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Polygenic and Multifactorial Disorders 4. Polygenic and Multifactorial Disorders 1 Single gene trait Environment GENE PHENOTYPE Other Genes 4. Polygenic and Multifactorial Disorders 2 Contribution of Genes or Environment • Genes rarely act completely alone • Environmental factors and other genes may modify expression • Traits can be described as – Mendelian or primarily due to a single gene – Polygenic or primarily due to multiple genes – Multifactorial or complex due to an interaction between genes and the environment 4. Polygenic and Multifactorial Disorders 3 Polygenic trait Environment Gene1 PHENOTYPE Gene 2 Gene 3 Gene 4 4. Polygenic and Multifactorial Disorders 4 Single gene diseases versus polygenic diseases Whereas the mutations causing single gene diseases have a major impact on the function of the gene product, and are therefore rare, those causing polygenic disease have a more moderate effect, and are therefore relatively common 4. Polygenic and Multifactorial Disorders 5 Polygenic trait characteristics • Common – Unlike single gene traits • Multi-gene involvement – Each gene has varying effects on trait occurrence and development • Often have major non-genetic influences – i.e. environmental factors • Unclear transmittance patterns 4. Polygenic and Multifactorial Disorders 6 Polygenic Traits • Variation is continuous, not discrete • Individual genes follow Mendel’s laws • Effect of genes is additive or synergistic • Also called quantitative trait loci (QTL) • Genes can have major or minor impacts Examples: – Height – Hair color – Body weight – Cholesterol levels 4. Polygenic and Multifactorial Disorders 7 Inheritance of Height (1920s) 4. Polygenic and Multifactorial Disorders 8 Inheritance of Height (1997) 4. Polygenic and Multifactorial Disorders 9 An Example of Variations in Eye Color • The number of human eye color genes is unknown • Analysis will probably reveal many genes • Mice have more than 60 eye color genes 4. Polygenic and Multifactorial Disorders 10 Multifactorial Traits • Are influenced by interaction of genes and by the environment • Examples: – Fingerprint, many genes and prenatal contact – Height, many genes and nutrition – Skin color, many genes and UV exposure 4. Polygenic and Multifactorial Disorders 11 Model for Variation in Skin Color 4. Polygenic and Multifactorial Disorders 12 Skin Color • Melanin production - skin pigmentation and protects skin from UV radiation • Skin color is a phenotype interaction between pigment genes + environment • In a genetic sense, race based on skin color has little meaning • Medical treatment differences/difficulties 4. Polygenic and Multifactorial Disorders Analyzing Multifactorial Traits • Difficult, requires multiple techniques • Use human genome sequences, population, and family studies • The frequency in a specific population = Empiric risk • The amount of inheritance due to genes = Heritability 4. Polygenic and Multifactorial Disorders 14 Empiric Risk of Cleft Palate The chance that a disease will occur in a family based upon experience (past history, medical records, etc.) rather than theory. 4. Polygenic and Multifactorial Disorders Heritability (H) Estimates the proportion of the phenotypic variation in a population due to genetic differences Heritability asks how much genetics are playing a role in differences in height between people. This is not the same as asking how much genetics usually cause height in any one person. 4. Polygenic and Multifactorial Disorders 16 4. Polygenic and Multifactorial Disorders Heritability: The proportion of total phenotypic variation in a population that is due to genetic variation, mathematically this is expressed as H2=Vg/Vp. the effects of one gene are modified by one or several other genes 17 Heritability Values • Heritability is estimated from the proportion of people sharing a trait compared to the proportion predicted to share the trait • May vary between populations and time period 4. Polygenic and Multifactorial Disorders 18 How does one initially assess whether such a disease has a genetic component? • Twin pair studies • Relative risk studies 4. Polygenic and Multifactorial Disorders 19 Analyzing Multifactorial Traits • Comparisons between and within families – Twins dizygotic and monozygotic – Twins raised apart – Adopted children 4. Polygenic and Multifactorial Disorders 20 Twin-pair studies 1 in 89 deliveries 1/3 Monozygotic 2/3 Dizygotic 4. Polygenic and Multifactorial Disorders 21 Separating Genes and Environment • Dizygotic twins: • Monozygotic twins: • Twins raised apart: • Adopted individuals: Shared environment and 50% of genes Identical genotype, and shared environment Shared genotype but not environment Shared environment but not genes 4. Polygenic and Multifactorial Disorders 22 Figure 7.7 Studies of twins reared apart suggest that they are remarkably similar 4. Polygenic and Multifactorial Disorders 23 Concordance • Concordance - the percentage of pairs in which both twins express the trait • Used to determine heritability 4. Polygenic and Multifactorial Disorders 24 % Concordance rates The presence of the same trait in both members of a pair of twins MZ DZ Cystic Fibrosis 100 25 Die on a Tuesday 14 14 Hypertension 30 10 Rheumatoid 30 