Mendel & The Gene Idea

Transcription

1 Introduction Mendel & The Gene Idea Every day we observe heritable variations (eyes of brown, green, blue, or gray) among individuals in a population. These traits are transmitted from parents to offspring. a-one mechanism for this transmission is the blending hypothesis, which proposes that the genetic material contributed by each parent mixes in a manner analogous to the way blue & yellow paints blend to make green. If this were true, then over many generations, a freely mating population should give rise to a uniform population of individuals. -However, the blending hypothesis appears incorrect as everyday observations and the results of breeding experiments contradict its predictions. b-an alternative model, particulate inheritance, proposes that parents pass on discrete heritable units - genes - that retain their separate identities in offspring. -Genes can be sorted & passed on, generation after generation, in undiluted form. Modern genetics began in an abbey garden, where a monk names Gregor Mendel documented the particulate mechanism of inheritance A. Gregor Mendel s Discoveries 1. Mendel brought an experimental & quantitative approach to genetics Mendel s Life Mendel grew up on a small farm in what is today the Czech Republic. -In 1843, Mendel entered an Augustinian monastery. -He studied at the University of Vienna from where he was influenced by a physicist who encouraged experimentation & the application of mathematics to science & by a botanist who aroused Mendel s interest in the causes of variation in plants. These influences came together in Mendel s experiments. -After the university, Mendel taught at the Brunn Modern School & lived in the local monastery, the monks of which had a long tradition of interest in the breeding of plants, including peas. Mendel s Experiments the Basic Ideas Around 1857, Mendel began breeding garden peas to study inheritance. Pea plants have several advantages for genetics: a-pea plants are available in many varieties with distinct heritable features (CHARACTERS, e.g. flower color) with different variants (TRAITS, e.g. red flower color). b-another advantage of peas is that Mendel had strict control over which plants mated with which. c-each pea plant has male (stamens) & female (carpal) sexual organs. In nature, pea plants typically self-fertilize, fertilizing ova with their own sperm. -However, Mendel could also move pollen from one plant to another to cross-pollinate plants. In a typical breeding experiment, Mendel would cross-pollinate (hybridize) two contrasting, TRUE-BREEDING (aka PUREBRED) pea varieties. -The true-breeding parents are the P GENERATION (short for parental) & their hybrid offspring are the F 1 GENERATION (short for FIRST FILIAL) -Mendel would then allow the F 1 hybrids to self-pollinate to produce an F 2 (SECOND FILIAL) GENERATION. *It was mainly Mendel s quantitative analysis of F 2 plants that revealed the two fundamental principles of heredity: (1) the Law Of Segregation (2) the Law Of Independent Assortment. 2. By the law of segregation, the two alleles for a character are packaged into separate gametes Mendel s Discoveries simple, but important If the blending model were correct, the F 1 hybrids from a cross between purple-flowered & white-flowered pea plants would have pale purple flowers. Instead, the F 1 hybrids all have purple flowers, just as purple as the purple-flowered parents.

2 -When Mendel allowed the F 1 plants to self-fertilize, the F 2 generation included both purple-flowered & whiteflowered plants. -The white trait, absent in the F 1, reappeared in the F 2. -Based on a large sample size, Mendel recorded 705 purpleflowered F 2 plants & 224 white-flowered F 2 plants from the original cross. -This cross-produced a trait ratio of 3 purple to 1 white in the F 2 offspring. Mendel reasoned that the heritable factor for white flowers was present in the F 1 plants, but it did not affect flower color. Purple flower is a dominant trait & white flower is a recessive trait. -The reappearance of white-flowered plants in the F 2 generation indicated that the heritable factor for the white trait was not diluted or blended by coexisting with the purple-flower factor in F 1 hybrids. Mendel found similar 3:1 ratios of two traits among F 2 offspring when he conducted crosses for 6 other characters, each represented by two different varieties. -e.g. when Mendel crossed two true-breeding varieties, one of which produced round seeds, the other of which produced wrinkled seeds, all the F 1 offspring had round seeds, but among the F 2 plants, 75% of the seeds were round & 25% were wrinkled. Mendel developed a hypothesis to explain these results that consisted of four related ideas: (1) Alternative version of genes (different alleles) account for variations in inherited characters. -Different alleles vary somewhat in the sequence of nucleotides at the specific locus of a gene. -e.g. the purple-flower allele & white-flower allele are two DNA variations at the flower-color locus. (2) For each character, an organism inherits two alleles, one from each parent. -A diploid organism inherits one set of chromosomes from each parent. -Each diploid organism has a pair of homologous chromosomes and therefore two copies of each locus. (These homologous loci may be identical, as in the true-breeding plants of the P generation, or they may differ.) -In the flower-color example, the F 1 plants inherited a purple-flower allele from 1 parent & a white-flower allele from the other. (3) If two alleles differ, then one, the DOMINANT ALLELE, is fully expressed in the organism s appearance. -The other, the RECESSIVE ALLELE, has no noticeable effect on the organism s appearance. e.g. Mendel s F 1 plants had purple flowers because the purple-flower allele is dominant & the white-flower allele is recessive. (4) The two alleles for each character segregate (separate) during gamete production. This segregation of alleles corresponds to the distribution of homologous chromosomes to different gametes in meiosis. -If an organism has identical alleles for a particular character, then that allele exists as a single copy in all gametes. -If different alleles are present, then 50% of the gametes will receive one allele & 50% will receive the other. -The separation of alleles into separate gametes is summarized as Mendel s LAW OF SEGREGATION. Mendel s law of segregation accounts for the 3:1 ratio that he observed in the F 2 generation. -The F 1 hybrids will produce 2 classes of gametes, ½ with the purple-flower allele & ½ with the white-flower allele. -During self-pollination, the gametes of these two classes unite randomly. This can produce four equally likely combinations of sperm & ovum. A PUNNETT SQUARE predicts the results of a genetic cross between individuals of known genotype. Using the Punnett square analysis of the flower-color example demonstrates Mendel s model: -1 in 4 F 2 offspring will inherit two white-flower alleles & produce white flowers. -½ of the F 2 offspring will inherit 1 white-flower allele & 1 purple-flower allele & produce purple flowers. -1 in 4 F 2 offspring will inherit two purple-flower alleles & produce purple flowers too. Mendel s model accounts for the 3:1 ratio in the F 2 generation. *Important Basic Terminology -An organism with two identical alleles for a character is HOMOZYGOUS for that character. -Organisms with two different alleles for a character is HETEROZYGOUS for that character. -A description of an organism s traits is its PHENOTYPE; a description of its genetic makeup is its GENOTYPE.

