2 Genetics is the scientific study of heredity or inheritance. Every day we observe variations of heritable traits, e.g. eyes of brown, green, blue, or gray) among individuals in a population.These traits are transmitted from parents to offspring.One proposed mechanism for this transmission is the “blending” hypothesis (J.B. Lamarck).This hypothesis proposes that the genetic material contributed by each parent mixes in a manner analogous to the way blue and yellow paints blend to make green.Over many generations, a freely mating population should give rise to a uniform population of individuals.
3 Offspring resemble their parents more than they do less closely related individuals of the same species
4 fw-wthw-wtfwhwfwhwVariation in the forewings and hind wings of the butter fly species Bicyclus anynana- First two photos on the left are of the wild type species - Others show the natural variation within the "normal" version of the same species.
5 However, the “blending” hypothesis appears incorrect as everyday observations and the results of breeding experiments contradict its predictions.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 and passed on, generation after generation, in undiluted form.Modern genetics began about 150 years ago in an abbey garden, where a monk named Gregor Mendel was the first to study and document the particulate mechanism of inheritance.
6 Grew up on a small farm in what is today the Czech Republic Enters an Augustinian monastery in 1843Studies at the University of Vienna from 1851 to 1853- becomes influenced by a physicist who encouraged experimentation and application of mathematics to science and a botanist who aroused Mendel’s interest in the causes of variation in plants.Teaches at the Brunn Modern School and lives in the local monastery with long tradition of interest in the breeding of plants, including peas.Begins breeding garden peas to study inheritance around 1857Johann Gregor Mendel(1822 – 1884)Augustinian monk,teacher & scientistOld Brno monastery with Mendel’s green housewhere he conducted his famous breeding experiments in the1850s with the common garden pea
7 Mendel’s experiments mark the beginning of the era of modern genetics The garden pea Mendel chose to conduct his breeding experiments had a series of favorable features largely responsible for his experimental success:1. Easy to grow and available in many distinguishable varieties e.g. blossom color, seed shape, pod color, etc.2. Strict control over plant matings by switching between the natural process of self-fertilization and the experimental procedure of cross fertilization3. Able to select from a series of easy-to-follow, heritable plant characteristics4. Ability to generate true-breeding varieties by performing famousbreeding experiments to generate hybridsHybrids are the offspring of two different, true-inbreed varieties
8 1. Many easily distinguishable heritable traits in the garden pea
9 2. Strict control over plant matings 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.
10 Mendel’s Mono-Hybrid Cross Experiments First Mendel cross-pollinated (hybridized) two contrasting, true-breeding pea varieties.The true-breeding parents are the P generation and their hybrid offspring are the F1 generation.He then allowed the F1 hybrids to self-pollinate to produce an F2 generation.It was mainly Mendel’s quantitative analysis of F2 plants that revealed the two fundamental principles of heredity: 1. The law of segregation & 2. The law of independent assortment.
11 When Mendel allowed the F1 plants to self-fertilize, the F2 generation included both purple-flowered and white-flowered plants.The white trait, absent in the F1, reappeared in the F2 generationBased on a large sample size, Mendel recorded 705 purple-flowered F2 plants and 224 white-flowered F2 plants from the original cross.
12 Mendel reasoned that the heritable factor for white flowers was present in the F1 plants, but it did not affect flower color.Purple flower is a dominant traitandwhite flower is a recessive trait.The reappearance of white-flowered plants in the F2 generation indicated that the heritable factor for the white trait was not diluted or “blended” by coexisting with the purple-flower factor in F1 hybrids.
13 Mendel found similar 3 to 1 ratios of two traits among F2 offspring when he conducted crosses for six other heritable characteristics, each represented by two different varieties.For example, after crossing two true-breeding varieties, one with round seeds, the other with wrinkled seeds.All the F1 offspring had round seeds, but among the F2 plants, 75% of the seeds were round and 25% were wrinkled.PF1
15 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.The purple-flower allele and white-flower allele are two DNA variations at the flower-color locus.
