BIO 340 - Gene Interaction, Linkage, and Mapping

Gene interaction, linkage and mapping

Patterns of inheritance

Learning goals

• Differentiate the types of interactions among genes and how they affect the phenotype
• Compare incomplete dominance with codominance

Gene interaction

• Dominance relationships between alleles have a molecular basis
• Gene expression can be affected by interactions with other genes, causing characteristic changes in Mendelian ratios
• Mutations to different genes can produce the same phenotype
• Complementation tests can determine the number of genes causing a mutant phenotype

The molecular basis of dominance

• The terms dominant and recessive have a phenotypic basis.
• The dominance of one allele over another is determined by the protein product of that allele.
• The overall phenotype results from the activities of the protein products of the alleles of the gene.

Recessive mutations

• The phenotype of a recessive mutation is seen only in homozygous individuals
  • $A^+$ = dominant wild-type allele
  • $a$ = recessive mutant allele
• Genotype
  • $A^+A^+$: Normal phenotype
  • $A^+a$: Normal phenotype
  • $aa$: Mutant phenotype

Example 1: Mutant allele recessive to wild type

• A wild-type allele ($R^+$) produces an active enzyme (50 units), and a mutant allele ($r$) produces little or no active enzyme (0 units).
• 40 or more units of enzyme activity will produce a wild type phenotype.
  • $R^+R^+$ (100 units) or $R^+r$ (50 units) individuals are wild type.
• $r/r$ individuals (0 units) have the mutant phenotype; thus, the mutant allele is recessive.

Phenylketonuria (PKU)

• The disease phenylketonuria (PKU) is caused by a recessive mutation in the PAH gene.
• PAH encodes phenylalanine hydroxylase, an enzyme that converts the amino acid phenylalanine into tyrosine.
• When a mutation eliminates functional enzyme, phenylalanine is turned into phenylpyruvic acid, a toxin.

PKU and loss-of-function mutations

• PKU, like many recessive phenotypes, is caused by a loss-of-function mutation.
• Loss-of-function mutations cause a gene to lose some or all of its normal function.
  • Hypomorphic mutations are those that have lost only some of their function.
  • Null mutations have lost all of their function.

Loss-of-function mutations and recessiveness

• Loss-of-function mutations are recessive if the normal allele is haplosufficient.
• Haplosufficient = one (haplo) copy is sufficient to produce the wild-type phenotype in the heterozygous genotype.
  • $A^+A^+$: Normal phenotype (Functional protein)
  • $A^+a$: Normal phenotype (Functional and non-functional protein)
  • $aa$: Mutant phenotype (Non-functional protein)

Fully dominant mutations

• The phenotype of a fully dominant mutation is seen in both heterozygous and homozygous individuals
• Genotype
  • $A^+A^+$: Normal phenotype
  • $A^+A$: Mutant phenotype
  • $AA$: Mutant phenotype

Example 2: Mutant allele dominant to wild Type

• An allele ($T1$) produces an active enzyme (10 units), and a mutant allele ($T2$) produces less active enzyme (5 units).
• 18 or more units of enzyme activity will produce a wild type phenotype, thus only $T1T1$ (20 units) individuals will be wild type.
• $T1T2$ (15 units) and $T2T2$ (0 units) individuals have a mutant phenotype because neither produces enough enzyme.

Loss-of-function mutations and dominance

• Loss-of-function mutations are dominant if the normal allele is haploinsufficient.
• Haploinsufficient = a single copy is not sufficient to produce the wild-type phenotype in the heterozygous genotype.
  • $A^+A^+$: Normal phenotype (Functional protein)
  • $A^+a$: Mutant phenotype (Functional and non-functional protein)
  • $AA$: Mutant phenotype (Non-functional protein)

Effects of mutation

• A wild type phenotype is produced when an organism has two copies of the wild type allele.
• Mutant alleles can be:
  • Gain-of-function: the gene product acquires a new function or expresses increased wild type activity.
  • Loss-of-function: there is a significant decrease or complete loss of functional gene product.

Incomplete dominance vs. codominance

• Incomplete dominance: The phenotype of the heterozygote is intermediate between those of the two homozygotes, on some quantitative scale (color, size, etc.).
• Codominance: The phenotype of both alleles is fully expressed in the heterozygote.

Incomplete dominance

• Often the dominance of one allele over the other is not complete; in this case, allele designations such as $A1, A2$ or $B1, B2$ are used instead of $A, a$ or $B, b$.
• Incomplete dominance, or partial dominance is when heterozygous individuals display intermediate phenotypes between either homozygous type.
• Typically, the heterozygote is more similar to one of the homozygous types than the other.

Incomplete dominance: Snapdragons

Incomplete dominance: Andalusian chickens

• $BB$ (black)
• $WW$ (white)
• $BW$ (blue)

Codominance

• Codominance leads to heterozygotes with a different phenotype than that of either homozygote.
• In this case, there is detectable expression of both alleles in the heterozygotes.
• More than one pattern of dominance may exist between different alleles of a gene, e.g. ABO blood type.

Codominance: heterozygotes express the phenotype of both their alleles

• Genotype | Phenotype (Blood type)
  • $I^AI^A$ or $I^Ai$ | A
  • $I^BI^B$ or $I^Bi$ | B
  • $I^AI^B$ | AB
  • $ii$ | O
• The alleles are: $I^A$, $I^B$ and $i$
  • $I^A$ and $I^B$ alleles are completely dominant over the $i$ allele but codominant with each other

Codominant Cross

• Genotypes
  • $AA$
  • $AB$
  • $BB$
• Genotype ratio
  • $AA$: 1
  • $AB$: 2
  • $BB$: 1

Codominance: Sickle cell anemia

• Also an autosomal recessive disease

Codominance: Shorthorn cattle

• Homozygous red (RR)
• Homozygous white (WW)
• Heterozygous (RW) with both red and white hairs

Codominance: Doberhuahua

The C gene system for mammalian coat color

• Many genes are required to produce and distribute pigment to the hair follicles or skin cells, where they give rise to skin or coat color
• The C gene is responsible for coat color in mammals like cats, rabbits and mice, etc.
• It produces an enzyme active in the production of melanin
• There are dozens of alleles of the gene, but four that form an allelic series (order of dominance among the alleles)

The allelic series of the C gene

• The wild type allele, C, produces a functional enzyme and full coat color
• $c^{ch}$ produces a “dilute” phenotype called chinchilla
• $c^h$ produces a phenotype called Himalayan with little pigment on the body but full color on the extremities
• $c$ is a fully recessive null allele and produces an albino phenotype

The allelic series of the C gene order of dominance among the alleles

• C > c^{ch} > c^h > c

The molecular basis of the C gene allelic series

• The C allele produces a tyrosinase enzyme that is 100% active, whereas that of the $c^{ch}$ allele is less than 20% active.
• The $c^h$ allele enzyme is temperature-sensitive; functional at lower temperatures (like the paws, ears and tail) and non-functional at higher temperatures (the trunk).
• The c allele produces no functional enzyme

Temperature sensitive mutations