Bio Ch. 14

Dominantly inherited disorders

- Achondroplasia, a form of dwarfism, is dominant. Heterozygous individuals have the dwarf phenotype. Thus, all people who aren't dwarfs are homozygous for the recessive allele. The recessive allele is much more prevalent than the dominant allele. - Dominant alleles that cause a lethal disease are much less common that recessive alleles that have lethal effects. All lethal alleles arise by mutations in cells that produce gametes; presumably, all mutations are equally likely to be dominant or recessive. A lethal recessive allele can be passed among generations by heterozygous carriers because the carriers have a normal phenotype; this is not true for dominant lethal alleles, which often cause death before an organism can mature and reproduce, meaning the lethal allele isn't passed on. - In cases of late-onset disease, a lethal dominant allele may be passed on. If the symptoms first appear after reproductive age, the individual may have already transmitted the allele to his or her children. Huntington's disease, a degenerative disease of the nervous system, is an example. It's negative phenotypic effects aren't expressed until an individual is 35 to 45; once the deterioration of the nervous system beings, it is irreversible and inevitably fatal. - DNA samples can e analyzed to see if a person contains the Huntington's allele.

Degrees of dominance

- Alleles can show different degrees of dominance and recessiveness in relation to each other. - Complete dominance: the phenotypes of the heterozygote and the dominant homozygote are indistinguishable. - Incomplete dominance: when either allele is completely dominant, meaning the F1 hybrids have a phenotype somewhere between those of the 2 parental varieties, e.g. red and white flowers producing pink flowers. This third intermediate phenotype results from flowers of the heterozygote having less red pigment than red homozygotes. - Codominance: 2 alleles each affect the phenotype in separate, distinguishable ways, e.g. MN blood type, where M and N molecules are both present on the red blood cells. The phenotype of codominant alleles is not intermediate between the M and N phenotypes, which distinguishes codominance from incomplete dominance; rather, both the M and N phenotypes are exhibited.

Fetal testing

- Amniocentesis: used to determine if a developing fetus has a certain disease; a physician inserts a needle into the uterus and extracts about 10 mL of amniotic fluid (the liquid that bathes the fetus), allowing some genetic disorders to be detected from the presence of certain molecules in the amniotic fluid itself; performed at 14-16 weeks of pregnancy. For some disorders, tests are performed on the DNA of cells culture in the laboratory, and a karyotype of these cells can be used to identify certain chromosomal defects. - Chronic villus sampling (CVS): a physician inserts a narrow tube through the cervix into the uterus and suctions out a tiny sample of tissue from the placenta (the organ that transmits nutrients and fetal waste between the fetus and mother), then the cells of the chronic villi of the placenta, which have the same genotype and DNA as the new individual, are karyotype immediately and analyzed; unlike amniocentesis, the cells don't have to be cultured for several weeks before karyotyping, and it can be performed in weeks 8-10 of pregnancy. - Scientists have now been able to isolate fetal cells and fetal DNA to analyze the entire genome of a fetus; this is a noninvasive method. - Imaging techniques allow a physician to examine a fetus directly for anatomical abnormalities that might not show up in genetic tests, such as through ultrasound (sound waves) and fetoscope (need-thin tone with viewing scope and fiber optics inserted into uterus).

The relationship between dominance and phenotype

- An allele is called dominant because it's seen in the phenotype, not because it somehow subdues a recessive allele. Alleles are simply variations in a gene's nucleotide sequence. When a dominant allele coexists with a recessive allele in a heterozygote, they don't actually interact at all. - For any character, the observed dominant/recessive relationship of alleles depends on the level at which we examine phenotype. Tay-Sachs disease, an inherited human disorder, is an example. The brain cells of a Tay-Sachs child can't metabolize certain lipids because a crucial enzyme doesn't work properly. As these lipids accumulate in the brain cells, the child suffers seizures, blindness, degenerated motor and mental skills, and is within a few years. Only children who inherit 2 copies of the Tay-Sachs allele (homozygotes) have the disease. Thus, at an organismal level, Tay-Sachs is recessive. However, the activity of the lipid-metabolizing enzyme in heterozygotes is intermediate between that in individuals homozygous for the normal allele and that in individuals with Tay-Sachs. Thus, the intermediate phenotype observed at the biochemical level show incomplete dominance. The heterozygote condition doesn't lead to disease symptoms. Heterozygotes produce equal numbers of normal and dysfunctional enzyme molecules, thus, at the molecular level, the normal all and the Tay-Sachs allele are codominant.

