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Genetics 1-csbrp
The document discusses genetic disorders and provides information on their incidence, causes, and examples. Some key points: - 2-3% of births result in congenital or genetically determined abnormalities. By age 25, around 5% of individuals will have a genetic disorder. - Examples of genetic disorders discussed include Down syndrome (trisomy 21), Fragile X syndrome, Marfan syndrome, and Klinefelter syndrome. - Genetic disorders can be caused by numerical chromosome abnormalities like trisomy or monosomy, or structural abnormalities such as translocations, deletions, duplications, inversions, and mutations.
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Genetics 1-csbrp
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- 2. Incidence of genetic disorders Weall carry genes that are potentially hazardous: 1. Some manifest even before our birth 2. Some are recessive 3. Some will be triggered by environment A working party of the Royal College of Physicians has estimated that 2-3% of births result in babies with either congenital or genetically-determined abnormalities.
- 3. Incidence of genetic disorders ~5%of individuals will develop some form of genetic disorder by the age of 25 years The lifetime risk of genetic diseases is estimated to be 670 per 1000
- 4. Some facts <2%of the human genome codes for proteins >½ represents blocks of repetitive nucleotide codes whose functions remain mysterious Humans have a 30,000 genes Any two individuals share 99.9% of their DNA sequences Humans differ from chimps by 1% genetic uniqueness
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- 6. Genetic Disorder Advancesin Molecular biology involving recombinant DNA technology Molecular basis of human diseases Functional Cloning - Classical Positional Cloning Production of human biologically active agents Eg. Growth hormone, Erythropoietin. Gene therapy Disease diagnosis
- 8. Karyotype Study ofchromosomes A karyotype is used to display the number, types and appearance of chromosomes Human somatic cell – 46 chromosomes 22 pairs of autosomes 2 sex chromosomes Diploid numbers – 2N
- 9. Karyotype Male –46, XY Female – 46, XX Human Germ cells – Haploid cells –N 23 chromosomes Sperms – 23 X or 23 Y Ovum – 23 X
- 10. Karyotype - preparation& analysis 1. Cells (from blood, amniotic fluid, etc) are grown in vitro to increase their number 2. Cell division is then arrested in metaphase with colchicine 3. Cells are centrifuged and lysed to release chromosomes 4. Chromosomes are stained, photographed, and grouped by size and banding patterns
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- 12. Karyotype Chromatid - Anarm of a chromosome Centromere is the place where two chromatid meet each other TelomereTelomere – is the distal end of chromosome
- 13. Karyotype Based onthe location of centromere chromosome grouped into 4 types – Metacentric – Central centromere Submetacentric - Short arm (p) , Long arm (q) Acrocentric – Eccentric centromere Telocentric
- 15. Karyotype Each armis divided into 2 or more regions Each region is divided into bands and sub bands They are numbered from centromere outwards ex. Xp 21.2
- 17. Karyotype Banding techniquesfor karyotype study G Banding – Giemsa stain (400 – 800 bands) Q Banding – Quinacrine florescent stain R Banding – Reverse Giemsa stain C Banding Based on the length of chromosomes they are divided into 7 groups – A to G (Denver classification)
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- 19. Numerical abnormality Diploid– 46 (2N) Haploid – 23 (N)
- 20. Numerical abnormality Polypoidy– No. of chromosomes which is EXACT multiple of haploid numbers • Triploid – 3N (69 ch) • Tetraploid – 4N (92 ch) Aneuploidy – No of chromosomes which is not an exact multiple of haploid numbers Monosomy – 45 Ch - 45 XO (Turner’s) Trisomy – 47 Ch - 47 XY + 21 (Down’s)
- 21. Name a normalcell with polyploidy? Megakaryocyte
- 22. Mechanism of Aneuploidy Non disjunction – Failure of chromosome to separate normally during cell division result in monosomy or trisomy Anaphase lag - One chromosome fail to reach the pole of dividing cell at the same time and is left out of nucleus of daughter cell Mosaicism – Individual has 2 or more types of cell lines derived from same zygote ex. cancers
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- 27. Structural abnormalities Translocation– Transfer of a segment of one chromosome to another non- homologous chromosome 1. Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11) 2. Robertsonian translocation
- 28. Structural abnormalities - Translocation Balancedtranslocation
- 29. Structural abnormalities 2. Robertsoniantranslocation – When two acrocentric chromosome lose their short arm and fuse at the centromere so that eventually the cell is left with 45 chromosomes.