16 Alternatively, the two alleles may differ 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.Alternatively, the two alleles may differIn the flower-color example, the F1 plants inherited a purple- flower allele from one parent and a white-flower allele from the other.maternalpaternalChromosomes
17 3. If two alleles differ, then one, the dominant allele “A”), is fully expressed in the organism’s appearance. The other, the recessive allele (“a”), has no noticeable effect on the organism’s appearance.
18 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 allele 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 and 50% will receive the other.The separation of alleles into separate gametes is summarized as Mendel’s law ofallele segregation.
19 Mendel’s law of segregation accounts for the 3:1 ratio that he observed in the F2 generation. F1 hybrids will produce two classes of gametes, 50% with the purple-flower allele and 50% with white-flower allele.During self-pollination and fertilization, gametes unite randomly.This can produce four equallylikely combinations of spermand ovum.
20 Genetics has some unique, useful vocabulary. 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 (‘allele combination”) is referred to as its genotype.Two organisms can have the same phenotype but have different genotypes if one is homozygous dominant and the other is heterozygous.
21 Test CrossIt 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 test cross = breeding of homozygous recessive, with dominant phenotype, but unknown genotypeTest cross can determine the identity of the unknown allele.
22 Dihybrid Cross Experiments In dihybrid cross experiments, Mendel studied the inheritance of seed color and seed shape.- allele for yellow seeds (Y) is dominant to the allele for green seeds (y).- 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).100% of the F1 plants had yellow, round seeds
23 One possibility is that the two characters are transmitted from parents to offspring as a package, i.e. the Y and R alleles and y and r alleles stay together 9”are linked”)If this were the case, the F1 offspring would produce yellow, round seeds.The F2 offspring would produce two phenotypes in a 3:1 ratio, just like a monohybrid cross.However, this hypothesis was not consistent with the results Mendel observed .
24 Dihybrid Cross Outcome An alternative hypothesis is that the two pairs of alleles segregate independently of each other.The presence of one specificallele for one trait has noimpact on the presence of aspecific allele for the secondtrait.The F1 dihybrid plants producefour classes of gametes (YR, Yr,yR, and yr) in equal amounts.
25 Law of Independent Assortment Mendel repeated the dihybrid cross experiment for other pairs of characters and always observed a 9:3:3:1 phenotypic ratio for the phenotypes in the F2 generation.Each character appeared to be inherited independently.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 F2 ratio for each, just as if this were a monohybrid cross.
26 Dominant-Recessive Traits in Humans Human cells like the cells of the garden pea have their geneticinformation encoded on genes which are packed intochromosomes.Human cells also produce haploid germ cells (= sperm and oocytes)by meiosis and reproduce by fertilization.Therefore, even though human cells contain many more genes( around 100,000 !!) than the garden pea, many heritable traits inhumans follows the same Mendelian principles of inheritance.Many human traits are known, which are determined bysimple dominant-recessive inheritance at one gene locus.
27 Trait Allele dominant recessive eye colorbrownblueearlobefree lobesattachedfrecklesyesno frecklesPTC paperable to tastenot able to tastefinger numbersixfivehairlineWidow’s peakstraight line
28 Autosomal recessive human disorders 1. Hereditary deafness2. Cystic fibrosis (CF)The most common lethal genetic disease in the US. 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 year five.The responsible allele is differently distributed amongst different ethnic groups. One in 25 whites is a carrier of CF.Probability p1/1800 Caucasian Americans births1/ African American births1/ Asian American birthsHomozygous individual (= with 2 copies of the defect CF allele) develops the CF.