Mendel's experimental approach

- Character: a heritable feature that varies among individuals, e.g. flower color. - Trait: each variant for a character, e.g. purple or white flowers. - In nature, peas self-fertilize. They have pollen-producing organs (stamens) as well as egg-bearning organs (carpels). Pollen grains from the stamen land on the carpel of the same flower, and sperm released from the pole grains fertilize eggs present in the carpel. Mendel removed the immature stamens of his plants before they made pollen and then dusted pollen from another plant onto the altered flowers. Each resulting zygote developed into a plant embryo encased in a seed (pea); thus, Mendel was always sure of the parentage of new seeds. - Mendel only tracked characters that occurred in 2 distinct, alternative forms. - True-breeding: varieties of a species that, over many generations of self-pollination, produce only the same variety as the parent plant. - Mendel typically cross-pollinated 2 contrasting, true-breeding pea varieties. - Hybridization: the mating, or crossing, of 2 true-breeding varieties. - P generation (parental generation): the true-breeding parents. F1 generation (first filial generation): the P generation's hybrid offspring. F2 generation (second filial generation): the offspring produced by the self-pollination of the F1 generation.

Cystic fibrosis (recessive)

- Cystic fibrosis is the most common lethal genetic disease in the U.S. 4% of people of European descent are carriers of the cystic fibrosis allele. - The normal allele for this gene codes for a membrane protein that functions the transport of chloride ions between certain cells and the extracellular fluid. These chloride transport channels are defective or absent in the plasma membranes of children who inherit 2 recessive alleles for cystic fibrosis, resulting in abnormally high concentrations of extracellular chloride, causing the mucus that coats certain cells to be thicker and stickier than usually. the mucus builds up in organs (pancreas, lungs, digestive tract), leading to multiple (pleiotropic) effects, including poor absorption of nutrients, bronchitis, and bacterial infections. - If untreated, cystic fibrosis can cause death by the age of 5.

Genetic testing and counseling

- Fetal and newborn testing can reveal genetic disorders. Pedigrees can be used to asses the risk of a particular genetic disorder before a child is conceived or during early stages of pregnancy.

Complex inheritance patterns

- For every trait Mendel tested (except for pea pod shape, which is determined by 2 genes), there are only 2 alleles: dominant and recessive. Not all heritable characters are so simple. - The inheritance of characters determined by a single gene deviates from simple Mendelian patterns when alleles are not completely dominant or recessive, when a particular gene has more than 2 alleles, or when na single gene produces multiple phenotypes.

Genetic vocabulary

- Homozygous: an organism that has a pair of identical alleles for a character, e.g. PP or pp. Breed true because all of the gametes contain the same allele. - Heterozygous: an organism that has 2 different alleles for a gene, e.g. Pp. Produce gametes with different alleles, so they are not true-breeding. - Phenotype: an organism's appearance or observable traits; includes physiological traits as well as those that relate directly to appearance. - Genotype: an organism's genetic makeup.

Using probability rules to solve genetic problems

- The rule of probability can be used to predict the outcome of crosses involving multiple characters. - Because of the law of independent assortment, a dihybrid or other multi character cross is equal to two or more independent monohybrid crosses occurring simultaneously. Thus, we can determine the probability of specific genotypes in the F2 generation without having to make Punnett squares. - For example, 2 YyRr parents reproduce. The probability of the F2 offspring being YYRR is 1/4 (YY) x 1/4 (RR) = 1/16. The probability of the F2 offspring being YyRR is 1/2 (Yy) x 1/4 (RR) = 1/8. - For example, a PpYyRr organism is crossed with a Ppyyrr organism. In this case, we have separate crosses for Pp x Pp, Yy x yy, and Rr x rr. The probably of the F2 offspring being ppyyRr is (1/4 x 1/2 x 1/2) 1/16. Etc. - The larger the sample size, the closer the results will conform to probability predictions.

