CHAPTER 6. Reproduction at the Cellular Level CONNECTIONS BETWEEN CELL DIVISION AND REPRODUCTION Like begets like, more or less. Like begetting like is strictly true only for organisms that reproduce asexually (the creation of offspring by a single parent, without the participation of sperm and egg). Single-celled organisms can reproduce asexually by dividing in two. Each daughter cell receives an identical copy of the parent’s genes. For multicellular organisms (and many single-celled organisms), the offspring are not genetically identical to the parents, but each is a unique combination of the traits of both parents. This type of reproduction is sexual (the creation of offspring by two parents by the union of egg and sperm), and assures genetic diversity among individuals of a population. Breeders of domestic plants and animals manipulate sexual reproduction by selecting offspring that exhibit certain desired traits. In doing so, the breeders reduce the variability of the breed’s population of individuals. Reduced variability in a population can impact its potential survivorship. For example, some species have reduced genetic variability due to being pushed to the verge of extinction by human behaviors. Cells arise only from preexisting cells. German physician Rudolf Virchow formulated this principle in 1858. Cell reproduction is called cell division. Cell division has two major roles: It enables a fertilized egg to develop through various embryonic stages, and for an embryo to develop into an adult organism. It ensures the continuity from generation to generation: it is the basis of both asexual reproduction and sperm and egg formation in sexual reproduction. Prokaryotes reproduce by binary fission. Genes of most prokaryotes are carried on a circular DNA molecule. Prokaryotic chromosomes are simpler than eukaryotic chromosomes. Packaging is minimal: DNA is complexed with a few proteins and attached to the plasma membrane at one point. Most of the DNA lies, non-membrane-bounded, and in a region of the cell called the nucleoid. Binary fission: Prior to dividing, an exact copy of the chromosome is made. The attachment point divides so that the two new chromosomes are attached at separate parts of the plasma membrane. As the cell elongates and new plasma membrane is added, the attachment points of the two chromosomes are actively moving away from each other. Finally, the plasma membrane and new cell wall “pinch” through the cell, separating the two chromosomes into two new, genetically identical cells.
THE EUKARYOTIC CELL CYCLE AND MITOSIS The large, complex chromosomes of eukaryotes duplicate with each cell division. Whereas a typical bacterium might have 3,000 genes, human cells, for example, have 50,000100,000 (recent evidence shows that there may be as few as 26,000 to 30,000 genes in humans). A gene is a discrete unit of hereditary information consisting of a specific nucleotide sequence in DNA. The majority of these genes are organized into several separate, linear chromosomes (DNA) that are found inside the nucleus. Note: the DNA of mitochondria and chloroplasts carries a few genes. The DNA in eukaryotic chromosomes is complexed with protein in a much more complicated manner. This organizes and allows expression of much greater numbers of genes. During the process of cell division, chromatin condenses and the chromosomes become visible under the light microscope. In multicellular plants and animals, the body cells (somatic cells) contain twice the number of chromosomes as the sex cells. Different species may have different numbers of chromosomes. The DNA molecule in each chromosome is copied prior to the chromosome’s becoming visible. As the chromosomes become visible, each is seen to be composed of two identical sister chromatids, attached at the centromere. It is the sister chromatids that are parceled out to the daughter cells (the chromatids are then referred to as chromosomes). Each new cell gets a complete set of identical chromosomes. The cell cycle multiplies cells. Note: The result of this process (more or less) is two daughter cells that are genetically identical to each other and to their parental cell. Most cells in growing, and fully-grown organisms, divide on a regular basis (i.e., once an hour; once a day), although some have stopped dividing. This process allows new cells to replace worn-out or damaged cells. Such dividing cells undergo a cycle, a sequence of steps that is repeated from the time of one division to the time of the next, called the cell cycle. Interphase represents 90% or more of the total cycle time and is divided into G1 (Gap 1), S (DNA synthesis), and G2 (Gap 2) sub-phases. During G1, the cell increases its supply of proteins and organelles and grows in size. During S, DNA synthesis (replication) occurs. During G2, the cell continues to prepare for the actual division, increasing the supply of other proteins, particularly those used in the process. Cell division itself is called the mitotic phase (it excludes interphase) and involves two subprocesses, mitosis (nuclear division, the M phase) and cytokinesis (cytoplasmic division).
The overall result is two daughter cells, each with identical sets of chromosomes. Mitosis is very accurate. In experiments with yeast cells, one error occurs every 100,000 divisions. Cell division is a continuum of dynamic changes. Mitosis is a dynamic, repeating, and continuous process. Biologists divide the overall process into what appear to be natural phases, to make it easier to follow. Interphase: Duplication of the genetic material ends when chromosomes begin being visible. Prophase (the first stage of mitosis): The mitotic spindle is forming, emerging from the centrosomes (also known as microtubule-organizing centers [MOTCs]). Prophase ends when the chromatin has completely coiled into chromosomes; nucleoli and nuclear membrane disperse. The mitotic spindle provides a scaffold for the movement of chromosomes and attaches to chromosomes at their kinetochore. NOTE: The mitotic spindle is made of microtubules. Metaphase: The spindle is fully formed; chromosomes are aligned single file with centromeres on the metaphase plate (the plane that cuts the spindle’s equator). Anaphase: Chromosomes separate from the centromere, dividing to arrive at poles. NOTE: The concept that a single chromosome can consist of a single chromatid or two chromatids and that when two chromatids separate they are then independent chromosomes can be confusing. The way to determine the number of chromosomes a cell contains is to count centromeres. Telophase is the reverse of prophase: Cell elongation continues, a nuclear envelope forms around chromosomes, chromosomes uncoil, and nucleoli reappear. Cytokinesis: the division of the cytoplasm. This usually, but not always, accompanies telophase. Cytokinesis differs for plant and animal cells. In animals, a ring of microfilaments contracts around the periphery of the cell, forming a cleavage furrow that eventually cleaves the cytoplasm. In plants, vesicles containing cell wall material collect among the spindle microtubules, in the center of the cell, then gradually fuse, from the inside out, forming a cell plate that gradually develops into a new wall between the two new cells. The membranes surrounding the vesicles fuse to form the new parts of the plasma membrane. NOTE: For the plant, the process of cytokinesis must accommodate the cell wall. NOTE: The cells of advanced plants do not have centrioles. Anchorage, cell density, and chemical growth factors affect cell division To grow and develop, or replenish and repair tissues, multicellular plants and animals must control when and where cell divisions take place. Most animal and plant cells will not divide unless they are in contact with a solid surface; this is known as anchorage dependence.