29 Autosomal recessive human disorders 3. Phenylketonuria (PKU)This recessively inherited human disorder occurs in 1/10,000 to 1/15,000 births.Individuals with this disorder have a lack or a dysfunctional enzyme due to a mutation in the gene coding for this enzyme. As a consequence the amino acid phenylalanine and its derivative phenypyruvate accumulate in the blood to toxic levels. This leads to serious mental retardation of the affected new born.If the disorder is detected, a special diet low in phenyalalanine usually promotes normal development.4. Sickle cell anemiaHomozygous persons have sickled red blood cells, which cause serious damage to many tissues in the body.Disorder affects 1/500 births of African-Americans; and 1/10 African Americans is a heterozygote carrier of the sickle cell allele. It is a very rare disease amongst other ethnic groups.
31 5. AlbinismPeople or mammals affected by this rare autosomal recessive disorder lack the UV light absorbing and DNA protecting pigment melanin in their skin, hairs and eyes.Their skin or fur therefore appears white and the iris of their eyes appears red colored.Affected persons or mammals (= albinos) are very easily sunburned and have a high risk of developing forms of skin cancer.
32 Many reasons account for the manifestation of a recessive genetic disorder within a human population1. Prolonged geographic isolation and inbreedingThere is an increased probability that a recessive allele breaks through, i.e. it becomes dominant in an homozygous individual if close relatives marry and have children (consanguinity).The manifestation of recessive disorders can frequently be observedin small societies which were geographically isolated for extendedperiods of times (e.g. on an island, in a hard-to-reach valley, etc.).Hereditary deafness is common amongst certain families living onMartha’s Vineyard in Massachusetts.2. Co-evolutionary aspects & Adaptive reasonsThe allele for sickle cell anemia manifested itself in a high percentage within the African American population. It gives its carriers a certain advantage/protection against malaria infection.Carriers of the sickle cell anemia allele in Africa are less likely affected by malaria-causing Plasmodium strains.
33 Autosomal dominant human disorders Dominant inherited human disorders are serious disorders caused by a dominant allele. Only one (dominant) allele is required to lead to the expressed phenotype, i.e. the human health-affecting disorder.Examples of prominent dominant disorders in humans are:Familial polydactylyAchondroplasiaAlzheimer’s disease (AD)
34 1. Familial PolydactylyIndividuals are born with extra fingers or toes. It is due to an allele dominant to the recessive allele for five digits per appendage.399 individuals out of 400 have five digits per appendage.
35 2. AchondroplasiaAutosomal dominant inherited or acquired (80% of all cases) genetic disorder which is responsible for most common form of dwarfism in humans.Characterized by the appearance of short stature with disproportionately short arms, short legs, a large head with pronounced forehead due to impaired cartilage formation.Connection to mutations in the gene coding for the receptor (FGFR) of the growth hormone fibroblast growth factor (FGF).
36 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.One example is Huntington’s disease, a fatal degenerative disease of the nervous system.The dominant lethal allele has no obvious phenotypic effect until an individuals is about 35 to 45 years old.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.
37 Genetic disorders are not evenly distributed among all groups of humans. For example: 1. Cystic fibrosis (CF) high prevalence (1/2,500) in Jews of eastern European descent 2. Tay-Sachs disease affects 1/3,600 births of Ashkenazic Jews about 100 times greater than the incidence among non Jews or Mediterranean (Sephardic) Jews 3. Sickle cell anemia affects one of 400 African Americans caused by the substitution of a single amino acid in hemoglobinResults from different genetic histories of the world’s people during times when populations were more geographically (and genetically) isolated.
38 Human genetics & Co-evolutionary aspects The high frequency of heterozygotes with the sickle-cell anemia trait is unusual for an allele with severe detrimental effects in homozygotes.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 sickle-cell 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.
39 Pedigree AnalysisRather 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.
40 For example, if an individual in the third generation lacks a widow’s peak, but both her parents have widow’s peaks, then her parents must be heterozygous for that geneIf some siblings in the second generation lack a widow’ 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.
42 While some diseases are inherited in a simple Mendelian fashion due to alleles at a single locus, many other human 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 diseasesThe best public health strategy is education about the environmental factors and healthy behavior.
