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Proof for the chromosome theory of inheritance Sex chromosomes Although Mendels data correlated with chromosome segregation during meiosis and these were convincing correlations, actual proof of the chromosome theory required the discovery of sex linkage. Remember, Mendel had found that reciprocal crosses produce equal results with respect to the progeny. In general geneticists confirmed his results. However exceptions did arise. The most famous exception was that discovered by Thomas Hunt Morgan in the fruit fly Drosophila melanogaster. Drosophila eyes are normally bright red. Morgan discovered an exceptional white-eyed male. He performed the following crosses: 1 Morgans crosses CROSS P1 White Red F1 Both males and females were Red Red is dominant to white Selfing 3:1 red:white (1 gene for eye color) All white eyed flies were male!!!! F2 Reciprocal cross CROSS P2 White Red F1 Red White All females were red and males were white in the F1!!! 2 X and Y chromosomes Somehow eye color was linked to sex The key to understanding this pattern of inheritance arose from work demonstrating that males and females of a given species often differ in the chromosome constitution. For example, they found that male and female Drosophila both have four chromosome pairs. However in males one of the pairs the members differed in size: Female Drosophila: Male Drosophila: Sex fourth second third 3 Sex chromosomes Morgan realized that difference in chromosome constitution was the basis of sex determination in Drosophila: Females produce only X-bearing gametes, while males produce X and Y-bearing gametes. X X X Y XX XY XX XY 2 :2 If the gene for eye color resides on a X chromosome There is no counterpart for this gene on the Y chromosome4 Morgans crosses CROSS1 White Red Red Selfing 3:1 red:white All white eyed flies were male!!!! 5 Formal explanation Females have 2 copies of the eye color gene and males have one copy W (red) is dominant over w (white) CROSS1 white XwY Red XWXW F1 Xw XW XW XW Xw y XWY Red Red XW Xw XWY Red Red 6 Formal explanation Females have 2 copies of the eye color gene and males have one copy W (red) is dominant over w (white) Self cross Red XWY Red XWXw F2 XW XW Xw XW XW y XWY Red Red XW Xw XwY Red White 7 Morgans crosses Reciprocal cross CROSS2 White Red Red White All females were red and males were white in the F1!!! 8 Formal explanation The reciprocal cross Red XWY White XwXw F1 XW Xw Xw XW Xw Red y XwY White XW Xw XwY Red White In the F1 all the females are red and all the males are white 9 Formal explanation White XwY Red XWXw F2 Xw XW Xw XW Xw y XWY Red Red Xw Xw XwY White White 10 Equal numbers of male and female progeny are produced. Morgan realized that he could explain the inheritance patterns of eye color by assuming: 1. The gene determining eye color resides on the X chromosome (red and white eyes represent normal and mutant alleles of this gene) 2. There is no counterpart for this gene on the Y chromosome Thus females carry two copies of the gene, while males carry only a single copy. 11 Red-green color blindness Red-green color blindness means that a person cannot distinguish shades of red and green. Males are affected 16 times more often than females, because the gene is located on the X chromosome. In color-blind men, the green or red cones worked improperly. The genes for the red and green receptors were altered in these men X-linked red-color blindness is a recessive trait. Females heterozygous for this trait have normal vision. The color perception defect manifests itself in females only when it is inherited from both parents. By contrast, males inherit their single X-chromosome from their mothers and become red green color blind if this X-chromosome has the color perception defect. The dominant (normal) X chromosome is represented as XCB. The recessive (mutant) chromosome is represented as Xcb. Since males have only one X-chromosome, if this chromosome has the red-green color blind allele, the males will have the color perception defect. Females have 2 X-chromosomes. Both X-chromosomes must carry the mutant allele for the females to be color blind. Red-green color blind females are homozygous for the recessive allele. Females with one mutant allele and one normal allele are heterozygous "carriers". They are not color blind, but they can pass the color blindness to their children. 