Nancy Padian PhD, MPH

• Adjunct Professor, Epidemiology

https://publichealth.berkeley.edu/people/nancy-padian/

Six connexins combine to form one connexon that extends from the plasma membrane of one cell to dock with a connexin of an adjacent cell anxiety head pressure best 10mg atarax, creating an intercellular gap (88) anxiety yelling 10 mg atarax free shipping. B: Expression of Cx43 (green) and -actinin (red) at different stages of human cardiac development anxiety symptoms for years generic atarax 25 mg line. Cx43 progressively relocalizes from the myocyte lateral membrane toward the intercalated disc (Upper left anxiety symptoms peeing buy generic atarax 25mg line, 10 anxiety symptoms natural remedies atarax 25mg visa. Arrows indicates less intense staining in the intercalated disc at the age of 5 years compared to the intensity of lateral signals anxiety videos buy atarax 10 mg with mastercard. Assembly of the cardiac intercalated disc during pre- and postnatal development of the human heart. During cardiac myocyte development and maturation, large changes in the spatiotemporal distribution of gap junctions, desmosomes, and adherens junctions occur. In the mature myocardium, all three are clustered in a bipolar pattern (perpendicular to the long axis) on the ends of the myocyte. However, during embryologic development, adherens junctions are also found on the lateral membranes where they seem to be able to sense mechanical forces along the transverse axis and are thought to play an important role in myofibrillogenesis (63,93). At the perinatal stage, the adherens junctions no longer surround the entire cell, but are restricted to intercalated discs between cells. Interestingly, this polarization coincides temporally with an increase in cardiac output at birth to support the needs of the newborn, suggesting that maturation of contractility provides mechanical inputs for cadherin movement to the longitudinal border (63). Most of the adherens junction proteins were completely localized to the intercalated disc by 12 months after birth. In contrast, there was sparse, diffuse connexin-43 expression in fetal hearts that gradually increased after birth but does not fully segregate to the intercalated disc until 7 years of age (94). The functional implications of these differences are unclear, but may partially explain the ability of neonatal cardiac myocytes to propagate electrical impulses in both the longitudinal and perpendicular axes ("isotropic"), compared to the "anisotropic" adult myocytes that predominantly exhibit longitudinal impulse conduction (94,95). Mutations in proteins in the adherens junctions are associated with heart failure and dilated cardiomyopathy (84). Coronary Vasculature the spontaneously contracting heart tube is initially formed as an avascular organ. The cells that form the tissues of the coronary system move onto the surface of heart after the looping stage of cardiogenesis, making first contact at the future site of the atrioventricular septum. The specific origins of the coronary endothelial cells have been the rigorously debated; as a number of different approaches for determining their origins have resulted in conflicting conclusions (99,100,101). Regardless of the cellular origins, the signals that regulate coronary development are derived from both the epicardium and cardiac myocytes (99). Both metabolic (hypoxia) and mechanical factors stimulate growth factors that promote angiogenesis (102). The coronary vessels begin to coalesce from mesenchymal cells via vasculogenic processes in the extracellular matrix-rich, subepicardial space between the epicardium and the myocardium (105). The subepicardial space is not only the initial site of coronary vessel formation, but also the site of large-caliber coronary vessels in adults. Once aortic perfusion has been established, these capillary beds quickly remodel into the left and right main coronary arteries and subsequent coronary vessels. In rodents this remodeling of capillary beds into muscular arteries happens over the course of hours. The signaling mechanisms that direct early coronary capillary beds to surround the aorta instead of the other great vessels such as the pulmonary artery are not clear. Nor is it unclear how the cusps are selected for coronary artery investiture and why one cusp is avoided. The noncoronary cusp is deeply embedded in the atrioventricular septum, specifically the annulus fibrosus, and thus the capillary beds have limited access to this sinus of the aortic valve. However, how atypical coronary vascular patterns affect cardiac performance or health are not always clear. It is generally thought that once formed, the coronary vessels sprout from their location in the subepicardial space and dive into the forming compact myocardium so that each cardiac myocyte is proximal to a capillary via angiogenic processes. Presumably, hemodynamics drive the rapid remodeling of the coronary capillary beds into the large-caliber main coronary arteries and the formation of the coronary system. Physiologic feedback between the myocardium and coronary vessel development is also affected by mechanical stimuli. As blood flows through the developing vessels, endothelial cells are exposed to shear stress, which is a function of fluid flow velocity and viscosity. Endothelial cells are equipped with a variety of "mechanosensors" that respond to shear stress and stimulate the expression of a variety of genes required for endothelial function and differentiation of arteries and veins (111). In humans, the number of arterioles and capillaries steadily increases during the first postnatal year (112). Myocardial Growth and Remodeling Cardiac myocytes display two types of growth during the fetal and neonatal transitioning from a proliferative phase to a hypertrophic phase. After their formation, the myocardial cells of the primitive heart tube undergo region-specific growth that drives cardiac morphogenesis (115). During this proliferative phase, mitosis and cell division are coupled as the myocardium rapidly expands. A second wave of mitosis without cytokinesis follows this phase and generates binucleated cardiac myocytes (116,117). Thus, myocardial growth transitions from cell division to cell hypertrophy during the perinatal period. An intermediate phase is associated with the binucleation of cardiac myocytes, which are particularly evident in ventricular myocytes (116). As cardiac myocytes are exiting the proliferative growth phase during the postnatal period, the myocardial mass dramatically increases. At the cellular level, cardiac myocytes are growing via hypertrophic mechanisms, adding sarcomeres in series (lengthwise) and in parallel (widthwise) (121). Also during this phase of heart development, interstitial fibroblasts begin to increase in cell number, becoming the predominant cell type of the myocardium (122). The postnatal myocardium has a limited ability to regenerate; however, as mentioned above, data support the concept that, the younger the myocardium, the more plastic and capable of reinitiating cardiac myocyte proliferation. Indeed, studies in neonatal mice found that the ability to regenerate after a traumatic injury (apical dissection) is lost by neonatal day 7, a time point that coincides with the loss of cardiac myocyte proliferative capacity (118,123,124). Neonatal mice are also capable of undergoing cardiac