- 30.
- 31. Structural abnormalities Translocation: Ex:Acute Myelogenous Leukemia Philadelphia chromosome t(9,22)
- 32. Structural abnormalities Deletion Loss of part of the DNA from a chromosome. Deletion may be from terminal portion/ Middle portion
- 33. Deletion – Terminal deletionof short arm
- 34. Deletion – Terminal deletionof long arm
- 35.
- 36. Can you giveone best example for deletion resulting in disease? Alfa-Thalassemia
- 37. Structural abnormalities Ring chromosome:When both ends of a chromosomes are lost and the damaged ends join together, they form Ring chromosomes
- 38.
- 39. Diseases in whichring chromosomes are seen include: Some tumors of adipose tissue Fanconi’s anemia
- 40. Structural abnormalities Duplications: Ex:Fragile X syndrome The most common form of mental retardation The X chromosome have over 700 repeats due to duplications (Normal upto 29) Affects 1:1500 males, 1:2500 females
- 41. Structural abnormalities Duplications: Ex:Fragile X syndrome
- 42. Structural abnormalities Isochromosomeformation result when the centromere divides in a tranverse plane rather than in a normal long axis of the chromosome Ex. One with 2 short arms & one with 2 long arms
- 43.
- 44. Structural abnormalities Inversion:Rearrangement that involves two breaks within a single chromosome with reincorporation of inverted segment Paracentric Pericentric
- 45. Inversion – (long arm) ParacentricPericentric
- 46. Mutation Permanent changein the DNA Mutation in germ cell – Inherited diseases Mutation in somatic cells – Cancer, congenital malformation
- 47. Mutation Genomic Mutation– Monosomy/ trisomy Chromosomal Mutation – rearrangement of genetic material with visible structural changes in chr. Gene Mutation – Submicroscopic 1. Point mutation 2. Frame shift mutation
- 48. Mutation Point mutation– single nucleotide base is substituted by different base. e.g. sickle cell disease – glutamic acid replaced by valine at 6th position from the aminoterminal of beta globin chain of Hemoglobin
- 49. Mutation Frame shiftmutation One or two base pairs may be inserted/ deleted from the DNA, leading to alterations in the reading frame of the DNA strand
- 50. Frameshift Mutation (1-2 bp(s)deletion) (1-2 bp(s) insertion)
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- 54. Down’s Syndrome Trisomy21, 47 XY + 21 Most common chromosomal disorder 1 in 700 live births Due to non disjunction Or Robertsonian translocation Parents – Normal karyotype Risk factor Mother over 35 years
- 55. The fertilization ofa genetically abnormal egg carrying an extra chromosome 21 (orange) by a normal sperm (green) produces an embryo with Down syndrome (purple).
- 56. Trisomy 21 --Down’s syndome
- 57. Click to seeanimation on Non- Disjunction
- 58. Down’s Syndrome ClinicalFeatures Major cause of mental retardation IQ 25-50 Very gentle, shy & friendly Diagnosed at birth by “mongol” look – Flat facial profile, oblique palpebral fissure, epicanthic folds 40 % of patients – CHD ASD, Ostium primum, A-V valve malformation, VSD
- 60. Down’s syndromeDown’s syndrome NormalMongols Down’s baby With Mongoloid look
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- 62. Down’s syndromeDown’s syndrome Normalhand Simian crease
- 63. Down’s syndromeDown’s syndrome SimiancreaseSimian crease
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- 68. Down’s Syndrome AcuteLeukemia – 10 to 20 fold ^ risk Alzheimer’s disease < 40 years of age Abnormal immune response – Infection Simian crease, Hypotonia, Umbilical hernia
- 69. Down’s Syndrome AcuteLeukemia – 10 to 20 fold increased risk Transient MyeloproliferativeTransient Myeloproliferative SyndromeSyndrome
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- 73. Marfan’s syndrome Normal : Tricuspidvalve : Pulmonary valve : Aortic valve : Mitral valve Marfan’s
- 74. Marfan’s syndrome Aortic aneurysmand Aortic dissection
- 75. Chromosomes 23 1 23 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y
- 76. first meiotic division:prophase: leptotene normal trisomy 21 chromosome 21 other chromosomes © 2003 H. NUMABE M.D.