Laboratory studies show that cells usually stop dividing when a single layer is formed and the cells touch each other. This density-dependent inhibition of cell growth is controlled by the depletion of growth factor proteins in masses of crowded cells. Growth factors are proteins secreted by cells that stimulate growth of other cells in close proximity. Growth factors signal the cell cycle control system. The cell cycle control system regulates the events of the cell cycle. Three major checkpoints exist: 1. At G1 of interphase 2. At G2 of interphase 3. At the M phase If, at these checkpoints, a growth factor is released, the cell cycle will continue. If a growth factor is not released, the cell cycle will stop. This type of regulation is a form of signal transduction. Nerve and muscle cells are non-dividing cells, stuck at the G1 checkpoint. Connection: Growing out of control, cancer cells produce malignant tumors. NOTE: Cancer is a general term for many diseases in multicellular animals and plants involving uncontrolled cell division with the resultant tumor metastasizing. The example given is the case of breast cancer. For females at age 90 there is a 1-in-8 lifetime risk of breast cancer – the risk of dying of cardiovascular disease (stroke, heart failure, hypertension, etc.) is much greater. Cancer cells grown in culture are not affected by the growth factors that regulate densitydependent inhibition of cell division. A malignant tumor consists of cancerous cells. These tumors metastasize. This is in contrast to benign tumors, which do not metastasize. NOTE: A benign tumor has the potential to kill, if it grows large enough to interfere with vital functions. NOTE: When someone dies of cancer, they rarely die as a result of the primary tumor, it is usually the metastases that kill him or her. This is why early detection and treatment is so important. Cancers are named according to the tissue or organ of origin. Usually, cancer cells do not exhibit density-dependent inhibition. Some cancer cells divide even in the absence of growth factors. Some cancer cells actually continually synthesize factors that keep them dividing. Thus, unlike normal mammalian cells (in culture) there is apparently no limit to the number of times that cancer cells can divide. Radiation and chemotherapy are two treatments for cancer. Radiation disrupts the process of cell division, and since cancer cells divide more often than most normal cells; they are more likely to be affected by radiation. Chemotherapy involves drugs that, like radiation, disrupt cell division. Some of these drugs – for example, the drug taxol targets the mitotic spindle.
Review of the function of mitosis: Growth, cell replacement, and asexual reproduction. Mitosis and cytokinesis (cell division) are used to add more cells to growing tissue. Cell division is also used to replace dead or damaged tissue. Cell division can be used in asexual reproduction, producing genetically identical offspring.
CHAPTER 7. The Cellular Basis of Inheritance MEIOSIS AND CROSSING OVER Chromosomes are matched in homologous pairs. In diploid organisms, somatic cells (non-sex cells) have pairs of homologous chromosomes. Homologous chromosomes share shape and genetic loci, and carry genes controlling the same inherited characteristics. Each of the homologues is inherited from a separate parent. NOTE: The sets are combined in the first cell following fertilization (zygote) and passed down together from cell to cell during growth and development by mitosis. In humans, 22 pairs, found in males and females, are autosomes. Two other chromosomes are sex chromosomes. In mammalian females, there are two X chromosomes; in male mammals, an X and a Y chromosome. Gametes have a single set of chromosomes. Adult animals have somatic cells with two sets of homologues (diploid, 2n). Sex cells (gametes = eggs and sperm) have one set of homologues (haploid, n). These cells are produced by meiosis. Sexual life cycles involve the alternation between a diploid phase and a haploid phase in the life of the organism. Fusion of haploid gametes in the process of fertilization results in the formation of a diploid zygote. Meiosis reduces the chromosome number from diploid to haploid. An understanding of the cell cycle is needed for an understanding of meiosis. Meiosis occurs only in diploid cells. Like mitosis, meiosis is preceded by a single duplication of the chromosomes. The overall result of meiosis is four daughter cells, each with half the number of chromosomes. Again, the process is dynamic but may stop at certain phases for long periods of time. The process includes two consecutive divisions (meiosis I and meiosis II). The halving of the chromosome number occurs in meiosis I. The end result is two haploid cells, with each chromosome consisting of two chromatids.
Sister chromatids separate in meiosis II. The end result is four haploid cells.
A comparison of mitosis and meiosis. All the events unique to meiosis occur in meiosis I. In prophase I, homologous chromosomes pair to form a tetrad and crossing over occurs between homologous chromatids. NOTE: This results in the formation of unique genetic combinations. Meiosis II is virtually identical to mitosis (except the cells are haploid). Mitosis results in two daughter cells, each with the same chromosomes as the parent cell. Meiosis results in four daughter cells (or, at least, nuclei), each with half the number of chromosomes as the parent cell. Meiosis happens only in diploid cells. Independent orientation of chromosomes in meiosis and random fertilization lead to varied offspring. During prophase I of meiosis, each homologue pairs up with its “other”. During this process, X and Y chromosomes behave as a homologous pair. NOTE: This pairing of homologues is called synapsis. When they separate at anaphase I, maternally and paternally inherited homologues move to one pole or the other independently of other pairs. NOTE: This is the basis of the laws of inheritance. Given n chromosomes, there are 2n ways that different combinations of the half-pairs can move to one pole. In humans, there are 223 (about 8 million) possible combinations of an individual’s maternally inherited and paternally inherited homologues. Combining gametes into zygotes suggests that there are 223 + 223 = 64 trillion potential combinations of these chromosomes in the human zygote (but see the next two modules). Note the marked difference in the large amount of genetic variation generated by sexual reproduction in contrast to the lower levels of genetic variation associated with asexual reproduction - and their respective consequences. Homologous chromosomes carry different versions of genes. Presented here are simplified examples: coat color and eye color in mice. C (agouti = brown) and c (white) for different versions of the coat-color gene, and E (black) and e (pink) for different eye-color genes. In this example, with the information up to this point, there would be two possible outcomes in a gamete (21) for the genes on the two chromosomes. Crossing over further increases genetic variability Crossing over is the exchange of corresponding segments between two homologues (sister chromatid exchange). The site of crossing over is called a chiasma. This happens between chromatids within tetrads as homologues pair up during synapsis (prophase I).