regeneration following myocardial infarction (125). Studies in humans have largely been hampered by the lack of available tissue from normal hearts. As expected, the number of cardiac myocytes in mitosis and cytokinesis were highest in infants and decreased to very low level by 20 years of age (127). These findings raise the exciting possibility that therapies targeting myocyte proliferation could be used to regenerate the myocardium in children and adolescents with congenital heart disease. It is becoming increasingly evident that miRs are important regulators of cardiac growth and function (4). For example, the miR15 family members have been found to act as potent inhibitors of cardiac myocyte proliferation by repressing the expression of multiple cell cycle genes (123). Thyroxine (T4) is released by the thyroid gland and is converted to the biologically active form T3 by deiodinases in the myocardium. Cell Death and Myocardial Structure Cells of the heart can die by either necrosis, apoptosis (programmed cell death), or autophagy (132). Apoptosis is a key mechanism of cardiomyocyte loss in adult heart failure and is associated with cell shrinkage and fragmentation into membrane-associated apoptotic bodies. In contrast, necrosis is associated with organelle swelling and loss of plasma membrane integrity leading to an inflammatory response (133). Both intrinsic (controlled by mitochondrial activity) and extrinsic (receptor-mediated) apoptotic pathways regulate necrosis and apoptosis (134). Regulatory proteins on the mitochondrial pathway include caspases (3,6,9) as well as proteins encoded by the mammalian Bcl-2 family of antiapoptotic genes (132). The extrinsic pathway involves tumor necrosis factor- or the Fas-ligand binding to their respective cell surface receptors (135). Autophagy is a lysosomal-mediated self-digestion process by which cells break down long-lived proteins and organelles. Regulated cell death is now recognized as important for normal cardiac development (136). During development, precursor cells are recruited to the heart where they proliferate and differentiate into cardiac myocytes, fibroblasts, smooth muscle cells, as well as endocardial and endothelial cells. Proper cardiovascular remodeling during development requires strict coordination between the ratio of proliferation/differentiation and temporal activation of apoptotic events. In this scenario, programmed death to remove "unfit" or defective cells is necessary to maintain a healthy myocardium during development and maturation (137). They concluded that there is a delicate balance between myocyte proliferation and death, and that this is a key mechanism in maintaining a proper heart weight/body weight ratio. Indeed, myocyte apoptosis remains relatively high up to 6 months after birth prior to declining into adulthood. Overall, it is clear that apoptosis plays a key role in the transition from fetal to postnatal life, and thus may be a target for the design of pharmacologic agents to enhance fetal heart development. Myocardial autophagy reaches a maximum several hours after birth and is thought to maintain organ function and survival in the postnatal starvation period until a consistent nutrient supply is restored via the maternal milk supply (141). Myocardial Function E-C coupling refers to the process that couples an action potential (excitation) with an intracellular Ca2+ transient and subsequent crossbridge cycling and contraction. In this section we will first provide an overview of E-C coupling in the mature myocardium, and then discuss how this process changes during development. The "excitation" component of E-C coupling depends upon the macromolecular complex termed the Ca2+ release unit. During E-C coupling, thousands of Ca2+ sparks are synchronized by the action potential, such that the local rises in [Ca2+]i completely overlap in time and space, making the Ca2+ transient appear uniform (28). As discussed in previous sections, the "contraction" portion of E-C coupling is mediated by sarcomeres. During myofilament activation, Ca2+ binds to Tn subunit TnC, resulting in a conformational change that releases the thin filament regulatory protein cTnI. This "untraps" tropomyosin, exposes myosin binding sites on actin, and leads to formation of weakly bound crossbridges. As tropomyosin is moved further into the actin groove, stronger crossbridges are formed (144). Diastolic relaxation is largely controlled at the myocyte level by changes in Ca2+ cycling, myofilament Ca2+ desensitization, and increased kinetics of crossbridge cycling. The amount of force developed depends on the amplitude and duration of the Ca2+ transients and the Ca2+ sensitivity of the myofilaments. Myofilament Ca2+ sensitivity is largely determined by the type of Tn isoform present. For instance, the presence of slow skeletal TnI in embryonic and early postnatal hearts is associated with an increased Ca2+ affinity and a decreased rate of Ca2+ dissociation from TnC (149). Conversely myofilament Ca2+ sensitivity is reduced by acidosis (28) and increased in response to a new class of inotropic drugs including levosimendan (150). Assembly of the mature E-C apparatus accelerates at birth and is completed in the rodent within 4 weeks. These oscillations may lead to subsarcolemmal release of Ca2+ from ryanodine receptors to elicit spontaneous contractions (153). Regulation of E-C Coupling As the heart continues to mature following birth, there are considerable changes in myocardial performance. The myocardium increases contractility, diastolic relaxation, volume, and cardiac output. These postnatal changes in cardiac function reflect the developmental regulation of ion channels, receptors for neurotransmitters, and alterations in cell signaling cascades. Multiple mechanisms underlie these phenotypic changes and are classified as intrinsic. The underlying cellular mechanisms are related to rate-dependent changes in Ca2+ availability (21) and myofilament Ca2+ sensitivity (157). Quite simply, this relationship describes the observation that when cardiac myocytes are stretched longitudinally, they develop proportionally more force at a given P. The molecular mechanisms that underlie this intrinsic regulatory mechanism are unclear, but have been proposed to involve myofilament lattice spacing (increase in the local concentration of myosin heads due to longitudinal stretch), titin (exertion of radial force at long sarcomere lengths to pull thick and thin filaments together), or increased Ca2+ sensitivity of the thin filament (159). Autonomic Innervation the sympathetic and parasympathetic nervous systems work in a reciprocal manner to regulate heart rate and contractility. The secretion of local trophic growth factors is crucial for normal sympathetic innervation. Interestingly, innervation is also modulated by "neurorepellants" such as semaphorin 3a (Sema3a) that inhibit neuronal growth. In fact Sema3a may be partly responsible for patterning of sympathetic innervation in an epicardial-to-endocardial gradient since Sema3a-deficient mice exhibit disrupted spatial patterning (163). The main neurotransmitters of the sympathetic nervous system are norepinephrine in presynaptic nerves and acetylcholine in postsynaptic ganglia (161). Similar to humans, the rodent heart expresses predominantly 1adrenergic receptors with a small fraction (15% to 25%) of 2-receptors (164).

