Extensions of Mendelian inheritance Epistasis and epigenetics
Remember Mendelian ratios? • True-breeding parents with dominant and recessive traits • Monohybrid (AA X aa parents) • F1 are heterozygous (Aa) with dominant phenotype • F2 are 3:1 dominant to recessive phenotype • Both are phenotypes that you see in the parents • Dihybrid (AABB X aabb parents) • F1 are heterozygous (AaBb) with dominant phenotype • F2 are 9:3:3:1 (9 A-B-: 3 aaB-; 3 A-bb: 1 aabb) • Note that you get some new phenotypes • Traits are inherited independently
Modified Mendelian ratio: gene interaction • Lethal alleles • “recessive lethal” example: the Manx cat • ML affects tail formation • MLML genotype is lethal • MM genotype: normal tail • Heterozygote“ lacks tail • Breed two Manx cats: 1/3 have normal tail, 2/3 lack a tail • www.manxcats.org
Effects of lethal genes? • Sometimes they are dominant • Sometimes fully recessive • Heterozygote may be unaffected • Heterozygote may have distinct effect (Manx cat) • Sometimes expressed in utero • Sometimes later in life • Metabolic disorder (PKU) • Structural disorder (muscular dystrophy; sickle cell anemia)
Modified Mendelian ratio: gene interaction • Dihybrid crosses (F1 cross is AaBb X AaBb) • Genes are still inherited in the Mendelian manner • Instead of 9:3:3:1 ratio, you see something else • One gene affects expression of the other • Common example: pigmentation
Breeding Labrador retrievers (black and yellow) B-E- Black (B) is dominant to chocolate (b) Yellow (E) blocks expression of black or chocolate when recessive bbE- B-ee or bbee
The Punnett square (like Labradors: the C gene affects expression of the B gene) Note a 9:3:4 ratio instead of 9:3:3:1
There are other types of epistasis • How can you tell? (We’re talking about two sets of alleles) • Phenotypic ratios are not 9:3:3:1, but something else (9:3:4; 9:7; 12:3:1, etc.- but all 16 gene combinations can be explained) • You will not see four distinct phenotypes, but a smaller number • Conclusion: sometimes genes act independently of each other, but often they don’t (Mendel’s laws apply, but outcomes vary)
Penetrance and expressivity • All individuals have allele P Variable penetrance Variable expressivity Variable penetrance and expressivity
Not all phenotypes are “either-or” Discontinuous variation Either-or Environment is not a factor Continuous variation Inheritance is Mendelian Genes may affect each other or multiple genes are involved (polygenic) Environment plays a role (multifactorial) Statistical analysis is more complex
The additive model for polygenic inheritance All-dominant or all-recessive are extremes Most individuals are somewhere in the middle The more genes involved, the more phenotypes
Multifactorial traits • Controlled by several genes (polygenic) • Each trait contributes to the phenotype (none is dominant over the others) • Environmental factors act on the genotype to produce the phenotype
Threshold model for multifactorial disorder How do you predict the effect? Relatedness How many affected children How severe is the effect Does it affect one gender more than the other?
Genes and the environment (what do we mean by “environment”?) • What is the genotypic contribution to phenotypic variation? • What is the environmental effect? • How do you measure it?
We study heritability in families • Ranges form zero (no heritability) to 1 (trait is controlled entirely by genes) • Families are studied because they share genes • Identical twins” 100% • Child to parent: 50% • Sibling to sibling: 50% • Uncle/aunt to niece/nephew: 25% • Parents will be zero unless they are related • Twin studies are used to estimate heritability of traits: http://ibgwww.colorado.edu/twinsites.html
If heritability is high, that means variation is due primarily to genes • If heritability is low, variation is due primarily to environment
Concordance in monozygotic (MZ) and dizygotic (DZ) twins • MZ twins share 100% of genes, DZ share half • Concordance: both have trait • Discordance: only one has trait • Trait MZ twins DZ twins Blood type 100 66 Handedness 79 77 Cleft palate 42 5
Nature and nurture • How to study it? • Twin and family studies • Twins raised together, and apart • Adoption studies • Can you completely separate genes from the environment?
Some risk factors are controlled, some uncontrolled • Example: coronary artery disease • It runs in the family- do you have to get it?
Animal models can be useful to locate specific genes • Obese mouse had a genetic defect (ob gene, that produces leptin) • Many genes are implicated in obesity • What are some controllable risk factors for obesity?
Complex traits are affected by genes and environment • Intelligence • Behavior • Phenotypes are not always fixed • There is a lot that we still don’t know • Effects of environment • The complete set of genes associated with a trait
What is epigenetics? • Gene sequence is important but not the only activity affected DNA • DNA can be modified chemically • Not just the bases (mutation) • Also addition of chemical groups that affect gene expression • Some of these changes are inherited