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10/25/15 Chapter 08 Lecture Outline 2 Copyright © 2016 McGraw-Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw-Hill Education. 1 • Genetic variation refers to differences in alleles and chromosomes, either between members of the same species or between different species 8.1 Microscopic Examination of Eukaryotic Chromosomes – Allelic variations are variations in specific genes • Typically single or a few nucleotide changes • The characteristics that are used to classify and identify chromosomes – Variations in chromosome structure and number • Typically affect more than one gene • Important in evolution • Can cause disease • Important for new strains of crops 3 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 4 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Variations in Chromosomes Can be Seen by Light Microscopy • Different chromosomes of the same species can be also distinguished from each other • Structure and number of chromosomes typically studied by light microscopy – Cytogeneticist – Scientist who studies chromosomes under the microscope • Different species can be distinguished from each other based on the number and size of chromosomes • Chromosomes can be classified by – Size – Position of centromere – Banding pattern • Staining reveals bands • Example: Giemsa stain – G bands © Scott Camazine /Photo Researchers © Michael Abbey/Photo Researchers Human © Carlos R Carvalho/Universidade Federal de Viçosa. Fruit fly Corn 5 6 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 1 10/25/15 Banding pattern during metaphase Centromere position • Metacentric – centromere near the middle • Submetacentric – slightly off center p 3 2 1 1 • Acrocentric – more off center q • Telocentric – centromere at the end 2 3 4 6 5 4 3 2 1 2 2 1 3 2 1 1 2 1 2 3 4 5 1 2 1 2 3 4 1 Short arm; For the French, petite q p q Metacentric 3 2 1 1 2 7 6 5 4 3 2 1 4 3 2 1 1 2 3 1 2 3 4 5 6 7 8 9 2 1 1 2 3 6 5 4 3 2 1 1 2 3 1 2 3 4 5 6 7 8 1 2 3 4 5 3 1 1 2 3 5 4 2 3 2 1 1 2 3 4 5 1 2 3 1 2 3 4 5 4 1 1 2 5 4 3 2 1 2 1 1 2 3 4 5 6 1 2 3 4 5 6 7 2 1 1 2 3 2 1 5 4 3 2 1 1 2 1 1 2 1 2 3 4 5 6 1 2 6 5 3 2 1 2 1 1 2 3 1 2 1 1 2 3 2 3 4 7 4 3 2 1 3 2 1 1 2 3 1 2 1 2 3 4 8 1 1 2 5 4 3 2 1 1 1 1 1 2 3 4 5 6 9 2 5 4 3 2 1 1 2 3 4 1 2 3 4 5 p p q Submetacentric q 1 2 3 3 2 1 1 2 3 4 1 2 1 2 3 4 1 1 2 3 13 1 3 2 1 1 2 3 1 2 3 4 1 2 1 2 14 3 2 1 1 2 3 4 5 1 2 3 4 5 6 10 1 1 2 15 3 2 1 1 2 3 1 2 3 4 1 1 2 3 2 1 1 2 1 2 3 4 5 16 1 1 2 2 1 1 2 1 2 3 17 1 1 3 2 1 1 2 3 1 1 18 19 1 1 2 20 3 2 1 1 1 2 1 1 21 3 2 1 1 2 3 1 1 2 3 4 5 1 2 3 4 1 2 11 12 1 1 3 2 1 1 2 3 3 2 1 2 1 p 2 1 p Long arm 1 5 4 3 2 1 6 5 4 3 2 1 1 2 3 4 1 2 3 4 1 2 3 4 5 6 7 Banding pattern during prometaphase 1 1 1 2 1 2 22 2 1 1 1 2 3 1 2 3 4 5 6 7 8 Y X q Acrocentric 7 8 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display • A karyotype is a micrograph of metaphase chromosomes from a cell arranged in standard fashion 8.2 Changes in Chromosome Structure: An Overview • Karyotypes can be used to – Detect abnormal chromosome number or structure, but not small changes of a few to a few thousand nucleotides q The four types of changes in chromosome structure 9 10 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Mutations Can Alter Chromosome Structure Mutations Can Alter Chromosome Structure • Primary ways chromosome structure can be altered: – Deletion (also called Deficiency) • Simple translocations – One way transfer • Portion of the chromosome is missing – Duplication 4 3 2 • A change in the direction of part of the genetic material along a single chromosome 1 3 1 2 3 Simple 21 1 • Reciprocal translocations – Two way transfer 4 3 2 • Portion of the chromosome is repeated – Inversion 1 1 2 translocation 1 1 2 4 3 2 4 3 2 21 1 21 1 3 1 2 3 Reciprocal 2 1 1 translocation 1 1 – Translocation • Segment of one chromosome becomes attached to a nonhomologous chromosome 11 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 12 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 2 10/25/15 q 4 3 p 2 1 1 2 3 4 3 1 1 2 3 Deletion 8.3 Deletions and Duplications (a) 4 3 2 1 1 2 3 4 3 2 3 2 1 1 2 4 3 1 1 2 3 1 3 3 Duplication (b) 4 3 2 1 1 2 3 2 