Transcript CYTOGENETICS AND MEDICAL GENETICS IN THE 1960s

Cytogenetics
SM Kalantar
Prof. Molecular Cytogenetic
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GENE
Mutated gene
(affacted gene)
Disease
Disease severity
Age at onset
Family history
Disease phenotype
Population group
differences
Family history test
or
physical examination
Phenotype - observable characteristics:·
Physical·
Biochemical·
Disease Status
Classification
• Three groups of genetic diseases
• 1. Disorders with multifactorial
inheritance (polygenic)
• 2. Monogenic (mendelian) disorders
• 3. Chromosomal aberrations
1) Single DNA strand.
(2) Chromatin strand (DNA with histones).
(3) Condensed chromatin during interphase with
centromere.
(4) Condensed chromatin during prophase. (Two
copies of the DNA molecule are now present)
(5) Chromosome during metaphase.
1.Chromatid. One of the two identical parts of the
phase
chromosome after S phase.
2.Centromere. The point where the two chromatids
touch, and where the microtubules attach.
3.Short arm.
4.Long arm.
•Cytogenetics is a relatively young science.
•The correct number of chromosomes in humans was
established less than 50 years ago
•The current explosion of knowledge in the field of
human and medical genetics is astonishing, with
discoveries being made monthly and sometimes
weekly.
•Progress has accelerated in the last few years, as a
result of the advent of the Human Genome Project,
whose goals include mapping all of the estimated
25,000 to 300,000 human genes and sequencing the
estimated 3 billion nucleotides in a haploid set of
chromosomes.
• The significance of Mendel’s contribution was
not recognized until 1900 when, within a twomonth period, Hugo de Vries of Amsterdam,
Holland,
• Carl Correns of Tubingen, Germany, and
Erich von Tschermak of Vienna, Austria,
rediscovered Mendel’s work during literature
searches in preparation for publication of their
own research.
• From that point onward, the pattern of nuclear
inheritance has been called “Mendelian.”
• Walter Fleming, professor of anatomy at Kiel, first
described chromosomes in 1876 and published
pictures of them in 1882.
• The term “chromosome,” derived from the Greek
word for “colored body,” was coined by Waldeyer in
1888
• The chromosomal basis of heredity was
discovered by William Sutton when he was still a
graduate student in genetics
• In 1909, Wilhelm Johannsen, a Danish biologist,
first coined the word “genes,” derived from the
Greek word for giving birth.
In 1914, Theodor Boveri proposed the somatic
mutation theory of cancer, which first suggested the
clonal origin of neoplasms Boveri proposed
that cancer developed from a single cell that acquires
a genetic alteration.
The elucidation of the structure of DNA as a double helix by
Watson and Crick occurred in 1953.
At that time, the number of human chromosomes was thought to
be 48. In 1956, Tjio and Levan exploited advances in tissue
culture, the use of colchicine to arrest cells in metaphase,
hypotonicity to disperse the chromosomes and to enhance the
quality of the cell preparation for study. Working with cultures of
embryonic fibroblasts, they first identified the correct number of
chromosomes
to be 46.
This finding was confirmed in the same year by Ford and
Hamerton using direct preparations of human testicular material.
By 1956 it was also known that a sexual dimorphism existed in the
interphase nuclei of humans.
A dense sex chromatin body is present in many cells of females, but
not in normal males.
In some conditions, notably Klinefelter syndrome and Turner
syndrome, the phenotypic sex is often at variance with the number
of chromatin bodies
However, in 1959 Jacobs and Strong found that individuals with
Klinefelter syndrome had an extra X chromosome in addition to the
X and Y chromosomes which normal males possess.
In 1959 Ford and colleagues found that Turner syndrome females
were missing one of the two X chromosomes which normal females
possess
These studies made it possible for researchers to conclude that the
genes on human Y chromosome was maledetermining and to deduce
the existence of a testis-determining factor (TDF).
Within a very short interval of time, the chromosomal bases for Patau
syndrome (trisomy D) and Edward syndrome (trisomy 18) were also
identified.
Another landmark discovery in cytogenetics during this era was the
demonstration of an extra G-group chromosome in Down syndrome
by Lejeune in 1959
This historic finding of trisomy 21 by Lejeune was described
by Hecht (16) in a short article after Lejeune’s death.
Despite the numerous advances cited above,
the discipline of medical genetics did not yet
exist as such nor as a recognized area of
specialization within the practice of medicine in
the United States.
Mark et al. (1995) pointed out, genetics was
still “an academic, ‘ivory tower’ topic far
removed from in-patient wards and out-patient
clinics.’
CYTOGENETICS AND MEDICAL GENETICS IN
THE 1960s
• Several areas began to converge into the
specialty of medical genetics in the early
1960s.
• A number of technical advances made this
process possible.