Crossing over produces new combinations of genes (genetic recombination). Because crossing over can occur several times in variable locations among thousands of genes in each tetrad, the possibilities are much greater than calculated above. Essentially, two individual parents could never produce identical offspring from two separate fertilizations. NOTE: It is for this reason that, with the exception of identical twins (and the like), everyone is a unique genetic entity never seen before and never to be seen again. Perhaps in the future this will not be the case (as mammalian cloning and the politics of scientific ethics progress). The mechanisms discussed here that result in new genetic combinations (meiosis and fertilization) do not occur in bacteria. However, there are several processes in which bacteria engage that result in the production of new genetic combinations. ALTERATIONS OF CHROMOSOME NUMBER AND STRUCTURE A karyotype is a photographic inventory of an individual’s chromosomes. Blood samples are cultured for several days under conditions that promote cell division of white blood cells. NOTE: Red blood cells lack nuclei and do not divide. The culture is treated with a chemical that stops cell division at metaphase. White blood cells are separated, stained, and squashed (to spread out the chromosomes) following the procedure. The individual chromosomes in a photograph are cut out and rearranged by number. From this the genetic sex of an individual can be determined and abnormalities in chromosomal structure and number can be detected. Connection: An extra copy of chromosome 21 causes Down syndrome. In most cases, human offspring that develop from zygotes with an incorrect number of chromosomes abort spontaneously. Trisomy 21 is the most common chromosome-number abnormality, occurring in about 1 out of 700 births. Down syndrome includes a wide variety of physical, mental, and disease-susceptibility features. The incidence of Down syndrome increases with the age of the mother. NOTE: Age of the father also correlates with an increased incidence of Down syndrome. Accidents during meiosis can alter chromosome number. Nondisjunction is the failure of chromosome pairs to separate during either meiosis I or meiosis II.
Fertilization of an egg resulting from nondisjunction with a normal sperm results in a zygote with an abnormal chromosome number. The explanation for the increased incidence of trisomy 21 among older women is not entirely clear but probably involves the length of time a woman’s developing eggs are in meiosis. Meiosis begins in all eggs before the woman is born, and finishes as each egg matures in the monthly cycle following puberty. Eggs of older women have been “within” meiosis longer. Connection: Abnormal numbers of sex chromosomes do not usually affect survival. Unusual numbers of sex chromosomes upset the genetic balance less than do unusual numbers of autosomes, perhaps because the Y chromosome carries fewer genes and extra X chromosomes are inactivated as Barr bodies in females. Abnormalities in sex chromosome number result in individuals with a variety of different characteristics, some more seriously affecting fertility or intelligence than others. The greater the number of X chromosomes (beyond 2), the more likely is (and the greater the severity of) mental retardation. These sex chromosome abnormalities illustrate the crucial role of the Y chromosome in determining a person’s sex. A single Y is enough to produce “maleness, even in combination with a number of Xs, whereas the lack of a Y results in “femaleness”. Connection: Alterations of chromosome structure can cause birth defects and cancer. Deletion, duplication, and inversion occur within one chromosome. Inversions are less likely to produce harmful effects than deletions or duplications because all the chromosome’s genes are still present. Duplications, if they result in the duplication of an oncogene in somatic cells, may increase the incidence of cancer. An oncogene is a cancer-causing gene; usually contributing to malignancy by abnormally enhancing the amount of activity of a growth factor made by the cell. Translocation involves the transfer of a chromosome fragment between nonhomologous chromosomes. Translocations may or may not be harmful. One type of translocation in Down syndrome involves the removal of a portion of the third chromosome 21 to another nonhomologous chromosome – so the individual has only part of a third chromosome 21. Chromosomal changes in somatic cells may increase the risk of cancer.
CHAPTER 8. Patterns of Inheritance The Science of genetics has ancient roots The ancient Greeks believed in pangenesis, the idea that particles governing the inheritance of each characteristic collect in eggs and sperm and are passed on to the next generation. But many, including Aristotle, realized there were problems with this idea: The potential to produce
characteristics is inherited, not pieces of the characteristics themselves. Reproductive cells are not changed by the development or activity of other cells. Based on artificial breeding, nineteenth-century observers believed in the “blending” hypothesis, in which characteristics from both parents blend in the offspring. Experimental genetics began in an abbey garden. Mendel was university trained in precise experimental technique. He studied peas because they offered advantages over other organisms. Peas grow easily They have relatively short life spans (one year) They have numerous and distinct characteristics The mating of individuals can be controlled so that the parentage of offspring can be known for certain Part of Mendel’s good biological experimentation resulted directly from his choice of a suitable study organism that enabled him to focus on particular questions. Mendel’s paper, published in 1866, argued that there are discrete, heritable factors (what we now call genes) that retain their individuality when transmitted from generation to generation. Mendel was ahead of his time, and his work on genetics remained unrecognized for nearly half a century. Mendel could intentionally self-fertilize a flower by covering it with a bag, or cross-fertilize two different plants by dusting the carpel of one with the pollen of another. A carpel is the female part of a flower, consisting of a stalk with an ovary at the base and a stigma, which traps pollen, at the tip. Note that the life history of flowering plants, for our purposes here, is similar to that of most animals, but with male and female gamete-producing organs found in flowers. By continuous self-fertilization for many generations, Mendel developed breeds of plants that bred true (continued to show a characteristic when self-fertilized) for each of the characteristics he followed. He found seven characteristics, each of which came in two distinct forms. Mendel developed two principles based on two types of experiments. Monohybrid crosses: he hybridized true-breeding plants for each of the two forms of a characteristic. Dihybrid and trihybrid crosses: he hybridized plants that combined two or more of the seven characteristics. In these experiments, the true-breeding parents are the P (parental) generation, their hybrid offspring is the F1 (first filial) generation, and the offspring of mating two F1 individuals is the F2 (second filial) generation. Mendel’s principle of segregation describes the inheritance of a single characteristic. Principle of segregation: Pairs of genes segregate (separate) during gamete formation; the fusion of gametes at fertilization pairs genes once again. Note that the principle of segregation is a reflection of the events of meiosis. Mendel conducted a monohybrid cross with flower color. The results of this experiment were that out of 929 F2 offspring, 705 were purple, and 224 were white. Note that because mating involves probabilities, these resulting proportions are not exactly ¾ and ¼.
