<5%
21 (Down)
1/800-1/826
85%
Source:http://www.krivda.net/books/human_genetics._concepts_and_applications__12.3_abnormal_chromosome_number_92
Trisomy 21 (Down Syndrome): Down syndrome is the most commonly occurring trisomy
(chromosomal abnormality) in 1–2:1000 in human populations. It was described more than a
century back. It is caused due to mal-segregation of chromosome 21 in meiosis in gametogenesis
(Figure 16). The meiotic 1 error attribute 75% and 25% are attributed by meiosis 2 while in
paternal non-disjunction meiosis 2 errors predominate. These meiotic errors are caused due to
increased maternal age. Mitotic (post-zygotic) mal-segregation of chromosome 21 in early embryo
results in 5% of trisomy cases. A child suffering from Down syndrome shows the following
symptoms
1. Mentally retarded (with an IQ in the 20-to-50 range).
2. They have a broad, flat face.
3. The eyes have an epicanthic fold.
4. They are short stature.
5. Their short hands possess a crease across the middle.
6. They possess a large, wrinkled tongue (Figure 17).
“Females may be fertile and may produce normal or trisomic progeny, but males do not reproduce.
Mean life expectancy is about 17 years, and only 8 percent of persons with Down syndrome survive
past age 40 (Pierce, 2008).”
Figure 16: Karyotype of fetus showing Trisomy 21-Down
Syndrome
Source:
http://comd281-
summerwiki.wikispaces.com/Group+5++Down+Syndrome
Figure 17: Features of Down syndrome child
Source: http://www.lucinafoundation.org/birthdefects-trisomy21.html Displayed with permission
Trisomy 18 (Edward Syndrome): As the name indicates it is the trisomy of chromosome
18. 1 in 7000 newborn is reported with this syndrome and is the second most common
chromosomal abnormality (trisomy) (Goldstein and Nielsen, 1988). Individuals with trisomy 18 have
different medical complications which are more potentially life-threatening in the early life. 50% of
babies with this syndrome will be stillborn, baby boys have higher stillbirth rate than baby girls.
Individuals have many physical and mental problems. Other phenotypic characteristics are
“faunlike” ears, a small jaw, a narrow pelvis, and rocker bottom feet (Figure 18). Early death is
reported in almost all babies with trisomy 18.
Figure 18: Trisomy 18 (Edward Syndrome)
Source: http://www.lucinafoundation.org/birthdefects-trisomy18.html Displayed with permission
Trisomy 13 (Patau Syndrome): It is the third most common chromosomal defect
in newborns, with a prevalence at birth of about 1:29,000 (Goldstein and Nielsen, 1988).
This syndrome is found very rare, but as is the case with trisomy 18, the number of
newborns with the abnormality reflects only a small percentage of affected conception.
“The phenotypic syndrome of trisomy 13 includes a harelip (Cleft lip), the nose is often
malformed, and commonly the eyes are absent or small (Figure 19). A few individuals
have survived until adulthood, but they do not show any progress in development beyond
the six month level.
Figure 19: Patau Syndrome (Trisomy 13)
Source: http://www.trisomy13archive.com/images/ella11-08b.jpg Displayed with permission
Numerical Abnormalities (Aneuploidy) in Sex Chromosome: Individuals
having sex chromosome aneuploidy, have an extra or missing chromosome. Table 2 shows
how these aneuploids can develop. These alternation results from nondisjunction during
oogenesis or spermatogenesis producing two types of eggs, XX and O, or two types of sperms
XY and O (O is absence of X or Y). Fertilization of abnormal gamete by a normal gamete
results in genetic imbalance, which produces genetic disorders in the affected individuals. The
common disorders are given below in table 3:
Table 3: How Nondisjunction cause the sex chromosome Aneuploids.
Situation
Normal
Female
disjunction
non-
Oocyte
Sperm
Consequence
X
Y
46, XY normal male
X
X
46, XX normal female
XX
Y
47,XXY
XX
X
syndrome
Y
47, XXX triple-X
Klinefelter’s
X
45, Y nonviable
45,X,Turner syndrome
Male
non-
disjunction
X
X
45,X Turner syndrome
XY
(meiosis I)
47,
XXY
Klinefelter
syndrome
Male
X
XX
47, XXX triple-X
Non-disjunction
X
XY
47,XYY, Jacobs syndrome
(meiosis II)
X
45,X Turner syndrome
Turner Syndrome (45, XO): This syndrome occurs when the zygote have only one X
chromosome its genotype is XO (i.e., monosomy X). Individuals with this syndrome sometimes
have only part of an X chromosome, with certain structural alteration in an X, and mosaics
also present in the remaining cases. It occurs in about 1 in 2,500 to 5,000 births. It is the
most reported chromosomal abnormality among spontaneous abortions. If embryo survives to
birth, these girls’ show typical growth patterns like short stature, and often have distinctive
webbed necks (i.e., extra folds of skin), small jaws, and high arched palates (Figure 20).
Figure 20: Picture of a girl suffering from Turner syndrome before and
after the operation for the webbing of neck.
