Simple Mendelian inheritance involves Classical Genetics Mendelian inheritance describes inheritance patterns that obey two laws Law of segregation Law of independent assortment Simple Mendelian inheritance involves A single gene with two different alleles Alleles display a simple dominant/recessive relationship

Prevalent alleles in a population are termed wild-type alleles These typically encode proteins that Function normally Are made in the right amounts Alleles that have been altered by mutation are termed mutant alleles These tend to be less common in natural populations They are likely to cause a reduction in the amount or function of the encoded protein Such mutant alleles are often inherited in a recessive fashion A particular gene variant is not usually considered an allele of a given gene unless it is present in at least 1% of the population. Rare gene variants (<1%) are termed polymorphisms rather than allelic variants

Consider, for example, the traits that Mendel studied Wild-type (dominant) allele Mutant (recessive) allele Purple flowers White flowers Axial flowers Terminal flowers Yellow seeds Green seeds Round seeds Wrinkled seeds Smooth pods Constricted pods Green pods Yellow pods Tall plants plants Another example is from Drosophila Wild-type (dominant) allele Mutant (recessive) allele Red eyes White eyes Normal wings Miniature wings 4-7 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Human genetic diseases caused by recessive mutant alleles The mutant alleles do not produce fully functional proteins

Extended Mendelian Inheritance Patterns Incomplete dominance Heterozygosity at a locus produces a third 3 phenotype intermediate to the two homozygous phenotypes Co-dominance Heterozygosity at a locus produces a single unique phenotype different from either homozygous condition Overdominance Heterozygosity at a locus creates a phenotype that is more beneficial or more deterimental than homozygosity of either locus with any allele Lethality Homozygosity of an allele kills the cell or organism Penetrance A measure of how variation in expression of a given allele occurs incomplete penetrance describes the lack of effect a deleterious allele might have in an individual carrying it

Extended Mendelian Inheritance Patterns Sex-linked inheritance of genes on that are unique to a sex chromosomes pseudoautosomal genes – genes on both sex chromosomes appear to be on autosomes Sex-influenced An allele is expressed differently in each sex. Behaving dominantly in one sex and recessively in the other Sex-limited An allele is only expressed in one or the other sex 4-5 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Complete Dominance/Recessiveness recessive allele does not affect the phenotype of the heterozygote two possible explanations 50% of the normal protein is enough to accomplish the protein’s cellular function The normal gene is “up-regulated” to compensate for the lack of function of the defective allele The heterozygote may actually produce more than 50% of the functional protein

Simple Mendelian Inheritance Figure 4.1

Lethal Alleles Essential genes are those that are absolutely required for survival The absence of their protein product leads to a lethal phenotype It is estimated that about 1/3 of all genes are essential for survival Nonessential genes are those not absolutely required for survival A lethal allele is one that has the potential to cause the death of an organism These alleles are typically the result of mutations in essential genes usually recessive, but can be dominant

Lethal Alleles Many lethal alleles prevent cell division Some lethal allele exert their effect later in life Huntington disease Characterized by progressive degeneration of the nervous system, dementia and early death The age of onset of the disease is usually between 30 to 50 Conditional lethal alleles may kill an organism only when certain environmental conditions prevail Temperature-sensitive (ts) lethals A developing Drosophila larva may be killed at 30 C But it will survive if grown at 22 C

An example is the “creeper” allele in chicken Semilethal alleles Kill some individuals in a population, not all of them Environmental factors and other genes may help prevent the detrimental effects of semilethal genes A lethal allele may produce ratios that seemingly deviate from Mendelian ratios An example is the “creeper” allele in chicken Creepers have shortened legs and must creep along Such birds also have shortened wings Creeper chicken are heterozygous 4-13 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Phenotypic Ratios Associated with Lethal Alleles Creeper X Normal Creeper X Creeper 1 creeper : 1 normal 1 normal : 2 creeper Creeper is lethal in the homozygous state Creeper is a dominant allele

Incomplete Dominance heterozygote exhibits a phenotype intermediate to the homozygotes Also called intermediate dominance or dosage effect Example: Flower color in the four o’clock plant governed by 2 alleles CR = wild-type allele for red flower color CW = allele for white flower color

Incomplete Dominance

1:2:1 phenotypic ratio NOT the 3:1 ratio observed in simple Mendelian inheritance In this case, 50% of the CR protein is not sufficient to produce the red phenotype Figure 4.2

Incomplete Dominance complete or incomplete dominance can depend on level of examination

Gene Dosage – A form of intermediate dominance Alleles of white – X-linked eye color gene in Drosophila W – red (wildtype gene) w - white we - eosin we allele was expressed with different intensity in the two sexes Homozygous females  eosin Males  light-eosin

eosin ♀ and eosin ♂ phenotypes

This is an example of gene dosage effect Morgan & Bridges hypothesized that difference in intensity was due to the difference in number of X chromosomes Female has two copies of the “eosin color producer” allele Eyes will contain more color Males have only one copy of the allele Eyes will be paler This is an example of gene dosage effect

Multiple Alleles The term multiple alleles is used to describe situations when three or more different alleles of a gene exist Examples: ABO blood Coat color in many species Eye color in Drosophila

Multiple Alleles ABO blood phenotype is determined by multiple alleles ABO type result of antigen on surface of RBCs Antigen A, which is controlled by allele IA Antigen B, which is controlled by allele IB Antigen O, which is controlled by allele i N-acetyl- galactosamine

Co-dominance Alleles IA and IB are codominant They both encode functional enzymes and are simultaneously expressed in a heterozygous individual Allele i is recessive to both IA and IB

Multiple Alleles coat color in rabbits C (full coat color) cch (chinchilla pattern of coat color) Partial defect in pigmentation ch (himalayan pattern of coat color) Pigmentation in only certain parts of the body c (albino) Lack of pigmentation INSERT Figure 4.4

Multiple Alleles Dominance hierarchy will exist for multiple alleles called an allelic series allelic series for ABO type IA = IB > i allelic series for rabbit coat color alleles : C > cch > ch > c allelic series for alleles of white gene W+/_ > we/we > we/w > w/w = w/Y

Conditional Mutations The ch allele is a temperature-sensitive conditional mutant The enzyme is only functional at low temperatures Therefore, dark fur will only occur in cooler areas of the body

Overdominance Overdominance is the phenomenon in which a heterozygote is more vigorous than both of the corresponding homozygotes Example: Sickle-cell heterozygotes are resistant to malaria increased disease resistance in plant hybrids

Incomplete Penetrance In some instances, a dominant allele is not expressed in a heterozygote individual Example = Polydactyly Autosomal dominant trait Affected individuals have additional fingers and/or toes A single copy of the polydactyly allele is usually sufficient to cause this condition In some cases, however, individuals carry the dominant allele but do not exhibit the trait

Figure 4.11 Inherited the polydactyly allele from his mother and passed it on to a daughter and son Does not exhibit the trait himself even though he is a heterozygote

Incomplete Penetrance The term indicates that a dominant allele does not always “penetrate” into the phenotype of the individual The measure of penetrance is described at the population level If 60% of heterozygotes carrying a dominant allele exhibit the trait allele, the trait is 60% penetrant Note: In any particular individual, the trait is either penetrant or not

Expressivity Expressivity is the degree to which a trait is expressed In the case of polydactyly, the number of extra digits can vary A person with several extra digits has high expressivity of this trait A person with a single extra digit has low expressivity

Penetrance & Expressivity The molecular explanation of expressivity and incomplete penetrance may not always be understood In most cases, the range of phenotypes is thought to be due to influences of the Environment and/or Other genes (genetic background)