3 2 organisms can have the same phenotype but have different genotypes if one is homozygous dominant & the other is heterozygous. -e.g. for flower color in peas, both PP & Pp plants have the same phenotype (purple) but different genotypes (homozygous & heterozygous). -The only way to produce a white phenotype is to be homozygous recessive (pp) for the flower-color gene. It is not possible to predict the genotype of an organism with a dominant phenotype. (The organism must have one dominant allele, but it could be homozygous dominant or heterozygous.) -A testcross (breeding a homozygous recessive with dominant phenotype but unknown genotype) can determine the identity of the unknown allele. 3. By the law of independent assortment, each pair of alleles segregates into gametes independently Mendel s experiments that followed the inheritance of flower color or other characters focused on only a single character via MONOHYBRID crosses. He conducted other experiments in which he followed the inheritance of 2 different characters, a DIHYBRID cross. In one dihybrid cross experiment, Mendel studied the inheritance of seed color & seed shape. -The allele for yellow seeds (Y) is dominant to the allele for green seeds (y). -The allele for round seeds (R) is dominant to the allele for wrinkled seeds (r). -Mendel crossed true-breeding plants that had yellow, round seeds (YYRR) with true-breeding plants that has green, wrinkled seeds (yyrr). There were 2 possible outcomes, depending on how alleles are arranged in gamete production: 1 st -One possibility is that the two characters are transmitted from parents to offspring as a package, the Y & R alleles and y & r alleles each staying together in pairs. -If this were the case, the F 1 offspring would produce yellow, round seeds. -BUT the F 2 offspring would produce two phenotypes in a 3:1 ratio, just like a monohybrid cross. -This was not consistent with Mendel s results WRONG!!! 2 nd -An alternative hypothesis is that the two pairs of alleles segregate independently of each other. -The presence of 1 specific allele for 1 trait has no impact on the presence of a specific allele for the 2 nd trait. -In our example, the F 1 offspring would still produce yellow, round seeds -However, when the F 1 s produced gametes, genes would be packaged into gametes with all possible allelic combinations. Four classes of gametes (YR, Yr, yr, & yr) would be produced in equal amounts. -When sperm with 4 classes of alleles & ova with 4 classes of alleles combined, there would be 16 equally probable ways in which the alleles can combine in the F 2 generation. (4 x 4 = 16) -These combinations produce four distinct phenotypes in a 9:3:3:1 ratio. This was consistent with Mendel s results. -Mendel repeated the dihybrid cross experiment for other pairs of characters & always observed a 9:3:3:1 phenotypic ratio in the F 2 generation. Each character appeared to be inherited independently RIGHT!!! *The independent assortment of each pair of alleles during gamete formation is now called Mendel s LAW OF INDEPENDENT ASSORTMENT -One other aspect that you can notice in the dihybrid cross experiment is that if you follow just one character, you will observe a 3:1 F 2 ratio for each, just as if this were a monohybrid cross. 4. Mendelian inheritance reflects rules of probability Mendel s laws of segregation & independent assortment reflect the same laws of probability that apply to tossing coins or rolling dice. Basic Rules of Probability -The probability scale ranged from zero (an event with no chance of occurring) to one (an event that is certain to occur). -The probability of tossing heads with a normal coin is ½. -The probability of rolling a 3 with a 6-sided die is 1/6, & the probability of rolling any other number is 1-1/6 = 5/6. -When tossing a coin, the outcome of one toss has no impact on the outcome of the next toss. -Each toss is an independent event, just like the distribution of alleles into gametes.

4 How this relates to Genetics -Like a coin toss, each ovum from a heterozygous parent has a ½ chance of carrying the dominant allele & a ½ chance of carrying the recessive allele. The same odds apply to the sperm. -We can use the RULE OF MULTIPLICATION to determine the chance that two or more independent events will occur together in some specific combination: 1-Compute the probability of each independent event. -Then, multiply the individual probabilities to obtain the overall probability of these events occurring together. -e.g. The probability that two coins tossed at the same time will land heads up is ½ x ½ = ¼ 2-Similarly, the probability that a heterogyzous pea plant (Pp) will produce a white-flowered offspring (pp) depends on an ovum with a white allele mating with a sperm with a white allele. -This probability is ½ x ½ = ¼ The rule of multiplication also applies to dihybrid crosses: -For a heterozygous parent (YyRr) the probability of producing a YR gamete is ½ x ½ = ¼. -We can use this to predict the probability of a particular F 2 genotype without constructing a 16-part Punnett square -The probability that an F 2 plant will have a YYRR genotype from a heterozygous parent is 1/16 (1/4 chance for a YR ovum & 1/4 chance for a YR sperm). The rule of addition also applies to genetic problems: Under the RULE OF ADDITION, the probability of an event that can occur two or more different ways is the sum of the separate probabilities of those ways. -e.g. there are two ways that F 1 gametes can combine to form a heterozygote: a-the dominant allele could come from the sperm & the recessive from the ovum (probability = ¼ ). b-or, the dominant allele could come from the ovum & the recessive from the sperm (probability = ¼ ). The probability of a heterozygote is ½ x ½ = ¼. Combining the rules of multiplication & addition to solve complex problems in Mendelian genetics: Let s determine the probability of finding two recessive phenotypes for at least two of three traits resulting from a trihybrid cross between pea plants that are PpYyRr & Ppyyrr. -There are five possible genotypes that fulfill this condition: ppyyrr, ppyyrr, Ppyyrr, PPyyrr, & ppyyrr. -We would use the rule of multiplication to calculate the probability for each of these genotypes & then use the rule of addition to pool the probabilities for fulfilling the condition of at least two recessive traits. -The probability of producing a ppyyrr offspring: -The probability of producing pp = ½ x ½ = ¼. -The probability of producing yy = ½ x 1 = ½. -The probability of producing Rr = ½ x 1 = ½. The probability of all three being present (ppyyrr) in one offspring is ¼ x ½ x ½ = 1/16. -For ppyyrr: ¼ x ½ x ½ = 1/16. -For Ppyyrr: ½ x ½ x ½ = 2/16 -For PPyyrr: ¼ x ½ x ½ = 1/16 -For ppyyrr: ¼ x ½ x ½ = 1/16 Therefore, the chance of at least two recessive traits is 6/ Mendel discovered the particulate behavior of genes: a review While we cannot predict with certainty the genotype or phenotype of any particular seed from the F 2 generation of a dihybrid cross, we can predict the probabilities that it will fit a specific genotype of phenotype. -Mendel s experiments succeeded because he counted so many offspring & was able to discern this statistical feature of inheritance & had a keen sense of the rules of chance. -Mendel s laws of independent assortment & segregation explain heritable variation in terms of alternative forms of genes that are passed along according to simple rule of probability. -These laws apply not just to garden peas, but to all other diploid organisms that reproduce by sexual reproduction. -Mendel s studies of pea inheritance endure not only in genetics, but as a case study of the power of scientific reasoning using the hypothetico-deductive approach.