In 1960, Peter Nowell, a pathologist teaching at the University of
Pennsylvania at the time, discovered that phytohemagglutinin (PHA), a
crude powder extracted from the common navy bean, Phaseolus vulgaris,
and used to agglutinate red blood cells, also served as a mitogen for
lymphocytes
The same year, Moorhead and his colleagues
from Philadelphia described the technique for
culturing peripheral blood lymphocytes
that still serves as the basis for chromosome
studies on peripheral blood and
bone marrow all over the world.
A picture of Dr. Moorhead with his granddaughter, Annie Rose, more than 30 years after this fundamental discovery
In 1960, Nowell and Hungerford reported the first consistent
chromosomal abnormality associated with a single cancer
type, chronic myelogenous (or myeloid) leukemia (CML)
The marker chromosome was given the name Philadelphia
chromosome (Ph), in honor of the city where it was
discovered.
Also in 1960, the “Bar Harbor Course” at the Jackson Laboratory in
Bar Harbor, Maine, was initiated as the “Short Course in Medical
Genetics” where, under the leadership of Dr. Victor A. McKusick and his
colleagues, many medical geneticists, faculty, or both.
The course was supported exclusively by the National Foundation-March
of Dimes through 1984.
Although March of Dimes support has continued, the prominent support
in recent years has come from the National Institute for Child Health and
Human Development of the National Institutes of Health and from the
Lucille P. Markey Charitable Trust
The Denver conference for standardization of human
cytogenetic nomenclature, at which autosomes were
arranged in seven groups (A to G) based on size and
position of centromere, was also held in 1960
In 1966, the first edition of McKusick’s MendeEian
inheritance in Man was released, with 1487 entries.
The 12th edition of this document is currently in
preparation, and a continuously updated electronic version
is available through the Internet
the Chicago Conference on the standardization of
nomenclature in human cytogenetics was held
The designations p and q were adopted for chromosome
arms.
The first banding technique, developed in 1968, was Qbanding using quinacrine fluorescence
This was followed by Giemsa banding , C-banding, and
R-banding
Another notable cytogenetic finding in this
decade was the first description of the marker X
chromosome in 1969
This subsequently became known as the fragile
X chromosome, associated with mental
retardation, and was the subject of numerous
reports in the modern cytogenetic literature
CYTOGENETICS AND MEDICAL GENETICS IN
THE 1970s
• In the early 1970s, medical genetics
began to expand as a medical discipline
• in part as a result of expanding
opportunities for fellowship training,
notably with Dr. Victor McKusick in
Baltimore, Maryland, and with Dr. Arno
Motulsky in Seattle, Washington
The Paris conference was held in 19’71 to standardize
the nomenclature used in human cytogenetics, and
banding numerology was introduced.
Rowley was able to identify the Philadelphia chromosome as a
reciprocal translocation between chromosomes 9 and 22.
It is now known that this translocation, in which the c-abE oncogene at
9q34 is fused to the breakpoint cluster region (bcr) locus on
chromosome 22, results in a hybrid gene, which produces a fusion
protein with increased tyrosine kinase activity that predisposes to
myeloid cell transformation.
the Association of Cytogenetic Technologists (ACT) was born in 197’4,
Over the years, this organization has served the needs of cytogenetic
technicians, technologists, supervisors, managers and laboratory directors
A protocol for preparing prometaphase spreads and expanded
chromosomes
was described by Yunis in 1976
This high-resolution technique has been especially useful for the
detection of microdeletions.
It was also in the 1970s that Jacobs and his colleagues introduced the
first method for conducting direct chromosome analysis of human
spermatozoa by allowing them to fertilize hamster eggs
CYTOGENETICS AND MEDICAL GENETICS IN
THE 1980s
• Among the many scientific developments
in the 1980s, three notable ones
• related to the development of the specialty
of medical genetics.
First and
foremost, the American Board of Medical Genetics (ABMG) was formed in
1980 under the initial sponsorship of the American Society of Human Genetics
(ASHG). The first certifying examination was given in 198
Second,
commercial laboratories, especially those involved with cytogenetics, began
to appear and flourish.
Third, important advances in molecular genetics
touched all areas of biology. Restriction fragment length polymorphism
(WLP) (49) was recognized as an important tool to map the human
genome.
It was also during the 1980s that the polymerase chain reaction (PCR)
was
born in the redwood forests of California
The 1980s also saw the application of
recently developed molecular
diagnostic techniques for cytogenetics, from
the creation of DNA probes for
the identification and mapping of oncogenes
to the widespread use of fluorescent probes
for chromosome staining (FISH).
CYTOGENETICS AND MEDICAL GENETICS IN
THE 1990s
The Human Genome Project, launched in 1990, is
making excellent progress.
New and powerful techniques of molecular cytogenetics
are being developed, including comparative genomic
hybridization (CGH) and spectral karyotyping (SKY