General Genetics/Non-Mendelian Genetics
Most traits are not mendelian (due to the influence of a single gene), but are multifactorial
Multifactorial inheritance definition from genereviews.org: The combined contribution of one or more often unspecified genes and environmental factors, often unknown, in the causation of a particular trait or disease.
Many people use the term "complex" to refer to multifactorial inheritance. People also use the terms "polygenic" and "multifactorial" synonymously when really, they are not. Polygenic refers to a trait that is due to multiple genetic factors (many genes). Although it usually does, by definition "polygenic" traits may not have an environmental component. An example of this is eye color. Multifactorial traits, on the other hand, may be due to only one gene but always are influenced by environmental factors as well as (the) inherited factor(s).
The definition of "polygenic" by genereview.org: A condition caused by the additive contributions of mutations in multiple genes at different loci. Loci are locations on a chromosome.
Multifactorial inheritance is an important and fundamental concept. Other variations from Mendelian inheritance are:
When both alleles are equally represented and neither overpowers the other; two different alleles are both expressed in a heterozygote. The phenotypes mix in a way that both appear at the same time, intact, and are not blended. An example of this is the ABO blood antigens.
Codominance vs incomplete dominance: if mixing black fur with white fur makes pups with gray fur, it is incomplete dominance. If mixing black fur with white fur creates pups that have mottled black and white fur, it is codominance (like black and white cows). Complete dominance: One allele is expressed while the other isn't expressed at all. At the level of the body, Tay-Sachs disease is completely dominant. Heterozygotes ("Tt" genotype) have no symptoms of Tay-Sachs disease. The TSD gene codes for an enzyme. Heterozygous TSD carriers ("Tt" genotype) have half the normal level of enzyme activity. At the level of the enzyme activity, carriers of Tay-Sachs show incomplete dominance. Since this half level of enzyme activity has no effect on health, at the level of the body Tay-Sachs disease shows complete dominance. Epistasis
One gene masks or otherwise effects the phenotype of another gene. Note, this involves 2 different genes, not 2 allele of the same gene. The expression of one gene is modified or blocked by the product of a different gene. An example of this is the Bombay Phenotype. Also, if a person has achondroplasia, then the mutant allele that causes dwarfism alters the height genes that would have been expressed. If a person has albinism, that alters the effects of the pigment genes that would have been expressed. The genome is a complex system and epistasis is not actually an exception but it is the rule. Many different genes are turned on and off by products of other genes to enable to cells to express the proteins we need to in a particular cell at a particular time. Epistasis leads to variability in phenotypes, even in a family where 2 people affected with a disease have the same mutation. Those 2 relatives may have the same disease - causing mutation but have or not have other alleles of different genes that exacerbate or reduce the effect of the mutant allele. Genetic Heterogeneity
Genetic Heterogeneity is when different genes produce the same phenotype (not different alleles but different GENES). Individuals with identical phenotypes may reflect different genetic causes. In this case, a person who is genotype "AAbb" could have the same phenotype as a person who is genotype "aaBB." Example: Hearing loss (deafness) There are 132 different forms of hearing loss. Many different genes, which code for different parts of hearing, can cause deafness. Incomplete Dominance
Incomplete dominance occurs when one allele is not completely dominant over the other. The phenotype of heterozygotes ("Aa") is intermediate between that of either homozygote ("AA" and "aa"). The heterozygote phenotype is a blend of the two homozygous phenotypes. Familial Hypercholestrolemia (FH) is an example of a disease with incomplete dominance. This is because individuals who have no mutant allele of the FH gene are unaffected, heterozygotes with one mutation are moderately affected, and people with 2 mutant alleles are severely affected. The heterozygote phenotype is a blending of the two homozygous phenotypes. Genomic Imprinting
Some regions of DNA are expressed differently when they are inherited from the mother versus the father. These regions of DNA are "imprinted." I think of it as "programming." The genes are expressed one way if they arrived in the fetus from the egg and the exact same genes are expressed a different way if they arrived in the fetus from the sperm. Beckwith Wiedemann syndrome is an example of a disease that can result from genomic imprinting. Lethal allele combinations
Lethal allele combinations is when having the homozygous genotype is lethal. The ratio of affected to unaffected is skewed because one of the genotype possibilities does not survive.
