* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download MULTIFACTORIAL DISORDERS
Genetic engineering wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Pathogenomics wikipedia , lookup
Essential gene wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Gene expression programming wikipedia , lookup
Medical genetics wikipedia , lookup
Transgenerational epigenetic inheritance wikipedia , lookup
Population genetics wikipedia , lookup
Genome evolution wikipedia , lookup
Human genetic variation wikipedia , lookup
Genomic imprinting wikipedia , lookup
History of genetic engineering wikipedia , lookup
Irving Gottesman wikipedia , lookup
Ridge (biology) wikipedia , lookup
Epigenetics of human development wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Minimal genome wikipedia , lookup
Gene expression profiling wikipedia , lookup
Birth defect wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Microevolution wikipedia , lookup
Genome (book) wikipedia , lookup
Public health genomics wikipedia , lookup
Designer baby wikipedia , lookup
Behavioural genetics wikipedia , lookup
Biology and consumer behaviour wikipedia , lookup
MULTIFACTORIAL DISORDERS Learning Objectives • • • Define multifactorial inheritance Define polygenic inheritance Enlist common diseases with multifactorial causes Terms • Polygenic traits are determined by two or more genes • Multifactorial traits are controlled by two or more genes and show significant interaction with the environment • Complex traits are ones where relative contribution of genes and environment are not yet established Polygenic Inheritance • • • • • Traits are usually quantified by measurement Two or more genes contribute to the phenotype Phenotypic variation varies across a wide range Better analyzed in populations than in individuals Example: human eye color As the number of loci increases, the number of classes increases • As classes increase, phenotypic difference between classes decreases • Averaging out of the phenotype is called regression to the mean. • • Multifactorial Traits Genotype does not change after fertilization (except by mutation) Phenotype is the sum of the observable characteristics and may change throughout life • Environment includes all genetic and nongenetic factors Characteristics of Multifactorial Traits • • • • Polygenic Genes controlling trait act additively Environmental factors interact with the genotype to produce the phenotype Assessing interactions can be difficult Methods Used to Study Multifactorial Traits • Threshold model Frequency of disorder among relatives is compared with the frequency of the disorder in the general population • Recurrence risk Estimates the risk that the disease will recurrance Threshold Model Familial Risk Phenotypic Variation Sources of phenotypic variation • Genotypes in the population • Variation in the environment Heritability – how much of the observed phenotypic variation is due to differences in genotype Factors that Contribute to Phenotypic Variance • • • Genetic variance Variance attributed to the genotypic differences Environmental variance Variance attributed to differences in the environment Correlation coefficients Measure the degree to which variables vary together Heritability of Fingerprints Twin Studies • Monozygotic twins – Single fertilization – Genetically identical • Dizygotic twins – Independent fertilizations – Share approximately half their genes Multifactorial inheritance • Inheritance controlled by many genes with small additive effects (polygenic) plus the effects of the environment • Clinical clue: One organ system affected Multifactorial inheritance • • Diseases that show familial clustering but do not conform to any recognized pattern of single gene inheritance are termed multifactorial disorders. They are determined by the additive effects of many genes at different loci together with the effect of environmental factors. Multifactorial inheritance: Factors increasing probability of recurrence in a particular family • • • • • Close relationship to proband High heritability of disorder Proband of more rarely affected sex Severe or early onset disease Multiple family members affected Multifactorial inheritance as a mode of inheritance for a condition is more likely if…… • • • • Condition is relatively common Incidence in relatives lower than for single gene disorder but higher than in general population Risks to sibs similar to that of children Incidence falls rapidly in more distant relatives • • • Incidence in relatives rises as the manifestations become more severe in the index case Risk to relatives higher when index case is of the least commonly affected sex Observed risk rises following the birth of two affected children Multifactorial traits • Genetic predisposition likely to be due to a particular combination of genes • The genes and environmental factors causing a particular multifactorial trait may vary from person to person • Most diseases with a genetic component are not inherited in Mendelian fashion but display multifactorial inheritance • Multifactorial disease usually polygenic -many genes each with small additive effects • Major effort to identify common disease susceptibility genes underway • Identification of SNPs associated with disease susceptibility. Examples of disorders of multifactorial inheritance • • • • • • A. Congenital malformations: congenital heart defects neural tube defects cleft lip/palate pyloric stenosis congenital hip dysplasia B. Common non-communicable diseases: asthma • • • schizophrenia diabetes mellitus hypertension Common diseases • Congenital malformations Cleft lip/palate Congenital hip dislocation Congenital heart defects Neural tube defects Pyloric stenosis Talipes Multifactorial • • • Examples include some cases of cleft lip and palate; neural tube defects; diabetes and hypertension Caused by a combination of genetic predisposition and environmental influences Pattern – more affected people in family than expected from incidence in population but doesn’t fit dominant, recessive or X-linked inheritance patterns. How can the probability of recurrence be determined for multifactorial disorders? • The recurrence risk for multifactorial disorders has to be determined through family studies • Observe the number of affected siblings in many families (empiric risk) How evidence is gathered for genetic factors in complex diseases • Familial risks (what is the incidence of a disorder in relatives compared with the incidence in the general population?) • Twin studies (what is the incidence in monozygotic compared with dizygotic twins?) • Adoption studies (what is the incidence in adopted children of the disorders which their parent had?) • Population and Migration studies (what is the incidence in people from a particular ancestry group when they move to a different geographical area?) Multifactorial traits • Several human characteristics show a continuous distribution in the general population, which closely resembles a normal distribution. This takes the form of a symmetrical bell-shaped curve distributed evenly about a mean. Polygenic inheritance • • This involves the inheritance and expression of a phenotype being determined by many genes at different loci, with each gene exerting a small additive effect. Additive implies that the effects of the genes are cumulative, i.e. no one gene is dominant or recessive to another. Polygenic / Multifactorial traits • A normal distribution (Gaussian or bell shaped curve) is generated by many genes, known as polygenes, each acting in an additive fashion. Conclusions • • Multifactorial disorders are more common than single gene and chromosomal disorders They are caused by the interaction of many genes with environmental • factors. Optimum preventive measures rely on avoidance of the bad environmental factors since avoidance of inheriting the bad genes is at present not possible. 4. These measures can be explained through counseling such as periconception and chronic noncommunicable diseases counseling. • Reference Kaplan Biochemistry and medical genetics