5 B. Extending Mendelian Genetics 1. The relationship between genotype & phenotype is rarely simple In the 20th century, geneticists have extended Mendelian principles not only to diverse organisms, but also to patterns of inheritance more complex than Mendel described. In fact, Mendel had the good fortune to choose a system that was relatively simple genetically. a-each character (but one) is controlled by a single gene. b-each gene has only two alleles, one of which is completely dominant to the other. c-the heterozygous F 1 offspring of Mendel s crosses always looked like one of the parental varieties because one allele was dominant to the other. However, some alleles show INCOMPLETE DOMINANCE where heterozygotes show a distinct intermediate phenotype, not seen in homozygotes. -BUT this is not blended inheritance because the traits are separable (particulate) as seen in further crosses. -Offspring of a cross between heterozygotes will show three phenotypes: both parentals & the heterozygote. -The phenotypic & genotypic ratios are identical, 1:2:1. -A clear example of incomplete dominance is seen in flower color of snapdragons. -A cross between a white-flowered plant & a red-flowered plant will produce all pink F 1 offspring. -Self-pollination of the F 1 offspring produces 25% white, 25% red, & 50% pink offspring. Incomplete & COMPLETE DOMINANCE are part of a spectrum of relationships among alleles, also including CODOMINANCE in which two alleles affect the phenotype in separate, distinguishable ways. -For example, the A, B, & AB blood groups of humans are due to the presence of two specific molecules on the surface of red blood cells. -The dominance/recessiveness relationships depend on the level at which we examine the phenotype. -e.g. humans with Tay-Sachs disease lack a functioning enzyme to metabolize gangliosides (a lipid) which accumulate in the brain, harming brain cells, & ultimately leading to death. (This is confusing; I leave it in the notes only for those of you who show a particular interest in bizarre little details ) -Children with two Tay-Sachs alleles have the disease. -Heterozygotes with one working allele & homozygotes with two working alleles are normal at the organismal level, but heterozygotes produce less functional enzymes. -However, both the Tay-Sachs & functional alleles produce equal numbers of enzyme molecules, codominant at the molecular level. So how exactly do dominant & recessive alleles work? Dominant alleles do not somehow subdue a recessive allele. -It is in the pathway from genotype to phenotype that dominance & recessiveness come into play. -e.g. wrinkled seeds in pea plants with two copies of the recessive allele are due to the accumulation of monosaccharides & excess water in seeds because of the lack of a key enzyme. -The seeds wrinkle when they dry. -Both homozygous dominants & heterozygotes produce enough enzymes to convert all the monosaccharides into starch & form smooth seeds when they dry. VERY IMPORTANT: Because an allele is dominant does not necessarily mean that it is more common in a population than the recessive allele. -For example, polydactyly, in which individuals are born with extra fingers or toes, is due to an allele dominant to the recessive allele for five digits per appendage. -However, the recessive allele is far more prevalent than the dominant allele in the population individuals out of 400 have five digits per appendage. Dominance/recessiveness relationships have 3 important points. (1) They range from complete dominance, though various degrees of incomplete dominance, to codominance. (2) They reflect the mechanisms by which specific alleles are expressed in the phenotype & do NOT involve the ability of one allele to subdue another at the level of DNA. (3) They do NOT determine or correlate with the relative abundance of alleles in a population.

6 Most genes have more than two alleles in a population The ABO blood groups in humans are determined by three alleles, I A, I B, & i. -Both the I A & I B alleles are dominant to the i allele -The I A & I B alleles are codominant to each other. -Because each individual carries two alleles, there are 6 possible genotypes & 4 possible blood types: -Individuals that are I A I A or I A i are type A & place type A oligosaccharides on the surface of their red blood cells. -Individuals that are I B I B or I B i are type B & place type B oligosaccharides on the surface of their red blood cells. -Individuals that are I A I B are type AB & place both type A & type B oligosaccharides on the surface of their red blood cells. -Individuals that are ii are type O & place neither oligosaccharide on the surface of their red blood cells. Matching compatible blood groups is critical for blood transfusions because a person produces antibodies against foreign blood factors. -If the donor s blood has an A or B oligosaccharide that is foreign to the recipient, antibodies in the recipient s blood will bind to the foreign molecules, cause the donated blood cells to clump together, & can kill the recipient. As if that wasn t enough, some genes affect more than one phenotypic character: Most genes are PLEIOTROPIC, affecting more than one phenotypic character. -Considering the intricate molecular & cellular interactions responsible for an organism s development, it is not surprising that a gene can affect a number of an organism s characteristics. -e.g. the wide-ranging symptoms of sickle-cell disease are due to a single gene In EPISTASIS, a gene at one locus alters the phenotypic expression of a gene at a second locus. -e.g. in mice & many other mammals, coat color depends on two genes. -One, the epistatic gene, determines whether pigment will be deposited in hair or not. -Presence (C) is dominant to absence (c). -The second determines whether the pigment to be deposited is black (B) or brown (b). -The black allele is dominant to the brown allele. -An individual that is cc has a white (albino) coat regardless of the genotype of the second gene. -A cross between two black mice that are heterozygous (BbCc) will follow the law of independent assortment. -BUT, unlike the 9:3:3:1 offspring ratio of a normal Mendelian expt., the ratio is 9 black, 3 brown, & 4 white.

7 And then some characters vary along a continuum: -Some characters do not fit the either-or basis that Mendel studied. QUANTITATIVE CHARACTERS vary in a population along a continuum. -These are usually due to POLYGENIC INHERITANCE, the additive effects of 2 or more genes on a single phenotypic character. -e.g. SKIN COLOR in humans is controlled by at least 3 different genes. -Imagine that each gene has two alleles, one light and one dark, that demonstrate incomplete dominance. -An AABBCC individual is dark and aabbcc is light. -A cross between two AaBbCc individuals (intermediate skin shade) would produce offspring covering a wide range of shades. -Individuals with intermediate skin shades would be the most likely offspring, but very light and very dark individuals are possible as well. -The range of phenotypes forms a normal distribution. Phenotype depends on environment and genes. -A single tree has leaves that vary in size, shape, and greenness, depending on exposure to wind and sun. -For humans, nutrition influences height, exercise alters build, sun-tanning darkens the skin, and experience improves performance on intelligence tests. -Even identical twins, genetic equals, accumulate phenotypic differences as a result of their unique experiences. The relative importance of genes and the environment in influencing human characteristics is a very old and hotly contested debate. -The product of a genotype is generally not a rigidly defined phenotype, but a range of phenotypic possibilities, the norm of reaction, that are determined by the environment. -In some cases the norm of reaction has no breadth (for example, blood type). -Norms of reactions are broadest for polygenic characters. -For these multifactorial characters, environment contributes to their quantitative nature. A reductionist emphasis on single genes and single phenotypic characters presents an inadequate perspective on heredity and variation. -A more comprehensive theory of Mendelian genetics must view organisms as a whole. -Phenotype has been used to this point in the context of single characters, but it is also used to describe all aspects of an organism. -Genotype can refer not just to a single genetic locus, but also to an organism s entire genetic makeup. An organism s phenotype reflects its overall genotype and unique environmental history. C. Mendelian Inheritance in Humans While peas are convenient subjects for genetic research, humans are not. The generation time is too long, fecundity too low, and breeding experiments are unacceptable. Yet, humans are subject to the same rules regulating inheritance as other organisms. New techniques in molecular biology have led to many breakthrough discoveries in the study of human genetics. 1. Pedigree analysis reveals Mendelian patterns in human inheritance Rather than manipulate mating patterns of people, geneticists analyze the results of matings that have already occurred. In a PEDIGREE analysis, information about the presence/absence of a particular phenotypic trait is collected from as many individuals in a family as possible and across generations. -The distribution of these characters is then mapped on the family tree. e.g. The occurrence of widows peak (W) is dominant to a straight hairline (w). -The relationship among alleles can be integrated with the phenotypic appearance of these traits to predict the genotypes of members of this family. e.g. If an individual in the 3 rd generation lacks a widow s peak, but both her parents have widow s peaks, then her parents must be heterozygous for that gene -If some siblings in the 2 nd generation lack a widow s peak and one of the grandparents (first generation) also lacks one, then we know the other grandparent must be heterozygous and we can determine the genotype of almost all other individuals.