The mobilization genes allow ColE1 to be transferred from cell-to-cell during conjugation mediated by the F-plasmid anxiety scale 0-10 cheap generic atarax canada. Most Colicins Kill by One of Two Different Mechanisms the Col plasmids allow the strains of E anxiety symptoms zoloft discount atarax 10mg fast delivery. A gene on the ColE1 plasmid encodes the colicin E1 protein that inserts itself through the membrane of the target cell and creates a channel allowing vital cell contents anxiety symptoms for a week purchase atarax 10 mg on-line, including essential ions anxiety symptoms talking fast purchase atarax 10 mg with amex, to leak out and protons to flood into the cell anxiety fatigue best 25 mg atarax. It blocks the active site of the colicin thus preventing the cell from killing itself social anxiety buy cheap atarax 10 mg line. A single molecule of colicin E1 that penetrates the membrane is enough to kill the target cell. Colicin M and Pesticin A1122 destroy the peptidoglycan of the cell wall rather than puncturing the cytoplasmic membrane. These colicins need to penetrate only as far as the outer surface of the cytoplasmic membrane. The ColE2 and ColE3 plasmids both encode nucleases, enzymes that degrade nucleic acids. The colicin E2 and E3 proteins are very similar over their N-terminal region and as a result they share the same receptor on the surface of sensitive bacteria. This abolishes protein synthesis and though much more specific than colicin E2, is just as lethal. Again, a single colicin molecule that enters the victim is enough to kill the target cell. Bacteria are Immune to Their Own Colicins Those bacterial cells producing a particular colicin are immune to their own type, but not to other types of colicin. Immunity is due to specific immunity proteins that bind to the corresponding colicin proteins and cover their active sites. For example, the ColE2 plasmid carries genes for both colicin E2 and a soluble immunity protein that binds colicin E2. This immunity protein does not protect against any immunity protein them harmless Protein that provides immunity. In particular bacteriocin immunity proteins bind to the corresponding bacteriocins and render 5. Plasmids May Provide Aggressive Characters 639 other colicin, including the closely-related colicin E3. Immunity to membrane active colicins is due to a plasmid-encoded inner membrane protein that blocks the colicin from forming a pore in the host cell. For example, the Ia immunity protein protects membranes against colicin Ia but not against the closely-related colicin Ib even though colicins Ia and Ib share the same receptor, have the same mode of action, and have extensive sequence homology. Although the immune systems of animals are much more complex, the concept of immunity is based on the ability of immune system proteins to recognize and neutralize specific alien or hostile molecules. Bacteria that make bacteriocins also make immunity proteins to protect themselves. Colicin Synthesis and Release In a population of ColE plasmid-carrying bacteria, most cells do not produce colicin. Every now and then an occasional cell goes into production and manufactures large amounts of colicin. Note that it is the burst and release mechanism that kills the producer cell, not the colicin. All sensitive bacteria in the area are wiped out, but those with the ColE plasmid have immunity protein and survive. Thus, release of colicin E is a communal action in the sense that a small minority of producer cells sacrifice themselves so that their relatives carrying the same ColE plasmid can take over the habitat. Colicin-E production involves expression of two plasmid genes, cea (colicin protein) and kil (lysis protein). These colicins tend to remain attached to the surface of the producer cell rather than being released as freely-soluble proteins, like the E colicins. When the producer bumps into a sensitive bacterium the colicin may be transferred, with lethal results. Virulence Plasmids Virulence plasmids help bacteria infect humans, animals, or even plants, by a variety of mechanisms. Some virulence factors are toxins that damage or kill animal cells, others help bacteria to attach to and invade animal cells. There is a similar variety of adhesins or "colonization factors," proteins that enable bacteria to stick to the surface of animal cells. Adhesins form filaments that vary in length and thickness, but generally resemble pili. Many pathogenic bacteria carry genes for virulence on plasmids or other mobile genetic elements. Same as colonization factor choleratoxin Type of toxin made by Vibrio cholerae the cholera bacterium colonization factor Protein that enables bacteria to attach themselves to the surface of animal cells. Same as adhesin enterotoxins Types of toxin made by enteric bacteria including some pathogenic strains of E. The bacteria contain plasmids that encode adhesins, which are protein filaments able to recognize and attach to cell-surface receptors found on animal cells. Once attached, the bacteria secrete toxins, which can penetrate the animal cell membrane and kill the cell. In Salmonella the majority of the virulence genes are on the chromosome, but there are also ones that are plasmid-borne. In addition to toxins and adhesins, these "professional" pathogens possess more sophisticated virulence factors that protect against host defenses. Although plasmids have been investigated most intensively in enteric bacteria, it is clear that virulence in many other bacteria often depends on at least some plasmid-borne genes. Therefore, many plasmids are degraded or destroyed after they are transferred to an incompatible cell. The Ti plasmid is carried by soil bacteria of the Agrobacterium group, in particular A. This results in tumorlike swellings on the stems of infected plants, a condition known as "crown gall disease. Plasmid that is carried by soil bacteria of the Agrobacterium group and confers the ability to infect plants and produce tumors 6. This region is transferred into the plant cell by the expression of the transfer genes found on the other part of the Ti plasmid. It then enters via the wound and transfers a portion of the Ti plasmid into the plant cell by a mechanism similar to bacterial conjugation. A slight abrasion that is trivial to the health of the plant is of course sufficient for the entry of a microorganism. The result is a crown gall tumor that provides a home for the Agrobacterium at the expense of the plant. Consequently, Ti plasmids have been widely used in the genetic engineering of plants. This activates VirG, which in turn switches on the other vir genes, including virD and virE2. The mechanism resembles bacterial conjugation and the "virulence" genes of the Ti-plasmid are equivalent to the tra genes of other plasmids. Only part of the Ti plasmid enters the plant cell, where it integrates into the plant chromosomes. The bacteria enter the plant through the open wound, and begin colonizing the area. When this happens rapidly in the absence of normal cell differentiation, the result is a tumor. These are unusual nutrient molecules that are made at the expense of the plant cell but can only be used by bacteria that carry special genes for opine breakdown. The genes for opine degradation are found on the part of the Ti plasmid that does not enter the plant cell. Other bacteria that might infect the plant are also excluded as they do not have opine breakdown genes either. The genes for plant hormones and opine synthesis are removed and the genes to be transferred into the plant are inserted in their place. In practice, Agrobacterium carrying an engineered Ti plasmid is used to transfer genes of interest into plants using plant tissue culture. In addition to inserting external genes into plants the Ti plasmid system may be used for analysis of plant gene function. The model plant, Arabidopsis thaliana, has been used to auxin Plant hormone that induces plant cells to grow bigger cytokinin Plant hormone that induces plant cells to divide 6. The genes for auxin and cytokinin are growth factors that induce the plant cells to grow at the site of infection, providing the space. These include insertions into almost all of the estimated 27,000 genes of Arabidopsis. These insertions may be used to investigate the functions of the inactivated genes by comparing the knockout mutants with the parental wild-type plant. Yeast, some filamentous fungi, and the cultivated mushroom Agaricus have all successfully received the Ti plasmid by conjugation from Agrobacterium. Whether the Ti plasmid can be