1MCB140 02-09-07 1“Simple Mendelian inheritance” in humansThe beginnings of complicationsMCB140 02-09-07 2Important distinction1. “Monogenic disorders” – human diseases whose etiology can in some more or less linear fashion be traced to a single-locus genetic lesion.2. Diseases with a “genetic component” or a “genetic predisposition” – disorders that mankind is known to be genetically polymorphic for (in terms of susceptibility) at multiple loci.3. All other disease (that may or may not be transcription based).MCB140 02-09-07 3A further distinction1. Phenomena affecting ploidy (e.g., aneuploidies such as Down, Edwards, Turner, Klinefelter).2. Phenomena affecting chromosome structure (e.g., translocations in leukemia).3. Phenomena affecting single loci (genes or relatively small chromosomal segments).MCB140 02-09-07 4Human “monogenic” disorders1. Help the patients (diagnose, cure, alleviate symptoms) and prospective parents (genetic counseling).2. Learn more about disease to learn about how the human genome works, and how genomes in general work.2MCB140 02-09-07 5 MCB140 02-09-07 6(A) Autosomal dominant; (B) autosomal recessive(C)X-linked recessive(D) X-linked dominant(E) Y-linked. MCB140 02-09-07 7Archibald Garrod (1902)Higher frequency of children with alkaptonuria (urine turns dark on standing and alkalinization) from consanguineous marriages.Why?“There is no reason to suppose that mere consanguinity of parents can originate such a condition as alkaptonuria in their offspring, and we must rather seek an explanation in some peculiarity of the parents, which may remain latent for generations…”http://www.esp.org/foundations/genetics/classical/ag-02.pdfMCB140 02-09-07 8Ah!“It has recently been pointed out by Bateson that the law of heredity discovered by Mendel offers a reasonable account of such phenomena. …”Garrod (1902) Lancet 2: 116.3MCB140 02-09-07 9Garrod (1902) Lancet 2: 116.MCB140 02-09-07 10Sickle-cell anemia – a brief history“In the western literature, the first description of sickle cell disease was by a Chicago physician, James B. Herrick, who noted in 1910 that a patient of his from the West Indies had an anemia characterized by unusual red cells that were sickle-shaped.”By 1923, it was realized the condition is hereditary.In 1949, Neel realized that patients with SCA are homozygous, and heterozygous carriers have a much milder condition (sickle cell trait).MCB140 02-09-07 11 MCB140 02-09-07 12Sickle cell anemiaNIH:“Sickle cell anemia is the most common inherited blood disorder in the United States, affecting about 72,000 Americans or 1 in 500 African Americans. SCA is characterized by episodes of pain, chronic hemolytic anemia and severe infections, usually beginning in early childhood.”4MCB140 02-09-07 13PleiotropySteinberg M. N Engl J Med 1999;340:1021-1030MCB140 02-09-07 14Linus Pauling, 1949: HbS has different charge!!MCB140 02-09-07 15V. Ingram, Nature 1956“On [the existing] evidence alone, it is not possible to decide whether the difference between the proteins, which is in any event small, lies in the amino-acid sequences of the polypeptide chains, or whether it lies in the folding of these chains leading to the masking of some amino-acid side chains.”V. Ingram (1956) Nature 178: 792.MCB140 02-09-07 16V. Ingram (1956)Nature 178: 792.The third most-famous experiment in the history of molecular biology• Digest Hb A and Hb S with trypsin (protease – cuts hemoglobin into ~30 peptides).• Separate resulting fragments by electrophoresis, and then by chromatography.• Trace the peptide map.5MCB140 02-09-07 17 MCB140 02-09-07 18V. Ingram (1956)Nature 178: 792.MCB140 02-09-07 19Correct“One can now answer at least partly the question put earlier, and say there there is a difference in the amino-acid sequence in one small part of one of the polypeptide chains. This is particularly interesting in view of the genetic evidence that the formation of hemoglobin S is due to a mutation in a single gene.”V. Ingram (1956) Nature 178: 792.MCB140 02-09-07 206MCB140 02-09-07 2111.7RFLP!!!MCB140 02-09-07 22MCB140 02-09-07 23Incomplete dominanceMCB140 02-09-07 247MCB140 02-09-07 25Well, you may think the world's black and whiteAnd you're dirty or you're cleanYou better watch out you don't slipThrough them spaces in betweenBruce Springsteen “Cross My Heart” MCB140 02-09-07 26Penetrance and expressivity“The terms penetrance and expressivity quantify the modification of the influence on phenotype of a particular genotype by varying environment and genetic background; they measure respectively the percentage of cases in which a particular phenotype is observed when the specific allele of a gene of interest is present and the extent of that phenotype.”MCB140 02-09-07 27Variable expressivityThe importance of genetic backgroundMCB140 02-09-07 28“Treatment Directed at the Relief of Symptoms – Painful Episodes”“In a given year, about 60 percent of patients with sickle cell anemia will have an episode of severe pain. A small minority of patients have severe pain almost constantly. These differences are one manifestation of the heterogeneity of this disease, which complicates the choice of treatment. Episodes of pain are sometimes triggered by infection, extreme temperatures, or physical or emotional stress, but more often they are unprovoked and begin with little warning.” Steinberg M. N Engl J Med 1999;340:1021-10308MCB140 02-09-07 29Calling Michael Crichton “Gene for …”?!“Patients who are homozygous for the sickle hemoglobin mutation can present with remarkably different clinical courses, varying from death in childhood, to recurrent painful vasoocclusive crises and multiple organ damage in adults, to being relatively well even until old age. Increasing numbers of genetic loci have now been identified that can modulate sickle cell disease phenotype, from nucleotide motifs within the beta-globin gene cluster, to genes located on different chromosomes. With recent success of the human genome project, it is anticipated that many more genetic modifiers of sickle cell disease will be discovered that can lead to the development of more effective therapeutic approaches. The multigenic origin of the variable phenotype in sickle cell disease will serve as a paradigm for the study of variation in phenotypes of all single gene disorders in man.”Curr Opin Pediatr. 2001 Feb;13(1):22-7.MCB140 02-09-07 30The ob
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