Mendel observed that each of the seven characteristics exhibited the same inheritance pattern. Mendel developed four hypotheses: 1. There are alternative forms of genes, the units that determine heritable characteristics. These alternative forms are called alleles. 2. For each inherited characteristic, an organism has two genes, one from each parent. They may be the same allele or different alleles. 3. A sperm and egg carries only one allele for each characteristic because the allele pairs segregate from each other during gamete production. 4. When two alleles are different, the one that is fully expressed is said to be the dominant and the one that is not noticeably expressed is said to be recessive. Conventions for alleles: P, the dominant (purple) allele, and p, the recessive (white) allele. P generation: PP x pp; their gametes P and p; F1 generation: Pp Homozygous dominant, homozygous recessive, and heterozygous refer to the genotypes (the nature of the genes as inferred from observations and knowledge of how the system works). The phenotypes are what you see. The Punnett square is used to keep track of the gametes (two sides of the square) and the offspring (cells within the square). Note that this pattern, whereby each gamete contains a single copy of each gene, is stated by Mendel’s principle of segregation and is based on the events of meiosis (anaphase I and anaphase II) Homologous chromosomes bear the two alleles for each characteristic. Review: homologous pairs. Although Mendel knew nothing about chromosomes, our knowledge of chromosome arrangements (in homologous pairs) strongly supports the principle of segregation. Alleles of a gene reside at the same locus on homologous chromosomes. Note that one of the chromosomes illustrated was inherited from the female parent, the other from the male parent. The principle of independent assortment is revealed by tracking two characteristics at once. Review: The principle of independent assortment is a reflection of the events of meiosis. Principle of independent assortment: each pair of alleles segregates independently during gamete formation. Experimental procedure: Breed two strains true, each exhibiting one of the two forms of two characteristics (in the example used, round yellow seeded plants (RRYY) and wrinkled green-seeded plants [rryy]). Hybridize these two strains as the P generation, resulting in hybrid offspring (F1: RrYy). Then allow the F1 to self-fertilize (RrYy x RrYy). Note that each of these individuals produces the same four gametes: RY, Ry, rY, and ry. Taking one gamete from each individual means that there are 42 = 16 possible gametic combinations.
Two hypotheses: The characteristics are inherited dependently of each other. The characteristics are inherited independently of each other. Results The F1 generation exhibits only the dominant phenotype (this is expected). The F2 generation exhibits a phenotypic ratio of 9:3:3:1 (round yellow: round green: wrinkled yellow: wrinkled green). Note that 9 + 3 + 3 + 1 = 16, the same as the number of possible gametic combinations. That the phenotypic ratio adds up to the number of possible gametic combinations serves as a check of the results of a cross. We use a Punnett square to analyze these results. The sides of the square represent the male and female gametes possible if alleles of two characteristics segregate independently. Notice that the genotypes that produce the same phenotype are not all the same. Fur color and vision defects (PRA) in Labradors follow this pattern of assortment if pure strains of black labs and chocolate labs are used as the P generation. B allele, black fur b allele, brown fur N allele, normal vision n allele, blind. If two Labs of genotype BbNn are bred, the phenotypic ratio will follow the expected ratio from the example with peas; 9:3:3:1. Four dogs will be blind; one of which is a chocolate Lab (bbnn). Geneticists use the testcross to determine unknown genotypes. A testcross involves crossing an unknown genotype expressing the dominant phenotype with the recessive phenotype (by necessity, homozygous). Each of two possible genotypes (homozygous or heterozygous) gives a different phenotypic ratio in the F1 generation. Homozygous dominant gives all dominant. Heterozygous gives half recessive, half dominant. Note that this technique uses phenotypic results to determine genotypes. Mendel’s principles reflect the rules of probability. Events that follow probability rules are independent events; that is, one such event does not influence the outcome of a later such event. If you flip a coin four times and get four heads, the probability for tails on the next flip is still ½. The rule of multiplication. The probability of two events occurring together is the product of the probabilities of the two events occurring apart. Thus, when studying how the alleles of two (or more) genes that segregate independently behave, use the probabilities of how they behave individually. Note that the probability of a recessive phenotype occurring in a monohybrid cross is 1out of 4 (¼). The probability of two recessives occurring together in a dihybrid cross is ¼ x ¼, or 1 out of 16 (recall 9 + 3 + 3 + 1 = 16). In a trihybrid cross, the probability of a triple recessive is 1 out of 64.
The rule of addition. If there is more than one way an outcome can occur, then these probabilities must be added, as in the case of determining the chances for heterozygous mixtures. Connection: Genetic traits in humans can be tracked through family pedigrees. Commonly used symbols on a pedigree chart: Male Female Affected or Unaffected or By applying Mendel’s principles, one can deduce the information on a pedigree chart from the patterns of phenotypes. Example given: inheritance of deafness in a family from Martha’s Vineyard. Assuming that Jonathan Lambert inherited his deafness from his parents, the only explanation is that his deafness is caused by a recessive allele because neither of his parents was deaf. Because some of his children were deaf, his wife, Elizabeth Eddy, must have been a carrier. From this it follows that all their hearing children were carriers. This final deduction shows the power of applying Mendelian principles to pedigrees and how to make predictions. Note that since the pattern in the pedigree is not tied to gender, the gene for congenital deafness is not sex-linked. Connection: Many inherited disorders in humans are controlled by a single gene. Over 1,000 known genetic traits are attributable to a single gene locus and show simple Mendelian patterns of inheritance. Many human characteristics are thought to be determined by simple dominant-recessive inheritance, and sometimes the ratio of dominant-to-recessive phenotype exhibits a Mendelian ratio. Most disorders are caused by recessive alleles and vary in the severity of the expressed trait. Note that the terms dominant and recessive refer only to whether or not a characteristic is expressed in the heterozygote, not to whether it is the most common. The vast majority of people afflicted with recessive disorders are born to normal, heterozygous parents. Note that it is really only the distribution of phenotypes in the offspring of one couple of known phenotype or genotype that will follow Mendelian principles. Cystic fibrosis is the most common lethal genetic disease in the U.S. Most genetic diseases of this sort are not evenly distributed across all racial and cultural groups because of the prior and existing reproductive isolation of various populations. Laws forbidding inbreeding may have arisen from observations that such marriages more often resulted in miscarriages, stillbirths, and birth defects. On the other hand, there is a debate over this issue because seriously detrimental alleles would likely be eliminated from populations when expressed in the homozygous embryo, and there are societies where inbreeding occurs without detrimental results. Some disorders are caused by dominant alleles. These disorders vary in how deadly they are. Some are nonlethal handicaps, some are lethal in the homozygous condition, and some are intermediate in severity. Achondrioplasia, a type of dwarfism, is lethal in the homozygous dominant condition: individuals who express the trait are heterozygous.
