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Genetic Principles

genetics, ADN animation
How a living organism is built and functions is determined and governed by genes. Understanding how genes work may enable researchers to:

    detect and cure genetic illnesses.
    determine an organism's features and behaviors.
    create a new organism.

The relationships between genes and features are very complex. Currently, we are unsure if it will ever be possible to change only one feature of an organism by changing one or a set of genes. If features are able to be genetically altered, there is a likelihood that any attempt may accompany other changes. The other changes could be small and/or ignorable however. Some changes are gradual, while changes in gene expression can result in rapid transformations in the physiological state of an organism.

Gregor Mendel and Peas

Gregor Mendel was an Austrian monk. He is credited as the father of modern genetics. While planting and harvesting pea plants on his monastery he noticed patterns of traits in pea plants. Most pea plants turned out to have green pods, some had yellow pods. Some had yellow seeds and while others had green seeds. Stem length, petal color, pod shape, location of flowers all these seemed to exhibit a pattern of inheritance. Mendel went on to breed pea plants to see how these traits acted. Through these experiments Mendel created 3 laws that govern how traits are passed on from parents to offspring.

Mendel's Laws

Law of Dominance - In a cross between contrasting traits only 1 appears in the F1 generation this is the dominant trait; the other is recessive Law of Segregation- During gamete formation the 2 traits responsible for each trait separate so each gamete has only 1 gene for each trait Law of Independent Assortment- when dihybrid plants are crossed the factors for 1 trait are distributed separately from other traits so that one can find all these changes Chromosomes, alleles and Mendel’s law: the behavior of homologous chromosomes during meiosis can account for the segregation of the alleles at each genetic locus to different gametes. The alleles for 2 or more genes located on different chromosomes. In Mendel’s experiment, the segregation and the independent assortment during meiosis in the F1 generation give rise to the F2 phenotype ratio observed by Mendel.

Dominant and Recessive Genes

When Mendel studied peas, one of the phenotypes showed complete dominance over the other one. If we look at pea height, and denote the gene for short as s and the gene for tall as S, then as every plant has two sets chromosomes each has two genes at this locus. So there are three possibilities: SS, Ss, ss (order doesn't matter) In this case S was fully dominant over s, so Ss individuals were phenotypically identical to SS individuals. Only ss pea plants were short. The S gene would be said to be Dominant While the s gene is said to be Recessive.

The Molecular Basis of Dominance

As has already been mentioned, all diploid organisms have two homologous chromosomes. At a specific locus on each homologous chromosome, there are homologous alleles for a particular trait. For example, the gene that codes for a dominant tall pea plant could be labeled A2 and for a short recessive pea plant could be labeled A1. Alternative Patterns of Inheritance Not all loci show this simple dominance. If we represent phenotype on a plot then Complete Dominance would be like this: AA/Aa aa Complete Dominance Other types are: AA Aa aa No Dominance AA Aa aa Incomplete Dominance Aa AA aa Over Dominance

Mendelian Inheritance

Gregor Johann Mendel was a monk in the Augustinian Monastery in the Brunn, Czech Republic. In 1854 he began the experiments which started modern genetics. His work with garden peas, Pisum sativum, was vital to our understanding of inheritance. He is known as the Father Of Genetics.

Mendel's Experiment

Mendel's first step was breeding pure breeding strains of peas. The traits he studied included: Pea colour Height of pea plants and whether the Peas were wrinkled or smooth. Mendel crossed the pure breeding Parental Generation (designated P). He found that the first generation (F1) was exclusively phenotypically one of the parental types. Mendel then crossed his F1 generation with itself. He found that the F2 generation showed a surprising trait, three quarters were like the F1 generation, while the remaining quarter were like the other Parents. From this Mendel realised that there were two versions of each loci, one of which expressed dominance over the other. He called this Biparticulate Inheritance. If a gene was following this 3:1 pattern it was said to be segregating Normally. By looking at multiple genes, Mendel showed that they were not linked to each other and that each loci he studied had no influence over the others. He called this Independent assortment. By studying cases where the Mendelian laws we can also learn a lot. For instance, if a gene isn't segregating normally it may be sex linked. If two genes aren't Assorting Independently they're probably on the same chromosome Mendel's laws are the first step to understanding Genetics, they lay down the basic concept of inheritance.

Non-Mendelian Genetics

Most traits are not mendelian (due to the influence of a single gene), but are multifactorial Multifactorial inheritance definition from 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 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: Codominance 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

Mitochondrial Inheritance

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.
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