q How deletions and duplications occur Inversion (c) q 4 3 2 1 1 2 3 1 2 How deletions and duplications may affect the phenotype of an organism. Simple 21 1 4 3 translocation 2 21 1 q (d) 4 3 2 1 1 2 21 1 3 1 2 Definition of copy number variation 3 Reciprocal 2 1 1 4 3 translocation 2 1 1 13 14 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display (e) Deletions • When deletions have a phenotypic effect, they are usually detrimental – Example: cri-du-chat syndrome in humans • Caused by a deletion in the short arm of chromosome • The phenotypic consequences of deletions depends on – Size of the deletion – Chromosomal material deleted • Are the lost genes vital to the organism? 4 3 2 1 1 2 3 4 3 2 1 1 2 3 Deleted region Two breaks and reattachment of outer pieces Single break 3 4 3 2 (Lost and degraded) (Lost and degraded) + 2 1 + 1 2 4 3 1 1 2 3 © Jeff Noneley (a) Terminal deletion 15 (b) Interstitial deletion 16 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Duplications • Like deletions, the phenotypic consequences of duplications tend to be correlated with size – Duplications are more likely to have phenotypic effects if they involve a large piece of the chromosome • A chromosomal duplication is usually caused by abnormal events during recombination • Called nonallelic homologous recombination • Repetitive sequences can cause this Repetitive sequences B C D A A B A A C B B D C C D Misaligned crossover A B C A B A B A B C C • Duplications tend to have less harmful effects than deletions of comparable size – In humans, relatively few well-defined syndromes are caused by small chromosomal duplications • Example: Charcot-Marie-Tooth disease D C D Duplication D D Deletion 18 D 3 10/25/15 • Duplications can provide additional genes, forming gene families - two or more genes that are similar to each other • Duplicated genes accumulate mutations which alter their function – – – – After many generations, they have similar but distinct functions They are now members of a gene family Two or more genes derived from a common ancestor are homologous Homologous genes within a single species are paralogs Gene • Example: The globin genes – Ancestral globin gene has been duplicated and altered • 14 paralogs on three different chromosomes – Different paralogs carry out similar but distinct functions • All bind oxygen • Myoglobin stores oxygen in muscle cells • Different globins in the red blood cells at different developmental stages – Characteristics correspond to the oxygen needs of the embryo, fetus and adult Abnormal genetic event that causes a gene duplication Gene Paralogs (homologous genes) Gene Over the course of many generations, the 2 genes may differ due to the gradual accumulation of DNA mutations. Mutation 19 Gene Gene Better at binding and storing oxygen in muscle cells Better at binding and transporting oxygen via red blood cells 20 Copy Number Variation • Copy number variation – a type of structural variation in which a DNA segment 1000bp or larger has copy number differences in members of the same species • A gene normally in two copies in a diploid cell may be found in one, three, or even more copies • Some chromosomes are missing the gene • Some chromosomes have extra copies • These carry a segmental duplication 8.4 Inversions and Translocations q A A A A A (a) Some members of a species Segmental duplication (b) Other members of the same species q q q Definition of pericentric and paracentric inversions How inversion heterozygotes produce abnormal chromosomes due to crossing over Two mechanisms that result in reciprocal translocations How reciprocal translocations align during meiosis and how they segregate. 