12 Sex determination Bridges a student of Morgan set up the cross outlined above in large numbers P cross: white females XwXw x x red males XWY As expected, he obtained red-eyed females (XwXW) and white-eyed males (XwY) About 1 in every 2500 progeny he obtained white-eyed fertile female or a red-eyed sterile male Cherish Your Exceptions 13 Primary exception About 1 in every 2500 progeny he obtained a white-eyed fertile female or a red-eyed sterile male. These were called primary exceptional progeny How can these exceptional progeny be explained? disjunction Non-disjunction 14 Primary exception About 1 in every 2000 progeny he obtained a white-eyed fertile female or a red-eyed sterile male. These were called primary exceptional progeny How can these exceptional progeny be explained? autosome X autosome X disjunction Non-disjunction Bridges suggested that occasionally during meiosis the X chromosomes fail to separate. キ Normal separation of the X chromosomes produces Xw gametes キ Failure of X chromosome separation (non disjunction) Creates XwXw and nullo gametes and these gametes give rise to the sterile red eyed males! 15 Bridges and non-dysjunction white red XWY XwXw F1 XW Xw Xw Xw Xw O y XW Xw XwY Red white XW Xw XwY Red White XW Xw Xw Xw XwY Lethal white female fertile XW Red male Sterile Y Lethal 16 Bridges assumed that XXX and Y0 progeny die The only two viable progeny types were XXY and X0 In this model sex is determined by the number of X chromosomes rather than the presence or absence of the Y chromosome This model makes a strong prediction -Hypothesis Genes reside on chromosome The exceptional red-eyed males should be X0 and The exceptional white eyed females should be XXY How do you show this? Look at the chromosomes under the microscope THAT IS WHAT BRIDGES SAW under the microscope in the females! 17 Non-Dysjunction in Meiosis I XaXA x XaY Replication XaXaXAXA x XaXaYY Non Dysjunction in Non Dysjunction in meiosisI in mother meiosis I in father XaXaXAXA and O XaXaYY and O Normal meiosis II XaXA and O XaY and O 18 Non Dysjunction in meiosis II XaXA x XaY Replication XaXaXAXA x XaXaYY Normal meiosisI in mom XaXa and XAXA Normal meiosis I in dad XaXa and YY Non Dysjunction in meiosis II XaXa or XAXA XaXa or YY Aneuploid: Having a chromosome number that is not a multiple of the haploid number for the species 19 Quiz What classes of progeny would be expected if you could do the following cross XwXwY x XWY 20 Answer-- Triploids White XwXwY XW XwXw Y Xw XwY XW XwXw lethal XWY Red male XW Xw red XWY Y Y XwXw white female YY lethal Y Xw Red female White male XW XwY Y XwY Red female White male Normal daughters are red eyed Normal sons are white eyed Non-disjunct daughters are white eyed Non-disjunct sons are red eyed 21 Sex in organisms Sex chromosomes and sex: In Drosophila, it is the number of X's that determine sex while in mammals it is the presence or absence of a Y chromosome that determines sex. Homogametic sex- Producing gametes that contain one type of chromosome (females in mammals and insects, males in birds and reptiles) Heterogametic sex- Producing gametes that contain two types of chromosomes (males in mammals and insects, females in birds and reptiles) Species XX XY XXY XO Drosophila Female male female male Human Female male male female Non-sex chromosomes are called autosomes Humans have 22 autosomes, Drosophila has 3 Hemizygous Gene present in one copy in a diploid organism Human males are hemizygous for genes on the X-chromosome 22 Karyotype Bridges confirmed aneuploidy by visualizing abnormal chromosome numbers in Drosophila using the microscope. Karyotype gives species specific chromosome organization It is usually a microscopic classification The number of chromosomes The size of each chromosome Position of centromere on each chromosome Telocentric Acrocentric Metacentric 23 Chromosome characteristics Centromere Telomere Centromere Chromosome arms Chromosome arms Telomere Unstained chromosome Stained chromosome 24 Chromosome number/size (haploid) Organism Yeast (S. cerevisiae) Mold (Dictyostelium) Arbidopsis Lily Nematode (C. elegans) Fly (Drosophila) Mouse Human number 16 7 5 12 6 4 20 23 Evolutionary