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The Chromosomal Basis of Inheritance

Chapter 15. The Chromosomal Basis of Inheritance. Mendelian inheritance has its physical basis in the behavior of chromosomes. Mendel’s “hereditary factors” were genes today we can show that genes are located on chromosomes the chromosome theory of inheritance states:

georgia-robertson
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The Chromosomal Basis of Inheritance

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  1. Chapter 15 The Chromosomal Basis of Inheritance

  2. Mendelian inheritance has its physical basis in the behavior of chromosomes • Mendel’s “hereditary factors” were genes • today we can show that genes are located on chromosomes • the chromosome theory of inheritance states: • Mendelian genes have specific loci (positions) on chromosomes • chromosomes undergo segregation and independent assortment

  3. 1 3 1 2 2 3 All F1 plants produceyellow-round seeds (YyRr). F1 Generation R R y y r r Y Y LAW OF INDEPENDENTASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation. Meiosis LAW OF SEGREGATIONThe two alleles for each gene separate during gamete formation. r R r R Metaphase I y Y Y y R r R r LAW OF INDEPENDENTASSORTMENT LAW OF SEGREGATION Anaphase I Y Y y y r R r R Metaphase II F2 Generation y Y y Y An F1 F1 cross-fertilization y Y Y y Y y Y y Gametes r R R r r r R R Fertilization recombines the R and r alleles at random. Fertilization results in the 9:3:3:1 phenotypic ratio in the F2 generation. 1/4 1/4 1/4 1/4 yr yR YR Yr • the behavior of chromosomes during meiosis accounts for Mendel’s laws of segregation and independent assortment : 3 : 3 : 1 9

  4. Morgan’s Experimental Evidence: Scientific Inquiry • the first solid evidence associating a specific gene with a specific chromosome came from Thomas Hunt Morgan- an embryologist • Morgan’s experiments with fruit flies (Drosophila melanogaster) provided convincing evidence that chromosomes are the location of Mendel’s heritable factors • several characteristics make fruit flies a convenient organism for genetic studies • they produce many offspring • a generation can be bred every two weeks • they have only four pairs of chromosomes • Morgan recorded wild type(or normal) phenotypes that were common in the fly populations • traits alternative to the wild type are called mutant phenotypes • Drosophila mutations • -white eyes (ABC gene mutation) • wingless (Wnt mutation) • curly winged, short winged (vestigial) • forked bristles • ebony color, yellow color

  5. Correlating Behavior of a Gene’s Alleles with Behavior of a Chromosome Pair • in one experiment, Morgan mated male flies with white eyes (mutant) with female flies with red eyes (wild type) • the F1 generation all had red eyes • the F2 generation showed the 3:1 red:white eye ratio • but only males had white eyes • Morgan determined that the white-eyed mutant allele must be located on the X chromosome • Morgan’s finding supported the chromosome theory of inheritance

  6. EXPERIMENT PGeneration • Morgan determined that the white-eyed mutant allele must be located on the X chromosome • Morgan’s finding supported the chromosome theory of inheritance F1Generation All offspringhad red eyes. RESULTS F2Generation CONCLUSION w w PGeneration X X Y X w w Sperm Eggs F1Generation w w w w w Sperm Eggs w w w F2Generation w w w w w

  7. 44 XY 44 XX Parents The Chromosomal Basis of Sex 22 X 22 Y 22 X or Sperm Egg 44 XY 44 XX or • in many organisms there is a chromosomal basis of sex determination • XX/XY determination – humans and most mammals and some insects • humans – Y determines the male • fruit flies – 2 X’s determine the female • XX/XO determination – some rodents • females = XX • males = XO (absence of a second sex chromosome) • ZW determination – birds, some reptiles and some insects • ZW = female • W chromosome possesses sex determining genes • ZZ = male • UV determination – some plants and algae • U = female gametophytes • V = male gametophytes • haplo-diploid system – bees and ants • diploid = female and sterile males • haplo = males (from unfertilized eggs) • so the queen and control gender Zygotes (offspring) (a) The X-Y system 22 X 22 XX (b) The X-0 system 76 ZZ 76 ZW (c) The Z-W system 16 (Haploid) 32 (Diploid) (d) The haplo-diploid system

  8. The Chromosomal Basis of Sex in humans and other mammals  XX/XY determination a larger X chromosome and a smaller Y chromosome for males one X chromosome is inactivated in females the Y chromosome – significantly lower numbers of genes vs. X chromosome (1846 vs. 454) most of them are responsible for sex determination and development of male reproductive structures the SRY gene on the Y chromosome codes for a protein that directs the development of male anatomical features BUT the ends of the Y chromosome have regions that are homologous with corresponding regions of the X chromosome = pseudoautosomal regions