8 e.g.#2 We can use the same family tree to trace the distribution of attached earlobes (f), a recessive characteristic -Individuals with a dominant allele (F) have free earlobes. Some individuals may be ambiguous, especially if they have the dominant phenotype and could be heterozygous or homozygous dominant. -A pedigree can help us understand the past and to predict the future. -We can use the normal Mendelian rules, including multiplication and addition, to predict the probability of specific phenotypes. -e.g. these rules could be used to predict the probability that a child with WwFf parents will have a widow s peak and attached earlobes. -The chance of having a widow s peak is ¾ (½ [WW] + ¼ [Ww]). -The chance of having attached earlobes is ¼ [ff]. -This combination has a probability of ¾ + ¼ = 3/ Many human disorders follow Mendelian patterns of inheritance 1000 s of genetic disorders, including disabling or deadly hereditary diseases, are inherited as simple recessive traits. -These range from relatively mild (albinism) to life-threatening (cystic fibrosis). -The recessive behavior of the alleles occurs because the allele codes for either a malfunctioning protein or no protein at all. Heterozygotes have a normal phenotype because 1 normal allele produces enough of the required protein. A recessively inherited disorder shows up only in homozygous individuals who inherit a recessive allele from each parent. -Individuals who lack the disorder are either homozgyous dominant or heterozygotes. -While heterozygotes may have no clear phenotypic effects, they are CARRIERS who may transmit a recessive allele to their offspring. Most people with recessive disorders are born to carriers with normal phenotypes. -Two carriers have a ¼ chance of having a child with the disorder, ½ chance of a carrier, and ¼ free. -Genetic disorders are not evenly distributed among all groups of humans. -This results from the different genetic histories of the world s people during times when populations were more geographically (and genetically) isolated. Details about some Major diseases affecting Humans: CYSTIC FIBROSIS, which strikes one of every 2,500 whites of European descent. -One in 25 whites is a carrier! -The normal allele codes for a membrane protein that transports Cl- between cells and the environment. -If these channels are defective or absent, there are abnormally high extracellular levels of chloride that causes the mucus coats of certain cells to become thicker and stickier than normal. -This mucus build-up in the pancreas, lungs, digestive tract, and elsewhere favors bacterial infections. -Without treatment, affected children die before five, but with treatment can live past their late 20 s. TAY-SACHS DISEASE is another lethal recessive disorder. -It is caused by a dysfunctional enzyme that fails to break down specific brain lipids. -The symptoms begin with seizures, blindness, and degeneration of motor and mental performance a few months after birth. -Inevitably, the child dies after a few years. -Among Ashkenazic Jews (those from central Europe) this disease occurs in one of 3,600 births, about 100 times greater than the incidence among non-jews or Mediterranean (Sephardic) Jews. The most common inherited disease among blacks is SICKLE-CELL DISEASE. -It affects one of 400 African Americans. -It is caused by the substitution of a single amino acid in hemoglobin! -When oxygen levels in the blood of an affected individual are low, sickle-cell hemoglobin crystallizes into long rods. -This deforms red blood cells into a sickle shape. -This sickling creates a cascade of symptoms, demonstrating the pleiotropic effects of this allele. -Doctors can use regular blood transfusions to prevent brain damage and new drugs to prevent or treat other problems.

9 Special philosophical Section: 2 Ways to look at sickle cell: a-at the organismal level, the non-sickle allele is incompletely dominant to the sickle-cell allele. Carriers are said to have the sickle-cell trait. These individuals are usually healthy, although some suffer some symptoms of sickle-cell disease under blood oxygen stress. b-at the molecule level, the 2 alleles are codominant as both normal and abnormal hemoglobins are synthesized. The high frequency of heterozygotes with the sickle-cell trait is unusual for an allele with severe detrimental effects in homozygotes. The evolutionary significance of the sickle cell gene (Or, how has such a lethal gene survived so long?): Interestingly, individuals with one sickle-cell allele have increased resistance to malaria, a parasite that spends part of its life cycle in red blood cells. -In tropical Africa, where malaria is common, the sicklecell allele is both a boon and a bane. -Homozygous normal individuals die of malaria, homozygous recessive individuals die of sickle-cell disease, and carriers are relatively free of both. -Its relatively high frequency in African Americans is a vestige of their African roots. -Normally it is relatively unlikely that two carriers of the same rare harmful allele will meet and mate. -However, consanguineous matings (those between close relatives) increase the risk. -These individuals who share a recent common ancestor are more likely to carry the same recessive alleles. Why do most societies and cultures have laws or taboos forbidding marriages between close relatives? -Although most harmful alleles are recessive, many human disorders are due to dominant alleles. -For example, Achondroplasia, a form of dwarfism, has an incidence of one case in 10,000 people. -Heterozygous individuals have the dwarf phenotype; those who are not achodroplastic dwarfs, 99.99% of the population, are homozygous recessive for this trait. Lethal dominant alleles are much less common than lethal recessives because if a lethal dominant kills an offspring before it can mature and reproduce, the allele will not be passed on to future generations. -BUT, a lethal dominant allele can escape elimination if it causes death at a relatively advanced age, after the individual has already passed on the lethal allele to his or her children. -e.g. HUNTINGTON S DISEASE, a degenerative disease of the nervous system. -The dominant lethal allele has no obvious phenotypic effect until an individual is about years old. -The deterioration of the nervous system is irreversible and inevitably fatal. -Any child born to a parent who has the allele for Huntington s disease has a 50% chance of inheriting the disease and the disorder. -Recently, molecular geneticists have used pedigree analysis of affected families to track down the Huntington s allele to a locus near the tip of chromosome 4. While some diseases are inherited in a simple Mendelian fashion due to alleles at a single locus, many other disorders have a multifactorial basis. -These have a genetic component plus a significant environmental influence. -Multifactorial disorders include heart disease, diabetes, cancer, alcoholism, and certain mental illnesses, such a schizophrenia and manic-depressive disorder. -The genetic component is typically polygenic. -At present, little is understood about the genetic contribution to most multifactorial diseases - The best public health strategy is education about the environmental factors and healthy behavior. 3. Technology is providing new tools for genetic testing and counseling -A preventative approach to simple Mendelian disorders is sometimes possible. -The risk that a particular genetic disorder will occur can sometimes be assessed before a child is conceived or early in pregnancy. -Many hospitals have genetic counselors to provide information to prospective parents who are concerned about a family history of a specific disease. Consider a hypothetical couple, John and Carol, who are planning to have their first child. -In both of their families histories a recessive lethal disorder is present and both John and Carol had brothers who died of the disease. -While neither John and Carol nor their parents have the disease, their parents must have been carriers (Aa x Aa). -John and Carol each have a 2/3 chance of being carriers and a 1/3 chance of being homozygous dominant. -The probability that their first child will have the disease = 2/3 (chance that John is a carrier) x 2/3 (chance that Carol is a carrier) x 1/4 (chance that the offspring of two carriers is homozygous recessive) = 1/9. -If their first child is born with the disease, we know that John and Carol s genotype must be Aa and they both are carriers. -The chance that their next child will also have the disease is ¼. -Mendel s laws are simply the rules of probability applied to heredity. -Because chance has no memory, the genotype of each child is unaffected by the genotypes of older siblings. -While the chance that John and Carol s first four children will have the disorder ( ¼ x ¼ x ¼ x ¼ ), the likelihood of having a 5 th child with the disorder is one chance in sixty four, still 1/4.