- 77. second meiotic division:second polar bodies normal trisomy 21 chromosome 21 other chromosomes © 2003 H. NUMABE M.D.
- 78. Marfan’s syndrome Autosomal dominantfibrillin-1(FBN1) gene mutation
Editor's Notes
- #3 Incidence of genetic disorders We all carry genes that are potentially hazardous. Some are hidden in recessive form and we may never know that we carry them. Some will only exert their influence through interactions with environmental triggers. Others are manifest from or even before our birth. A working party of the Royal College of Physicians has estimated that 2-3% of births result in babies with either congenital or genetically-determined abnormalities. This means that approximately 13 000 births a year in the UK are so affected. Some conditions manifest themselves later in life. 5.5% of the population will have developed a genetic condition by age 25. Later in life, this figure rises to approximately 60% if we include conditions in which genetics plays some role. The incidence of many Mendelian disorders varies from one ethnic group to another. The highest frequency of sickle cell anaemia is to be found in populations with a mid-African background, for example. Cystic fibrosis is most common amongst North Europeans and their descendants. The figures presented below represent UK populations in general. Furthermore, the list is restricted to conditions caused by single gene defects. Many comparatively common Mendelian forms of blindness, deafness and mental retardation are probably caused by a number of different genes. Late onset conditions are probably underestimated in the figures below as diagnosis at an early stage is often missed. &lt;http://www.gig.org.uk/education3.htm&gt;
- #4 Genetic disorders in children and young adults: a population study. P A Baird, T W Anderson, H B Newcombe, and R B Lowry Department of Medical Genetics, University of British Columbia, Vancouver, Canada. --------------------------------------------------------------------------------- Am J Hum Genet. 1988 May; 42(5): 677–693. --------------------------------------------------------------------------------- The data base of an ongoing population-based registry with multiple sources of ascertainment was used to estimate the present population load from genetic disease in more than 1 million consecutive live births. It was found that, before approximately age 25 years, greater than or equal to 53/1,000 live-born individuals can be expected to have diseases with an important genetic component. This total was composed of single-gene disorders (3.6/1,000), consisting of autosomal dominant (1.4/1,000), autosomal recessive (1.7/1,000), and X-linked recessive disorders (0.5/1,000). Chromosomal anomalies accounted for 1.8/1,000, multifactorial disorders (including those present at birth and those of onset before age 25 years) accounted for 46.4/1,000, and cases of genetic etiology in which the precise mechanism was not identified accounted for 1.2/1,000. Previous studies have usually considered all congenital anomalies (ICD 740-759) as part of the genetic load, but only those judged to fit into one of the above categories were included in the present study. Data for congenital anomalies are therefore also presented separately, to facilitate comparison with earlier studies. If all congenital anomalies are considered as part of the genetic load, then greater than or equal to 79/1,000 live-born individuals have been identified as having one or other genetic disorder before approximately age 25 years. These new data represent a better estimate of the genetic load in the population than do previous studies. &lt;http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1715177&gt;
- #5 The draft sequence of the human genome is complete and much has been learned about the &quot;genetic architecture&quot; of humans. Some of what has been revealed was quite unexpected.[2] For example, we now know that less than 2% of the human genome codes for proteins, whereas more than one half represents blocks of repetitive nucleotide codes whose functions remain mysterious. What was totally unexpected was that humans have a mere 30,000 genes rather than the 100,000 predicted only recently. Quite remarkably, this figure is not much greater than that of the mustard plant, with 26,000 genes! However, it is also known that by alternative splicing, 30,000 genes can give rise to greater than 100,000 proteins. In addition, very recent studies indicate that fully formed proteins can be sliced and stitched together to give rise to peptides that could not have been predicted from the structure of the gene.[2a] Humans are not so poor, after all. Another surprising revelation from the recent progress in genomics is that, on average, any two individuals share 99.9% of their DNA sequences. Thus, the remarkable diversity of humans is encoded in about 0.1% of our DNA. The secrets to disease predisposition and response to environmental agents and drugs must therefore reside within these variable regions. Although small as compared to the total nucleotide sequences, this 0.1% represents about 3 million base pairs.