  9. The Chromosomal Basis of Sex • a gene that is located on either sex chromosome is called a sex-linked gene • genes on the Y chromosome are called Y-linked genes • genes on the X chromosome are called X-linked genes • X chromosomes have genes for many characters unrelated to sex • whereas the Y chromosome mainly encodes genes related to sex determination • e.g. SRY gene

  10. X-linked Genes XNXn XNY XnY XNXn XnY XNXN • X-linked genes follow specific patterns of inheritance • for a recessive X-linked trait to be expressed • a female needs two copies of the allele (homozygous) • a male needs only one copy of the allele (hemizygous) • X-linked recessive disorders are much more common in males than in females Sperm XN Xn Sperm Sperm Y Y Xn Y XNXn XNXN XNY XNY XNXn XNY Eggs XN XN XN Eggs Eggs XnY XN XNXn XnY XnXn XNXn XNY Xn Xn (a) (b) (c)

  11. Some disorders caused by recessive alleles on the X chromosome in humans • Color blindness (mostly X-linked) • Duchenne muscular dystrophy • Hemophilia A and B

  12. X chromosomes Allele fororange fur X Inactivation in Female Mammals Early embryo: Allele forblack fur • the coloration of a calico cat is the physical manifestation of a phenomenon called X-inactivation • X-inactivation or lyonization process in mammalian females where one of the two X chromosomes in each cell is randomly inactivated • in marsupials – always the paternally derived X • prevents the female from having twice as many X chromosome gene products as a male = dosage compensation • the inactive X condenses into a Barr body Cell division andX chromosomeinactivation Two cellpopulationsin adult cat: Active X Inactive X Active X Orange fur Black fur

  13. X Inactivation in Female Mammals X inactivation begins at embryonic development – occurs in the inner cell mass of the blastocyst once a specific X chromosome is inactivated – that one will remain inactive throughout its lifetime will also be inactivated in all cellular progeny inactivation is an epigenetic change high methylation of DNA and low acetylation of histones methylation results in the packaging of the X chromosome into heterochromatin DNA is now a transcriptionally inactive structure reversed in female germ cells undergoing meiosis X chromosomes Allele fororange fur Early embryo: Allele forblack fur Cell division andX chromosomeinactivation Two cellpopulationsin adult cat: Active X Inactive X Active X Orange fur Black fur

  14. X Inactivation in Female Mammals active X chromosome is called Xa inactive one is designated Xi if multiple X chromosomes are present (i.e. 3 vs. 2) – only one X chromosome is still Xa default state is the inactive form hypothesis: autosomally-encoded blocking factor binds to the Xa chromosome and prevents its inactivation sequence known as the XIC – X inactivation center may bind these binding factors and prevent inactivation?? the XIC of the the Xi chromosome produces a non-coding RNA called Xist RNA coats the Xi chromosome  inactivation despite the fact that the X chromosome is inactivated – there are genes on Xi that ESCAPE inactivation these genes are also found on the Y chromosome of males so there is dosage compensation

  15. Mosaicism • Mosaicism – two or more populations of cells with different genotypes within a single organism • most common forms rise from errors in the first few mitotic divisions of a fertilized zygote • mitotic crossing over! • Source of genetic variation in asexually reproducing organisms • Can occur in sexually reproducing organisms • Takes place during interphase (G1) • other mosaicisms – result from non-disjunction during meiosis and produce trisomies • true mosaicism should NOT be confused with X-inactivation!!! • all the cells in this cat have the same genotype BUT a different X is active in different cells

  16. Linked genes tend to be inherited together because they are located near each other on the same chromosome • each chromosome has hundreds or thousands of genes (except the Y chromosome) • genes located on the same chromosome that tend to be inherited together are called linked genes

  17. How Linkage Affects Inheritance P Generation (homozygous) Double mutant(black body,vestigial wings) Wild type(gray body, normal wings) b b vg vg b b vg vg • Morgan did other experiments with fruit flies to see how linkage affects inheritance of two characters • Morgan crossed flies that differed in traits of body color and wing size • found a higher percentage of parental phenotypes in the offspring • concluded that these genes do not assort independently • body color and wing size are inherited together • reasoned that they were on the same chromosome