transferred from Agrobacterium to eukaryotes other than plants in the natural environment is unknown. Laboratory data suggest that if this does happen it will be at much lower frequency than to the "natural" plant hosts. The 2 Plasmid of Yeast Plasmids are found in higher organisms, although they are less common than in bacteria. The yeast Saccharomyces cerevisiae has been used as a model organism for the investigation of eukaryotic molecular biology. The 2 plasmid has been widely used in genetic engineering as the basis for multicopy eukaryotic cloning vectors. The 2 plasmid contains two perfect inverted repeats of 599 bp that separate the plasmid into two regions of 2774 and 2346 bp, respectively. Flp is functional in bacteria, plants, and animals provided the correct recognition sites are present. P1 can exist in a lysogenic state as a plasmid, using bidirectional replication to divide when the host cell divides. During such lytic growth, P1 divides by the rolling circle mechanism, creating a large number of copies. It then packages genome-sized units into new virus particles and lyses the bacterial cell. This is known as lytic growth since the host cells are "lysed" (derived from the Greek word for broken). Alternatively, P1 can choose to live as a plasmid and divide in step with the host cell. This state is known as lysogeny and a host cell containing such a virus in its plasmid mode is called a lysogen. Changing conditions may stimulate a lysogenic virus to return to destructive virus mode. The virus decides to make as many virus particles as possible before the cell dies. If, on the other hand, the host cell is growing and dividing in a healthy manner, the virus will most likely decide to lie dormant and divide in step with its host. Many larger plasmids make toxins that kill the cell if the plasmid is lost, a phenomenon referred to as plasmid addiction. Colicin plasmids carry genes for toxic proteins that bacteria use to kill related bacteria. Bacteria are immune to the colicins they produce themselves due to synthesis of a specific immunity protein. Virulence plasmids carry genes that enable bacteria to damage the host animal or plant cell. Ti plasmids are transferred from bacteria to plants and hence are used for the genetic engineering of plants. The best-known plasmid of yeast is the 2 plasmid that is widely used in genetic engineering. Same as latency, but generally used to describe bacterial viruses lysogen Host cell containing a lysogenic virus lytic growth Growth of virus resulting in death of cell and release of many virus particles Review Questions 647 Review Questions 1. What is the term used to describe the ability of a plasmid to move from one cell to another What is the difference between linear plasmids in bacteria and linear chromosomes What are some examples of plasmid-encoded genes that are beneficial to a host cell What is the usual difference between antibiotic resistance due to chromosomal mutations and plasmid-borne resistance to antibiotics How does the mechanism of tetracycline resistance differ from chloramphenicol and aminoglycosides Why does tetracycline not affect human cells even though it is able to inhibit human cell ribosomes What would happen to the bacterial cell if the genes for immunity proteins were not present What compound attracts Agrobacterium tumefaciens to a wounded plant and also induces virulence gene expression Why is the relationship between Agrobacterium tumefaciens and the infected plant not considered a symbiotic relationship Describe the ways in which the bacteriophage P1 can live as either a virus or a plasmid. Fill in the following table: Bacterialresistance proteins Antibiotic How it kills bacteria Mechanism of bacterial resistance proteins tetracycline kanamycin sulfonamide chloramphenicol neomycin 2. Many different naturally-occurring antibiotic resistance genes are used as genetic markers in laboratory experiments. In order to study promoter elements, promoters are fused to genes encoding different enzymes so when the promoter is active the enzyme is made. Using your knowledge of its function in resistant bacteria, discuss how you would use the cat gene to make promoter fusions. He decided to clone each gene and put it into a plasmid so that he can express it in bacteria. He takes all the bacteria he transformed and plates them onto ampicillin and chloramphenicol. The following two plasmids were created by the lab down the hall from where you work. They give you the following map, but do not give you any information of how to grow the bacteria after you transform the plasmid into E.

Consequently anxiety upset stomach discount 10 mg atarax fast delivery, an elaborate process is needed to disassemble the nucleus anxiety symptoms every day atarax 10 mg low cost, replicate the chromosomes anxiety symptoms confusion order atarax online from canada, partition them among the daughter cells anxiety quiz purchase atarax 10 mg line, and finally anxiety symptoms before sleep discount 10mg atarax with visa, reassemble the nuclear envelope anxiety young living purchase atarax with amex. Disassembly of the nuclear membrane of the mother cell Alignment of the chromosomes at the center axis Partition of the chromosomes Reassembly of nuclear membranes around each of the two sets of chromosomes Final division of the mother cell, or cytokinesis Mitosis itself is only one of several phases of the eukaryotic cell cycle. The S-phase is separated from the actual physical process of cell division (mitosis or M-phase) by two gap phases, or G-phases, in which nothing much appears to happen (except the normal processes of cellular activity and metabolism). The result is a complex cell cycle that includes dissolution and reassembly of the nucleus as well as duplication of the chromosomes. The -subunit (DnaQ) of the core enzyme has proofreading ability and 3-exonuclease activity to ensure that replication is accurate from generation to generation. In bacteria, there is one origin of replication that has three 13-base pair repeats and four 9-base pair repeats. This complex of enzymes removes the new incorrect nucleotide and replaces it with the correct one. Hemi-methylation of the origin of replication helps control how often bacterial chromosomes are replicated. Replication finishes at the terminus, which has several termination sites and the Tus protein. Circular chromosomes of bacteria can tangle during replication or even become covalently joined due to odd numbers of crossovers. The post-translational modifications to histones are also faithfully reconstructed by methyltransferases, acetyltransferases, and other histone modification enzymes. What is the fate of linear chromosomes in most bacteria and how are they protected in some bacteria The results are shown below: lightest heaviest Control Experiment (only regular nitrogen) E. If each replication fork travels at 2000 nucleotides per minute, how many replication forks would be needed to copy the entire chromosome 4 in 20 minutes Label each of the numbered ends of the diagram with either 5 or 3, and indicate which strand is a leading strand and which strand is a lagging strand for the replication fork. For unicellular organisms, the division of the cell results in a new, complete organism. Additionally, the cells of multicellular organisms are able to divide by two distinct processes, with different results dependent upon the final goal. Mitosis is a form of cell division that is used by a majority of cells in the multicellular body to add mass or repair tissue. During mitosis, two daughter cells are produced, each being genetically identical to the parent cell. The other form of cell division, called meiosis, produces four cells that only contain half the number of chromosomes of the parental cell. This type of cell division occurs in germ cells for the production of gametes, sperm and egg. Replication forks can travel in either direction along a double-stranded template. The separation occurs at the origin of replication (oriC) by the replisome, which is a large complex of enzymes with various functions that will be discussed in the next few Key Concepts. The opened double helix forms a replication bubble at the oriC, with each end of the bubble having a replication fork. Replication occurs at both replication forks simultaneously and proceeds in opposite directions. Each replisome at each replication fork is synthesizing both (opposite) strands simultaneously, but the entire replisome is moving in the same direction. The two outermost phosphate groups (and phosphates) are removed