Other dominant disorders, such as Huntington’s disease, are lethal only in older adults, so the allele can be passed to children before it is realized that the parent has the condition. These diseases are, or will be in the future, treatable by use of the techniques of genetic engineering. Connection: Fetal testing can spot many inherited disorders early in pregnancy. Amniocentesis involves taking a sample of the amniotic fluid that bathes the fetus, at 14-16 weeks. This fluid contains living fetal cells (from skin and the mouth cavity) and can be karyotyped. Some chemical tests can be performed on the fluid itself. Chorionic villus sampling involves removing tissue from the fetal side of the placenta nurturing a fetus, at 8-10 weeks. These cells are rapidly dividing and can be immediately karyotyped. Some biochemical tests can be performed. Ultrasound imaging of the fetus provides a noninvasive view inside the womb. Fetoscopy provides a more direct view of the fetus through a needle-thin viewing scope inserted into the uterus. Amniocentesis, chorionic villus sampling, and fetoscopy carry a small risk and are reserved for situations with higher probabilities of disorders (for example, older parents or situations where genetic counseling has uncovered a higher risk). Analysis of the mother’s blood can detect abnormal levels of certain hormones (HCG and estriol) or proteins produced by the fetus (alpha-fetoprotein). Abnormal levels may indicate that the fetus has Down syndrome or a neural tube defect. If fetal testing suggests that there is a problem that cannot be helped by routine surgery or other therapy, the difficult choice must be made between terminating a pregnancy by abortion or carrying a defective baby to term.
Patterns of Inheritance - Variations on Mendel’s Principles The Relationship of genotype to phenotype is rarely simple. The inheritance of many characteristics among all eukaryotes follows the principles that Mendel discovered. However, most characteristics are inherited in ways that follow more complex patterns. Before looking at the chromosomal explanation of Mendel’s principle of independent assortment, we will look at four such complex patterns: Incomplete dominance Multiple alleles at a gene locus Pleiotropy Polygenic inheritance These patterns are extensions of Mendel’s principles, not exceptions to them. Incomplete dominance results in intermediate phenotypes. Incomplete dominance describes the situation where one allele is not completely dominant in the heterozygote; the heterozygote usually exhibits characteristics intermediate between both homozygous conditions.
Snapdragon color is a good example of how this works. Note that the possibilities of each genotype are the same as in a case of complete dominance, but the phenotype ratios are different. Another example: the inheritance of alleles that relate to hypercholesterolemia: Normal individuals, HH, have normal amounts of LDL receptor proteins hh individuals (rare in the population, about 1 in 1 million) have no receptors and five times the amount of blood cholesterol Hh individuals (1 in 500) have half the number of receptors and twice the amount of blood cholesterol Many genes have more than two alleles in the population. The ABO blood groups in humans follow this pattern, in which individuals can have two alleles from a set of three possible alleles. These blood type alleles code for two carbohydrates (or the absence of any carbohydrate) on the surface of red blood cells (a total of three alleles). There are six possible genotypes and four possible phenotypes. Type O (universal donor) has neither carbohydrate and can receive no other type. Type AB (universal recipient) has both carbohydrates and can receive any type. The AB blood type is an example of codominance. Type A has carbohydrate A and can receive A or O. Type B has carbohydrate B and can receive B or O When blood is transfused, recipients develop antibodies for the types of carbohydrate on the donor red blood cells that the recipients lack. Blood type can be used as evidence to disprove or suggest parentage in paternity suits: however, more sophisticated blood analyses are needed to prove parentage. A single gene may affect many phenotypic characteristics. This common situation is known as pleiotropy. An example is the inheritance of an allele that codes for abnormal hemoglobin and, in the homozygous condition, causes sickle-cell disease. The sickle shape of the red blood cells confers a whole suite of symptoms on homozygous individuals, attributable to three underlying difficulties resulting from the abnormal cell shape. These normal and abnormal alleles are another good example of codominance, so heterozygous individuals (carriers) can exhibit some symptoms, although normally they are healthy. The incidence of the allele is relatively high in individuals of African descent (one in 10 African Americans is heterozygous), because sickle-cell carriers are somewhat protected from malaria, a protozoan-caused disease prevalent in tropical regions. Connection: Genetic testing can detect disease-causing alleles. The field of genetic testing (genetic screening) has expanded dramatically in the last decade. There are four major categories of genetic testing: Carrier testing: The purpose of this analysis is to determine if a potential parent will pass on a harmful trait to offspring.
Diagnostic testing: This type of genetic analysis is used to confirm or rule out the existence of a genetic disorder. This procedure can be used on the unborn (prenatal testing) as well as after birth, particularly adults. Newborn screening: This type of genetic screening is designed to catch childhood disease that can be treated effectively when detected early. Predictive testing: This type of testing is designed to identify a person predisposed to certain disorders such as colon cancer (FAP) or breast cancer (BRCA1 or BRCA2).
Ethical, moral, and medical issues are being raised by the increased use of genetic testing. Insurability of persons with detected genetic disorders is also an issue of concern. A single characteristic may be influenced by many genes. This situation is known as polygenic inheritance. Skin pigmentation is just such a phenotypic character whose underlying genetics has not been completely determined. Hypothetically, the phenotypic outcome of mixtures of three genes, each with two alleles coding for “additive units,” produces the overall characteristic. Note that it is much easier to solve genetic problems such as these using probabilities rather than Punnett squares.
The Chromosomal Basis of Inheritance Chromosome behavior accounts for Mendel’s principles. While the existence and behavior of chromosomes was not appreciated by Mendel himself, the significance of his work was understood later, in the late 1800s and early 1900s. Out of this understanding came the chromosome theory of inheritance. We have already seen that the fact that there are homologous pairs of chromosomes accounts for the principle of segregation (the law of segregation). The fact that there are several sets of homologous pairs of chromosomes accounts for the principle of independent assortment (the law of independent assortment). Note that Mendel's seven garden pea characteristics all sorted independently of each other because the genes governing each characteristic are all on separate chromosomes. Genes on the same chromosome tend to be inherited together. Linked genes are located close together on the same chromosome. The inheritance of such genes does not follow the pattern described by the principle of independent assortment because the two genes are normally inherited together on adjoining portions of the same chromosome. The phenotypic ratios of such dihybrid crosses approach that of a monohybrid cross (3:1), rather than the typical pattern of the dihybrid cross (9:3:3:1). Crossing over produces new combinations of alleles. In the case of many linked genes (for example, pollen grain length and flower color in sweet peas), there are some offspring of a dihybrid cross that do involve independent assortment of the genes.
