Molecular Anthropology Genetics Research Tutorial 1 gen155/lectures/restut.ppt.
Lectures 12 - 13 Genetics of Human Disease: Hemoglobinopathies November 7 - 8, 2002.
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Transcript of Lectures 12 - 13 Genetics of Human Disease: Hemoglobinopathies November 7 - 8, 2002.
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Lectures 12 - 13
Genetics of Human Disease: Hemoglobinopathies
November 7 - 8, 2002
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Learning Objectives
• Understand how the basic anatomy of a gene has a direct bearing on the occurrence of genetic disease.
• Know the normal and abnormal expression patterns of the hemoglobin genes.
• Understand the mutations that cause quantitative abnormalities in globin.– Unequal crossing over, and every other possible type
of mutation• Recognize mutations that cause qualitative
abnormalities in globin.– Missense mutations primarily
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Textbook Figure 5.2
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Textbook Figure 6.3
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Textbook Figure 6.2
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Textbook Figure 6.4
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Textbook Figure 6.5
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Textbook Figure 6.14
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Textbook Figure 6.15
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Textbook Figure 6.16
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α-thal is almost always related to unequal crossing over or deletions.
Rarely, loss of function of an α-globin gene arises from point mutations, but in contrast to β-thal, these mutations are in the minority.
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Textbook Figure 6.15
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Textbook Figure 6.17
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Textbook Figure 6.12
Example of unequal crossing over as a mechanism of inactivating the β-globin gene.
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Textbook Figure 6.13
Unequal crossing over between δ and β genes…clinically leads to a combined quantitative and qualitative abnormality (Lepore).
Notice that individuals with an anti-Lepore chromosome make normal amounts of δ and β , but also make the novel anti-Lepore hemoglobin.
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Textbook Figure 6.11
Loss of the normal termination codon near the end of β-globin gene
Loss of the normal termination codon near the end of -globin gene
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Textbook Figure 6.19
Mutations in the β globin promoter can give rise to β + thalassemia
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Textbook Figure 6.20
Splicing abnormalities lead to predictable phenotypes
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Textbook Figure 6.21
Most common cause of β+ thalassemia in Mediterranean is related to an abmormal splice acceptor site.
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Textbook Figure 6.22
Hgb E – this mutation gives rise to a quantitative abnormality (activation of a cryptic splice donor site) and a qualitative abnormality (missense mutation at codon 26)
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Textbook Figure 6.18
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Untreated β thalassemia
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Treatment of thalassemia major
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Textbook Figure 6.24
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Textbook Figure 6.25
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Textbook Figure 6.26
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NEJM 347: 1162-1168, 2002
10 large Pakistani families with hemoglobinopathies
5 large Pakistani families without hemoglobin disorders
All carriers & married couples with 2 carriers genetic counseling
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NEJM 347: 1162-1168, 2002
Half-solid symbols represent those who are heterozygous for β-thalassemia
Solid symbols represent those with β-thalassemia major
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• Average cost of Fe chelation therapy is $4,400, or 10 times the average annual income.
• Treatment costs for 1 year – currently 4% of government health-expenditures.
• 183 / 591 (31%) of persons in families with an index case tested were carriers
• All carriers reported using the information provided in counseling
• “Testing of extended families is a feasible way of deploying DNA-based genetic screening in communities in which consanguineous marriage is common.”
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Cao & Galanello, NEJM 347: 1202, 2002
Screening for β-thalassemia in Sardinia
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Summary
• Understand how the basic anatomy of a gene has a direct bearing on the occurrence of genetic disease.
• Know the normal and abnormal expression patterns of the hemoglobin genes.
• Understand the mutations that cause quantitative abnormalities in globin.– Unequal crossing over, and every other possible type
of mutation• Recognize mutations that cause qualitative
abnormalities in globin.– Missense mutations primarily