to form pyrophosphate. The synthesis of the nucleotides needed in replication is a target for some pharmaceuticals. Methotrexate, trimethoprim, and sulfonamide antibiotics are all examples of pharmaceuticals that target some aspect of nucleotide synthesis. DnaE (subunit) is involved in the phosphodiester bond formation between nucleotides. Finally, HolE (subunit) has an unknown function but likely helps stabilize the -subunit. Leading and Lagging Strands e153 the authors of this associated paper examined the E. Through their investigation, the authors determined the order of clamp-loader assembly. The authors were only able to detect in all four oligomeric states when the ionic strength of the buffer was high. Discussion points One single clamp loader is needed for assembly of the replication complex. For such an important aspect of life, cell division, do you think that these subunits and other proteins involved in replication are conserved across the domains of life This discontinuous synthesis results in the generation of fragments on the lagging strand called Okazaki fragments. As previously discussed in a Key Concept above, the origin of replication (oriC) is the site of replication initiation. Several enzymes localize to the region, most of them involved in the initiation of each new strand. Any erroneous base inserted during replication is recognized by the mismatch repair enzymes. These enzymes recognize the methylated parental strand and use it as a template to remove the incorrect base and insert the correct base on the complementary, new strand. There are different Ter sites for counterclockwise and clockwise movement of the replisome on the circular, bacterial chromosome. The outermost sites likely serve as a backup in case the first Ter sites fail to stop the replication fork from moving forward. Tus binding at the terminus physically blocks helicase from moving forward, thus stalling the replication forks. The Bacterial Cell Cycle e155 Circular chromosomes may become catenated after replication, that is, interlocked, which would prevent the chromosomes from separating into the daughter cells. Similar to eukaryotes, prokaryotic chromosomes can undergo recombination between the two daughter chromosomes while replication is proceeding. An even number of crossing over events is ideal as this leaves two distinct chromosomes. However, if an odd number of crossovers occurs, the two chromosomes can become covalently linked (see textbook. As replication proceeds in both directions around the circular chromosome, eventually the two replication forks meet and the daughter chromosomes separate from each other. Each daughter chromosome remains attached to the interior of the cell membrane, so as each cell elongates, the chromosomes completely separate. One daughter cell is a stalked cell and may begin replication and cell division immediately. The other daughter cell is a swarmer cell and must differentiate into a stalked cell before replication can begin. Additionally, CtrA binds to the origin of replication to silence it in swarmer cells until differentiation has occurred. The regulation of replication in Caulobacter is still largely unknown, although a cascade of two-component regulatory systems seems a likely target. The authors of this associated paper utilize time-lapse fluorescence microscopy to investigate the role each of these proteins plays in replication regulation. The authors used fluorescently-labeled origins of replication and were able to observe, in real-time, the origins of replication for both stalked and swarming cells of Caulobacter. After replication, one origin remained attached at the polar end of the stalked cell, while the second origin of replication (from the other newly synthesized chromosome) moved to the opposite pole. Finally, the daughter swarmer cell must differentiate into a stalked cell before it can initiate replication. The replication cycle of a stalked cell takes about 67 minutes and the replication cycle for a swarmer cell takes about 80 minutes. They did, however, determine that the presence of CtrA in cells that were prohibited from dividing, actually delayed the initiation of replication. The researchers overexpressed DnaA protein in cells and observed the effects on chromosome copy number. The number of chromosome copies per cell significantly increased, indicating a role for DnaA in overinitiation of replication. Overexpression of DnaA was also conducted with fluorescently labeled origins of replication. This suggests that DnaA regulates the initiation of replication independent of CtrA. Replication is silenced in the swarming cell type by the regulatory protein, CtrA, at least until the swarmer differentiates into a stalked cell type and can replicate. Discussion points In Caulobacter, DnaA regulates the initiation of replication and CtrA silences replication in swarmer cells until they differentiate into stalked cells. The authors investigated the effects of overexpression of DnaA protein in Caulobacter. Because of the linear nature of eukaryotic chromosomes, these chromosomes must have special structures to help protect the ends. These are the telomeres, which contain short, tandem repeats of about 6 bases long. Therefore, after each round of replication, the telomeres are shortened by about the length of a primer. As such, multiple origins of replication exist to ensure that the entire chromosome is quickly replicated prior to cell division. Replication initiation in vertebrates is less understood, mostly because Sld2 and Sld3 are not conserved in vertebrates. Another protein, RecQ4, is a homolog of Sld2, but no homolog for Sld3 has been found. Treslin is well conserved in vertebrates but no homolog in budding yeast or other model organisms was found. In addition to replication initiation, what role do you think Treslin might play in checkpoint regulation Both processes are semi-conservative, that is each daughter strand contains one strand from the parent and one newly-synthesized strand. Finally, both eukaryotic and prokaryotic replication complexes use a sliding clamp and clamp-loader complex. In another study, the authors showed that Asf1 interacts with the eukaryotic helicases, which link the histone chaperone to the replication fork. This group also suggests that histones removed during replication are retained near the replication fork by Asf1 complexes until replication is resumed, at which point the histones are recycled. In conclusion, H3K56Ac enhances the interaction with histone posttranslational modification proteins, such as Rtt109, and histone chaperones, including Asf1. After replication, the histones must be reintroduced, along with their posttranslational modifications. Also, what do you think would happen if the histones were reintroduced but never received their appropriate modifications Besides H3, other histone proteins are targeted for posttranslational modifications. The authors examined Gcn5 from Saccharomyces l Eukaryotes control the timing of replication and cell division with a cell cycle. Cell division in eukaryotes is further complicated by the presence of the nucleus, which must be removed prior to the separation of the chromosomes and then reassembled after separation. This is then used to make proteins, the ultimate gene products, by the process of translation, as described in Chapter 13. This allows different genes to be expressed under different conditions and allows the organism to adapt to its surroundings. Regulating gene expression may be extremely complex, especially in higher organisms, and several later chapters (Ch. Here, we limit ourselves to discussing the basic role of regulatory proteins in turning genes on or off. Other names for the antisense strand are the non-coding or template strand; other names for the sense strand are non-template or coding strand. Short Segments of the Chromosome Are Turned into Messages Although a chromosome carries hundreds or thousands of genes, only a fraction of these are in use at any given time. In a typical bacterial cell, about 1000 genes, or about 25% of the total, are expressed under any particular set of growth conditions. Humans have around 22,000 protein coding genes whose expression varies under different conditions and in different tissues. Some genes are required for the fundamental operations of the cell and are therefore expressed under most conditions. In the cells of more complex organisms, which have many more genes than do bacteria, the proportion of genes in use in a particular cell at a particular time is much smaller.

