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Human Genetics

Human Genetics. Multifactorial Traits. Genes and the Environment. Genes and the environment interact to mold many of our traits. Mendelian trait due to a single gene. Polygenic trait due to multiple genes. Multifactorial trait results from action of

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Human Genetics

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  1. Human Genetics Multifactorial Traits

  2. Genes and the Environment

  3. Genes and the environment interact to mold many of our traits. Mendelian trait due to a single gene Polygenic trait due to multiple genes Multifactorial trait results from action of genes and the environment

  4. Discontinuous Variation • Phenotypesfall into two or more distinct non-overlapping classes • Example - short and tall phenotypes in pea plants • no in betweens

  5. Continuous Variation • Phenotypes distribute from one extreme to another in an overlapping (continuous) fashion. • Examples - height, skin color, eye color, intelligence

  6. Height is Continuous

  7. Except when it is Discontinuous

  8. Seven heights produced through the interaction of 3 genes

  9. Polygenic Traits • Polygenic Traits are produced by the action of multiple genes. • Variation is continuous, not discrete • Effect of genes is additive or synergistic • Also called quantitative trait loci (QTL) • Genes can have major or minor impacts

  10. QTL takes time and lots of chromosomal Markers. Nature Genetics31, 235 - 236 (2002) doi:10.1038/ng0702-235

  11. QTL is the First Step

  12. Congenital malformations Cleft palate Congenital dislocation of the hip Congenital heart defects Neural tube defects (spina bifida etc.) Pyloric stenosis Club Foot (Talipes) Adult onset diseases Osteoporosis Diabetes Mellitus Cancer Epilepsy Glaucoma Hypertension Ischaemic heart disease Manic depression Schizophrenia Diseases can be Polygenic

  13. Osteoporosis • Osteoporosis is defined as low bone mineral density (BMD) and associated fractures. • Osteoporosis causes morbidity and mortality in the elderly. • It has a significant genetic components that are largely unknown. • In Iceland, a linkage analysis in a large number of extended osteoporosis families in Iceland, (using a phenotype that combines osteoporotic fractures and BMD measurements) showed linkage to Chromosome 20p12.3.

  14. QTL on Chromosome 20 for Osteoporosis • Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, et al. (2003) Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol 1(3): e69

  15. Other QTLs for Osteoporosis in Humans

  16. Osteoporosis QTL Gene Identification • Three variants in the bone morphogenetic protein 2 (BMP2) gene, a missense polymorphism and two anonymous single nucleotide polymorphism haplotypes, were determined to be associated with osteoporosis in the Icelandic patients.

  17. Eye color: A polygenic trait? Five eye colors can be produced by the interaction of just two genes.

  18. Number of dominant alleles at two genes produces five phenotypes

  19. Polygenic Inheritance • Each allele for all the genes involved contributes to the expression of the trait • Not necessarily the same for each gene • Some alleles will make no contribution • Expressed trait is the sum of all the small contributions.

  20. Polygenic Inheritance Challenge • Phenotypic expression can vary over a wide range • Traits are often quantified by measurement rather than by counting. • Height- relatively easy • Eye Color- need instrumentation • Skin Color- Environmental component like tanning- use unexposed skin • Needs to analyzed populations rather than individuals.

  21. Multifactorial Traits • Traits produced through gene-gene interactions and gene interactions with environment factors. • What are “environmental factors”? Non-genetic factors • physical – pregnancy, obesity, diet • chemical - diet, smoking, alcohol , medicine • social - illness, stress • Age • How much of a given phenotype is genetic (inherited) and how much is environment?

  22. Multifactorial Traits - are influenced by genes and by the environment Many genes + Trait environment fingerprints prenatal touch height nutrition skin color sun exposure

  23. Fingerprints -Multifactorial Traits

  24. Height is influenced by genes and environment during growth 1997 Maximum 6’5” Improved nutrition can impact height.

  25. Empiric Risk • Based on incidence in a specific population. • Empiric Risk is a Statistic • Incidence is the rate a trait occurs- like number of new diagnoses • Prevalence is how common the trait is in the population a a particular time. • If a trait is inherited, the closer the relationship, the greater the risk.

  26. Empiric Risk • Empiric risk for an individual increases with •  severity of the disorder • number of affected family members • relatedness of the individual to the affected individual • We have to use the frequency of occurrence of the trait in a specific population to predict its reoccurrence.

  27. Genes are shared “on the average”

  28. Relationship Identical Twin Sibling Child Niece/Nephew First Cousin General Population (no affected relatives) Empiric Risk 40% 4.1% 3.5% 0.8% 0.3% 0.1% Empiric Risk of Cleft Lip

  29. Heritability: H • Portion of the phenotypic differences due to genetic inheritance at any particular point in time. • Highly related trait, in a large group of siblings, 50% will share the trait. • Heritability =1 when a trait is completely genetic • Heritability= 0 (0%) when a trait is completely envoronmental

  30. Multifactorial Polygenic Trait Genetic Variation Environmental Variation Additive Effects of Recessive Alleles (small) Dominant Alleles (few) Epistasis

  31. Check out Reading 7.1 in the Text • Each direct degree of relationship shares 50% of genes (1/2) • You and first cousin once removed • You to mom 1/2 • Your mom to her mom (grandmother) 1/2 • Your grandmother to her brother 1/2 • Your great uncle to his daughter (your first cousin) 1/2 • ½ X ½ X ½ X ½ = 1/16

  32. How do we advised people on relative risks with poorly understood inheritance patterns?  • We need to understand the components of phenotypic variation • genetic variance • number of different genotypes within the population • environmental variance • number of different environments in which all the genotypes have been expressed

  33. Calculating Heritabilty Useful to study - Relatives in pedigrees - Adopted children - Twins - Twins raised apart

  34. Relation%concordance % expected MZ twins 0.81 1.00 DZ twins 0.42 0.5 Heritability Calculation Estimated from the proportion of people sharing a trait compared to the proportion predicted to share the trait. Concordance - % of pairs of individuals that share the trait (both affected or both unaffected) Language skills (measured by vocabulary at age 2)

  35. Adopted individuals - Share environment, but not genes Dizygotic twins - Share environment and 50% of genes Monozygotic twins - Identical genotype, shared environment - Twins raised apart - Share genotype, but not environment How do we isolate environmental and genetic components to determine heritability?

  36. Correlations between relatives for total ridge count (TRC).

  37. Heritability of Human Traits

  38. Adoption Studies • Danish Adoption Register 1924-1947 • One study looked at causes of death • If a biological parent died of infection before age 50, then the Adoptive child was 5 times more likely to die of infection at a young age relative to the general population. • Suggests a strong genetic component

  39. Adoption Studies • Danish Adoption Register 1924-1947 • Regarding cardiovascular disease • Adoptive parents who died of cardiovascular disease before age 50, their adoptive children were 3 times more likely to die of cardiovascular disease than a person in the general population. • suggests a strong environmental component

  40. Twin Studies • Powerful genetic tool • Identical twins (experiment) • Genotype is identical • Same environment at the same age • Fraternal twins (controls) • Different Genotypes (50%) • Same environment at the same age

  41. What do we measure in twin studies? Concordance - the expression of a trait in both twins  - measured as a percentage of pairs in which both twins express the trait.   - if both twins don’t share the trait - discordant Bottom line: concordance values A trait observed to be present more often in both members of a MZ twin pair than in both members of a DZ twin pair is presumed to have a significant inherited component.

  42. Concordance values in monozygotic (MZ) and dizygotic (DZ) twins.

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