Source: https://en.wikipedia.org/wiki/File:Neck_Turner.JPG
Secondary sexual characteristics did not develop as they one X chromosome. They have
exceptionally small, widely spaced breasts, broad shield-shaped chests, and turned-out
elbows. Poorly developed ovaries and do not ovulate. Few oocytes produced are destroyed by
the age of two. They are in a sense postmenopausal from early childhood and are sterile.
However, they can become pregnant and give birth if fertilized eggs from a donor are
implanted. They are more prone to thyroid disease, vision and hearing problems, heart
defects, diabetes, and other autoimmune disorders. Early diagnosis of this condition in
childhood and hormonal therapy can increase their stature by a few inches. Hormonal therapy
at the normal age of puberty can result in some breast development and menstruation. Turner
syndrome women treated will appear relatively normal (Pierce, 2005).
Extra X chromosomes: It is a sex chromosome abnormality in male and was first
described in 1942 by Dr. Harry Klinefelter. Affected individuals may have three (48,XXXY) or
four (49,XXXXY) X chromosomes. “About 80% of boys with Klinefelter syndrome will have
47,XXY in all cells of the body. About 6% will show a normal chromosome complement i.e.
46,XY in some cells and 46,XXY in the others (mosaicism). In 5% of cases there is a
46,XX/47,XXY mosaic pattern and in the remainder, three or four X chromosomes or other
arrangements of an X chromosome.” It is characterized by hypogonadism, testicular atrophy,
azoospermia and a eunuchoid body with a lack of male secondary sexual characteristics. It
occurs approximately 1 in 1000 male births (Pierce, 2005) (Figure 21).
Figure 21: Signs and symptoms of Klinefelters syndrome.
Source:https://www.andrologyaustralia.org/wpcontent/uploads/Klinefelters_WEB.jpg
For
educational and non-commercial use only
XYY Syndrome: XYY males have an extra Y chromosome. These "super-males" are usually
tall (above 6 feet), light weight compared to stature, have larger craniofacial areas. Their
appearance and behavior is normal although they have high levels of testosterone. They often
are slender, have severe facial acne during adolescence. They are usually fertile and lead
ordinary lives as adults. 1 in 1000 male births is reported with this condition. XYY syndrome is
also known to as Jacobs syndrome.
Figure 22: XYY Syndrome
Source: https://upload.wikimedia.org/wikipedia/commons/b/b9/XYY.jpg
Monoploidy
Monosomy is defined as “the loss of one chromosome which produces a 2n - 1
complement.” Monosomy only for the X chromosome have been reported in humans, (45,
XO Turner syndrome), whereas monosomy for the autosomes is untolerated both in
humans or other animals. Drosophila flies exhibiting monosomy for the chromosome IV
develop very slowly, have a reduced body size, and impaired viability. But monosomy for
the larger autosomal chromosomes II and III is probably lethal because these flies have
never been recovered. The question is why don’t the monosomic individuals survive
although a single copy of every gene is present in the individual? The probable reason is
the presence of certain genes having a lethal allele on the remaining chromosome, which
result in the death of the organism. Thus, monosomy unmasks recessive lethal alleles
which are otherwise tolerated in heterozygotes due to the presence of the corresponding
wild-type alleles. The second probable reason for lethality due to monosomy is the
insufficient gene product encoded by a single copy of a recessive gene which is unable to
sustain the organism. This phenomenon is known as haploinsufficiency.
Figure 23: Turner’s Syndrome
Source: http://www.lucinafoundation.org/birthdefects-turnerssyndrome.html displayed
with permission
Aneuploidy is somehow better tolerated in plants although these plants are less viable
than their corresponding diploid derivatives. Examples of plants monosomic for autosomal
chromosomes are maize, tobacco, evening primrose (Oenothera), and the jimson weed
(Datura).
Polyploidy
Polyploidy refers to the failure of separation of chromosomal sets in meiosis or mitosis that
result in the presence of more than two chromosomal sets. Polyploids are triploids (3n)
tetraploids (4n), pentaploids (5n), and even higher numbers of chromosome sets. Polyploidy is
commonly observed in plants and sometimes results in evolution of new plant species with
better yield. 40% of angiosperm species and from 70% to 80% of Graminae are found to be
polyploids and include a number of agriculturally important crops, such as wheat, oats, cotton,
potatoes, and sugar cane. It is less common in animals, but is found in animals, such as fishes,
salamanders, frogs, and lizards although it occurs in some tissues, especially in the liver. A
polyploid organism containing odd numbers of chromosome sets does not produce genetically
balanced gametes therefore, triploids, pentaploids, and so on, are commonly absent in plant