Arthritis Type I diabetes (IDDM) 36 4. Polygenic and Multifactorial Disorders 5 5 25 Potential pitfalls (drawback) of twin pair studies • MZ twins are the same sex whereas 50% DZ twins aren’t – Remedy - use same-sex DZ twins • MZ twins often treated differently than DZ twins, which could influence behavioral traits – Remedy - study twins separated at birth (if enough!) • Intrauterine differences – MZ twins share more intrauterine tissues than DZ twins during gestation, making it difficult to distinguish intrauterine environmental causes from genetic causes • Bias of ascertainment – People often focus on twins who have strikingly similar behavioral traits but overlook those who don’t 4. Polygenic and Multifactorial Disorders 26 Coefficients of Relatedness for Pairs of Relatives Table 7.4 Figure 7.6 4. Polygenic and Multifactorial Disorders 27 Allele sharing in relatives Degree of relationship 2nd Percent shared genes 2nd 25% 25 2nd 25 0 1st 50 1st 50 1st 3rd 50 12.5 proband 4. Polygenic and Multifactorial Disorders 28 Allele sharing in sibs What is the frequency of disease in the siblings of affected individuals compared to the population frequency? Sibling recurrence risk ratio - s s = Risk to a sib Population prevalence 4. Polygenic and Multifactorial Disorders 29 Overall, twin pair and relative risk studies enable one to assess whether a common disease has a genetic component 4. Polygenic and Multifactorial Disorders 30 4. Polygenic and Multifactorial Disorders Two types of polygenic traits • Continuous – Also termed quantitative • Discontinuous – Also termed dichotomous or qualitative 31 4. Polygenic and Multifactorial Disorders 32 Continuous trait F R E Q U E N C Y Phenotype parameter i.e. Height , Blood pressure 4. Polygenic and Multifactorial Disorders 33 How do genes generate such a normal distribution? 4. Polygenic and Multifactorial Disorders 34 One locus with two alleles of equal frequency A - big effect a - small effect genotype frequency 1 Aa 70 80 0 2 aa AA 90 100 110 Trait measure Number of copies of a “big effect” allele 120 4. Polygenic and Multifactorial Disorders 130 35 genotype frequency Two loci with two alleles each 1 Aabb aaBb 2 AAbb AaBb aaBB 0 aabb 70 80 Number of copies of a “big effect” allele 3 AABb AaBB 4 AABB 90 100 110 Trait measure 120 4. Polygenic and Multifactorial Disorders 130 36 Three loci with two alleles each genotype frequency 3 2 1 0 AAbbcc AaBbcc AabbCc aaBbCc aabbCC aaBBcc AABbcc AAbbCc AaBbCc AabbCC 4 AaBBcc aaBBCc AABBcc aaBbCC AABbCc AAbbCC AaBbCC AaBBCc aaBBCC Aabbcc aaBbcc aabbCc Number of copies of a “big effect” allele 5 AABBCc AABbCC AaBBCC aabbcc 70 6 AABBCC 80 90 100 110 Trait measure 120 4. Polygenic and Multifactorial Disorders 130 37 genotype frequency Three loci with two alleles each 70 80 90 100 110 Trait measure 120 4. Polygenic and Multifactorial Disorders 130 38 Conclusion: genes can generate a continuous trait when they act together 4. Polygenic and Multifactorial Disorders 39 Discontinuous Traits • Yes/No characteristic • For example: colour mutations, birth defects, and common behavioral disorders. • The disease manifests once a certain threshold of susceptibility has been surpassed (exceeded) Threshold Model of Susceptibility 4. Polygenic and Multifactorial Disorders 40 Distribution of liability (responsibility) The threshold model is used to explain discontinuous traits. It simply states that the underlying variable has a continuous distribution (as shown by the graph), but the disorder does not appear until a certain threshold is reached (the dotted line). low liability Threshold unaffected average liability 4. Polygenic and Multifactorial Disorders affected high liability 41 Crossing the threshold A combination of the genes one has inherited and the exposure one has had to environmental risk factors 4. Polygenic and Multifactorial Disorders 42 Recurrence risk • Risk that a disease will occur elsewhere in a pedigree, given that at least one member of the pedigree exhibits the disease • RR increases as the number of affected family members increase 4. Polygenic and Multifactorial Disorders 43 Type II diabetes • Hyperglycaemia, developing in the adult – Pancreas produces insulin but cells are resistant • Polygenic disease with major environmental risk factors – High calorie intake and low exercise – Up to 10 times more prevalent in the obese • Prevalence is increasing as populations become “westernized” 4. Polygenic and Multifactorial Disorders 44 Type II diabetes and the thrifty gene hypothesis 4. Polygenic and Multifactorial Disorders 45 Type II diabetes and the thrifty gene hypothesis • Metabolically thrifty genes – Permit efficient food utilization, fat deposition and weight gain at occasional times of food abundance – Make the bearer able to survive periods of famine • Examples of thrifty genes include those resulting in high levels of insulin and leptin – Insulin - mediates the uptake of glucose by cells – Leptin - hormone released by fat cells that regulates appetite 4. Polygenic and Multifactorial Disorders 46 Pre-modern times Feast Famine Feast Survive Genes persist as they offer a survival advantage Modern times Feast Feast Premature death Genes lost? Frequency of disease will peak and then reduce? 4. Polygenic and Multifactorial Disorders 47