Parent's genotypes: Aa X Aa Offspring genotypes: AA, Aa, aA, and aa If the "AA" genotype is lethal then the offspring phenotype ratio is: 2/3 phenotype of Aa or aA genotype 1/3 recessive ("aa") genotype If the "aa" genotype is lethal, then the offspring phenotype ratio is: 1/3 dominant ("AA") genotype, 2/3 phenotype of Aa or aA genotype
The mitochondria is unique. It is an organelle that converts energy to a form the cell can use. The mitochondria has its own DNA! Most DNA is in the nucleus (in chromosomes). The mitochondrial DNA is in the mitochondria. People can have mutations in the DNA in their mitochondria. These mutations can interfere with the function of the mitochondria and cause diseases. "Mitochondrial diseases" are a category with many different diseases that are due to abnormalities of the mitochondria, many of which are due to mutations in mtDNA. mtDNA disease pedigrees: passed to ALL of the children of the affected mother and NONE of the children of the affected son. This is b/c the mitochondria in the zygote (fertilized egg) are all from the egg and none are from the sperm. In other words, mitochondrial Genes are maternally inherited. This is very useful for ancestry studies. Mitochondrial DNA has a higher mutation rate than nuclear DNA; the repair mechanisms the nuclear DNA uses are not present in the mitochondria. There are many mitochondria per cell, therefore you see heteroplasmy (some mitochondria in a cell have a mutation and others do not). An example of this is Leber's Optic Atrophy. A defect in the gene can produce other symptoms such as vision impairments, which can begin in early adulthood. Multiple Alleles Specifying One Trait
Each person has 2 alleles for any autosomal gene: one is inherited from their mother and the other is inherited from their father. There are 2 alleles per gene per person, but there are many more alleles per gene in gene pool. Recall that the "gene pool" consists of the alleles for a gene in an entire population. For many genes, there are over 1000 different alleles in a gene pool. There are many different alleles that are just "polymorphisms" and do not affect the function of a protein. In other words, there is not just one "normal" allele but actually many varieties of "normal" alleles. Of the mutations that are not benign, not all are equally harmful. Some alleles cause mild changes in the protein, others cause moderate or severe changes in the protein, and some alleles make the protein completely non-functional or absent. The fact that there are many different allele combinations means that a person can have 2 mild mutations and have mild disease, and another person can have severe mutations in the same gene and have severe disease. Most diseases have multiple alleles. Phenocopies
A "phenocopy" is when a phenotype mimics a genetic disease but actually has an environmental cause. A person who is deaf due to exposure to the rubella virus in utero is a phenocopy of genetic deafness. Another example: phocomelia (a limb deformity translation "flipper-like limbs") due thalidomide exposure in utero looks like the genetic disease Roberts syndrome. Phenocopies- environmental trait that appears to be inherited. Example is birth defect from the drug thalidomide. Infection:AIDS that was acquired from mother. Someone who has failure to thrive due to malnutrition may look a lot like a child who has cystic fibrosis and does not have access to medical care to treat digestive dysfunction. Pleitropy
Pleitropy is when a single gene disorder effects more than one organ/organ system and leads to various different symptoms. (at times these symptoms seem to be distinct conditions rather than symptoms for a single disorder). This happens because a gene that controls several functions will have more than one effect. The product of that gene may play a role in many different organs. Example: Osteogenesis Imperfecta. People with OI have multiple fractures. The gene at fault codes for collagen, a major component of connect tissue. However, people with OI may also have a blue tint to the whites of their eyes and hearing loss. Many single gene disorders demonstrate pleiotropy, leading to a "syndrome." The "syndrome" refers to many manifestations all stemming from the same underlying cause. Reduced / Incomplete Penetrance
Penetrance and expressitivity describe degrees of expression of a single gene. Incomplete Penetrance: A gene that is not phenotypically represented by all family members who have the mutation in that gene. Penetrance is ALL OR NONE expression, not DEGREE. In incomplete penetrance, some people who have the genotype have NO expression of the expected phenotype. An example would be Polydactyly. Not all affected individuals with polydactyly genotype have extra digits. Another example is Von Hippel-Lindau Disease, a disease that greatly increases the chance of developing cancer. Not everyone with the mutation that causes VHL gets cancer. Those that don't show non-penetrance. Complete penetrance is less common that incomplete penetrance. Huntingtons disease shows complete penetrance. HD is an autosomal dominant adult-onset neurological disorder. If you die before you are 40 years it LOOKS like incomplete penetrance b/c you didn't live long enough to develop symptoms. BUT if you live to be 80 y of age and are genotype "Hh," you WILL get the disease. It has complete penetrance. Uniparental Disomy
When a child inherits two copies of the same gene from one parent and none from the other parent. Means "two bodies from one parent". Prader Willi syndrome and Angelman syndrome are examples of diseases that can result from UPD. Variable Expressivity Variable Expressivity is when symptoms and severity vary between affected individuals. "Expressivity" refers to the severity or extent of symptoms. The expression of a mutant allele may vary due to multiple different mutations with different severities, and also doe to genetic background -- the influence of all the other genes that individual has influencing the phenotype--, and also environmental influences modifying the effects of the mutation. Example: Polydactyly (again). Some affected individuals may have one extra finger while others have multiple extra fingers and toes.