©2000 Timothy G. Standish Matthew 18:11 11For the Son of man is come to save that which was lost.

©2000 Timothy G. Standish Chromosomal Basis of Inheritance Timothy G. Standish, Ph. D.

©2000 Timothy G. Standish Introduction- Gregor Mendel Father of classical genetics. Born 1822 to peasant family in the Czech village of Heinzendorf, part of the Austro-Hungarian empire at the time. Austrian Augustinian monk (Actually from Brunn which is now in the Czech Republic).

©2000 Timothy G. Standish Gregor Mendel - Education Studied mathematics in Olmutz college. Attended University of Vienna Influenced by: –Franz Unger, a plant physiologist who believed new species could come about via hybridization. –Christian Doppler, physicist who discovered the Doppler effect. Sharpened his math skills.

©2000 Timothy G. Standish Gregor Mendel - Work Studied peas which he grew in a garden outside of the Abbey where he lived starting 1856 (3 years prior to publication of Origin of Species). Showed that the traits he studied behaved in a precise mathematical way and disproved the theory of "blended inheritance."

©2000 Timothy G. Standish Gregor Mendel - Work Cont. Published rules of transmission of genes in 1866 (handwritten in German, not Latin!). Work was totally ignored. Mendel’s work was rediscovered in 1900 by three botanists: –Carl Correns (Germany) –Erich von Tschermak (Austria) –Hugo de Vries (Holland)

©2000 Timothy G. Standish 3 Reasons Mendel’s Work Was Ignored Mendel was not on the ball Biologists didn’t know mathematics Lack of independent supporting discoveries

©2000 Timothy G. Standish Reasons Mendel’s Work Was Ignored: 1) Mendel was not on the ball Wrote in an obscure journal (Proceedings of the Natural History Society of Brunn). Wrote in German, not Latin. Mendel was not well known and did not persevere in his attempt to push his ideas.

©2000 Timothy G. Standish Reasons Mendel’s Work Was Ignored: 2) Biologists didn’t know math Biologists didn’t understand math very well. Biologists were interested in the explaining the transmission of continuous traits like height, esp. after publication of Origin of Species in Mendel suggested that inherited characteristics were discrete units (discontinuous).

©2000 Timothy G. Standish Reasons Mendel’s Work Was Ignored: 3) Lack of independent supporting discoveries: There was no physical element in which Mendel’s inherited particles could be identified. By the turn of the century, chromosomes had been discovered (physical particles) and biologists were better at math.

©2000 Timothy G. Standish Chromosomes: The Physical Basis of Inheritance 1866 Mendel published his work 1875 Mitosis was first described 1890s Meiosis was described 1900 Mendel's work was rediscovered 1902 Walter Sutton, Theodore Boveri and others noted parallels between behavior of chromosomes and alleles.

©2000 Timothy G. Standish Chromosomal Theory of Inheritance Genes have specific loci on chromosomes. Chromosomes undergo segregation (meiosis) and independent assortment, Thus alleles of genes are independently assorted.

©2000 Timothy G. Standish E n e N Chromosomal Theory of Inheritance e N E n Father Mother N e E n N E n ee n E N e n E N e n E N e N E n Telophase II Replication Telophase I Prophase I Crossing Over

©2000 Timothy G. Standish EnEn eNeN enen ENEN Sperm e ne ne Ne NE nE nE NE N Eggs Independent Assortment n E e N e n N E n E e n e N N E EeNnEeNnEeNNEENnEENN EennEeNnEeNnEEnnEENn eeNneeNNEeNnEeNnEeNN eenneeNnEennEeNnEeNn As long as genes are on different chromosomes, they will assort independently

©2000 Timothy G. Standish E A a e Two Genes On One Chromosome Telophase II Father Mother e a E A Telophase I A e E A E a e a E AA e E aa e Replication e a E A Prophase I E A A a e a As long as genes on the same chromosome are located a long distance apart, they will assort independently due to crossing over during Prophase I of meiosis

©2000 Timothy G. Standish Thomas Hunt Morgan First to associate a trait (gene) with a chromosome. Worked with fruit flies (Drosophila melanogaster) Why fruit flies? –Short generation time (≈ 2 weeks) –Survive and breed well in the lab –Very large chromosomes in some cells –Many aspects of phenotype are genetically controlled.