10 Most children with recessive disorders are born to parents with a normal phenotype. -A key to assessing risk is identifying if prospective parents are carriers of the recessive trait. -Recently developed tests for several disorders can distinguish between normal phenotypes in heterozygotes from homozygous dominants. -The results allow individuals with a family history of a genetic disorder to make informed decisions about having children. -However, issues of confidentiality, discrimination, and adequate information and counseling arise. -Tests are also available to determine IN UTERO if a child has a particular disorder. One technique, AMNIOCENTESIS, can be used beginning at the 14th to 16th week of pregnancy to assess the presence of a specific disease. -Fetal cells extracted from amniotic fluid are cultured and karyotyped to identify some disorders. -Other disorders can be identified from chemicals in the amniotic fluids. A second technique, CHORIONIC VILLUS SAMPLING (CVS) can allow faster karyotyping and can be performed as early as the eighth to tenth week of pregnancy. -This technique extracts a sample of fetal tissue from the chrionic villi of the placenta. -This technique is not suitable for tests requiring amniotic fluid. Other techniques, ULTRASOUND and fetoscopy, allow fetal health to be assessed visually in utero. -Both fetoscopy and amniocentesis cause complications in about 1% of cases, including maternal bleeding or fetal death. -Therefore, these techniques are usually reserved for cases in which the risk of a genetic disorder or other type of birth defect is relatively great. -If fetal tests reveal a serious disorder, the parents face the difficult choice of terminating the pregnancy or preparing to care for a child with a genetic disorder. Some genetic tests can be detected at birth by simple tests that are now routinely performed in hospitals. -One test can detect the presence of a recessively inherited disorder, PHENYKETONURIA (PKU). This disorder occurs in one in 10,000 to 15,000 births. Individuals with this disorder accumulate the amino acid phenylalanine and its derivative phenypyruvate in the blood to toxic levels. This leads to mental retardation. If the disorder is detected, a special diet low in phenyalalanine usually promotes normal development. The Chromosomal Basis Of Inheritance Relating Mendelism to Chromosomes * Means denotes a major objective Describe the contributions that Walter Sutton, Theodor Boveri, and Thomas Hunt Morgan made to current understanding of chromosomal inheritance. *Explain why Drosophila melanogaster is a good experimental organism. *Define and compare linked genes and sex-linked genes. Explain why the inheritance of linked genes is different from independent assortment. Distinguish between parental and recombinant phenotypes. Explain why linked genes do not assort independently. *Explain how crossing over can unlink genes. Explain how Sturtevant created linkage maps. Define a map unit. Explain why Mendel did not find linkage between seed color and flower color. Explain how genetic maps are constructed for genes located far apart on a chromosome. Explain the impact of multiple crossovers between loci. Explain what additional information cytological maps provide over linkage maps. Sex Chromosomes *Explain how sex is genetically determined in humans and the significance of the SRY gene. *Explain why sex-linked diseases are more common in human males. *Describe the inheritance patterns and symptoms of color blindness, Duchenne muscular dystrophy, and hemophilia. Describe the process of X inactivation in female mammals. Explain how this phenomenon produces the tortoiseshell coloration in cats. Errors and Exceptions in Chromosomal Inheritance *Distinguish among nondisjunction, aneuploidy, trisomy, triploidy, and polyploidy. Explain how these major chromosomal changes occur and describe the consequences. *Distinguish among deletions, duplications, inversions, and translocations. Describe the type of chromosomal alterations implicated in the following human disorders: Down syndrome, Klinefelter's syndrome, extra Y, triple-x syndrome, Turner's syndrome, cri du chat syndrome, and chronic myelogenous leukemia. Define genomic imprinting and provide evidence to support this model. *Give some exceptions to the chromosome theory of inheritance. Explain why extranuclear genes are not inherited in a Mendelian fashion and how they can contribute to disease.

11 Introduction -It was not until 1900 that biology finally caught up with Gregor Mendel. -Independently, Karl Correns, Erich von Tschermak, and Hugo de Vries all found that Mendel had explained the same results 35 years before. *Still, resistance remained about Mendel s laws of segregation and independent assortment until evidence had mounted that they had a physical basis in the behavior of chromosomes; it would turn out that Mendel s hereditary factors are actually the genes located on chromosomes. A. Relating Mendelism to Chromosomes 1. Mendelian inheritance has its physical basis in chromosomal behavior during sexual life cycles Around 1900, cytologists and geneticists began to see parallels between the behavior of chromosomes and the behavior of Mendel s factors. -Chromosomes and genes are both present in pairs in diploid cells. -Homologous chromosomes separate and alleles segregate during meiosis. -Fertilization restores the paired condition for both chromosomes and genes. Around 1902, Walter Sutton, Theodor Boveri, and others noted these parallels and a CHROMOSOME THEORY OF INHERITANCE began to take form. Be able to describe how the chromosomes in the diagram illustrate Mendel s laws. 2. Thomas Hunt Morgan traced a gene to a specific chromosome T.H. Morgan was the first to associate a specific gene with a specific chromosome in the early 20th century. Like Mendel, Morgan made an insightful choice as an experimental animal, Drosophila melanogaster, a fruit fly species that eats fungi on fruit. Why choose fruit flies? -Fruit flies are prolific breeders and have a generation time of two weeks. -Fruit flies have three pairs of autosomes and a pair of sex chromosomes (XX in females, XY in males). Morgan s Fly Experiments Morgan spent a year looking for variant individuals among the flies he was breeding. -He discovered a single male fly with white eyes instead of the usual red. The normal character phenotype is the WILD TYPE. -Alternative traits are mutant phenotypes. -When Morgan crossed his white-eyed male with a red-eyed female, all the F 1 offspring had red eyes, -The red allele appeared dominant to the white allele. Crosses between the F 1 offspring produced the classic 3:1 phenotypic ratio in the F 2 offspring. -Surprisingly, the white-eyed trait appeared only in males. -All the females and half the males had red eyes. Morgan concluded that a fly s eye color was linked to its sex. Morgan deduced that the gene with the white-eyed mutation is on the X chromosome alone, a SEX- LINKED GENE. -Females (XX) may have 2 red-eyed alleles and have red eyes or may be heterozygous and have red eyes. -Males (XY) have only a single allele and will be red eyed if they have a red-eyed allele or whiteeyed if they have a white-eyed allele.