- #6 With the completion of the human genome project, a new term, called genomics, has been added to the medical vocabulary. Whereas genetics is the study of single or a few genes and their phenotypic effects, genomics is the study of all the genes in the genome and their interactions. DNA microarray analysis of tumors ( Chapter 7 ) is an excellent example of genomics in current clinical use.[3] However, the most important contribution of genomics to human health will be in the unraveling of complex multifactorial diseases (discussed later) that arise from the interaction of multiple genes with environmental factors.[4] Just as genomics involves the study of all the DNA sequences, proteomics concerns itself with the measurement of all proteins expressed in a cell or tissue. First, however, we clarify several commonly used terms—hereditary, familial, and congenital. Hereditary disorders, by definition, are derived from one&apos;s parents and are transmitted in the germ line through the generations and therefore are familial. The term congenital simply implies &quot;born with.&quot; Some congenital diseases are not genetic; for example, congenital syphilis. Not all genetic diseases are congenital; patients with Huntington disease, for example, begin to manifest their condition only after their twenties or thirties. --------------- HEMIZYGOUS: Males are said to be &quot;hemizygous&quot; for any X-chromosome genes, meaning that there are only half (&quot;hemi&quot;) as many alleles as normally present for a diploid individual. As a consequence, if males (but not females) inherit an X-linked recessive trait from their mothers, they display the recessive phenotype. ---------------
- #7 Much of the progress in medical genetics has resulted from the spectacular advances in molecular biology, involving recombinant DNA technology. The details of these techniques are well known and are not repeated here. Some examples, however, of the impact of recombinant DNA technology on medicine are worthy of attention. • Molecular basis of human disease: Two general strategies have been used to isolate and characterize involved genes ( Fig. 5-1 ). The functional cloning, or classic, approach has been successfully used to study a variety of inborn errors of metabolism, such as phenylketonuria and disorders of hemoglobin synthesis. Common to these genetic diseases is knowledge of the abnormal gene product and the corresponding protein. When the affected protein is known, a variety of methods can be employed to isolate the normal gene, to clone it, and ultimately to determine the molecular changes that affect the gene in patients with the disorder. Because in many common single-gene disorders, such as cystic fibrosis, there was no clue to the nature of the defective gene product, an alternative strategy called positional cloning, or the &quot;candidate gene,&quot; approach had to be employed. This strategy initially ignores the biochemical clues from the phenotype and relies instead on mapping the disease phenotype to a particular chromosome location. This mapping is accomplished if the disease is associated with a distinctive cytogenetic change (e.g., fragile-X syndrome) or by linkage analysis. In the latter, the approximate location of the gene is determined by linkage to known &quot;marker genes&quot; or SNPs that are in close proximity to the disease locus. Once the region in which the mutant gene lies has been localized within reasonably narrow limits, the next step is to clone several pieces of DNA from the relevant segment of the genome. Expression of the cloned DNA in vitro, followed by identification of the protein products, can then be used to identify the aberrant protein encoded by the mutant genes. This approach has been used successfully in several diseases, such as cystic fibrosis, neurofibromatosis, Duchenne muscular dystrophy (a hereditary disorder characterized by progressive muscle weakness), polycystic kidney disease, and Huntington disease. In addition to this step-by-step approach to cloning single genes, cDNA microarray analysis allows simultaneous detection of thousands of genes and their RNA products. When normal and diseased tissues are analyzed in this fashion, changes in the