Since the two recognition sites are altered in their flanking regions anxiety management order atarax without prescription, cannot be excised by Int alone but needs another protein anxiety in toddlers buy discount atarax online, known as excisionase or Xis anxiety symptoms 97 purchase atarax 25mg overnight delivery, in addition anxiety symptoms muscle twitching buy 25 mg atarax fast delivery. The first round of cutting and joining gives a Holliday junction and the second round resolves it leading to integration anxiety symptoms vs heart attack symptoms discount 10 mg atarax overnight delivery. Int protein cannot carry out recombination between these hybrid sites and cannot therefore reverse the integration event anxiety symptoms muscle twitches buy genuine atarax. The control of Xis and Int activity determines whether or not stays latent in the bacterial chromosome or emerges and replicates. Recombination in Higher Organisms Recombination in eukaryotes occurs mostly during the early stages of meiosis. For crossing over to occur between the pairs of homologous chromosomes, doublestranded breaks must be introduced into them-a hazardous procedure. Doublestranded breaks appear in eukaryotic chromosomes during the first stage of meiosis (prophase I), known as leptotene, and the paired chromosomes are joined together during the next stage (zygotene) to form the hybrid junction structures needed for recombination. It is assumed that these resemble the Holliday junction of bacteria, but the details are obscure. Resolution of the crossovers then occurs during the third stage of meiosis (pachytene). Finally, the crossovers dissociate, releasing recombinant chromosomes in the final stage of meiosis (diplotene). The breaks disappear as hybrid molecules are made during the zygotene phase of meiosis. Recombinant molecules appear approximately 120 minutes after the appearance of double-stranded breaks. A complex of a dozen or more proteins, many poorly characterized, is needed to generate the double-stranded breaks. In yeast, the Spo11 protein is probably responsible for making the double-stranded breaks. In particular, the Rad51 During meiosis in eukaryotic cells, frequent recombination occurs between pairs of homologous chromosomes. However, recombination during meiosis is 100-fold more frequent and needs additional factors. It has been suggested that alterations in Dcm1 may be responsible for some cases of human infertility. When homologous recombination is defective the frequency of mutations, including chromosome rearrangements, increases. Formation of crossovers requires resolution of the Holliday junction by resolvase enzymes. This paper describes the characterization of two resolvases in budding yeast, Mus81 and Yen1. Mutants in mus81 accumulate meiotic intermediates, although the extent varies in different types of yeast. Budding yeast, where the effect of mus81 mutations is relatively mild, also possesses the Yen1 resolvase, whereas fission yeast where mus81 mutations are severe does not. When both are defective, there is a major increase in the faulty segregation of chromosomes. In other words, when two parents reproduce sexually, different alleles from each parent should appear with equal frequency in the offspring. The mechanism involves the mismatch repair system operating upon the intermediate structures generated by recombination. C) If meiosis occurs before mismatch repair, then the four haploid spores will have two "R" alleles and two "r" alleles. D) If mismatch repair fixes the mistakes, then one of the mismatched bases will be removed and replaced with the correct complementary base (shown in red). E) When mismatch repair fixed the G/T and A/C mismatch, T was changed to C and A was changed to G. F) When mismatch repair fixed the G/T and A/C mismatched base pairs, the G was changed to A and the C was changed to T. If the crossover occurs within the coding sequence of the gene of interest, then heteroduplexes will be formed in which there is a mismatched base. This allows the observation of Mendelian ratios from a single occurrence of meiosis. Alternatively, the mismatch repair system may correct the mismatched base pairs in the heteroduplex region before replication. For example, the G/T mismatch can be repaired back to G/C, which is the sequence for the "r" allele. When meiosis occurs here, the four haploid spores all have the "r" allele, and "R" is not passed onto the next generation. In a similar manner, the other possibility exists where the G/T mismatch is repaired to an A/T, and the A/C mismatch is repaired to A/T also. After meioisis, all four haploid genomes now contain the "R" allele, and "r" is not passed onto the next generation. Such occasional deviations are difficult to detect since gene conversion is equally likely in either direction. Two of these four possible repairs look just like the parent and are not detectable after meiosis. Only the two events on the far left and far right actually skew the Mendelian segregation of the parental genotype. Gene conversion is thought to occur in all or most organisms, but is only detectable under special circumstances. In practice, it is seen most easily in fungi of the Ascomycete group (yeasts, Neurospora, etc. Sexual reproduction results in the formation of a zygote from the fusion of egg and sperm. Meiosis in these fungi then produces a cluster of four spores all derived from the same zygote. These four (or eight) "ascospores" all stay together inside a special bag-like structure, the ascus. It is thus possible to count the Mendelian ratio separately for each group of four (or eight) offspring derived from the same individual zygote. Recombination in higher organisms occurs mostly during the early stages of meiosis by a process similar to that in bacteria. What is the function of the attachment sites on the bacterial chromosome and the lambda genome Explain the mechanism of integration of bacteriophage lambda into the chromosome of E. The one parent has two identical alleles of the dominant gene Sss, and the other parent is heterozygous such that it has one dominant allele Sss, and one recessive allele designated sss. After meiosis, the majority of the resulting asci have four haploid spores with three containing Sss, and one spore with sss. For organisms that undergo sexual reproduction, recombination events during meiosis increase the genetic diversity of the gametes. The resulting offspring after the fusion of gametes have different combinations of alleles, which is advantageous from an evolutionary standpoint. Genetic exchange also occurs in prokaryotes and viruses, even though they do not necessarily have a sexual life cycle. A single crossover only results in a short-lived hybrid molecule and does not constitute recombination. The reasons for this are physical proximity, the homology-dependent nature of most recombination events, and the fact that distantly-related genetic material has the potential to decrease the fitness of the recipient, barring any major environmental change. With bacterial genomes now being sequenced at a higher rate, a large amount of data is present to investigate the role of homologous recombination among bacteria. This also allows for a more comprehensive approach at studying the rates of recombination and the evolutionary impact on bacterial populations. Gene transfer among prokaryotes occurs by three mechanisms: conjugation, transduction, and transformation. These mechanisms allow the bacterial cells to acquire new genes, which ultimately give rise to new phenotypes. The authors of this associated paper review the impact of homologous recombination on bacterial evolution. Specifically, they discuss three aspects of recombination: frequency, exchanged segments, and the source of imported genetic material. The regions within the genome that are usually affected by recombination include regions that are normally under positive selection at the given time. Discussion points Recombination is more likely to occur between members of closely related species. However, there are examples of distantly-related species undergoing recombination. Recombination is subdivided into homologous and non-homologous, depending upon the homology of the target sequence. Non-homologous recombination occurs between sequences that have no homology and is a much rarer event. Special proteins are needed to form the crossovers between the two unrelated sequences. The displaced strand pairs with the remaining single strand and the crossover is resolved. This type of recombination occurs between sequences that have little An Allele May Be Converted to Another Allele During Gene Conversions e617 homology