21 22 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Inversions • A chromosomal inversion is a segment that has been flipped to the opposite orientation – Total amount of genetic information stays the same • Therefore, the great majority of inversions have no phenotypic consequences • Pericentric inversion – the centromere is within the inverted region • Paracentric inversion – the centromere is outside the inverted region Centromere lies within inverted region A B C D E FG H I Centromere lies outside inverted region (a) Normal chromosome A B C GF E DH I Inverted region (b) Pericentric inversion A E D C B FG H I Inverted region • In rare cases, inversions can alter the phenotype of an individual – Breakpoints • The breaks leading to the inversion occur in a vital gene – Position effect • A gene is repositioned in a way that alters its gene expression • About 2% of the human population carry inversions that are detectable with a light microscope – Most of these individuals are phenotypically normal – However, a few can produce offspring with genetic abnormalities 24 (c) Paracentric inversion 4 10/25/15 • During meiosis I, homologous chromosomes synapse with each other – For the normal and inversion chromosome to synapse properly, an inversion loop must form – If a crossover occurs within the inversion loop, highly abnormal chromosomes are produced Inversion Heterozygotes • Individuals with one copy of a normal chromosome and one copy of an inverted chromosome Replicated chromosomes A B C D E F G H I A B C Normal: • Such individuals may be phenotypically normal – But they have a high probability of producing abnormal gametes • Due to crossing-over in the inverted segment Replicated chromosomes D E F G H I Normal: A B C D E F G H I e d a b With inversion: c g f a b c g f e d h i Homologous pairing during prophase With inversion: D E a e d c b a e d c b Crossover site F E D A BC h i A B C e f d ef g d g C B G H I a b c h A b c a i D E A B C D E I H G F A B C F G H I f g c b a e d h i Duplicated/ deleted 25 a b c g f e d h i Acentric fragment f g D d e Crossover site E I FGH D E F G H I A B C d e a I G F E D c b d c Dicentric chromosome a H e h i f g h i Homologous pairing during prophase f g h i Products after crossing over Products after crossing over A B C F G H I f g h i Dicentric bridge b f g h i 26 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display (a) Pericentric inversion Translocations • Reciprocal translocations lead to a rearrangement of the genetic material, not a change in the total amount – Thus, they are also called balanced translocations Nonhomologous chromosomes • A chromosomal translocation occurs when a segment of one chromosome becomes attached to another 22 22 2 2 Environmental agent causes 2 chromosomes to break. • In reciprocal translocations two non-homologous chromosomes exchange genetic material – Reciprocal translocations arise from two different mechanisms 1. Chromosomal breakage and DNA repair 2. Non-homologous crossovers (b) Paracentric inversion 1 1 7 7 Crossover between nonhomologous chromosomes Reactive ends 1 DNA repair enzymes recognize broken ends and incorrectly connect them. 7 Reciprocal translocation • Reciprocal translocations, like inversions, are usually without phenotypic consequences • In a few cases, they can result in position effect • In simple translocations the transfer of genetic material occurs in only one direction – These are also called unbalanced translocations (b) Nonhomologous crossover • Unbalanced translocations are associated with phenotypic abnormalities or even lethality Reciprocal translocation 27 28 (a) Chromosomal breakage and DNA repair • Example: the Robertsonian translocation – Most common type of chromosomal rearrangement in humans • Approximately one in 900 births – The majority of chromosome 21 is attached to chromosome 14 8.5 Changes in Chromosome Number: An Overview • This translocation occurs such that – Breaks occur at the extreme ends of two non-homologous chromosomes – The small acentric fragments are lost – Larger fragments fuse at centromeric regions to form a single chromosome 21 Robertsonian translocation q Definition of euploid and aneuploid q Polyploidy and aneuploidy 21 + 14 21 14 14 Crossover Translocated chromosome containing long arms of chromosome 14 and 21 Translocated chromosome containing short arms of chromosome 14 and 21 (usually lost) 30 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 5 10/25/15 Chromosome composition Normal female fruit fly: Variation in Chromosome Number Polyploid organisms have three or more (a) sets of chromosomes • Chromosome numbers can vary in two main ways – Aneuploidy • Variation in the number of particular chromosomes