species depending only on sexual reproduction for their propagation. Polyploidy is of two types:
autopolyploidy,
where
all
the
chromosome
sets
are
from
the
same
species;
allopolyploidy, “allo” means different i.e. chromosome sets from two or more species.
and
Figure
22:
The
above
diagram
depicts
the
possible
origin
and
propagation of an amphidiploid organism.
Source:
https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Haploid,_diploid_,triploid_and_t
etraploid.svg/2000px-Haploid,_diploid_,triploid_and_tetraploid.svg.png
Autopolyploidy
The autopolyploids contain multiple sets of chromosomes each of which is identical to the
parent species. Autotriploids arise in a number of ways.
a) The failure of all chromosomes to segregate during meiosis gives rise to a diploid gamete
which when fertilized by a haploid gamete, the resulting zygote has three sets of
chromosomes.
b) A triploid zygote may result due to the chance fertilization of an ovum by two sperms.
c) Triploids can be generated experimentally by crossing diploids with tetraploids.
The autotetraploids (4n) have an even number of chromosomes, and produces genetically
balanced gametes therefore are more likely to be found in nature in comparison to the
autotriploids. Theoretically, if chromosomes undergo replication, but the parent cell fails to
divide and enters interphase, it results in the doubling of the chromosome number.
Autotetraploids can be produced experimentally from diploid cells by the application of a cold or
heat shock to the meiotic cells.
Addition of colchicine to somatic cells actively undergoing
mitosis prevents the replicated chromosomes from separating during anaphase by interfering
with spindle formation. Upon removal of colchicine the cell can reenter interphase during which
the paired sister chromatids separate and uncoil. Thus, the nucleus now has four sets of
chromosomes giving rise to autotetraploids (4n).
Generally the autopolyploids are larger in size than the diploids. The flower and fruit of
polyploidy plants are large in size, increasing their horticultural or commercial value.
Economically important triploid plants are propagated asexually and include Solanum
tuberosum, Winesap apples, commercial bananas, seedless watermelons, and tiger lily (Lilium
tigrinum). Diploid bananas have hard seeds, while the commercial triploid bananas have edible
seeds. The tetraploid plants such as alfalfa, coffee, peanuts, and McIntosh apples are of
economic value because either they are large in size or show robust growth in comparison to
their diploid or triploid counterparts. The commercial available strawberry is an octoploid.
Figure 22: Example of triploid plants is Tiger Lily
Source: https://c1.staticflickr.com/9/8429/7636338820_51a4d83f8a_b.jpg CC
Allopolyploidy
Polyploidy also occurs when two closely related species are hybridized. For example, when a
haploid ovum belonging to species A (with chromosome sets AA) is fertilized by a sperm from a
species B with chromosomal sets BB, it results in the generation of a hybrid AB. Such a hybrid
plant is generally sterile because it is unable to produce viable gametes as not all the “a” and
“b” chromosomes are not homologous to each other and thus cannot synapse in meiosis. But if,
the AB hybrid undergoes a natural or an induced chromosomal doubling, then two copies of
both a b chromosomes will be present. Thus, they will be able to pair during meiosis and
producea fertile AABB tetraploid (Figure 22). The polyploid that contains four haploid genomes
derived from separate species, is called as an allotetraploid. The term amphidiploid is used for
describing an allotetraploid when both original species are known. Although the amphidiploid
plants are commonly found in nature Amphidiploidy is rare in most animals as mating behavior
is species-specific, and therefore the initial step in hybridization rarely occur.
Figure
22:
The
above
diagram
depicts
the
possible
origin
and
propagation of an amphidiploid organism.
Source:
ILLL in house
An excellent example of amphidiploidy is the American cotton, Gossypium which has 26 pairs of
chromosomes. Upon careful examination it was found that it has 13 are large and 13 are
smaller sized chromosomes. The Old World cotton has 13 pairs of large chromosomes, while the
wild American cotton has 13 pairs of small chromosomes. Thus, amphidiploidy was suspected
which was confirmed by the experiment done by J. O. Beasley. He crossed the Old World strain
with the wild American strain and treated the resulting hybrid with colchicine. This led to the
doubling of the chromosome number and generation of a fertile amphidiploid having 26 pairs of
chromosomes and other characteristics of the cultivated variety of cotton, Gossypium.
Figure 22: Example of amphidiploidy is the American cotton, Gossypium
which has 26 pairs of chromosomes.