These situations of recombination are accounted for by crossing over, which occurs between the genes on homologous pairs of the same chromosome during some meiotic divisions, but not all. Recall that crossing over and genetic recombination were discussed earlier. Early examples of recombination were demonstrated in fruit flies by embryologist T.H. Morgan and colleagues in the early 1900s. The percentage of recombinant offspring is called the recombination frequency. Geneticists use crossover data to map genes. The study of fruit-fly genetics resulted in considerable additional understanding of genetic principles. Note that this is another example of the use of an experimental organism that lends itself to study. Fruit flies have many phenotypic characters, are easily raised and bred in captivity, and have a short life cycle. In addition, they have only four chromosomes (simplifying the situation), and these chromosomes can be easily visualized in non-dividing cells in the salivary glands. A.H. Sturtevant, one of Morgan’s colleagues, developed a technique of using crossover data to map the locations of genes on chromosomes on which they were linked. Sturtevant assumed that the rate of recombination is proportional to the distance between two genes on a chromosome and this information can be used to construct a genetic map.
Sex Chromosomes and Sex-Linked Genes Chromosomes determine sex in many species. Sex chromosomes in humans are non-identical members of a homologous pair. In humans, XX individuals are female, and XY are male. The SRY (sex-determining region of the Y chromosome) gene plays a crucial role in the human sex determination. This gene initiates the development of testes. An individual who does not have a functioning SRY gene develops ovaries. In other species, other patterns of sex chromosomes exist. In some species, the chromosome number rather than chromosome type determine sex. In some invertebrates, diploid individuals are female and haploid are male. Note that in sea turtles, for example, the temperature at which the fertilized eggs are incubated will determine sea turtles’ sex. Plants that produce both eggs and sperm are said to be monoecious. Animals that produce both eggs and sperm are hermaphroditic. Sex-linked genes exhibit a unique pattern of inheritance. Sex chromosomes contain genes specifying sex and other genes for characteristics unrelated to sex. These genes are said to be sex-linked. Because of linkage and location, the inheritance of these characteristics follows peculiar patterns. Examples are given using eye color in fruit flies (X-linked recessive for white eyes. Depending on the genotypes of the parents, three patterns emerge.
In humans, most sex-linked characteristics result from genes on the X chromosome. Thus mostly males are affected. Note that other sex-related patterns of inheritance include sex-influenced genes, sex-limited genes, genome imprinting, and mitochondrial inheritance. Pattern baldness is an example of a sex-influenced trait; the allele for pattern baldness behaves as a recessive in females and a dominant in males (its expression requires sufficient testosterone). A sex-limited gene is one that can be expressed in only one sex or the other; for example, some testicular tumors are the result of inheriting a particular allelic variant (obviously, testicular tumors cannot be expressed in females). In genome imprinting the same DNA sequence is expressed differently based on whether it was inherited from the female or male parent. For example, if an individual is missing a particular segment of paternal chromosome 15, the result is Prader-Willi syndrome; if the same segment is missing from maternal chromosome 15, the result is Angelman syndrome. Mitochondrial genes are all inherited from the female parent. Connection: Sex linked disorders affect mostly males. Examples of such characteristics are red-green color blindness, a type of muscular dystrophy, and hemophilia. Because the male has only one X chromosome, his recessive X-linked characteristic will always be exhibited. Most known sex-linked traits are caused by genes (alleles) on the X chromosome. When these traits are recessive (most are), males express them because they have only one X. Females who have the allele are normally carriers and will exhibit the condition only if they are homozygous. Males cannot pass sex-linked traits to sons (who get a Y from their father). Red-green color blindness is a complex of sex-linked disorders, each of which is caused by an allele on the X chromosome. The result is considerable variation in the changes in color perception. Hemophilia is a sex-linked trait with a particularly well-studied history because of its incidence among the intermarrying royal families of Europe. Note that hemophilia contributed to the Russian revolution of 1917, Rasputin gained influence over Czar Nicholas II and Czarina Alexandra by his apparent ability to control hemophilic episodes experienced by their child, Alexis. Duchenne muscular dystrophy (DMD) is a severe disease that causes progressive loss and weakening of muscle tissue and has been traced to a particular nucleotide sequence. Note that a particular version of the protein dystrophin is missing in individuals with DMD. Dystrophin is found in the plasma membrane (sarcolemma) of muscle fibers. It appears that the result of not having a functional version of dystrophin is an increase in Ca2+ levels in the sarcoplasm (cytoplasm of a muscle fiber). The excess Ca2+ appears ultimately to lead to degeneration of the muscle fiber.
CHAPTER 9 Molecular Biology of the Gene The chromosome theory of inheritance set the historical and structural stages for the development of a molecular understanding of the gene. Many of the basics of molecular biology began to be understood by studying viruses and the mechanism used by viruses to gain control over DNA replication and the transcriptional and translational machinery of the cell. Are viruses living things? Recall some of the characteristics of life (that viruses do not exhibit), particularly cellular structure and metabolism. Viruses are composed of a protein coat and internal DNA (or RNA), and they depend on the metabolism of their host to make more viral particles. Viruses infect all living things. Experimental systems using phages were a logical choice for early experiments on the molecular biology of the gene. Phages are simple, with simple genes infecting relatively simple and easily manipulated bacteria. This chapter focuses on the structure of DNA, how it is replicated, and the process of protein synthesis through transcription and translation.
THE STRUCTURE OF THE GENETIC MATERIAL Experiments showed that DNA is the genetic material. In 1928, Griffith showed that some substance (he did not know what) conveyed traits (pathogenicity) from heat-killed bacteria to living bacteria without the trait. Evidence gathered during the 1930s and 1940s showed it was DNA rather than protein (both complex macromolecules found in chromosomes) that was the genetic material. In 1952, Hershey and Chase, using a virus called T2, showed that it was the DNA in the virus that infected the bacterial cell. Viruses of this type are called bacteriophages (phages for short). The structure of a T2 phage is very simple, consisting of a protein coat and a DNA core. Hershey and Chase devised a simple experiment using T2 phage and demonstrated that the radioactive isotope of sulfur (found only in proteins) was not transferred into new viral particles, whereas the radioactive isotope of phosphorus (found only in DNA) was transferred. The life cycle of a T2 phage results in the production of multiple copies of the T2 phage and the death of the infected bacterial cell. DNA and RNA are polymers of nucleotides. Review the polymeric nature of DNA and RNA polynucleotides. Focus on the chemical structure of the three components of each monomer nucleotide: a phosphate group, acidic; deoxyribose, a five-carbon sugar; and nitrogenous bases. Note the presence of ribose sugar, rather than a deoxyribose sugar, in RNA. Note the structural similarities and differences between the four nitrogenous bases: thymine(T), cytosine(C), adenine(A), and guanine(G) that occur in DNA and the one, uracil(U), that occurs instead of thymine in RNA. Note also their commonly used abbreviations.