and requires specific proteins to initiate the event. Integrase, or the Int protein, makes a staggered double-strand cut within these attachment sequences. Recombination Occurs During Meiosis of Higher Organisms l Recombination in higher organisms occurs mostly during the early stages of meiosis by a process similar to that in bacteria. The details of the mechanism are obscure, but it is thought that a hybrid junction resembling the bacterial Holliday junction is formed. In mitosis, recombination serves to repair double-stranded breaks or singlestranded gaps in the chromosomes. In this study, the Mus81 and Yen1 nucleases (resolvases) were found by association with Rad proteins. Furthermore, these double mutants were defective in their growth, particularly within the diploid cells. Overall, the authors identified nucleases, Mus81 and Yen1, that were involved in the formation of crossovers in budding yeast cells. They also determined that even though Mus81 is the primary nuclease and Yen1 is the backup, both nucleases are required for crossovers to occur in mitosis. Why do you think these effects were more pronounced for the diploid cells as opposed to the haploid cells An Allele May Be Converted to Another Allele During Gene Conversions l Gene conversion is when one allele is converted to another during recombination. The result is that one of the alleles exactly matches the other allele and a gene conversion occurs. Gene conversion is difficult to detect, assuming that the conversion can occur for either allele. The discovery of gene transfer in bacteria, and the involvement of plasmids in the mechanism for this, provided the foundations for molecular cloning. Firstly, bacteria are generally haploid, with one copy of each gene on a single circular chromosome (unlike eukaryotes, which are diploid with multiple linear chromosomes). Secondly, gene transfer in bacteria is normally unidirectional; that is, a donor cell transfers genes to a recipient cell rather than two cells sharing genetic information to generate progeny as seen in the more familiar forms of reproduction in higher organisms. Gene transfer in bacteria occurs by one of three major mechanisms, which form the main topics of this chapter. Reproduction versus Gene Transfer Sex and reproduction are not at all the same thing in all organisms. In animals, reproduction normally involves sex, but in bacteria, and in many lower eukaryotes, these are two distinct processes. First, they replicate their single chromosome and then the cell elongates and divides down the middle. From a biological perspective, sexual reproduction serves the purpose of reshuffling genetic information. This will sometimes produce offspring with combinations of genes superior to those of either parent (and, of course, sometimes worse! Although bacteria normally grow and divide asexually, gene transfer may occur between bacterial cells. During sexual reproduction in higher organisms, germline cells from two parents fuse to form a zygote that contains equal amounts of genetic information from each parent. In contrast, in bacteria gene transfer is normally unidirectional and cell fusion does not occur. The transfer of genes between bacteria fulfils a similar evolutionary purpose to the mingling of genes during sexual reproduction in higher organisms. Consequently, some scientists regard bacterial gene transfer as a primitive or aberrant form of sex, whereas others believe that it is quite distinct, and that use of the same terminology is misleading. Molecular biologists use bacteria together with their plasmids and viruses to carry most cloned genes, whether they are originally from cabbages or cockroaches. Consequently, an understanding of bacterial gene transfer is needed to understand the genetic engineering of plants and animals. For survival in the vast majority of bacteria, this means that it must be circular. For any of its genes to survive, they must be incorporated into the chromosome of the recipient cell by the process of recombination (see Ch. For genetic engineering purposes, it is usually more convenient to avoid adding genes into the bacterial chromosome via recombination.

Although anthropologists take both theories seriously anxiety symptoms joins bones purchase atarax with a mastercard, few geneticists regard the multiregional model as plausible anxiety levels discount 25 mg atarax with mastercard. This model implies continuous genetic exchange between widespread and relatively-isolated tribes over a long period of prehistory anxiety symptoms guilt discount atarax 25 mg mastercard. Although mitochondria evolve fast anxiety 8 year old discount atarax 10mg with visa, the overall variation among people of different races is surprisingly small anxiety symptoms red blotches buy atarax cheap online. Calculations based on the observed divergence and the estimated rates suggest that our common ancestor lived in Africa between 100 anxiety 7 cups of tea order atarax with american express,000 and 200,000 years ago. Since mitochondria are inherited maternally, this ancestor has been named "African Eve. The European and Asian races are derived from those relatively few groups of African ancestors who emigrated into Eurasia via the Middle East. Scientists believe that modern Homo sapiens evolved in eastern Africa, around the Olduvai Gorge. Descendents of these early ancestors migrated to Europe and Asia as well as other areas in Africa. Descendents of some Asian groups crossed the Bering Strait to inhabit the American continent. In other words, different subgroups of Africans branched off from each other before the other races branched off from the Africans as a whole. The colonization of parts of Oceania is even more recent and still controversial (see Focus on Relevant Research). They also give a primary African-non-African split, and if anything, they suggest an even more recent date for the common ancestor, nearer 100,000 years ago. The shorter human Y-chromosome does not recombine with its longer partner, the X-chromosome over most of its length. This allows us to follow the male lineage without complications due to recombination. However, recent data from a much larger number of genetic markers on the Y-chromosome dates Y-guy to somewhat less than 100,000 years ago. Recent analyses of clusters of mutations on the Y-chromosome are incompatible with the multiregional model and confirm the recent African origin of modern humans. The occupation of "Near Oceania" (including Borneo, New Guinea, and Australia) occurred around 27,000 years ago. This was followed more recently by the settlement of "Remote Oceania" (including Fiji and Polynesia). One theory proposes a rapid dispersal of maternal lineages from Taiwan approximately 4000 years ago. The authors argue that later movements of relatively-small numbers of people were responsible for the transmission of language and culture. Improved analysis suggests that the Neanderthals probably did interbreed to some small extent with modern Man. In particular, Neanderthals show more sequence similarities with modern humans in Eurasia than those from Africa. This implies cross-breeding in those regions where Neanderthals and modern Man co-existed, rather than inheritance from shared ancestry. What is especially fascinating is that both Neanderthals and modern humans were also present in the area at the same time! This implies that three species of humans shared this region for several thousand years. Sequence data suggest that the common ancestor of the Denisovans and Neanderthals split off from the ancestral modern human lineage around 800,000 years ago. Apparently, the Denisovans interbred to some extent with the ancestors of modern Melanesians (inhabitants of Oceania only distantly related to typical Polynesians). It has been suggested, although it is still controversial, that the miniature humans (nicknamed "hobbits") found on the island of Flores in Indonesia also constitute a separate human species, Homo floresiensis. The markers included deletions and insertions, sequence polymorphisms, and repetitive sequences. However, about 8% of Asian males carry Y-chromosomes with the same (or almost the same) combination of genetic markers. Furthermore, the Asian men with the special "Mongol cluster" of genetic markers were found only among those populations who formed part of the Mongol Empire of Genghis Khan. For example, the "Mongol cluster" was absent from Japan and southern China, which were not incorporated into the Mongolian Empire, but was present in 15 different populations throughout the area of Mongolian domination. The Hazara are known to be of Mongolian origin and claim to be direct