12 3. Linked genes tend to be inherited together because they are located on the same chromosome Each chromosome has hundreds or thousands of genes. Genes located on the same chromosome, LINKED GENES, tend to be inherited together because the chromosome is passed along as a unit. -Results of crosses with linked genes deviate from those expected according to independent assortment. Morgan observed this linkage and its deviations when he followed the inheritance of 2 characters: body color & wing size. -The wild-type body color is gray (b + ) and the mutant black (b). -The wild-type wing size is normal (v + ) and the mutant has vestigial wings (v). Morgan crossed F 1 heterozygous females (b + bv + v) with homozygous recessive males (bbvv). -According to independent assortment, this should produce 4 phenotypes in a 1:1:1:1 ratio. -Surprisingly, Morgan observed a large number of wild-type (i.e. gray-normal) and double-mutant (i.e. black-vestigial) flies among the offspring, phenotypes identical to the parents. Morgan reasoned that body color and wing shape are usually inherited together because their genes are on the same chromosome. The other 2 phenotypes (gray-vestigial and blacknormal) were fewer than expected from independent assortment (and totally unexpected from dependent assortment). -These new phenotypic variations must be the result of crossing over. 4. Independent assortment of chromosomes and crossing over produce genetic recombinants The production of offspring with new combinations of traits inherited from 2 parents is GENETIC RECOMBINATION. Genetic recombination can result from independent assortment of genes located on nonhomologous chromosomes or from crossing over of genes located on homologous chromosomes. Mendel s dihybrid cross experiments produced some offspring that had a combination of traits that did not match either parent in the P generation. -If the P generation consists of a yellow-round parent (YYRR) crossed with a green-wrinkled seed parent (yyrr), all F 1 plants have yellow-round seeds (YyRr). -A cross between an F 1 plant and a homozygous recessive plant (a test-cross) produces 4 phenotypes. -Half are be PARENTAL TYPES, with phenotypes that match the original P parents (i.e. either yellow-round seeds or green-wrinkled seeds.) -Half are RECOMBINANTS, new combination of parental traits (i.e. yellow-wrinkled or green-round seeds.) A 50% frequency of recombination is observed for any 2 genes located on different (nonhomologous) chromosomes. The physical basis of recombination between unlinked genes is the random orientation of homologous chromosomes at metaphase 1. -The F 1 parent (YyRr) can produce gametes with 4 different combinations of alleles: YR, Yr, yr, & yr. -The orientation of the tetrad containing the seed color gene has no bearing on the orientation on the tetrad with the seed shape gene. In contrast, linked genes, genes located on the same chromosome, tend to move together through meiosis & fertilization. (i.e. no independent assortment) Under normal Mendelian genetic rules, we would not expect linked genes to recombine into assortments of alleles not found in the parents. -If the seed color & seed coat genes were linked, we would expect the F 1 offspring to produce only 2 types of gametes, YR and yr when the tetrads separate. -One homologous chromosome from a P generation parent carries the Y and R alleles on the same chromosome and the other homologous chromosome from the other P parent carries the y & r alleles. The results of Morgan s testcross for body color & wing shape did not conform to either independent assortment or complete linkage. -Under independent assortment the testcross should produce a 1:1:1:1 phenotypic ratio. -If completely linked, we should expect to see a 1:1:0:0 ratio with only parental phenotypes among offspring. Most of the offspring had parental phenotypes, suggesting linkage between the genes. -However, 17% of the flies were recombinants, suggesting incomplete linkage. -Morgan proposed that some mechanism occasionally exchanged segments between homologous chromosomes, thus occasionally switching alleles between homologous chromosomes. This mechanism we now call crossing over (occurring in prophase I) results in the production of more types of gametes than one would predict by Mendelian rules alone. The occasional production of recombinant gametes during prophase I accounts for the occurrence of recombinant phenotypes in Morgan s testcross. 5. Geneticists can use recombination data to map a chromosome s genetic loci One of Morgan s students, Alfred Sturtevant, used crossing over of linked genes to develop a method for constructing a GENETIC MAP.

13 -This map is an ordered list of the genetic loci along a particular chromosome. -Sturtevant hypothesized that the frequency of recombinant offspring reflected the distances between genes on a chromosome. The farther apart 2 genes are, the higher the probability that a crossover will occur between them and therefore a higher recombination frequency. Sturtevant & His Linkage Maps Sturtevant used recombination frequencies from fruit fly crosses to map the relative position of genes along chromosomes, a LINKAGE MAP. Sturtevant used the testcross design to map the relative position of three fruit fly genes, body color (b), wing size (vg), and eye color (cn). -The recombination frequency between cn and b is 9%. -The recombination frequency between cn and vg is 9.5%. -The recombination frequency between b and vg is 17%. -The only possible arrangement of these three genes places the eye color gene between the other two. Sturtevant expressed the distance between genes, the recombination frequency, as MAP UNITS; one map unit (sometimes called a centimorgan) is equivalent to a 1% recombination frequency. You may notice that the three recombination frequencies in our mapping example are not quite additive: 9% (b-cn) + 9.5% (cn-vg) > 17% (b-vg). -This results from multiple crossing over events. -A second crossing over cancels out the first and reduces the observed number of recombinant offspring. -Genes farther apart (for example, b-vg) are more likely to experience multiple crossing over events. Some genes on a chromosome are so far apart that a crossover between them is virtually certain. -In this case, the frequency of recombination reaches is its maximum value of 50% and the genes act as if found on separate chromosomes and are inherited independently. -In fact, several genes studied by Mendel are located on the same chromosome. -e.g. seed color & flower color are far enough apart that linkage is not observed. (Plant height and pod shape should show linkage, but Mendel never reported results of this cross.) More Tidbits on Linkage Maps Genes located far apart on a chromosome are mapped by adding the recombination frequencies between the distant genes and intervening genes. Sturtevant and his colleagues were able to map the linear positions of genes in Drosophila into 4 groups, one for each chromosome. A linkage map provides an imperfect picture of a chromosome. *Map units indicate relative distance and order, not precise locations of genes. The frequency of crossing over is not actually uniform over the length of a chromosome. -Combined with other methods like chromosomal banding, geneticists can develop cytological maps. -These indicated the positions of genes with respect to chromosomal features. More recent techniques show the absolute distances between gene loci in DNA nucleotides. *A moment for thought: Consider how the 3 maps just discussed could themselves be arranged along a continuum, showing increasingly detailed information about the location of genes on a chromosome. Can you describe how they are related?