©2000 Timothy G. Standish Drosophila Nomenclature + = Wild type, phenotype in nature (i.e., red eyes and round wings) Mutants are alternatives to the wild type Fruit fly genes are named after the mutant Dominant mutations are capitalized (i.e., Hairless or H and Bar or B) Recessive mutants are named using lower case letters (i.e., black or b and white or w)

©2000 Timothy G. Standish Drosophila Mutations

©2000 Timothy G. Standish More Drosophila Mutations ebony body ee Wild Type ++ white eyes ww

©2000 Timothy G. Standish Sex Determination Two ways in which sex can be determined: Environment: Turtles - Temperature of development Some fish - Social structure Chromosomes - Three methods: XO - Haploid/diploid, i.e., bees, haploid males diploid females ZW - Heterogametic (ZW) females, homogametic (ZZ) males, i.e., birds XY - Heterogametic (XY) males, homogametic (XX) females, i.e., humans and Drosophila

©2000 Timothy G. Standish X-Chromosome Human and Drosophila Genes Are Easy To Find In humans and Drosophila, males are XY Thus males are haploid for the X chromosome Because of this, recessive genes on the X chromosome show up far more commonly in male than female phenotypes

©2000 Timothy G. Standish Morgan’s Discovery Of An X- Linked Drosophila Gene A white-eyed male was discovered X + X+YX+Y Xw X+Xw X+ XwYXwY X+X+ XwXw X+X+ Y Xw X+Xw X+ X+YX+Y Xw X+Xw X+ X+YX+Y X+X+ X+X+ XwXw Y X P X F1F1 F2F2 1/2 1/4

©2000 Timothy G. Standish The Key To Morgan’s Discovery The key to Morgan’s discovery was the observation that all the white-eyed individuals in the F 2 generation were males Without this vital data on the association of white eyes with being male, the gene for white eyes could have been seen as a simple recessive trait on an autosome This illustrates the importance of recording all the data possible and being alert to the possibility of interesting things being present in the data “Fate favors the prepared mind” (Louis Pasteur)

©2000 Timothy G. Standish Human X-linked Recessive Genes Brown enamel - Tooth enamel appears brown rather than white Hemophilia - Two types: –A - Classic hemophilia, deficiency of blood-clotting factor VIII –B - Christmas disease, deficiency of blood-clotting factor IX

©2000 Timothy G. Standish X-linked Recessive Genes Related to Sight Coloboma iridis - A fissure in the eye’s iris Color Blindness - Two types: –Deutan - Decreased sensitivity to green light –Protan - Decreased sensitivity to red light Congenital night blindness - Not due to a deficiency of vitimin A Microphthalmia - Eyes fail to develop Optic atrophy - Degeneration of the optic nerves

©2000 Timothy G. Standish Variation In Chromosome Number - Polyploidy Polyploid individuals have more than two sets of chromosomes Many important commercial plants are polyploid: –Roses –Navel oranges –Seedless watermelons Polyploid individuals usually result from some sort of interruption during meiosis Pro or Metaphase I Interruption of meiosis Metaphase II 2n Gametes + 1n Gamete 3n Zygote

©2000 Timothy G. Standish Variation In Chromosome Number - Aneuploidy Polyploid humans are unknown, but individuals with extra individual chromosomes are known. Having extra chromosomes or lacking some chromosomes is called aneuploidy Aneuploid individuals result from nondisjunction during meiosis Metaphase IAnaphase I Zygote + +

©2000 Timothy G. Standish Aneuploidy In Humans Most human aneuploids spontaneously abort The most viable variations in chromosome number are those that deal with the sex chromosomes: XO - Turner’s Syndrome - Phenotypically females XXX…- “Super” females XYY… - “Super” Males - On average tend to be larger and less intelligent XXY - Klinefelter’s Syndrome - Phenotypically male Of the non-sex chromosome aneuploids, Down’s Syndrome, extra chromosome 21, tends to be the most viable Down’s Syndrome is more common in children of mothers who gave birth after age 40

©2000 Timothy G. Standish Gene Dosage There seem to be elegant mechanisms for maintaining the correct dosage of genetic material in each cell When aneuploidy causes a change in the relative dose of one chromosome, problems result Another way in which dosage of genetic material can be changed is via macromutations

©2000 Timothy G. StandishMacromutations Four major types of Macromutations are recognized: 1Deletions - Loss of chromosome sections 2Duplications - Duplication of chromosome sections 3Inversions - Flipping of parts of chromosomes 4Translocations - Movement of one part of a chromosome to another part

©2000 Timothy G. Standish Macromutation - Deletion Chromosome Centromere A B C D E F G H Genes E F A B C D G H

©2000 Timothy G. Standish A B C D E F E F G H Macromutation - Duplication Chromosome Centromere A B C D E F G H Genes E F Duplication

©2000 Timothy G. Standish Macromutation - Inversion Chromosome Centromere A B C D F E G H Genes A B C D E F G H Inversion

©2000 Timothy G. Standish Macromutation - Translocation A B E F C D G H Centromere Chromosome Genes A B C D E F G H