descendents of Genghis Khan. This particular variant has therefore been proposed to be the Y-chromosome of Genghis Khan the great Mongolian conqueror. About 800 years ago the warlord Temujin united the Mongols and in 1206 assumed the title of Genghis Khan ("Lord of Lords"). The Mongols massacred many of the males and impregnated many of the women in areas they conquered. The present-day distribution of Y-chromosomes apparently reflects these practices. Whether this special variant of the Y-chromosome was present in Genghis Khan himself or just frequent among his Mongol warriors cannot be known for certain. Nonetheless, it is more likely than not that Genghis Khan himself had this Y-chromosome, as all the warriors in such tribes were usually closely related. Evolving Sideways: Horizontal Gene Transfer Standard Darwinian evolution involves alterations in genetic information passed on from one generation to its descendants. However, it is also possible for genetic information to be passed "sideways" from one organism to another that is not one of its descendents or even a near relative. The term vertical gene transfer refers to gene transmission from the parental generation to its direct descendants. Vertical transmission thus includes gene transmission by all forms of cell division and reproduction that create a new copy of the genome, whether sexual or not. Horizontal gene transfer (also known as "lateral gene transfer") happens when genetic information is passed sideways, from a donor organism to an unrelated organism. For example, when antibiotic resistance genes are carried on plasmids they can be passed between unrelated types of bacteria (see Ch. Since genes carried on plasmids are sometimes incorporated into the chromosome, a gene can move from the genome of one organism to that of an unrelated one in a couple of steps. The effects of horizontal transfer are especially noticeable in a clinical context. Both virulence factors and antibiotic resistance are commonly carried on transmissible bacterial plasmids. Horizontal gene transfer over long distances depends on carriers that cross the boundaries from one species to another (see Focus on Relevant Research). Viruses, plasmids, and transposons are all involved in such sideways movement of genes and have been discussed in their own chapters (see Chs. An extreme example among the bacteria is Thermotoga, which shares extremely hot environments with thermophilic Archaea. Perhaps more curious is that around 40% of their genes are closely related to those of thermophilic clostridia. Genetic information may be passed "vertically" from an organism to its direct descendents or "horizontally" to other organisms that are not descendents. Surprisingly, a version of this gene closely related to the one in baboons was identified in North African and European cats. Since baboons and cats are not closely related, the gene must have moved from one group to another via horizontal transfer. Further supporting the idea of horizontal transfer, the gene is not found in cats like the lion or cheetah, which developed before the North African and European cats branched off. One such example of horizontal transfer in animals concerns the type-C virogene shared by baboons and all other Old World monkeys. This gene was present in the common ancestor of these monkeys, about 30 million years ago, and since then has diverged in sequence like any other normal monkey gene. Only the smaller cats of North Africa and Europe possess the baboon type-C virogene. Furthermore, the sequence in North African cats resembles that of baboons more closely than the sequences in monkeys closer to the ancestral stem. However, other cats that diverged more than 10 million years ago lack these sequences. The most common cases occur between bacterial symbionts, which live permanently in insects and nematodes, and their hosts. Many insects contain bacterial symbionts, such as Wolbachia or Buchnera, within their cells. Horizontal gene transfer from animals to bacteria is also known, although with fewer examples. Many other possible cases of animal to bacteria transfer exist, but few have been fully investigated. Problems in Estimating Horizontal Gene Transfer When the human genome was sequenced, several hundred human genes were at first attributed to horizontal transfer from bacteria. However, later analyses indicated that very few of these were genuine cases of horizontal transfer (see Ch. Several factors have contributed to such over-estimates of horizontal transfer, both for the human genome and in other cases: a. Relatively few eukaryotic genomes have been fully sequenced, whereas hundreds of bacterial genomes have been sequenced. Thus, the absence of sequences homologous to a human gene from a handful of other eukaryotes is insufficient evidence for an external (bacterial) origin. As more eukaryotic sequence data has become available many genes supposedly of "bacterial" origin have been found in other eukaryotes. The loss of homologs in related lineages may suggest that a gene originated externally to the group of organisms that retain it. As in the related case (a) above, the solution to this artifact is the collection of more sequence data from many related lineages. Gene duplication followed by rapid divergence may give rise to apparently novel genes that are missing from the direct vertical ancestor of a group of organisms. Intense evolutionary selection for a particular gene may result in a greatly increased rate of sequence alteration. Rapidly-evolving genes will tend to be misplaced when sequence comparison is used to construct evolutionary trees. The ease of horizontal transfer of genetic information by plasmids, viruses, and transposons under laboratory conditions is misleading. Such genes tend to be acquired in response to selection such as antibiotic resistance and, conversely, they will be lost when the original selective conditions disappear. Many of the originally proposed examples of widespread horizontal gene transfer have been severely compromised by the above factors. One of the most interesting is the recent finding of relativelyfrequent horizontal gene transfer between the mitochondrial genomes of flowering plants. The genes for certain mitochondrial ribosomal proteins have apparently been transferred from an early monocotyledonous lineage to several different dicotyledonous lineages. Examples include transfer of the rps2 gene to kiwifruit (Actinidia) and the rps11 gene to bloodroot (Sanguinaria). Carotenoids are not normally made by animals and this is the only known case of carotenoid genes in any animal genome. The carotenoid pigments provide the red, yellow, and green colors typical of these insects. Red and green versions of the aphids are found that are recognized and eaten by different predators. The green variants have a defect in carotenoid desaturase and consequently lack the red version of the pigment. The chemical theory of the origin of life was put forward by the Russian biochemist Alexander Oparin in the 1920s. Polymerization of monomers into biological macromolecules requires the removal of water. The autotrophic theory of origins argues that the earliest life forms used energy released by the reaction of iron and sulfur compounds. New genes may also be created by mixing and shuffling segments of pre-existing genes. Although the Archaea share prokaryotic cell structure with the Bacteria, they are more closely related to Eukaryotes genetically. The mitochondria and chloroplasts of eukaryotic cells are derived from symbiotic bacteria that gradually lost their independence. Several protozoan lineages have arisen by engulfing other single-celled algae and thus have chloroplasts acquired by what is known as secondary endosymbiosis. Horizontal (or lateral) gene transfer occurs when genetic information is passed "sideways" to a relatively unrelated organism (as opposed to a direct descendent). The extent of horizontal gene transfer is difficult to measure accurately and has often been over-estimated. What alternatives may have allowed polymerization of amino acids on the early Earth Describe an example of how gene duplication can lead to the formation of a gene family. Describe a process by which many new genes can evolve that occurs mostly in plants. What could you infer about a protein that evolves very quickly and whose sequence is highly divergent among various species What molecules are most appropriate to determine evolutionary relatedness between two closely-related species Explain how it is possible to sequence a gene without actually isolating or culturing the organism.

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