Source: http://bio3400.nicerweb.com/Locked/media/ch08/08_12-amphidiploid-cotton.jpg
Amphidiploids generally show the traits of both the parental species. Two interesting example,
from the plant kingdom are noteworthy. The first is that of Brassicoraphanus and the second is
of Triticale. A Russian agronomist, Georgi Dmitrievich Karpechenko experimentally crossed the
radish (Raphanus sativus) and the cabbage (Brassica oleracea). Both the species have 9 pairs
of chromosomes and therefore the hybrid formed consisted of nine Raphanus and nine Brassica
chromosomes (9R + 9B). Although majority of the hybrids were sterile, but some fertile
amphidiploids (18R + 18B) were produced. This experiment resulted in the generation of a
hybrid with no practical economic importance because the root of this hybrid plant is like that of
cabbage while its shoot is like that of radish. If the reverse had occurred, the hybrid would have
been of great economic importance.
The plant Triticale represents an example of a successful commercial hybridization between the
grasses wheat and rye. Both wheat (genus Triticum) and rye (genus Secale) has a haploid
genome consisting of seven chromosomes. In case of wheat in addition to normal diploids (2n
= 14), there exists cultivated autopolyploids such as the tetraploid (4n = 28) and hexaploid (6n
= 42) species. Whereas in case of rye only the diploid species is cultivated. When tetraploid
wheat was experimentally crossed with diploid rye and the resulting F1 plants are treated with
colchicine, a new hexaploid variety (6n = 42) is obtained. This hybrid was designated as
Triticale, a new genus. Fertile hybrids obtained from different wheat and rye species have been
crossed or backcrossed which have helped in creating many varieties of the genus Triticale. The
Triticale species show characteristics of both wheat and rye and therefore, can significantly aid
in increasing grain production. For example, certain hybrids have a high-protein content found
in wheat along with high lysine content found in rye. The amino acid lysine is present in low
amount in wheat and therefore acts as a limiting nutritional factor. Wheat is a high-yielding
grain, while rye is known for its adaptability of growth in unfavorable environments.
Endopolyploidy
Endopolyploidy is defined as a condition where only some cells in a diploid organism are
polyploid. In these cells the chromosomes replicate repetitively but without nuclear division.
Examples of endopolyploidy include the stem and parenchymal tissue of apical regions of
flowering plants, vertebrate liver cell nuclei such as human nuclei containing 4n, 8n, or 16n
chromosomal sets. The guts of mosquito larvae are lined by cells having 16n ploidy, but during
the pupal stages, these cells undergo reduction divisions, attaining diploidy. An interesting
example is that of water strider Gerris, which shows wide variations in chromosome numbers in
different tissues. In the cells of the salivary glands there are some 1024 to 2048 copies of each
chromosome. Since the diploid number is 22, the nuclei of Gerris salivary gland cells may
contain more than 40,000 chromosomes.
Figure 22: Example of Endopolyploidy is water strider Gerris
Source:
https://upload.wikimedia.org/wikipedia/commons/1/1d/Water_strider_Gerris_lacustris.jpg
The exact role of endopolyploidy is not clear, but the probable reason could be the requirement
for high levels of certain gene products. Certain genes product are required in large amounts
during development therefore, multiple copies of such genes naturally exist in the genome.
Examples of such genes are the ribosomal and transfer RNA genes. Sometimes even this
strategy may prove effective enough to provide sufficient amount of a particular gene product,
therefore it might be necessary for the entire genome to replicate thereby providing an even
greater rate of gene expression.
Summary
Cytogenetics is the study of chromosome aberrations and their effects on phenotype.
Mutations can occur at the chromosomal level. Deletion and duplication can result from
crossing over after pairing errors in synapsis and leads to abnormal chromosome
structure. Crossing over in an inversion heterozygote can also generate deletions and
duplications.
In
Robertsonian
translocation,
the
short
arms
of
two
acrocentric
chromosomes break, and the long arms join forming an unusually large chromosome. In a
reciprocal translocation, two non-homologous chromosomes exchange parts. In both types
of translocation, a translocation carrier may have an associated phenotype if the
translocation disrupts a vital gene. A translocation carrier also produces predictable
percentage of unbalanced gametes, which can lead to birth defects and spontaneous
abortions. Besides, there are a number of abnormalities in the chromosome numbers.
Aneuploids have extra or missing chromosome. Trisomies (an extra chromosome) are less