14 B. Sex Chromosomes 1. The chromosomal basis of sex varies with the organism Although the anatomical and physiological differences between women and men are numerous, the chromosomal basis of sex is rather simple. In human and other mammals, there are two varieties of sex chromosomes, X and Y. -An individual who inherits two X chromosomes usually develops as a female, whereas an individual who inherits an X and a Y chromosome usually develops as a male. -Note that this X-Y system of mammals is not the only chromosomal mechanism of determining sex. Other options include the X-0 system, the Z-W system, and the haplo-diploid system. You should become familiar with some of these alternate options -In the X-Y system, Y and X chromosomes behave as homologous chromosomes during meiosis, but in reality, they are only partially homologous and rarely undergo crossing over. In both testes (XY) and ovaries (XX), the two sex chromosomes segregate during meiosis and each gamete receives one. -Each egg receives an X chromosome. -Half the sperm receive an X chromosome and half receive a Y chromosome. -Because of this, each conception has about a fifty-fifty chance of producing a particular sex. In individuals with the SRY GENE (Sex-determining Region of the Y-chromosome), the generic embryonic gonads are modified into testes. -Activity of the SRY gene triggers a cascade of biochemical, physiological, and anatomical features because it regulates many other genes. (In humans, the anatomical signs of sex first appear when the embryo is about two months old. ) -In addition, other genes on the Y chromosome are necessary for the production of functional sperm. -In individuals lacking the SRY gene even those who have an otherwise normal Y chromosome) the generic embryonic gonads still develop into ovaries, as if they never received the signal to..uh, teste-ize 2. Sex-linked genes have unique patterns of inheritance In addition to their role in determining sex, the sex chromosomes, especially the X chromosome, have genes for many characters unrelated to sex. -These sex-linked genes follow the same pattern of inheritance as the white-eye locus in Drosophila. -If a sex-linked trait is due to a recessive allele, a female will have this phenotype only if homozygous; heterozygous females will be carriers. -Because males have only one X chromosome (hemizygous), any male receiving the recessive allele from his mother will express the trait. -The chance of a female inheriting a double dose of the mutant allele is much less than the chance of a male inheriting a single dose. Therefore, males are far more likely to inherit sexlinked recessive disorders than are females. Several serious human disorders are sex-linked. Duchenne muscular dystrophy affects one in 3,500 males born in the United States. -Affected individuals rarely live past their early 20s. -This disorder is due to the absence of an X-linked gene for a key muscle protein, called dystrophin. -The disease is characterized by a progressive weakening of the muscles and a loss of coordination. HEMOPHILIA (literally blood-loving ) is a sexlinked recessive trait defined by the absence of one or more clotting factors. -These proteins normally slow and then stop bleeding. -Individuals with hemophilia have prolonged bleeding because a firm clot forms slowly. -Bleeding in muscles and joints can be painful and lead to serious damage. -Individuals can be treated with intravenous injections of the missing protein.

15 Something you probably never knew Female cells have the same number of active X chromosomes as male cells Although female mammals inherit two X chromosomes, only one X chromosome in each cell is active. -Therefore, males and females have the same effective dose (one copy) of genes on the X chromosome. -During female development, one X chromosome per cell condenses into a compact object, a BARR BODY, a process which inactivates most of its genes. (Although the condensed Barr body chromosome is reactivated in ovarian cells that produce ova.) -Mary Lyon, a British geneticist, has demonstrated that the selection of which X chromosome to form the Barr body occurs randomly and independently in embryonic cells at the time of X inactivation WEIRD: As a consequence, females actually consist of a mosaic of cells, some with an active paternal X, others with an active maternal X. -After Barr body formation, all descendent cells have the same inactive X. If a female is heterozygous for a sex-linked trait, approximately half her cells will express one allele and the other half will express the other allele. -A good example of this in humans is the mosaic pattern seen in women who are heterozygous for a X-linked mutation that prevents the development of sweat glands: A heterozygous woman will have patches of normal skin and skin patches lacking sweat glands. -Similarly, the orange and black pattern on tortoiseshell cats is due to patches of cells expressing an orange allele while others have a nonorange allele. X inactivation involves the attachment of methyl ( CH 3 ) groups to cytosine nucleotides on the X chromosome that will become the Barr body. Details, in case you re interested: -One of the two X chromosomes has an active XIST gene (X-inactive specific transcript). -This gene produces multiple copies of an RNA molecule that almost cover the X chromosome where they are made. -This initiates X inactivation, but the mechanism that connects XIST RNA and DNA methylation is unknown. -What determines which of the two X chromosomes will have an active XIST gene is also unknown. C. Errors and Exceptions in Chromosomal Inheritance -Sex-linked traits are not the only notable deviation from the inheritance patterns observed by Mendel. -Also, gene mutations are not the only kind of changes to the genome that can affect phenotype. -Major chromosomal aberrations and their consequences produce exceptions to standard chromosome theory. -In addition, two types of normal inheritance also deviate from the standard pattern. 1. Alterations of chromosome number or structure cause some genetic disorders NONDISJUNCTION occurs when problems with the meiotic spindle cause errors in daughter cells. -This may occur if tetrad chromosomes do not separate properly during meiosis I. -Alternatively, sister chromatids may fail to separate during meiosis II. -As a consequence of nondisjunction, some gametes receive two of the same type of chromosome and another gamete receives no copy.