The structural similarities between DNA and RNA molecules are important. The only differences are the ribose sugar and the use of uracil in RNA. DNA is a double-stranded helix. Some of the data that went into the Watson-Crick model: The chemical structure of DNA, including that of the component structures Wilkins and Franklin’s X-ray crystallographs (from which one can deduce helical form and width and repeating length of the helix) Chargraff’s chemical analysis showing that the amounts of A and T, and G and C, were always equal, and previous knowledge that the ratios of A + T to G + C varied from species to species. The model that fit all the observations was a double helix (a twisted rope ladder) with sugar backbones on the outside and hydrogen-bonded nitrogenous bases on the inside. G always bonds with C and A always bonds with T, but there are no restrictions on the linear sequence of nucleotides along the length of the helix. The combination of one purine and one pyrimadine accounts for the known width of the double helix. Adenine and thymine are joined by two hydrogen bonds, and guanine and cytosine are joined by three hydrogen bonds. Two strands of the double helix run in opposite directions (the strands are antiparallel). The Watson-Crick model was proposed in a short paper in 1953 and almost immediately led to the proposed mechanisms about DNA function.
DNA REPLICATION DNA replication depends on specific base pairing. The nature of the reproductive process, and of the cell cycle involved in it, requires that complete and faithful copies of DNA be produced (replicated). Watson and Crick stated that their model suggested a copying mechanism. The mechanism proposed and confirmed by the end of the 1950s involved each half of the double helix functioning as a template upon which a new, missing half is built. Note that each new double helix consists of one old and one new strand; thus the mechanism of replication is semiconservative. The actual mechanism involves a complex arrangement of molecular players, the help of enzymes, particularly DNA polymerases, and some geometric contortions including untwisting of the parent helix and retwisting the daughter helices. Despite its speed (50-500 pairs per second), replication is very accurate, with approximately one mistaken nucleotide pair in a billion. Question: What (if any) would life look like on Earth if DNA replication were mistake free? DNA replication: a closer look.
Replication occurs simultaneously at many sites (replication bubbles) on the double helix. This allows DNA replication to occur in a shorter period of time than replication from a single origin would allow. DNA polymerases can only attach nucleotides to the 3' end of a growing daughter strand. Thus replication always proceeds in the 5' to 3' direction. Within the replication bubbles, one daughter strand is synthesized continuously while the other strand must be synthesized in short pieces, which are then joined together by DNA ligase. Note that these short pieces of DNA are called Obazaki fragments. DNA polymerases also proofread the new daughter strands. This replication process assures that daughter cells will carry the same genetic information as each other and as the parental cell.
THE FLOW OF GENETIC INFORMATION FROM DNA TO RNA TO PROTEIN The DNA genotype is expressed as proteins, which provide the molecular basis for phenotypic traits. Briefly review the roles that proteins play in organisms. The molecular basis of phenotypic traits are the proteins an organism can make (with a variety of functions). The molecular basis of genotype is now recognized as DNA. The one gene-one enzyme hypothesis was formulated in the 1940s by Beadle and Tatum, who were studying nutritional mutants of the mold, Neurospora. They found that genetic mutants lacked single enzymes needed to complete metabolic pathways. This idea was soon extended to include all proteins (adding a variety of structural types) and later restricted to individual polypeptides (because some proteins are composed of several distinct polypeptide chains). This flow is now known to occur in two stages: transcription of the genetic code in the nucleus to a messenger RNA (mRNA) molecule, and translation of the mRNA message in the cytoplasm. Genetic information written in codons is translated into amino acid sequences. The nucleotide monomers represent letters in the alphabet that can form words in a language. Each word codes for one amino acid in a polypeptide. There are four letters (A, T, G, and C) and 20 amino acids. One-letter words would create 4 distinct words. Two-letter words would create a vocabulary of 16 words (4 X 4). Three-letter words would create a vocabulary of 64 words (4 X 4 X 4). --- remember the discussion of probability. Triplets of bases are the smallest words of uniform length that can specify all the amino acids. These triplets are known as codons. The genetic code is the Rosetta stone of life.
Nirenberg deciphered the first codon in 1961. Nirenberg added polyuracil (an artificially made RNA polynucleotide) to a mixture containing ribosmes and other cell fractions required for translation. The polypeptide polyphenylalanine was produced, which indicated UUU was the codon for phenylalanine. The code, completely known by the end of the 1960s, shows redundancy but not ambiguity. Make a polypeptide using an arbitrary sequence of bases. The code is virtually the same for all organisms. Thus, bacterial cells can translate the genetic messages of human cells, and vice versa. This gives evidence of the relatedness of all life, and suggests that the genetic code was established early in the history of life. Recombinant DNA techniques enable biologists to transfer genes of one organism to another and have them expressed. Transcription produces genetic messages in the form of RNA. In transcription, one strand of DNA serves as a template for the new RNA strand. RNA polymerase constructs the RNA strand. Transcription is initiated from one strand of the DNA, as indicated by a promoter region (the site at which RNA polymerase attaches); the DNA unwinds; and RNA polymerization and elongation occur. Finally, the mRNA sequence is terminated when the process reaches a special terminator region of the DNA. Note that transcription means copying a message into a new medium. Two other types of RNA (ribosomal RNA or rRNA and transfer RNA or tRNA) play a role in translation and are transcribed by this process. Eukaryotic RNA is processed before leaving the nucleus. RNA that encodes an amino acid sequence is called messenger RNA (mRNA). In prokaryotes, transcription and translation both occur in the cytoplasm. In eukaryotes, a completed mRNA molecule leaves the nucleus and the message is translated in the cytoplasm. Prior to leaving the nucleus, however, RNA is modified in a process called RNA splicing. The regions of DNA that are not used in the production of protein (introns) must be removed, leaving only the exons. Exons are ligated and the ends of the modified RNA molecule have additional nucleotides added in an effort to reduce enzymatic attack. The players in the translation process include ribosomes, tRNA molecules, enzymes and protein factors, and sources of cellular energy. Note that translation means rewording a message into a new language. The new language in this case is the linear sequence of amino acids in polypeptides. Transfer RNA molecules serve as interpreters during translation. Amino acids that are to be joined in correct sequence cannot recognize the codons on the mRNA.