harmful than monosomies (lack of chromosome) and sex chromosome aneuploidy is less
severe than autosomal aneuploidy. Nondisjunction is uneven division of chromosomes in
meiosis which causes aneuploidy.
Most autosomal aneuploidy ceases development of
embryos. The most common at birth are trisomies 21, 13, and 18, because they are genepoor.
Sex chromosome anomalies such as XXY; 45, XO; XXX; XYY are less severe.
Polyploid cells have extra chromosome sets.
Questions
Q.1. Differentiate between:
(a) Robertsonian translocations and reciprocal translocation.
(b) Deletion and deficiency.
(c) Inversion and translocation.
(d) Pericentric and paracentric inversion
(e) Down’s and Turner’s syndrome.
(f) Balanced and Unbalanced rearrangement.
Q.2. Explain the following:
(a) Trisomy 13.
(b) Trisomy 18.
(c) Translocation.
(d) Down’s syndrome.
(e) Mutations.
(f) cri du chat syndrome.
Q.3. Answer the following question in short:
(a) Name the human disorder produced by the lack of one sex chromosome.
(b) Which disorder is caused in man by presence of one extra sex chromosomes?
(c) Give an account of Turner syndrome.
(d) Name three genetic disorders of different kinds found in man. Describe any one.
Q.4. Answer the following question in detail:
(a) What is aneuploidy? What are the conditions caused by the aneuploidies?
(b) Down syndrome is caused by trisomy for 21-chromosome. A few cases of Down syndrome
are reported with 46-chromosomes? How?
(c) What is the cause of Down’s syndrome?
(d) Polyploidy has played an important role in the evolution of plants whereas it has been
insignificant in case of animals. Discuss.
(e) Differentiate between autopolyploids and allopolyploids.
Glossary
Anaphase: The stage of mitosis when centromere of replicated chromosomes part.
Aneuploid: A cell with one or more extra or missing chromosomes.
Centromere: Chromosomal region to which the spindle fibers attach during mitosis or meiosis.
It appears as a constriction at metaphase. It contains chromosome-specific repetitive DNA
sequences.
Chromatid: A single, very long DNA molecule and its associated proteins forming half of a
replicated chromosome.
Chromosomal mosaic: An individual in whom some cells have a particular chromosomal
anomaly, and other do not.
Cytogentics: A discipline that matches phenotype to detectable chromosomal abnormalities.
Deletion: A missing sequence of DNA or part of a chromosome.
Deletion loop: The pairing of chromosomes during meiosis the unpaired region generated by a
deletion results in formation of a deletion/compensation loop.
Dicentric: A chromosome that is abnormal because it has two centromeres.
Diploid cell: A cell containing two sets of chromosomes.
Duplication: An extra copy of a gene or DNA sequence, usually caused by misaligned pairing
in meiosis; a chromosome containing repeats of part of its genetic material.
Gamete: A sex cell.
Gene: A sequence of DNA that instructs a cell to produce a particular protein.
Haploid cell: A cell containing one set of chromosome (half the number of chromosomes of
somatic cell).
Inversion: A defect in the chromosome in which a segment of the chromosome breaks off and
is
reinserted
in
the
same
place
but
in
the reverse direction
relative
to the
rest
of the chromosome.
Karyotype: A chart that displays chromosome pairs in the order of size.
Meosis: A type of cell division that takes place during gamete formation in which chromosomal
number is halved to form haploid gametes.
Mitosis: Division of somatic (nonsex) cells.
Mutation: A change in a protein encoding gene (that has an effect on the phenotype).
Non-disjunction: The unequal partitioning of chromosomes into gametes during meiosis.
Pachytene: The third stage of the prophase of meiosis during which the chromosomes become
shorter and thicker and divide into chromatids.
Paracentric inversion: An inverted chromosome that does not include the centromere.
Pericentric inversion: An inverted chromosome that includes the centromere.
Phenotype: The expression of a gene in traits or symptoms.
Prophase: The first stage of mitosis and meiosis when chromatin condenses.
Pseudogenes: A gene that does not encode protein, but whose sequence very closely
resembles that of a coding gene.
Reciprocal
translocation:
A
chromosome
aberration
in
which
two
non-homologous
chromosomes exchange parts, conserving genetic balance but rearranging genes.
Robertsonian translocation: A chromosome aberration in which two short arms of nonhomologous chromosomes break and the long arms fuse, forming one unusual, large
chromosome.
Translocations: Exchange of genetic material between non-homologous chromosomes.
Trisomy: A human cell with 47 (one extra) chromosomes.
References/Suggested Books
1. Klug WS, and Cummings MR. 2006. Concepts of Genetics. 7th Edition. Pearson Education
Pte. Ltd.
2. Klug WS, and Cummings MR. 2010. Concepts of Genetics. 10th Edition. Pearson Education
Pte. Ltd.
Useful Weblinks