expression levels of multiple genes can be detected, thus providing a more comprehensive profile of genetic alterations in diseased tissues. • Production of human biologically active agents: An array of ultrapure biologically active agents can now be produced in virtually unlimited quantities by inserting the requisite gene into bacteria or other suitable cells in tissue culture. Some examples of genetically engineered products already in clinical use include soluble TNF receptor for blocking TNF in treatment of rheumatoid arthritis, tissue plasminogen activator for the treatment of thrombotic states, growth hormone for the treatment of deficiency states, erythropoietin to reverse several types of anemia, and myeloid growth and differentiation factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) to enhance production of monocytes and neutrophils in states of poor marrow function. • Gene therapy: The goal of treating genetic diseases by transfer of somatic cells transfected with the normal gene, although simple in concept, has yet to succeed on a large scale. Problems include designing appropriate vectors to carry the gene and unexpected complications resulting from random insertion of the normal gene in the host genome. In recent well-publicized cases, gene therapy in patients with x-linked SCID (severe combined immunodeficiency, Chapter 6 ) who lack the common γ chain of cytokine receptors had to be put on hold because the transduced gene inserted next to a host gene that controls proliferation of cells. The resulting dysregulation gave rise to T-cell leukemia in the patient. • Disease diagnosis: Molecular probes are proving to be extremely useful in the diagnosis of both genetic and non-genetic (e.g., infectious) diseases. The diagnostic applications of recombinant DNA technology are detailed at the end of this chapter.
- #8 A simple example of how a desired gene is inserted into a plasmid. In this example, the gene specified in the white color becomes useless as the new gene is added.
- #11 Karyotype preparation and analysis: Cells (from blood, amniotic fluid, etc) are grown in vitro (in a cell culture dish) to increase their number Cell division is then arrested in metaphase with colchicine (prevents mitotic spindle from forming) Cells are centrifuged and lysed to release chromosomes Chromosomes are stained, photographed, and grouped by size and banding patternsThis is a photograph of the 46 human chromosomes in a somatic cell, arrested in metphase. Can you see that they are duplicated sister chromatids? 2. Normal male karyotype (a Cytogeneticist has lined these chromosomes up, matching homologues up and arranging them by size)
- #12 Figure 5-20 Normal male karyotype with G banding.
- #13 Each chromosome is composed of pair of double helix of chromosomal DNA called chromatid.
- #17 Figure 5-21 Details of banding pattern of the X chromosome (also called &quot;idiogram&quot;). Note the nomenclature of arms, regions, bands, and sub-bands. On the right side, the approximate locations of some genes that cause disease are indicated.
- #19 Figure 5-20 Normal male karyotype with G banding.
- #25 Origins of monosomy and trisomy. (a) During mitotic metaphase or meiotic metaphase II, one pair of sister chromatids does not align at the equatorial plane. Consequently, both sister chromatids move to the same cell. One daughter cell will show trisomy and another daughter cell will have monosomy. (b) During meiotic metaphase I, two homologous pairs of sister chromatids do not align at the equatorial plane and subsequently move to the same cell (a phenomenon called nondisjunction). The resulting daughter cells also have either monosomy or trisomy.
- #27 Inversion, Deletion and Ring Structure Two breaks in a single chromosome can cause inversion, deletion or ring structure as shown in the figure. Chromosomal abnormality resulting from two breaks in a single chromosome. Inversion: The segment between two breakpoints is inverted before resealing the breaks. Deletion: The breaks reseal without including the segment between breakpoints. Examples: cri-du-chat syndrome and William&apos;s syndrome. Ring chromosome: Two ends of the segment between breakpoints are joined to form a circular structure.