43 Genetic Testing Methods 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.Important genetic tests are: 1. Amniocentesis 2. Chorionic villi sampling (CVS) 3. Ultrasonic 4. FISH and PCR
44 1. AmniocentesisCan be used at beginning of 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.
45 2. Chorionic Villi 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.
46 3. DNA-based, genetic tests Tests such as PCR, RFLP and FISH, detect genetic mutations or chromosomal defects at birth; many of these 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.
47 Incomplete DominanceIn the 20th century, geneticists have extended Mendelian principles not only to diverse organisms, but also to patterns of inheritance more complex than Mendel described.Not all heritable traits behave in a “classical” dominant-recessive patternIn fact, Mendel had the good fortune to choose a system that was relatively simple genetically.Each character (but one) is controlled by a single gene.Each gene has only two alleles, one of which is completely dominant to the other.
48 A clear example of incomplete dominance is seen in the inheritance of the petal color of snapdragons.A cross between a white-flowered plant and a red-flowered plant will produce all pink F1 offspring.Self-pollination of the F1 offspring produces 25% white, 25% red, and 50% pink offspring.
50 While heterozygous F1 offspring of Mendel’s pea crosses always looked like one of the parental varieties, heterozygotes in incomplete dominance show a distinct intermediate (”blended’) phenotype, not seen in homozygotesHowever, this is not blended inheritance because the traits are separable (particulate) as seen in the F2 generational plants and in further crosses.Offspring of a cross between heterozygotes will show three phenotypes: both parentals and the heterozygotesIncomplete dominance does NOT violate the Mendelian laws
51 - / - - / + + / + Familial Hyper PhenotypeFamilial Hypercholesterolemia (fHC) Clinical manifestations/ symptoms:High LDL and cholesterol levels in blood plasma.Early arteriosclerosis (usually before age 40).Xanthomas in skin and tendons.Reduced life expectancy.1000800600= Plasma CholesterolConcentration(mg/dl)400200FHHomozygousFHHeterozygousNormalGenotype- / -- / ++ / +
52 Co-DominanceMost genes have more than two alleles in a population.For example, the ABO blood groups in humans are determined by three alleles, IA, IB, and I.Both the IA and IB alleles are dominant to the i alleleThe IA and IB alleles are codominant to each other.Because each individual carries two alleles, there are six possible genotypes and four possible blood types.
53 CodominanceMore than two alleles responsible for one characteristic (or heritable trait). In some cases the genotype does not always dictate the phenotype in a classical Mendelian pattern. Classical example is the inheritance of blood types in humans. The ABO blood groups in humans are determined by not only two but three alleles.ALLELEFOR SIMPLICITY WE CALL THESE:IAAIBBIO
56 PleiotropyNot all genes 9and its allele versions) affect only one phenotypic character.Most genes are rather pleiotropic, which means that they are affecting more than one phenotypic character.For example, the wide-ranging symptoms of sickle-cell disease are due to a single gene.Considering the intricate molecular and cellular interactions responsible for an organism’s development, it is not surprising that a gene can affect a number of an organism’s characteristics.
57 Polygenic Inheritance Some characters do not fit the “either-or” basis that Mendel studied.Quantitative characters vary in a population rather along a continuum.These are usually due to polygenic inheritance, the additive effects of two or more genes on a single phenotypic character.For example, skin color in humans is controlled by at least three 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.
58 Polygenic Inheritance Many characters vary in a population along a continuum due to the additive effects of two or more genes on a single phenotype.EXAMPLES OF POLYGENIC INHERITANCE PATTERNS IN HUMANS ARE: 1. SKIN COLOR 2. HAIR COLOR 3. BODY HEIGHT
59 A life forms phenotype depends not only on the impact of genes but on the influence of environmental factors as well.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 (“nature”) and the environment (“nurture”) in influencing human characteristics is a very old and hotly contested debate.
