Simple Mendelian inheritance in humans The beginnings of complications MCB140 09 14 07 1 MCB140 09 14 07 2 Important distinction 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 Well you may think the world s black and white And you re dirty or you re clean You better watch out you don t slip Through them spaces in between Bruce Springsteen Cross MCB140 My Heart 09 14 07 3 A further distinction MCB140 09 14 07 4 Human monogenic disorders 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 MCB140 09 14 07 5 1 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 MCB140 09 14 07 6 1 A Autosomal dominant B autosomal recessive C X linked recessive D X linked dominant E Y linked MCB140 09 14 07 7 MCB140 09 14 07 8 Sickle 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 Garrod 1902 Lancet 2 116 MCB140 09 14 07 9 MCB140 09 14 07 10 Sickle cell anemia NIH 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 MCB140 09 14 07 11 MCB140 09 14 07 12 2 Linus Pauling 1949 HbS has different charge Pleiotropy Steinberg M N Engl J Med 1999 340 1021 1030 MCB140 09 14 07 13 MCB140 09 14 07 14 The third most famous experiment in the history of molecular biology V 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 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 MCB140 09 14 07 15 V Ingram 1956 Nature 178 792 MCB140 09 14 07 16 MCB140 09 14 07 17 V Ingram 1956 Nature 178 792 MCB140 09 14 07 18 3 Correct 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 09 14 07 19 MCB140 09 14 07 20 RFLP MCB140 09 14 07 21 Incomplete dominance MCB140 09 14 07 22 Penetrance 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 09 14 07 23 MCB140 09 14 07 24 4 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 Variable expressivity The importance of genetic background MCB140 09 14 07 25 Steinberg M N Engl J Med 1999 340 1021 1030 MCB140 09 14 07 26 The ob mouse Calling 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 09 14 07 27 MCB140 09 14 07 28 Variable penetrance The importance of the environment and genetic background MCB140 09 14 07 29 MCB140 09 14 07 30 5 Hereditary breast cancer caused by mutations in BRCA1 is incompletely penetrant Risk of breast cancer and physical exercise in BRCA1 2 mutation carriers an example of how the norm of reaction illuminates the modification of a genetic tendency by environment Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset MCB140 09 14 07 31 M C King et al Science 2003 MCB140 09 14 07 32 Norm of reaction A plot of carefully measured phenotype in large pool of genetically identical individuals grown under a range of environments MCB140 09 14 07 33 Three mutants that affect facet D Rio UCB MCB140 09 14 07 34 Norm of reaction of different genotypes of the bar locus to temperature Note in general that wild
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