Multifactorial Traits Human Genetics Multifactorial Traits 1

Genes and the Environment 2

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

Discontinuous Variation Phenotypes fall into two or more distinct non-overlapping classes Example - short and tall phenotypes in pea plants no in betweens

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

Height is Continuous Why do we need to understand how genes form continuous traits? 1) The genes underlying continuous traits are following Mendelian principles of segregation and independent assortment.   2) Many human traits and genetic disorders show continuous variation. Mechanism: - traits are being determined by more than one gene. - it is the sum of the genes that produces the trait.

Except when it is Discontinuous

As the number of loci involved in a trait increase, the number of resulting phenotype classes increase.   Look at 3 loci use height as a model trait - assume we have only 3 loci each with only 2 alleles A,a, B,b and C,c - each dominant trait makes an equal contribution to phenotype - each recessive trait contribute nothing - effect of each dominant trait is small, but additive - genes are not linked – (they sort independently) assume - a base height of 5 ft - each dominant allele adds 3 inches to the base height

Seven heights produced through the interaction of 3 genes

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

QTL takes time and lots of chromosomal Markers. Nature Genetics  31, 235 - 236 (2002) doi:10.1038/ng0702-235

QTL is the First Step

Diseases can be Polygenic 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

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.

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 Example of a Scan for Quantitative Trait Loci (QTL) on a single chromosome; this study was performed on patients with osteoporosis; 1,100 microsatellite markers were used for a Genome-wide Scan, and the main finding was a major QTL on chromosome 20 which is shown here with the detailed QTL data; see also this image for the complete results of all chromosomes Source 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

Other QTLs for Osteoporosis in Humans Example of a Genome-wide Scan for Quantitative Trait Loci (QTL); this study was performed on patients with osteoporosis; 1,100 microsatellite markers were used, and the main finding is a major QTL on chromosome 20; see also this image for a more detailed map of chromosome 20SourceStyrkarsdottir 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

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.

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

Number of dominant alleles at two genes produces five phenotypes

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.

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.

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?

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

Fingerprints -Multifactorial Traits

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

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.

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.

Genes are shared “on the average” Degree of Relationship % of Genes in Common Example First Degree 50% Parent, Child Siblings Second Degree 25% Aunts, Uncles Niece Nephew Grandparents Third Degree 12.5% First Cousins

Empiric Risk of Cleft Lip 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%

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

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

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

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

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

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) Relation %concordance % expected MZ twins 0.81 1.00 DZ twins 0.42 0.5

How do we isolate environmental and genetic components to determine heritability? 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

Correlations between relatives for total ridge count (TRC).

Heritability of Human Traits Clubfoot 0.8 Height Blood Pressure 0.6 Body Mass Index 0.5 Verbal Aptitude 0.7 Mathematical Aptitude 0.3 Spelling Aptitude Total fingerprint Ridge Count 0.9 Intelligence 0.5-0.8 Total Serum Cholesterol

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

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

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

Bottom line: concordance values 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.

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

SNP (single nucleotide polymorphism) Nucleotide site with more than one allele is a polymorphism. On average between two random individuals, there is one SNP every 1000 bases => 3 million differences!