Transfer RNA molecules, one or more of each type of amino acid, match the right amino acid to the right codon. Each tRNA contains a region (the anticodon) that recognizes and binds to the correct codon for its amino acid on the mRNA. The right tRNA for each amino acid and its codon are temporarily joined by the aid of a specific enzyme (at least one for each tRN-amino acid complex) and the expenditure of one ATP molecule. Ribosomes build polypeptides. Ribosomes are composed of ribosomal RNA (rRNA) and protein, arranged in two subunits . The shape of ribosomes provides a platform on which protein synthesis can take place. There are locations for the mRNA, and two tRN-amino acid complex binding sites (an A site and a P site). An initiation codon marks the start of a mRNA message. Translation can be divided into the same three phases as transcription: initiation, elongation, and termination. An mRNA molecule is longer than the genetic message it contains. It contains a starting nucleotide sequence that helps in the initiation phase and an ending sequence that helps in the termination phase. Initiation is a two-step process. The initial sequence helps bind the mRNA to the small ribosomal subunit; a specific start codon binds with an initiator tRNA anticodon carrying the amino acid methionine. The large ribosome binds to the small subunit as the initiator tRNA fits into the P site on the large subunit. Elongation adds amino acids to the polypeptide chain until a stop codon terminates translation. Elongation involves three steps. Codon recognition: The anticodon of an incoming tRN-amino acid complex binds with the codon at the ribosome’s A site. Peptide bond formation: A polypeptide bond is formed between the growing polypeptide (attached to the tRNA at the P site) and the new amino acid. Translocation: The P-site tRNA leaves the complex, and the A-site tRNA-polypeptide chain complex moves to the P site. An enzyme within the ribosome structure catalyzes the formation to the polypeptide bond. Elongation continues until a special stop codon (UAA, UAG, or UGA) causes termination of the process. The finished polypeptide is released, and the ribosome splits into its two subunits. A polypeptide develops its tertiary structure both during and after translation. Review: The flow of genetic information in the cell is DNA → RNA → protein.
There are five stages of transcription and translation. The synthesis of a strand of mRNA complementary to a DNA template is transcription (stage 1). The conversion of the information encoded within a strand of mRNA into a polypeptide is translation (stages 2 through 5). Review: Following their synthesis, several polypeptides may come together to form a protein with quaternary structure. Mutations can change the meaning of genes. Many differences in inherited traits in humans have been traced to their molecular deviation. A change in the nucleotide sequence of DNA is known as a mutation. Certain substitutions on one nucleotide base for another will lead to mutations, resulting in the replacement of one amino acid for another in a polypeptide sequence. Base substitutions usually cause a gene to produce an abnormal product, or they result in no change if the new codon still codes for the same amino acid. A base substitution is known to account for the type of hemoglobin produced by the sickle-cell allele. Base substitutions rarely lead to improved or changed genes that may enhance the success of the individual in which it occurs. These types of mutations provide the genetic variability that may lead to the evolution of new species. The addition or subtraction of nucleotides may result in a shift of the three-base reading frame; all codons past the affected one are likely to code for different amino acids. The profound differences that are produced will almost always result in a nonfunctional polypeptide. Mutagenesis can occur spontaneously or because of physical (radiation) or chemical mutagens. Such mutagenesis may result in cancer.
Molecular Biology of the Gene - VIRUSES: GENES IN PACKAGES Viral DNA may become part of the host chromosome. Viruses depend on their host cells for the replication, transcription, and translation of their nucleic acid. Some bacteriophages are known to reproduce in two ways. In the lytic cycle, a phage immediately directs the host cell to replicate the viral nucleic acid, transcribes and translates its protein-coding genes, assembles new viruses, and causes host cell lysis, releasing the reproduced phages. In the lysogenic cycle, a phage’s DNA is inserted into the host cell DNA by recombination and becomes a prophage. This DNA sequence is replicated with the host cell’s DNA over many generations. Finally, some environmental cue directs the prophage to switch to the lytic cycle. Such prophages may cause the host cell to act differently than if the prophage were not there. Connection: Many viruses cause disease in animals. Viruses have a great variety of infectious cycles in eukaryotes. Those that infect plants or animals can cause disease. Note that organisms from all kingdoms have viruses that infect their cells.
In one type (enveloped RNA virus, such as the virus that causes mumps), the viral genes are in the form of RNA, which functions as a template to make complementary RNA. Complementary RNA functions either as mRNA to direct virus protein synthesis directly or as a template from which more RNA is made. Newly assembled viral particles leave the cell by enveloping themselves in host plasma membrane. Other viruses of eukaryotes, such as the herpes viruses that cause chickenpox, shingles, mononucleosis, cold sores, and genital herpes, reproduce inside the host cell’s nucleus and can insert as a provirus in the host DNA, much like a prophage in the lysogenic cycle. Note that viruses that cause cold sores and genital herpes are different strains. Animals defend themselves against viruses through their immune systems. Vaccines, which induce the immune system’s delayed responses to viral coat molecules, offer a possible defense against future viral infection. Note that antibiotic drugs (used to treat bacterial infections) cannot be used to treat viral infections. Connection: Plant viruses are serious agricultural pests. Most plant viruses are RNA viruses. Insects, farmers, and gardeners may all serve as vectors to spread plant viruses to healthy plants. In other cases, infected plants may pass certain viruses to their offspring through seed or vegetative propagation. There are no known cures for viral diseases of plants. Research has focused on prevention and the selective breeding of resistant plant varieties for many crops and horticultural plants. Connection: Emerging viruses threaten human health. HIV, the virus that causes AIDS, is an example of an emerging virus, as are Ebola and hantavirus. Viruses are thought to have arisen from cellular nucleic acid fragments. Support for this concept comes from viral nucleic acid being more similar to its host DNA than to the nucleic acid of viruses that infect different hosts. Mutation of existing viruses is the major source of new viral diseases. High rates of mutation, particularly of RNA viruses, accounts for the difficulty the immune system has in dealing with the viruses. This high mutation rate plays a major role in the difficulty of developing treatments and vaccines for HIV. The AIDS virus makes DNA on an RNA template. The virus that causes AIDS is human immunodeficiency virus, or HIV. HIV infects cells involved in the human immune system. The HIV particles are enveloped, like those that cause mumps. Although they carry genes in the form of RNA, these genes are expressed by being first transcribed back to DNA (reverse transcription), at which time they enter the host cell’s chromosomes as a provirus and remain unexpressed for several years. HIV finally becomes active by using the host cell’s machinery to reassemble new viruses, much like a DNA virus. Virus research and molecular genetics are intertwined. On the one hand, virus research played an important role in experiments on the molecular structure and activity of genes, and continues to do so. On the other hand, viruses cause some of the worst diseases we are dealing with today.