60 Gender & X chromosome-linked heritable traits (X-linked inheritance patterns) 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. The human Y chromosome is much smaller than the X-chromosomeAn individual who inherits two X chromosomes usually develops as a female.An individual who inherits an X and a Y chromosome usually develops as a male.
61 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.
62 The SRY gene located on the Y chromosome determines male gender; the generic embryonic gonads are modified into testes.In addition to their role in determining sex, the sex chromosomes, especially the larger 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.
64 In the common fruit fly Drosophila, the alleles for eye color and for body color are located on the X chromosome, but are not found on the Y chromosome. Eye color is an X-linked trait.Red eye color allele (W) is dominant inherited, the white eye color (w) is the recessive allele. The tan body color (y+) is dominant over the yellow body color (y). Geneticists say, that red eyes are dominant, X-linked, while white eyes are X-linked, recessive inherited.
65 X-linked Inheritance in Drosophila flies While the female parent is homozygous, white eye-colored, and the male parent is red eyed, the female offspring have red eye color and the male offspring are hemizygous white eye colored.F1 offspring
67 4. Red-green color blindness X-linked Inherited Traits in humansCertain traits and disorders in humans are inherited X-linked. Examples are; 1. Hemophilia “blood coagulation disorder” is due to a mutation of a gene coding for a cogulation factor, e.g. CF VIII mutated coagulation factor protein is defect and not able to contribute to blood clot formation- affected individuals (“bleeders’) are permanently bleeding 2. X-linked (“Duchenne-type) muscular dystrophy mutated dystrophin gene causes muscle weakening 3. XSCID (X-linked severe combined immunodeficiency immune system is defective in “bubble boys”4. Red-green color blindness
68 All daughters inherit an X chromosome with the mutation from their father, and will be carriers; all the sons inherit a normal X chromosome from their mother and will be phenotypically normal (no bleeders).
69 X-Inactivation & Barr Body Although female mammals inherit two X chromosomes, only one X chromosome is active.Therefore, males and females have the same effective dose (one copy ) of genes on the X chromosome.During early female development, one X chromosome per cell condenses into a compact object, a Barr body which inactivates most of its genes.Selection of X chromosome is randomConsequentially, females consist of mosaic of cellsThe condensed Barr body chromosome is reactivated in ovarian cells that produce ova.FISHDAPI stain
70 A mosaic pattern is evident in women who are heterozygous for a X-linked mutation that prevents the development of sweat glands. A heterozygous woman has patches of normal skin and skin patches lacking sweat glands.The orange and black fur pattern on cats is due to patches of cells expressing orange allele while others have non-orange allele.
71 Linked Alleles (Genes) & Recombination frequency Genes on the same chromosome tend to be inherited together (= linked genes)Linked genes are genes whose loci are on the same chromosome and usually close together; they are passed on together and don’t follow the Mendelian law of independent assortment of genesFirst evidence of linked genes was shown by W. Bateson & R. Punnett while doing crossing experiments with doubly heterozygous sweet pea plants. They studied two characteristics (= Dihybrid cross)ALLELEFLOWER COLOR: dominant purple Precessive red pPOLLEN SHAPE: dominant long Lrecessive short lP PPLL x ppllF1 all (100%) = PpLl Purple-Long
72 Linked genes/alleles X Purple-Long 215 284 Purple-Round 71 21 The Bateson/Punnett experiment with sweet pea plants (1908)Two F1 hybridPea plantsXPhenotypePpLlPpLlGenotypePhenotypesPredictedOffspring(9:3:3:1)ObservedOffspringPurple-LongPurple-RoundRed-LongRed-RoundRecombinants due toCrossing over events in Meiosis I
73 Discrepancy in the phenotypic ratio is explained by the fact that the gene coding for the color (P = purple; r = red) and the gene coding for the pollen shape (L = long; l = round) were located on the same chromosome; both gene versions were linked genes.They were not independently assorted during meiosis; the observed new phenotypes in F2 can be explained by recombination events which happened during Prophase I of meiosis..