within a set • Regarded as abnormal • Examples: trisomy (2n+1), monosomy (2n-1) Polyploid fruit flies: 1(X) 2 3 Individual is said to be trisomic 4 Diploid; 2n (2 sets) Aneuploid fruit flies: Triploid; 3n (3 sets) Trisomy 2 (2n + 1) – Euploidy • Variation in the number of complete sets of chromosomes • Occur occasionally in animals and frequently in plants • Examples: triploid (3n), tetraploid (4n) Tetraploid; 4n (4 sets) (b) Variations in euploidy Monosomy 1 (2n – 1) (c) Variations in aneuploidy Individual is said to be monosomic 32 31 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 8.6 Variation in the Number of Chromosomes Within a Set: Aneuploidy Aneuploidy • Aneuploidy – Variation in the number of particular chromosomes within a set 1 100% 2 100% 3 100% Normal individual • Aneuploidy commonly causes an abnormal phenotype – It leads to an imbalance in the amount of gene products – Three copies can lead to 150% production of the hundreds or even thousands of gene products from a particular chromosome Why aneuploidy usually has a detrimental effect on phenotype q Examples of aneuploidy in humans q 100% 100% 33 150% 100% Trisomy 2 individual 50% Monosomy 2 individual 100% 34 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display • Alterations in chromosome number occur frequently during gamete formation – About 5-10% of embryos have an abnormal chromosome number – Indeed, ~ 50% of spontaneous abortions are due to such abnormalities • In some cases, an abnormality in chromosome number produces an offspring that can survive • But this is relatively rare • Autosomal aneuploidies that are most compatible with survival are trisomies 13, 18 and 21 • Sex chromosome aneuploidies generally have less severe effects – Explained by X inactivation • All but one X chromosome transcriptionally suppressed • Phenotypes of X chromosome aneuploidies may be due to – Expression of X-linked genes prior to X-inactivation – Imbalance in the expression of pseudoautosomal genes 35 36 6 10/25/15 • Some human aneuploidies are influenced by parental age – Older parents more likely to produce abnormal offspring – Example: Down syndrome (Trisomy 21) • Incidence rises with the age of either parent, especially mothers • Age of oocytes may play a role – Primary oocytes are produced in the ovary of fetus prior to birth • Oocytes arrested in prophase I until the time of ovulation • Length of time that oocytes are arrested in prophase I may contribute to an increased frequency of nondisjunction Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Infants with Down syndrome (per 1000 births) 90 1/12 80 70 60 50 40 1/32 30 20 10 1/1925 1/1205 1/885 25 30 1/365 1/110 0 20 35 40 45 • Down syndrome – Failure of chromosome 21 to segregate properly due to chromosomal nondisjunction, usually in meiosis I in the oocyte 50 Age of mother 37 38 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 8.7 Variation in the Number of Sets of Chromosomes Euploidy • Euploidy – Variation in the number of complete sets of chromosomes q Examples in animals that involve variation in euploidy q Definition of endopolyploidy q The process of polytene chromosome formation • Most species of animals are diploid q • In many cases, changes in euploidy are not tolerated – Polyploidy in animals is generally a lethal condition The effects of polyploidy among plant species and its impact in agriculture 39 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 40 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Polyploidy • Some euploidy variations are naturally occurring – Example: Bees are haplodiploid • Common in plants – 30-35% of ferns and flowering plants are polyploid – Many fruits and grains are polyploids • Female bees are diploid • Male bees (drones) are monoploid – Contain a single set of chromosomes • A few examples of vertebrate polyploid animals have been discovered – Example: The frog Hyla • In many instances, polyploid strains of plants display outstanding agricultural characteristics – They are often larger in size and more robust Tetraploid 41 © James Steinberg/Photo Researchers (a) Cultivated wheat, a hexaploid species Diploid (b) A comparison of diploid and tetraploid petunias 