- #28 Translocation – Transfer of a segment of one chromosome to another non-homologous chromosome Balanced translocation – When two fragments of chromosomes exchange materials without any loss of genetic materials. ex. Philadelphia chromosome – t(9:22) (q34:q11)
- #30 Robertsonian translocation is caused by breaks at the centromeres of two nonhomologous acrocentric chromosomes (chromosomes with centromeres near their ends, e.g., chromosome 13, 14, 21, and 22). After the breaks, the long arms of two chromosomes join together to form a single chromosome. The short arms may join to form another chromosome, but it is usually lost within a few cell divisions. Therefore, the karyotype of a person with Robertsonian translocation usually exhibits only 45 chromosomes.
- #32 Translocation: a fragment of a chromosome is moved (&quot;trans-located&quot;) from one chromosome to another - joins a non-homologous chromosome. The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment. Can also cause difficulties in egg or sperm development and normal development of a zygote. Acute Myelogenous Leukemia is caused by this translocation.
- #41 Fragile X: the most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip - seen &quot;hanging by a thread&quot; under a microscope. Most people have 29 &quot;repeats&quot; at this end of their X-chromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females.
- #42 Fragile X: the most common form of mental retardation. The X chromosome of some people is unusually fragile at one tip - seen &quot;hanging by a thread&quot; under a microscope. Most people have 29 &quot;repeats&quot; at this end of their X-chromosome, those with Fragile X have over 700 repeats due to duplications. Affects 1:1500 males, 1:2500 females.
- #55 Mechanism: Due to non disjunction during meiosis in one of the parents In addition to the trisomy 21 mentioned above, the Down&apos;s syndrome may also be caused by Robertsonian translocation, in which the long arm of chromosome 21 is attached to another chromosome, usually chromosome 14 or itself.
- #62 Palpebral slant The direction of the slant of a line drawn from the outer corner of the eye to the inner corner is known as the palpebral slant. The most commonly recognized syndrome associated with an abnormal palpebral slant is Down&apos;s syndrome.
- #66 An abnormal crease is seen on the hand of this baby with trisomy 21 (Down syndrome). A single transverse crease extends transversely across the palm. There is also just a single flexion crease on the fifth finger, a feature seen in about 20% of babies with Down syndrome. Note: There is an increased risk of Trisomy 21 in individuals with only 11 ribs. If you measure out the long bones of the limbs, the humeri and femurs come out to be relatively shorter than the middle segments in Down syndrome, and the middle phalanges of the fifth fingers will be hypoplastic or unmineralized in Down Syndrome. If you have any of these other findings, IUGR, or other anomalies, you should get a karyotype. Galen Schauer &lt;Galen.Schauer@kp.org&gt; Kaiser Permanente, Oakland CA.
- #67 Characteristic Palmar Features in Down&apos;s Syndrome Cheiromorphognomy: - short, broad palms with short fingers - short Air fingers (55% cases) (normally only found in 5% hands) - clinodactyly of Air finger (55% of cases) (normally only found in 6% of hands) - single interphalangeal crease on Air finger (26%) (virtually never seen normally) - hyperflexive lower thumb joint (77%) (normally only found in 28% of hands) - Simian lines commonly present (53%) (normally only found in 1-2% of hands)
- #70 Transient Myeoloproliferative Syndrome: Seen in Down’s patients which resembles acute leukemia, but reverses to normalcy on it’s own. With such recurrent events the patient’s may land in acute leukemia – AML.
- #72 [Original image] Cover design: The front cover of Human Reproduction: shows the results of fluorescence in-situ hybridization analyses of a Klinefelter syndrome patientÕs spermatozoa and spare preimplantation embryos using DNA probes specific for chromosomes X (green) Y (red) and 18 (aqua). An abnormal sperm nucleus XY18 is shown (top left) along with abnormal nuclei from one chaotic embryo: XXYY1818 (top right), X1818 (bottom left), Y18 (bottom right). The frequency of sex chromosome hyperploidy in the spermatozoa of the Klinefelter patient was higher than normal. Only 3 out of the 10 spare embryos were normal for the chromosomes tested.