#4 Extensions of Mendelian Inheritance

Chi-Squared Test (X²)

Determines how close observed data “fits” a null hypothesis

*Doesn’t prove anything, just assess “goodness of fit”

X² = (observed - expected)² / expected

• Observed = data that is collected, #’s of progeny of each phenotype

• Expected = Depends on null hypothesis, usually that progeny will have typical mendelian ratios (3:1, 9:3:3:1)

High χ²

Large deviation → the data likely do not fit the null hypothesis well

• Low p-value

Low χ²

Small deviation → the observed results are close to expected, so the null hypothesis may be valid.

• high p-value

Simple Mendelian Genetics

• A single gene with two different alleles

• Alleles display a simple dominant/ recessive relationship

Wild-type Alleles

Genes that are “normal/prevalent” standard phenotype

• Encodes proteins that: function normally and are made in proper amounts

• Mutations in wild type = mutant allele

Mutant alleles

Defective in ability to express a functional protein

• Often inherited in a recessive fashion

Loss of Function

Disrupts function

• Called “Knockout” alleles in lab setting

• Rare and usually recessive

Why are recessive alleles not observed in heterozygous individuals?

Ex: No phenotype when Tt

1. 50% of a normal protein is enough to accomplish the protein’s cellular function

2. The wild type upregulated to compensate (higher gene expression) for lack of function in the defective allele

Gain-of-function mutation

A genetic change that makes the gene more active

• Often dominant

• Gains a new or abnormal function

A mutation in a potassium channel now allows potassium ions to flow into and out of a cell without regulation. This mutation could be considered:

Dominant-negative mutation

The altered gene product not only loses its normal function but also interferes with the function of the wild type allele’s product

• Dominant

A protein functions as part of a homodimer (protein that binds to another copy of the same protein). A mutation arises in this gene that disrupts the binding interactions that form the dimer, leading to a non-functioning protein complex. This mutation could be considered:

Haploinsufficiency

Mutant is loss-of-function (disrupts function), BUT heterozygote, wild type, does not make enough product to compensate

There is an allele of a gene with a loss of function mutation. Heterozygote individuals have a phenotype This is:

Incomplete Penetrance

Sometimes a dominant allele does not influence the outcome of a trait in a heterozygote individual (doesn’t penetrate into the phenotype)

• 60% of hetero individuals show trait = 60% penetrance

• Pedigree: the parents will NOT show the trait (Skipped generation), but their kids do, meaning that they have the trait, it just didn’t penetrate.

Expressivity 

Degree to which a trait is express

• Variation in a trait

• 50% expressivity = 50% of full phenotype

• Ex: Polydactyly, a person with several extra digits has high expressivity of this trait, while person with single extra digit has low 

• Due to influence of environment or other “modifier” genes

Environmental Effect

Environmental factors influence how a gene is expressed

Ex: Siamese cat, color of fur depends on temperature; cooler areas of the body have darker fur

Incomplete Dominance

Heterozygote shows a phenotype that is intermediate between the two homozygotes

• Heterozygote has a blended trait

• EX: RR x rr (Red x white flower)

• Will produce Rr = pink flower (F1)

• F2: 1:2:1 phenotype ratio

Overdominance

Heterozygote has a greater reproductive success compared to homozygotes

• “Heterozygote advantage”: survival advantage

Ex: Sickle-cell

• AA (normal hemoglobin) → healthy, but vulnerable to malaria.

• aa (sickle-cell disease) → serious health problems.

• Aa (heterozygote) → mostly healthy and resistant to malaria.

1. Disease resistance

2. Homodimer formation

3. Functional activity

Sickle Cell

Red blood cells deform in to sickle shape under conditions of low oxygen

1. Shortens life span of red blood cells -→ Anemia

2. Odd-shaped cells clump → partial or complete blocks in capillary circulation

Blood type

Blood type determined by the type of antigen present on the surface of cells

• Allele IA: produces antigen A

• Allele IB: produces antigen B

• Allele i: does not produce either antigen

Co-dominance

Both alleles are expressed and affect phenotype

• Allele i is recessive (encode defective enzyme) to both IA and IB

• Alleles IA and IB = co-dominant, they are both expressed in a heterozygous individual

• IA = adds N-acetylgalactosamine

• IB = adds galactose

Type O

ii: can donate to anyone (since no antigen)

Type A

IAi or IAIA: can receive from A and O, donate to AB

Type B

IBi or IBIB: can receive from B and O, donate to AB

Type AB

IAIB: can receive from A, B, O and donate to AB

A couple thinks the hospital has switch their baby with another. The mother has type A blood and the father has type AB, and the baby they currently have has type O. Is this their baby?

NO