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Cytogenetics SM Kalantar Prof. Molecular Cytogenetic.

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1 Cytogenetics SM Kalantar Prof. Molecular Cytogenetic


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8 GENE Mutated gene (affacted gene) Disease Mutation to be altered the gene MG, to be alte red the mRNA, & the Product (Protein) A-T-C-C-G-T-C-A-C-G-G-T-A A-T-C-C-A-G-C-A-C-G-G-T-A al-val-luc-al al-val-val-al

9 Disease phenotype Family history test or physical examination Age at onset Disease severity Family history Population group differences

10 Phenotype - observable characteristics:· Physical· Biochemical· Disease Status

11 Classification Three groups of genetic diseases 1. Disorders with multifactorial inheritance (polygenic) 2. Monogenic (mendelian) disorders 3. Chromosomal aberrations


13 1) Single DNA strand. (2) Chromatin strand (DNA with histones). (3) Condensed chromatin during interphase with centromere.interphase (4) Condensed chromatin during prophase. (Two copies of the DNA molecule are now present)prophase (5) Chromosome during metaphase.metaphase

14 1.Chromatid. One of the two identical parts of the chromosome after S phase.S phase 2.Centromere. The point where the two chromatids touch, and where the microtubules attach. 3.Short arm. 4.Long arm. S phase

15 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.


17 The significance of Mendel’s contribution was not recognized until 1900 when, within a two- month 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.”

18 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.

19 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.

20 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.

21 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

22 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.

23 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.’

24 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.

25 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 A picture of Dr. Moorhead with his granddaughter, Annie Rose, more than 30 years after this fundamental discovery 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.

26 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.

27 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

28 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

29 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 Q- banding using quinacrine fluorescence This was followed by Giemsa banding, C-banding, and R-banding

30 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

31 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

32 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.

33 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

34 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.

35 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

36 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).

37 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

















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