16 Different Results of Nondisjunction Offspring results from fertilization of a normal gamete with one after nondisjunction will have an abnormal chromosome number or aneuploidy. -Trisomic cells have three copies of a particular chromosome type and have 2n + 1 total chromosomes. (TRISOMY) -Monosomic cells have only one copy of a particular chromosome type and have 2n - 1 chromosomes. (MONOSOMY) If the organism survives, aneuploidy typically leads to a distinct phenotype. -Aneuploidy can also occur during failures of the mitotic spindle. -If aneuploidy happens early in development, this condition will be passed along by mitosis to a large number of cells, which is likely to have a substantial effect on the organism. Organisms with more than two complete sets of chromosomes, have undergone POLYPLOIDY. -This may occur when a normal gamete (n) fertilizes another gamete in which there has been nondisjunction of all its chromosomes (2n). -The resulting zygote would be triploid (3n). -Alternatively, if a 2n zygote failed to divide after replicating its chromosomes, a tetraploid (4n) embryo would result from subsequent successful cycles of mitosis. Polyploidy is relatively common among plants and much less common among animals. -The spontaneous origin of polyploid individuals plays an important role in the evolution of plants. -Both fishes and amphibians have polyploid species. -Recently, researchers in Chile have identified a new rodent species that may be the product of polyploidy. Interestingly, polyploids are more nearly normal in phenotype than aneuploids one extra or missing chromosome apparently upsets the genetic balance during development more than does an entire extra set of chromosomes. Breakage of a chromosome can lead to 4 types of changes in chromosome structure. 1-A DELETION occurs when a chromosome fragment lacking a centromere is lost during cell division. This chromosome will be missing certain genes. 2-A DUPLICATION occurs when a fragment becomes attached as an extra segment to a sister chromatid. 3-An INVERSION occurs when a chromosomal fragment reattaches to the original chromosome but in the reverse orientation. 4-In TRANSLOCATION, a chromosomal fragment joins a nonhomologous chromosome. -Some translocations are reciprocal, others are not. Deletions and duplications are common in meiosis. -Homologous chromatids may break and rejoin at incorrect places, such that one chromatid will lose more genes than it receives. -A diploid embryo that is homozygous for a large deletion or male with a large deletion to its single X chromosome is usually missing many essential genes and this leads to a lethal outcome. -Duplications and translocations are typically harmful. -Reciprocal translocation or inversion can alter phenotype because a gene s expression is influenced by its location. Several serious human disorders are due to alterations of chromosome number and structure. -Although the frequency of aneuploid zygotes may be quite high in humans, most of these alterations are so disastrous that the embryos are spontaneously aborted long before birth. -These developmental problems result from an imbalance among gene products. -Certain aneuploid conditions upset the balance less, leading to survival to birth and beyond. -These individuals have a set of symptoms a SYNDROME characteristic of the type of aneuploidy. One aneuploid condition, DOWN SYNDROME, is due to three copies of chromosome 21. -It affects one in 700 children born in the United States. -Although chromosome 21 is the smallest human chromosome, it severely alters an individual s phenotype in specific ways. -Most cases of Down syndrome result from nondisjunction during gamete production in one parent. -The frequency of Down syndrome correlates with the age of the mother. -This may be linked to some age-dependent abnormality in the spindle checkpoint during meiosis I, leading to nondisjunction. -Trisomies of other chromosomes also increase in incidence with maternal age, but it is rare for infants with these autosomal trisomies to survive for long.

17 Nondisjunction of sex chromosomes produces a variety of aneuploid conditions in humans. Unlike autosomes, this aneuploidy upsets the genetic balance less severely. This may be because the Y chromosome contains relatively few genes. Also, extra copies of the X chromosome become inactivated as Barr bodies in somatic cells. a) KLINEFELTER S SYNDROME, an XXY male, occurs once in every 2000 live births. -These individuals have male sex organs, but are sterile. -There may be some feminine characteristics. -Their intelligence is normal, and there is even an organization/support network b) Males with an extra Y chromosome (XYY) tend to somewhat taller than average. c) Trisomy X (XXX), which occurs once in every 2000 live births, produces healthy females. d) Monosomy X or TURNER S SYNDROME (X0), which occurs once in every 5000 births, produces phenotypic, but immature females. (see photo ) Structural alterations of chromosomes can also cause human disorders. -Deletions, even in a heterozygous state, cause severe physical and mental problems. One syndrome, cri du chat, results from a specific deletion in chromosome 5; these individuals are mentally retarded, have a small head with unusual facial features, and a cry like the mewing of a distressed cat. This syndrome is fatal in infancy or early childhood. Really Bad nondisjunctions Other nondisjunctions are less fortunate. The list of -Chromosomal translocations have been implicated severe defects associated with in certain cancers, including chronic Trisomy-13 (Patau Syndrome) is myelogenous leukemia (CML). extensive, and you can see the -CML occurs when a fragment of physical defects alone are not chromosome 22 switches places with a pretty small fragment from the tip of Chromosomal translocations chromosome 9. between nonhomologous -In fact, some individuals with Down chromosomes are also associated syndrome have the normal number of with human disorders. chromosomes but have all or part of a third chromosome 21 attached to another chromosome by translocation. 2. Very strange: The phenotypic effects of some mammalian genes depend on whether they were inherited from the mother or the father (imprinting) For most genes it is a reasonable assumption that a specific allele will have the same effect regardless of whether it was inherited from the mother or father. -However, for some traits in mammals, it does depend on which parent passed along the alleles for those traits. -The genes involved are not sex linked and may or may not lie on the X chromosome. 2 disorders with different phenotypic effects, Prader- Willi syndrome & Angelman syndrome, are caused by the same deletion of a specific piece of chromosome Prader-Willi syndrome is characterized by mental retardation, obesity, short stature, and unusually small hands and feet. These individuals inherit the abnormal chromosome from their father. 2-Individuals with Angelman syndrome exhibit spontaneous laughter, jerky movements, and other motor and mental symptoms. This is inherited from the mother. The difference between the disorders is due to GENOMIC IMPRINTING. 1-In this process, a gene on one homologous 3-In the new generation, both maternal and paternal chromosome is silenced, while its allele on the imprints are apparently erased in gameteproducing cells. homologous chromosome is expressed. 2-The imprinting status of a given gene depends on 4-Then, all chromosomes are reimprinted according whether the gene resides in a female or a male. to the sex of the individual in which they reside. -The same alleles may have different effects on offspring, depending on whether they arrive in the zygote via the ovum or via the sperm.

18 Methylation it s not just for breakfast anymore In many cases, genomic imprinting occurs when methyl groups are added to cytosine nucleotides on one of the alleles. -Heavily methylated genes are usually inactive, so the animal uses the allele that is not imprinted. In other cases, the absence of methylation in the vicinity of a gene plays a role in silencing it. -The active allele has some methylation. Several hundred mammalian genes, many critical for development, may be subject to imprinting; in fact, imprinting is critical for normal development. And, like everything else that is critical for normal development, we see what happens when it doesn t occur properly FRAGILE X SYNDROME, which leads to various degrees of mental retardation, also appears to be subject to genomic imprinting. -This disorder is named for an abnormal X -Inheritance of fragile X is complex, but the chromosome in which the tip hangs on by a thin syndrome is more common when the abnormal thread of DNA. chromosome is inherited from the mother. -This disorder affects one in every 1,500 males and -This is consistent with the higher frequency in one in every 2,500 females. males. -Imprinting by the mother somehow causes it. 3. Extranuclear genes exhibit a non-mendelian pattern of inheritance Not all of a eukaryote cell s genes are located in the nucleus. Extranuclear genes are found on small circles of DNA in mitochondria and chloroplasts. -These organelles reproduce themselves. -Their cytoplasmic genes do not display Mendelian inheritance. -They are not distributed to offspring during meiosis. Karl Correns first observed these cytoplasmic genes in plants in He determined that the coloration of the offspring was determined only by the maternal parent. -These coloration patterns are due to genes in the plastids which are inherited only via the ovum, not the pollen. Because a zygote inherits all its mitochondria only from the ovum, all mitochondrial genes in mammals demonstrate maternal inheritance. -Several rare human disorders are produced by mutations to mitochondrial DNA. -These primarily impact ATP supply by producing defects in the electron transport chain or ATP synthase. -Tissues that require high energy supplies (for example, the nervous system and muscles) may suffer energy deprivation from these defects. -Other mitochondrial mutations may contribute to diabetes, heart disease, and other diseases of aging. Extra Diagrams