http://upload.wikimedia.org/wikipedia/commons/c/cb/Translocation-4-20.png

http://upload.wikimedia.org/wikipedia/commons/thumb/9/9d/Deletionvectorized.svg/30
0px-Deletion_vectorized.svg.png

http://zlgc.seu.edu.cn/jpkc/2010jpkc/jykc2/Content/jxzy/genetics/chapt13/photo_librar
y/text_photo_library/13_04.jpg

http://www.mun.ca/biology/scarr/MGA2-11-24smc3.jpg

http://classconnection.s3.amazonaws.com/89/flashcards/754089/jpg/robertsonian_tran
slocation1350956515002.jpg

http://bio3400.nicerweb.com/Locked/media/ch08/08_01-nondisjunction.jpg

http://i681.photobucket.com/albums/vv177/akucic_biology/downsyndromekaryotype.jp
g

http://www.turmericforhealth.com/turmeric-benefits/turmeric-benefits-for-downsyndrome

http://img.medscape.com/fullsize/migrated/496/393/adnc496393.fig8.jpg

http://www.trisomy13archive.com/images/ella11-08b.jpg

http://www.sanpatricio.co.uk/Innexins/inxpicviewer.php?thebigpic=35

https://en.wikipedia.org/wiki/File:Neck_Turner.JPG

https://pathologyproject.wordpress.com/2012/01/22/klinefelter-syndrome-2/

Chromosomal Mutations Lesson: Chromosomal Mutations Lesson

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