significance of variability in number is not known Human chromosomes Ch # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y Chromosome size 246.1 243.6 199.3 191.7 181.0 170.9 158.5 146.3 136.3 135.0 134.4 132.0 113.0 105.3 100.2 90.0 81.8 76.1 63.8 63.7 46.9 49.3 153.6 22.7 Chromosomes also vary in size 25 Banding Chromosomes can be stained Cells in metaphase can be fixed and stained with dyes. Dyes stain chromosomes and each chromosome has a characteristic banding pattern. In a diploid, homologous chromosomes have the same banding pattern. Stained chromosomes are photographed, cut and arranged in decreasing size 26 Karyotype • The human karyogram. The chromosomes are shown with the Gbanding pattern obtained after Giemsa staining. Chromosome numbers and band numbers • Constitutive heterochromatin is very compact chromatin which has few or no genes 27 Karyotyping Karyotyping provides a rapid means to identify alterations in the number of chromosomes Chromosome 21 In humans a very large number of conceptions are aneuploid Over 70% of spontaneous abortions and early embryonic deaths are caused due to Aneuploidy ~5-7% of early childhood deaths are to aneuploidy Humans have a rate of aneuploidy that is 10 times greater than other mammals Non-dysjunction in meiosis is the primary cause Monosomy- one chromosome of a pair is missing Trisomy- extra chromosome is present Only chromosome 21 trisomies survive to adulthood Downs syndrome occurs in 1 in 200 conceptions and 1 in 900 live births 28 A Aneuploidy a A a A A a A A a A Non-dysjunction In MeiosisI a a (Trisomy21) a A A A A A a a a A A a Non-dysjunct In MeiosisII a a a 29 Triploidy Species that are triploid, reproduce asexually (plant species) What are the consequences of triploidy during mitosis and meiosis? Haploid Diploid Triploid Mitosis 30 Triploidy Species that are triploid, reproduce asexually (plant species) What are the consequences of triploidy during mitosis and meiosis? Haploid Diploid Triploid Mitosis in triploid 31 Meiosis and triploids MeiosisI Meiosis I Triploids produce unbalanced gametes This is for one chromosome. If there are n chromosomes in an organism, then balanced gametes (equal copies of all chromosomes) is very rare. 32 What happens when you cross a triploid plant to a triploid plant? 4N 3N 3N 2N 33 Seedless watermelons Triploidy is useful in agriculture. Take a diploid watermelon species and add colchicine- disrupt microtubules. Chromosomes replicate but do not segregate resulting in tetraploids Cross a tetraploid watermelon with a diploid watermelon Triploid watermelon seeds are produced by cross-pollination between a tetraploid watermelon with a diploid watermelon. The resulting triploid plants could be distinguished in the field by the use of a genetic marker for fruit color. The diploid parents have dark green (D) fruit, Tetraploid parents have light green (d). Triploid plants will have striped green (ds) fruit. Tetraploid plants resulting from self-pollination will have light green fruit and can be culled from production fields, leaving the triploid plants with striped green fruit. Triploid watermelon produced. This grows but gametes are aneuploid- resulting in white seeds (after fertilization) which are incapable of producing a plant. Biological control: Triploid carp- eat weeds in waterways but are unable to replicate and compete with beneficial fish species. 34 And triploid toads Triploid toads Nature Genetics 30, 325 - 328 (2002) Tetraploid toads reproduce through diploid eggs and sperm cells. A new taxon was discovered at an isolated site in the Karakoram mountain range. Every wild toad caught from eight localities was triploid Did not find a single diploid or tetraploid Batura toad. Both males and females were found to be triploid. 