42 7 10/25/15 • Polyploids having an odd number of chromosome sets are usually sterile – These plants produce highly aneuploid gametes • Although sterility is generally a detrimental trait it can be agriculturally desirable • Example: In a triploid organism there is an unequal separation of homologous chromosomes (three each) during anaphase I Each cell receives one copy of some chromosomes and two copies of other chromosomes – Seedless fruit • Watermelons and bananas – Triploid varieties – Propagated by cuttings – Seedless flowers • Marigold flowering plants – Triploid varieties – Keep blooming – Need to buy seeds 43 8.8 Mechanisms That Produce Variation in Chromosome Number 44 Chromosome Number Variation • There are three natural mechanisms by which the chromosome number of a species can vary How meiotic and mitotic nondisjunction occur and their possible phenotypic consequences 1. Meiotic nondisjunction q Autopolyploidy, alloploidy, and allopolyploidy 2. Mitotic nondisjunction q How colchicine is used to produce polyploid species 3. Alloploidy (interspecies crosses) q 45 46 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Meiotic Nondisjunction • Nondisjunction – Failure of chromosomes to segregate properly during anaphase • Meiotic nondisjunction can produce cells that have too many or too few chromosomes – If such a gamete participates in fertilization, the zygote will have an abnormal number of chromosomes – Nondisjunction can occur in meiosis I – Nonduisjunction can occur in meiosis II 47 These gametes can produce a trisomic zygoyte These gametes can produce a monosmic zygote All four gametes are abnormal 48 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 8 10/25/15 • In rare cases, all the chromosomes can undergo nondisjunction and migrate to one daughter cell • This is termed complete nondisjunction – It results in one diploid cell and one without chromosomes • The chromosome-less cell is nonviable • The diploid cell can participate in fertilization with a normal gamete, yielding a triploid individual 50 % Abnormal gametes 50 % Normal gametes 49 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Mitotic Nondisjunction • Occurs after fertilization • Usually only a subset of cells affected - mosaicism This cell will be monosomic • The size and location of the mosaic region depends on the timing and location of the original abnormality This cell will be trisomic – Most severe example is when abnormality occurs during the first mitotic division after fertilization – Mitotic nondisjunction – Sister chromatids separate improperly – Leads to trisomic and monosomic daughter cells – Chromosome loss 50 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display This cell will be monosomic This cell will be normal – One of the sister chromatids does not migrate to a pole and is degraded if not included in reformed nucleus – Leads to normal and monosomic daughter cells Will be degraded if left outside of the nucleus when nuclear envelope reforms 52 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Alloploidy Autopolyploidy • Complete nondisjunction can produce an individual with one or more extra sets of chromosomes • Much more common mechanism for changes in the number of sets of chromosomes – Result of interspecies crosses – Most likely occurs between closely related species Diploid species Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Species 1 Species 2 Polyploid species (tetraploid) Alloploid (a) Autopolyploidy (tetraploid) (b) Alloploidy (allodiploid) 53 54 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 9 10/25/15 Experimental Treatments Can Promote Polyploidy Allopolyploidy • Polyploid and allopolyploid plants often exhibit desirable traits • An allopolyploid contains a combination of both autopolyploidy and alloploidy Species 1 Caused by complete nondisjunction • Can be induced by abrupt temperature changes or drugs – The drug colchicine is commonly used to promote polyploidy • Binds to tubulin (a protein found in the spindle apparatus), promoting nondisjunction Species 2 An allotetraploid: Two complete sets of chromosomes from two different species Allopolyploid (c) Allopolyploidy (allotetraploid) 55 56 10