The Law of Independent Assortment

- Mendel derived the law of segregation from experiments in which he followed a single character. All the F1 progeny produced by his crosses of true-breeding plants were monohybrids (heterozygous for the particular character being followed). A cross between such heterozygotes is called a monohybrid cross. - Mendel identified the Law of Independent Assortment by following 2 characters at the same time. When crossing two true-breeding plants that differ in two characters (e.g. YYRR and yyrr), the F1 progeny are dihybrids. Dihybrids are individuals heterozygous for the 2 characters being followed in the cross (YyRr). - Are these 2 characters transmitted as a package? A dihybrid cross, which is a cross between F1 dihybrids, shows that the F2 offspring do not transmit their alleles in the same combinations in which they inherited their alleles from the P generation. Thus, the 2 paris of alleles segregate independently of each other, i.e. genes are packaged into gametes in all possible allelic combinations, as long as each gamete has one allele for each gene. In this case, the organism produces 4 gametes (YR, Yr, Ry, and ry) in equal amounts. - The phenotypic ratio of a dihybrid cross for organism heterozygous for both trials (YyRr) is 9:3:3:1. - Thus, alleles for one gene are sorted into gametes indecently of the alleles of other genes. The Law of Independent Assortment, in other words, states that 2 or more gens assort independently (that is, each pair of alleles segregates independently of each other pair of alleles) during gamete formation. - This law applies only to genes (allele pairs) located on different chromosomes (non homologous chromosomes), or to genes that are very far apart on the same chromosome.

Mendel's model

- Mendel developed a model to explain the 3:1 inheritance pattern he observed among F2 offspring. We described 4 related concepts making up this model. - (1) Alternative versions of genes account for variations in inherited characters. For example, many genes exist in 2 versions (e.g. white and purple flower color). These alternative variousness of a gene are called alleles. Each gene is a sequences of nucleotides at a specific place, or locus, along a particular locus; that DNA at that locus can vary slightly in its nucleotide sequence, and this variation in information content can affect the function of the encoded protein and thus the phenotype of the organism. - (2) For each character, an organism inherits two copies (i.e. 2 alleles) of a gene, one from each parent. Each somatic cell in a diploid organism has 2 sets of chromosomes, one set inherited from each parent. Thus, a genetic locus is actually represented twice in a diploid cell, one on each homolog of a specific pair of chromosomes. The 2 alleles at a particular locus may be identical (as in true-breeding plants) or may differ. - (3) If 2 alleles at a locus differ, then one, the dominant allele, determines the organism's appearance; the other, the recessive allele, has no noticeable effect on the organism's appearance. - (4) The law of segregation states that the 2 alleles for a heritable character segregate (separate from each other) during gamete formation and end up in different gametes. Thus, a sex cell gets only one of the 2 alleles that are present in the somatic cells of the organism making the gamete. If an organism has identical allies for a particular character (the organism is true-breeding), then that allele is present in all gametes. But if different alleles are present, then 50% of the gametes receive the dominant allele and 50% receive the recessive allele. - Punnett square: a diagram device for predicting the allele composition of offspring from a cross between individuals of known genetic makeup. Capital letters symbolize dominant alleles; lowercase letters symbolize recessive alleles.

Tests for identifying carriers

- Most children with recessive disorders are born to parents with normal phenotypes. Thus, the key to accurately assessing the genetic risk for a particular disease is to find out whether the prospective parents are carriers of the recessive allele. - There are now tests that can be used to identify carriers of certain disorders, such as Tay-Scahs, sickle-cell, and the most common form of cystic fibrosis.

Multiple alleles

- Most genes exist in more than 2 allelic forms, e.g. ABO blood groups. - Denoted with an I, e.g. IA, IB, or ii (O type blood). - 4 blood types: A, B, AB, and O. These letters refer to carbohydrates found on the surface of red blood cells.

Pleiotropy

- Most gens have multiple phenotypic effects, a property known as pleiotropy. E.g. Pleiotropy is responsible for multiple symptoms associated with hereditary diseases in humans, such as cystic fibrosis and sickle-cell disease. - Pleiotropy: a single gene can affect a number of characteristics.

Multiplication and addition rules in monohybrid crosses

- Multiplication rule: to determine the probability of 2 or more indent events occurring together, we multiply the probability of one event (1/2) by the probability of the other event (1/2) to produce the probability that both will occur (1/2 x 1/2 = 1/4). - The F1 gametes combine to produce offspring in 2 mutually exclusive ways: for any particular heterozygous F2 plant, the dominant allele can come from the egg OR the sperm, but not both. According to the addition rule, the probably that one will occur is calculated by adding their individual probabilities. The probably for one way of obtaining an F2 heterozygote (the dominant all from the egg, the recessive from the sperm) is 1/4; the probability of the reverse is also 1/4. Using the rule of 1/4, we can calculate the probability of F2 heterozygote as 1/4 + 1/4 = 1/2.

