Lecture Title PATHOLOGY

Dr. Who | August 1, 2017

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1.01
OUTLINE
I. Subtopic 1
A. Contents
1. Contents
II. Subtopic 2
A. Contents
1. Contents
III. References
IV. Quiz

LEGEND
Remember Book Lecturer Other Trans
Trans Comm Figure 1. Meiotic non-disjunction occurring in the mother (in
Meiosis I). In this case, the fathers normal sperm combines with the
mothers gamete containing an extra set of chromosomes, resulting in
OBJECTIVES trisomy. If the father's sperm had combined with the ovum lacking a
At the end of the lecture, the student should be able to: chromosome, this would result to a monosomy.
1. Master shadow clone jutsu
2. Learn how conquer the iron throne in Westeros

III. TYPES OF MUTATIONS

Genome Mutations
Whole chromosomes are lost
Only single nucleic acid mutations or several nucleic acids are
involved, not affecting the structure of your chromosomes.
Causes an abnormality in the chromosomal number
Due to non-disjunction or anaphase lag

Non-disjunction
Failure of the chromosome to separate in anaphase
If it occurs during gametogenesis (meiosis), the gametes
formed have either an extra chromosome or one less
chromosome.
Fertilization of such gametes by normal gametes results in two
Figure 1. Meiotic non-disjunction occurring in the mother (in
types of zygotes: trisomic of monosomic
Meiosis II). In this case, meiotic non-disjunction occurs in Meiosis II.
The difference in non-disjunction happening in Meiosis I vs Meiosis II is
that in non-disjunction in Meiosis II, there is still 50% chance of
producing normal daughter cells.

Non-disjunction may also occur during mitosis (after

Figure 1. Non-disjunction in the meiosis during gametogenesis.
The chromosome (encircled in red) fails to separate, producing one cell
with a double set (trisomy) and another with an absent chromosome
(monosomy).
fertilization), a condition referred to as mosaicism.
A mosaic is an individual wherein the chromosome numbers
are different from one part of the body to another (e.g. the
chromosome number of a cell from the left hand is different the
chromosome number of a cell from the right hand) indicating
that there is not just a single cell line.
In the division of the fertilized ovum, an error may lead to one
of the daughter cells receiving three sex chromosomes,
whereas the other receives only one, yielding for example, a
45, X/47,XXX mosaic.
An error in an early mitotic division affecting the autosomes
usually leads to a nonviable mosaic due to autosomal
monosomy.

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Ring chromosome
Produced when a break occurs at both ends of a chromosome
with fusion of the damaged ends
If significant genetic material is lost, phenotypic abnormalities
result.

Figure 1. Mitotic non-disjunction in a fetus. A few cells would be

monosomic whereas some would be trisomic. Happens during
embryogenesis.

NOTES:
Meiosis I/II Non-disjunction GAMETOGENESIS
Mitotic Non-disjunction - EMBRYOGENESIS
Inversion
Anaphase Lag 2 breaks in a single chromosome at the ends with
One homologous chromosome in meiosis or one chromatid in rearrangement of genetic material
mitosis lags behind and is left out of the cell nucleus. Paracentric inversion
A chromosome lags behind before the nuclear membrane is o Inversion involving one arm of the chromosome
formed. Pericentric inversion
Such that during the occurrence of cell membrane/ nuclear o If the breaks are on opposite sides of the centromere
membrane, that lagging chromosome is lost on the next cycle.

Isochromosome formation
One arm of a chromosome is lost and the remaining arm is
duplicated

Figure 1. Anaphase lag in a cell. This results to one normal cell

and one monosomic cell.

Chromosomal mutations
Change in the structure of chromosomes
Result from chromosome breakage followed by loss or
rearrangement of material Translocation
Severity of manifestation depends on the volume of genetic A segment of one chromosome is transferred to another
material lost Balanced reciprocal translocation
o There are single breaks in each of two chromosomes
Deletion o No lost of genetic material
Loss of a portion of a chromosome Robertsonian translocation
Mostly interstitial o Translocation between two acrocentric chromosome
o Two breaks WITHIN a chromosome arm,followed by loss o Transfer of segments leads to one very large
of the chromosomal material between the breaks and chromosome and one extremely small one (the small
fusion of the broken ends product is lost)
Rarely terminal
o Single break in a chromosome arm, producing a
fragment with no centromere. This fragment is lost at the
next cell division.

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IV. CAUSES OF MUTATIONS
Increasing age
Chromosomal instability
Ionizing radiation
Drugs
Viruses

V. IMPORTANT CANCER GENES

Oncogenes
o Mutant or overexpressed versions of proto-oncogenes
that function autonomously without a requirement for
normal growth promoting signals
o Promotes cancer
o Proto-oncogenes, on the other hand, are normal cellular
genes whose products promote cell proliferation.
Figure 14: BCR-ABL fusion gene, aka Philadelphia
Burkitts Lymphoma chromosome. The ABL gene is translocated from its normal abode
o The affected genes are MYC 8q24 and IGH 14q32 on chromosome 9 to chromosome 22 where it fuses with the BCR
o t(8;14)(q24;q32) gene.
o It is a very aggressive tumor of B cells that usually arises
at extra nodal sites Tumor suppressor genes
Form a network of checkpoints that prevent uncontrolled
Philadelphia chromosome growth
o First ever gene that was related to a malignancy They suppress cancer
o Translocation between chromosome 9 and 22
o Encodes a constitutively active, oncogenic BCR-ABL RB gene
tyrosine kinase Increased tyrosine kinase activity leads 13q14 (point mutation)
to increased production of transcription factors for Retinoblastoma (RB) protein
proliferation leading to uncontrolled mitosis. governor of the cell cycle
o Seen in CML (chronic myelogenous leukemia) Function: inhibitor of G1/S transition during cell cycle
o t(9;22) progression

WT-1 gene
11p13
Wilms tumor-1
Function: transcription factor

APC gene
5q21
Adenomatous polyposis coli protein
gatekeeper of colonic neoplasia

p53
17p13.1
guardian of the genome
Function: cell cycle arrest and apoptosis in response to
DNA damage

NF-1 gene
17q11.2
neurofibromin-1 protein
Figure 1. Spectral Karyotype showing translocation in Function: inhibitor of RAS/MAPK signaling
Philadelphia chromosome. A portion of chromosome 8 (pink) and
portions of chromosome 22 (yellow, green and blue) are transferred BRCA gene
to chromosome 9. 17q
Function: repair of double stranded breaks in DNA

DCC gene
18q21

VI. QUIZ
1. First ever gene that was related to a malignancy
a. RB gene
b. Philadelphia chromosome
c. BRCA gene
d. APC gene

2. Type of inversion mutation where the breaks are on the

opposite sides of the centromere

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a. Paracentric
b. Acrocentric
c. Pericentric
d. Metacentric

Answer key: B, C

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APPENDIX

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Column 1 Column 2 Column 3
Row 1 Row 1 and contents Row 1 and contents
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