©2000 Timothy G. Standish The Lyon Hypothesis Having extra chromosomes causes problems (e.g., Down’s Syndrome) Men have only one X chromosome and they are normal (at least they think so) Women have two X chromosomes and they are normal Mary Lyon proposed that the extra dosage of X chromosome that women have is compensated for by turning off one of the X chromosomes. This turned-off chromosome can be observed as a “Barr Body” in metaphase female nuclei

©2000 Timothy G. Standish Consequences of X-Chromosome Dosage Compensation During early development, X chromosomes are randomly turned off in female cells All daughter cells have the same X chromosome inactivated as their parental cell. Thus, females are a mosaic of patches of cells, some patches expressing the genes on the paternal X chromosome, other patches expressing the maternal X chromosome

©2000 Timothy G. Standish Consequences of X-Chromosome Dosage Compensation XX At some point (probably later than the 4-cell stage) half the X chromosomes are turned off Daughter cells inherit the mother cell’s mixture of off and on X chromosomes Because of dosage compensation, females are thought to be a mosaic of patches of cells with each patch expressing the same X chromosome, but none expressing both chromosomes Different patches of cells inherit different act X chromosomes XX Cell division XX Zygote X X XX

©2000 Timothy G. Standish Why Calico Cats Are Usually Female Orange coat color is a sex-linked trait in cats (it is on the X chromosome) A female cat heterozygous for orange, has skin patches expressing the orange X with the other X chromosome turned off. In other patches the opposite occurs.

©2000 Timothy G. Standish Problem 1 In Drosophila, vermilion (v) is recessive to red (v + ) eyes and miniature (m) wings are recessive to normal (m + ) wings. The following cross was made: Male v + v + m + m + x vvmm Female A What was the phenotype of the F 1 generation? B What F 2 phenotypic ratio would you expect? C If the actual F 2 phenotypic numbers were: – 147 red-eyed normal winged –49 vermilion-eyed miniature winged, – 2 red-eyed miniature winged, –2 vermilion-eyed normal winged, How would you explain this?

©2000 Timothy G. Standish Solution 1 A What was the phenotype of the F 1 generation? v + v + m + m + makes v + m + gametes vvmm makes vm gametes Thus the F 1 must be v + vm + m B What F2 phenotypic ratio would you expect? 9 red-eyed normal winged (v + _m + _) 3 red-eyed miniature winged (v + _mm) 3 vermilion-eyed normal winged (vvm + _) 1 vermilion-eyed miniature winged (vvmm)

©2000 Timothy G. Standish Solution 1 Continued C If the actual F2 phenotypic numbers were: – 147 red-eyed normal winged –49 vermilion-eyed miniature winged, – 2 red-eyed miniature winged, –2 vermilion-eyed normal winged, How would you explain this? mv m+m+ v+v mv+v+ m+m+ v mv m+m+ v+v+ mv+v+ m+m+ v F1 Gametes

©2000 Timothy G. Standish Solution 1 Continued vvm + m vvm + m vvm + m vvmm 0.01 vm vm 0.49 v + m v + m 0.24 vvmm (0.24*200=48) 0.01 vm vm 0.49 v + m v + m v + vmm v + vmm v + v + mm v + vm + m v + vm + m v + vm + m v + vm + m v + vm + m v + v + m + m v + v + m + m v + v + m + m v + vm + m 0.01 vvm + _ (0.01*200=2) 0.01 v + _mm (0.01*200=2) 0.74 v + _m + _ (0.74*200=148) mv m+m+ v+v mv+v+ m+m+ v mv m+m+ v+v+ mv+v+ m+m+ v

©2000 Timothy G. Standish Solution 1 Continued Vermilion and miniature winged are closely linked genes on the same chromosome The distance between vermilion and miniature is 1 centimorgan The reason numbers in the cross do not fit the prediction of 1 centimorgan exactly is that the numbers are the result of chance and thus would not be expected to fit the predicted ratio perfectly mv 1cM

©2000 Timothy G. Standish Problem 2 How is the gene tracked in the pedigree shown below inherited? In other words, what is its mode of inheritance? A. ? Answer - Either sex linked recessive (most likely) or autosomal recessive Use deductive reasoning to solve this problem Hypothesis 3 - Sex linked dominant Hypothesis 2 - Autosomal recessive Hypothesis 1 - Autosomal dominant Hypothesis 4 - Sex linked recessive Aa A_ Aa aa Aa aa A_ aa A_

©2000 Timothy G. Standish Problem 2 How is the gene tracked in the pedigree shown below inherited? In other words, what is its mode of inheritance? B.

©2000 Timothy G. Standish Problem 3 If two genes A and B are linked on the same chromosome and located 10 centimorgans apart, how many recombinant offspring would be expected in 1,000 F 2 offspring from the following cross: AABB x aabb

©2000 Timothy G. Standish