Pedigree analysis

- Pedigree: a collection of information about a family's history for a particular trait assembled into a tree describing the traits of parents and children across generations. - If a trait is recessive, and both parents have the recessive phenotype, then all of their offspring must have the recessive phenotype. If a trait is dominant and both parents are heterozygous for the phenotype, then some of the offspring can be homozygous recessive and not exhibit the dominant phenotype. - If a trait is recessive, and both parents are heterozygous for the trait, they both may not exhibit the phenotype, but their offspring might. If a child has a phenotype that is a due to a dominant allele, then at least one parent also has to exhibit that phenotype. - A pedigree allows us to calculate the probability that a future child will have the particular genotype and phenotype. We calculate this chance with the help of Punnett squares.

Multifactional disorders

- People are susceptible to disease that have a multifactorial basis: a genetic component plus a significant environmental influence, e.g. heart disease, diabetes, cancer, alcoholism, certain mental illnesses, and more. In these cases, the hereditary component is polygenic. - For example, many genes affect cardiovascular health, making some of us more prone that others to heart attacks and strokes, but our lifestyle has a tremendous effect on phenotype for cardiovascular health and other multifunctional characters.

Polygenic inheritance

- Polygenic inheritance: multiple genes independently affect a single trait. - For many characters, such as skin color or height, vary in the population in gradations along a continuum; these are called quantitative characters. - Quantitative variation usually indicates polygenic inheritance, an additive effect of 2 or more genes on a single phenotypic character. - In a way, this is the opposite of pleiotropy, where a single gene affects several phenotypic characters. - For skin color, AABBCC is very dark, aabbcc is very light, and other variations are in between.

Recessively inherited disorders

- Recessively inherited disorders range in severity from relatively mild (albinism) to life-threatening (cystic fibrosis). - An allele that causes a genetic disorder either codes for a malfunctioning protein or no protein at all. In recessive disorders, heterozygotes are usually normal in phenotype because one copy of the normal allele (the dominant one) produce enough of the necessary protein. Thus, a recessively inherited disorder only shows up in homozygous recessive individuals who inherit one recessive allele from each parent. - Carriers: heterozygotes who are phenotypically normal but carry and may transmit the recessive allele to their offspring. - Most people who have recessively inherited disorders are born to parents who are carriers of the disorder but have a normal phenotype. A mating between 2 carriers means that there's a 25% chance their offspring will exhibit the recessive disorder. 50% of their offspring will also be carriers. - Homozygous recessive individuals account for a much smaller percentage of the population than heterozygous carriers. - Genetic disorders aren't evenly distributed among all groups of people. This is because groups of people have different genetic histories from when populations were more geographically (and therefore genetically) isolated. - The probability of passing on recessive traits (which is very unlikely in the general population) becomes significantly more likely if 2 people who have recent common ancestors mate; this i because they are more likely to carry the same recessive alleles. (Consanguineous = same blood; indicated by double lines in a pedigree). - Many deleterious alleles have such severe effects that a homozygous embryo spontaneously aborts long before birth.

Sickle-cell (recessive)

- Sickle-cell disease is the most common inherited disorder among people of African descent. - Caused by the substitution of a single amino acid in the hemoglobin protein of red blood cells. In homozygous individuals, all hemoglobin is of the sickle-cell (abnormal variety). When oxygen content is low in an affected individual, the sickle-cell hemoglobin proteins aggregate into long fibers that deform the red cells not a sickle shape, which may clog small blood vessel, leading to physical weakness, pain, organ damage, and paralysis. - Regular blood transfusions can help prevent damage, while drugs can help prevent or treat other problems. - Two sickle-cell alleles are needed for an individual to manifest full-blown sickle-cell disease, but the presence of one sickle-cell allele can affect the phenotype. Thus, at the organismal level, the normal allele is incompletely dominant to the sickle-cell allele. At the molecular level, the 2 allele are do dominant, since both normal and sickle-cell hemoglobins are made in heterozygotes (carriers). - Why is the sickle-cell allele so prominent? One hypothesis is that it reduces the frequency and severity of malaria attacks, especially among young children.