3N female 3N male N elimination N elimination 2N 2N 2N N N 3N 35 Mendelian genetics in Humans: Autosomal and Sexlinked patterns of inheritance Obviously examining inheritance patterns of specific traits in humans is much more difficult than in Drosophila because defined crosses cannot be constructed. In addition humans produce at most a few offspring rather than the hundreds produced in experimental genetic organisms such as Drosophila It is important to study mendellian inheritance in humans because of the practical relevance and availability of sophisticated phenotypic analyses. Therefore the basic methods of human genetics are observational rather than experimental and require the analysis of matings that have already taken place rather than the design and execution of crosses to directly test a hypothesis To understand inheritance patterns of a disease in human genetics you often follow a trait for several generations to infer its mode of inheritance --dominant or recessive? Sex-linked or autosomal? For this purpose the geneticist constructs family trees or pedigrees (genetic analyses and interviews with family members) Pedigrees trace the inheritance pattern of a particular trait through many generations. Pedigrees enable geneticists to determine whether a trait is genetically determined and its mode 36 of inheritance (dominant/recessive, autosomal/sex-linked) Pedigree symbols: Male Female Sex Unknown 5 Affected individual Spontaneous abortion Number of individuals Deceased Termination of pregnancy 37 Pedigree symbols: relationship line Sibship line line of descent individual’s lines consanguinity Monozygotic Dizygotic 38 Characteristics of an autosomal recessive trait: There are several features in a pedigree that suggest a recessive pattern of inheritance: 1. Rare traits, the pedigree usually involves mating between two unaffected heterozygotes with the production of one or more homozygous offspring. 2. The probability of an affected child from a mating of two heterozygotes is ~25% 3. Two affected individuals usually produce offspring all of whom are affected 4. Males and females are at equal risk, since the trait is autosomal 5. In pedigrees involving rare traits, consanguinity is often involved. In the pedigree shown below, an autosomal recessive inheritance pattern is observed: I II:1 II:2 III:9 39 Characteristics of an autosomal dominant trait: 1. Every affected individual should have at least one affected parent. 2. An affected individual has a 50% chance of transmitting the trait 3. Males and females should be affected with equal frequency 4. Two affected individuals may have unaffected children 40 The following pedigree outlines an inheritance pattern Does this fit an autosomal recessive or autosomal dominant pattern of inheritance? 41 Pedigree of Queen Victoria and the transmission of hemophilia. Albert Victoria Alice carrier Irene carrier Beatrice carrier Alix carrier Alice carrier Victoria carrier carrier carrier 42 Characteristics of a X (sex)-linked recessive trait: Hemizygous males and homozygous females are affected Phenotypic expression is much more common in males than in females, and in the case of rare alleles, males are almost exclusively affected Affected males transmit the gene to all daughters but not to any sons Daughters of affected males will usually be heterozygous and therefore unaffected. Sons of heterozygous females have a 50% chance of receiving the recessive gene. GG gY GY gG GY GY GY gG gG GY 43 Surname project Y Y Y Y All males in this pedigree will have the SAME Y-chromosome!!! 44 Surname project Y Y Y Y All males in this pedigree will have the SAME Y-chromosome!!! X1/Y1; A1/A2 (grandpa) x X2/X3; A3/A4 (grandma) X2/Y1; A2/A4 (dad) x X4/X5; A5/A6 (mom) X4/Y1 (son) A4/A6 X5/X2 A2/A6 (daughter) 45 Sex linkedGene Tree After the death of a wealthy individual (II:3), a man claiming to be his son (III:3) filed a paternity suit and claimed the inheritance. The deceased had only two living nephews (III:1 and III:2 who were sons of his brothers (II:1 and II:2). In determining whether the man was actually the son and had the rights to the inheritance which of the following markers would be most useful Autosomal X-linked II:1 Y-linked mitochondr $$$ III:1 III:2 III:3 ??? 46 Surnames/paternity 47 Y-chromosome migration 48 The Lemba The Lemba in Africa, who practice circumcision, keep one day a week holy and avoid eating pork or pig-like animals, have long asserted they are of Jewish heritage. An analysis of the male Y chromosome found (1997) that a particular pattern of DNA changes was much more common among cohanim priests than among lay Jews and very rare in nonJewish populations. A team of geneticists have discovered that Lemba men carry the same DNA sequence that is distinctive to the cohanim. 49 Jefferson 50 Jefferson family tree 51