浙江大学医学院：《遗传学》课程教学资源（PPT课件）复杂性状和疾病的遗传学 Genetics of Complex Traits and Diseases

Genetics of Complex Traits and diseases 张咸宁 zhangxianning@zju.edu.cn Tel:13105819271;88208367 Office: A705, Research Building 2012/09

Genetics of Complex Traits and Diseases 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A705, Research Building 2012/09

Genetic Susceptibility易感性 An inherited predisposition to a disease or disorder which is not due to a single-gene cause and is usually the result of a complex interaction of the effects of multiple different genes, l.e. polygenIc inheritance

Genetic Susceptibility易感性 • An inherited predisposition to a disease or disorder which is not due to a single-gene cause and is usually the result of a complex interaction of the effects of multiple different genes, i.e. polygenic inheritance

Any disease is the result of the combined action of genes and environment Classification of genetic disorders 1. Chromosome disorders 2. Single-gene disorders 3. Complex (multifactorial. polygenic) disorders: 4. Somatic cell genetic disorders: 5. Mitochondrial genetic disorders

Any disease is the result of the combined action of genes and environment Classification of genetic disorders: 1. Chromosome disorders: 2. Single-gene disorders: 3. Complex (multifactorial, polygenic) disorders: 4. Somatic cell genetic disorders: 5. Mitochondrial genetic disorders:

ABO Rhesus blood hemolytic Hirschsprung adu group disease disease stature Mendelian polygenIc (monogenic Figure 3.1 Human Molecular Genetics, 4ed (o Garland Science) ABO blood group depends (with rare exceptions) on the genotype at just one locus, the AB0 locus at chromosome 9q34 rhesus hemolytic disease of the newborn depends on the genotypes of mother and baby at the RHD locus at chromosome 1p36, but also on mother and baby's being aBo compatible. Hirschsprung disease depends on the interaction of several genetic loci. Adult stature is determined by the cumulative small effects of many loci. Environmental factors are also important in the etiology of rhesus hemolytic disease, Hirschsprung disease, and adult height

• ABO blood group depends (with rare exceptions) on the genotype at just one locus, the ABO locus at chromosome 9q34. Rhesus hemolytic disease of the newborn depends on the genotypes of mother and baby at the RHD locus at chromosome 1p36, but also on mother and baby's being ABO compatible. Hirschsprung disease depends on the interaction of several genetic loci. Adult stature is determined by the cumulative small effects of many loci. Environmental factors are also important in the etiology of Rhesus hemolytic disease, Hirschsprung disease, and adult height

Why study the genetics of common diseases? Understanding the underlying genetics will lead to understanding the causes, which may lead to better and more specific therapies Identification of the responsible genes helps to identify those who are at risk in families and in the population, allowing individualized health assessment and targeted prevention

Why study the genetics of common diseases? • Understanding the underlying genetics will lead to understanding the causes, which may lead to better and more specific therapies • Identification of the responsible genes helps to identify those who are at risk in families and in the population, allowing individualized health assessment and targeted prevention

How to Determine the Genetic Components of Complex Diseases? Family, twin and adoption studies Segregation analysis Linkage analysis Association studies and linkage disequilibrium Identification of DNA sequence variants conferring susceptibility

How to Determine the Genetic Components of Complex Diseases? • Family, twin and adoption studies • Segregation analysis • Linkage analysis • Association studies and linkage disequilibrium • Identification of DNA sequence variants conferring susceptibility

Trait: Any detectable phenotypic property or character Qualitative trait: A genetic disease trait that either present or absent. The pattern of inheritance for a qualitative trait is typically monogenetic, which means that the trait is only influenced by a single gene Quantitative trait: are measurable characteristics such as height, blood pressure, serum cholesterol, and body mass index. a quantitative trait shows continued variation under the influence of many different genes

• Trait: Any detectable phenotypic property or character. • Qualitative trait: A genetic disease trait that either present or absent. The pattern of inheritance for a qualitative trait is typically monogenetic, which means that the trait is only influenced by a single gene. • Quantitative trait: are measurable characteristics such as height, blood pressure, serum cholesterol, and body mass index. A quantitative trait shows continued variation under the influence of many different genes

Quantitative trait: Normal distribution Height · Weight Shape Color Blood pressure metabolic activit reproductive rate Polygenes: small-but-equal effect QtL(quantitative trait loci)

Quantitative trait:Normal distribution • Height • Weight • Shape • Color • Blood pressure • metabolic activity • reproductive rate Polygenes: small-but-equal effect QTL (quantitative trait loci)

Successive approximations to a Gaussian Distribution: OTL (A)One loc (B)Two loci AaBb BB AAB aaBb 100 110 120 AaBBCC 70 110 120 (C)Three loci (D)Many loci AABBCC 708090100110120130 100 110 120

Successive Approximations to a Gaussian Distribution: QTL

Aa Genotypes A Short Tall aabb aBb aaBS A2BB AA66 abb AaBb AAb Abb Genotypes Short Tall 是 Tall carey et al: Medical Genetics, 4th Edition