Newborn screening

- Some genetic tests can be detected at birth by simple biochemical tests, such as testing for phenylketonuria (PKU), a recessively inherited disorder that doesn't allow the body to metabolize the amino acid phenylalanine properly. this compound and its by-product, phenylpyruvate, can accumulate to toxic levels in the blood, causing intellectual disability. However, if PKU is detected in a newborn, a special diet low in phenylalanine will usually allow normal development.

Environmental impact on phenotype

- Sometimes a phenotype depends on environment as well as genotype. E.g. a tree's leaves vary in size and greenness depending on their exposure to wind and sun. For humans, nutrition influences height, exercise alters, built, etc. Even identical twins accumulate phenotypic differences as a result of their unique experiences. - Whether human characteristics are more influenced by genes or the environment is debatable. However,r a genotype generally isn't associated with a rigidly defined phenotype, but a range of phenotypic possibilities due to environmental influences (number of blood cells), while others are not (blood type). - Phenotypic range, in general, is broadest for polygenic characters. Geneticists refer to such characters as multifunctional, meaning that many factors, both genetic and environmental, collectively influence phenotype.

The law of segregation

- The "heritable factor" for the recessive trait is no destroyed, deleted, or blending in the F1 generation, but merely masked by the presence of the factor of the dominant trait. - 3:1 ratio in the F2 generation of a true-breeding P generation. - Allele pairs separate or segregate during gamete formation, and randomly unite at fertilization. - 4 main points related to this concept: (1) A gene can exist in more than one form, (2) Organisms inherit two alleles for each trait (one from each parent), (3) When sex cells are produced (by meiosis), allele pairs separate leaving each cell with a single allele for each trait, and (4) When the two alleles of a pair are different, one is dominant and the other is recessive.

Introduction

- The blending hypothesis: genetic material contributed by 2 parents mixes. - The gene idea: parents pass on discrete heritable units (genes) that retain their separate identities in offspring.

Testcross

- The breeding of an organism of an unknown genotype with a recessive homozygote. - Used to find out the genotype of an unknown organism. - The organism is crossed with a recessive homozygous organism.

Frequency of dominant alleles

- The dominant allele is not necessarily more common than the recessive allele in a gene pool, e.g. polydactyly (being born with extra fingers or toes). The dominant allele for polydactyly is far less common than the recessive allele for five fingers and toes based on statistics of babies born with extra appendages.

Probability laws

- The probability scale ranges from 0 to 1: an event that is certain to occur has a probability of 1; an event that is certain not to occur has a probability of 0. - The probability of all outcomes in a scenario must add up to 1. - The outcome of any particular event is unaffected by what has happened on previous trials; they are independent events. - The alleles of one gene segregate into gametes independently of another gene's alleles.

Mendelian view of heredity and variation

- The term phenotype can refer not only to specific characters, such as flower color, but also to an organism in its entirety: its appearance, internal anatomy, physiology, and behavior. - Similarly, the term genotype can refer to an organism's entire genetic makeup, not just its alleles for a single genetic locus. In most cases, a gene's impact on phenotype is affected by other genes and by the environment. Thus, an organism's phenotype reflects its overall genotype and unique environmental history. - Mendel's 2 laws (law of segregation and law of independent assortment) explain heritable variations in terms of alternative forms of genes (i.e. alleles) that are passed along, generation after generation, according to the simple rules of probability. We can extend the principles of segregation and independent assortment to help explain hereditary patterns as epistasis and quantitative characters.

Epistasis

- Two or more genes can be involved isn determining a particular phenotype. - Epistasis: one gene affects the phenotype of another because the 2 gene groups interact; the phenotypic expression of a gene at one locus alters that of a gene at a second locus. - E.g. color in labradors. Brown (bb). There is a second gene, E that determines whether or not pigment will be deposited. The dominant allele, E, results in deposition of black or brown pigment, depending on the genotype at the first locus. But if the lab's homozygous recessive for the second locus (ee), then the coat is yellow, regardless of the genotype at the first locus (black or brown). In this case, the gene for pigment deposition is said to be epistatic to the gene that codes for black or brown pigment. - All epistatic interactions produce phenotypic ratios that are modifications of 9:3:3:1 (if the parents are heterozygous for both traits).

Counseling based on Mendelian genetics and probability rules

- When we use Mendel's laws to predict possible outcomes of matings, it's important to remember that each child represents an independent event in the sense that its genotype is unaffected by the genotypes of older siblings.