MCB140 02 09 07 1 MCB140 02 09 07 3 1 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 A further distinction The beginnings of complications Simple Mendelian inheritance in humans MCB140 02 09 07 4 2 Learn more about disease to learn about how the human genome works and how genomes in general work 1 Help the patients diagnose cure alleviate symptoms and prospective parents genetic counseling Human monogenic disorders MCB140 02 09 07 2 1 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 Important distinction 1 MCB140 02 09 07 7 Garrod 1902 Lancet 2 116 MCB140 02 09 07 8 It has recently been pointed out by Bateson that the law of heredity discovered by Mendel offers a reasonable account of such phenomena 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 pdf Ah MCB140 02 09 07 6 Archibald Garrod 1902 MCB140 02 09 07 5 E Y linked D X linked dominant C X linked recessive B autosomal recessive A Autosomal dominant 2 Garrod 1902 Lancet 2 116 MCB140 02 09 07 11 MCB140 02 09 07 9 MCB140 02 09 07 12 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 NIH Sickle cell anemia MCB140 02 09 07 10 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 Sickle cell anemia a brief history 3 V Ingram 1956 Nature 178 792 MCB140 02 09 07 15 V Ingram 1956 Nature 178 792 MCB140 02 09 07 16 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 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 MCB140 02 09 07 14 The third most famous experiment in the history of molecular biology MCB140 02 09 07 13 Linus Pauling 1949 HbS has different charge V Ingram Nature 1956 Steinberg M N Engl J Med 1999 340 1021 1030 Pleiotropy 4 V Ingram 1956 Nature 178 792 MCB140 02 09 07 19 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 Correct MCB140 02 09 07 17 V Ingram 1956 Nature 178 792 MCB140 02 09 07 20 MCB140 02 09 07 18 5 11 7 Incomplete dominance MCB140 02 09 07 23 MCB140 02 09 07 21 RFLP MCB140 02 09 07 24 MCB140 02 09 07 22 6 The importance of genetic background MCB140 02 09 07 27 Bruce Springsteen Cross MCB140 My Heart 02 09 07 25 Variable expressivity Through them spaces in between You better watch out you don t slip And you re dirty or you re clean Well you may think the world s black and white Steinberg M N Engl J Med 1999 340 1021 1030 MCB140 02 09 07 28 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 Treatment Directed at the Relief of Symptoms Painful Episodes MCB140 02 09 07 26 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 Penetrance and expressivity 7 MCB140 02 09 07 29 MCB140 02 09 07 31 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 Calling Michael Crichton Gene for The ob mouse The importance of the environment and genetic background Variable penetrance MCB140 02 09 07 32 MCB140 02 09 07 30 8 A plot of carefully measured phenotype in large pool of genetically identical individuals grown
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