  18. How Linkage Affects Inheritance P Generation (homozygous) Double mutant(black body,vestigial wings) Wild type(gray body, normal wings) b b vg vg b b vg vg • Mated true-breeding wild type flies with gray bodies and normal wings (b+b+vg+vg+) with mutants with black bodies and short, vestigial wings • all F1 offspring looked like parents and were heterozygotes • performed a test-cross of female F1 with true-breeding male mutants (bbvgvg) • expected a 1:1:1:1 ratio of dominant to recessive • most offspring looked like the parents • only possible if the b and vg genes are linked and did not sort independently during meiosis Double mutant F1 dihybrid(wild type) TESTCROSS b b vg vg b b vg vg Testcrossoffspring Eggs b vg bvg bvg b vg Wild type(gray-normal) Black-normal Black-vestigial Gray-vestigial bvg Sperm b bvg vg bbvgvg b bvgvg bbvg vg PREDICTED RATIOS If genes are located on different chromosomes: : 1 : 1 1 1 : If genes are located on the same chromosome and parental alleles are always inherited together: 1 0 1 0 : : : RESULTS : 944 185 : 965 : 206

  19. b vg b+ vg+ F1 dihybrid femaleand homozygousrecessive malein testcross b vg b vg • however, nonparental phenotypes were also produced • so body color and wing size are not always linked genetically and can be recombined as a result of crossing over or genetic recombination b vg b+ vg+ Most offspring or b vg b vg

  20. Recombination of Unlinked Genes: Independent Assortment of Chromosomes Gametes from yellow-rounddihybrid parent (YyRr) • offspring with a phenotype matching one of the parental phenotypes = parental types • offspring with nonparental phenotypes (new combinations of traits) = recombinant types, or recombinants • a 50% frequency of recombination is observed for any two genes on different chromosomes yr Yr yR YR Gametes from green-wrinkled homozygousrecessive parent (yyrr) yr Yyrr yyrr yyRr YyRr Recombinant offspring Parental-type offspring

  21. Gray body, normal wings(F1 dihybrid) Black body, vestigial wings(double mutant) Testcrossparents bvg bvg bvg bvg Replicationof chromosomes Replicationof chromosomes bvg bvg bvg bvg bvg bvg bvg bvg Meiosis I bvg Meiosis I and II bvg bvg bvg Meiosis II Recombinantchromosomes bvg bvg bvg bvg bvg Eggs Sperm Recombination of Linked Genes: Crossing Over • MEIOSIS I: crossing over between the homologous chromosomes of the female parent produces new combinations of alleles (b+ vg and b vg+) • MEIOSIS II: some of the eggs are parental and some are recombinants

  22. Recombinantchromosomes bvg bvg bvg bvg Eggs 206Gray-vestigial 944Black-vestigial 185Black-normal 965Wild type(gray-normal) Testcrossoffspring bvg bvg bvg bvg bvg bvg bvg bvg bvg Sperm Parental-type offspring Recombinant offspring 391 recombinants2,300 total offspring Recombinationfrequency  100  17% 

  23. New Combinations of Alleles: Variation for Normal Selection • recombinant chromosomes bring alleles together in new combinations in gametes • random fertilization increases even further the number of variant combinations that can be produced • this abundance of genetic variation is the raw material upon which natural selection works

  24. Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry • Alfred Sturtevant, one of Morgan’s students, constructed a genetic map, an ordered list of the genetic loci along a particular chromosome • Sturtevant predicted that the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency

  25. Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry RESULTS • a linkage map is a genetic map of a chromosome based on recombination frequencies • distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency • map units indicate relative distance and order, not precise locations of genes Recombinationfrequencies 9% 9.5% Chromosome 17% • b-vg recombination frequency = 17% • b-cn recombination frequency = 9% b cn vg

  26. genes that are far apart on the same chromosome can have a recombination frequency near 50% • such genes are physically linked - but genetically unlinked • they behave as if found on different chromosomes

  27. Mutant phenotypes Blackbody Cinnabareyes Vestigialwings Browneyes Shortaristae 104.5 48.5 57.5 67.0 0 Long aristae(appendageson head) Gray body Red eyes Redeyes Normalwings Wild-type phenotypes • Sturtevant used recombination frequencies to make linkage maps of fruit fly genes • using methods like chromosomal banding - geneticists can develop cytogenetic maps of chromosomes • Cytogenetic maps indicate the positions of genes with respect to chromosomal features

  28. Meiosis I Nondisjunction Abnormal Chromosome Number • in nondisjunction -pairs of homologous chromosomes do not separate normally during meiosis • as a result, one gamete receives two of the same type of chromosome, and another gamete receives no copy

  29. Nondisjunction of homo-logous chromosomes inmeiosis I (b) (a) Nondisjunction of sisterchromatids in meiosis II Meiosis I Nondisjunction Meiosis II Non-disjunction Gametes n 1 n n 1 n 1 n n 1 n 1 n 1 Number of chromosomes

  30. Aneuploidy results from the fertilization of gametes in which nondisjunction occurred • offspring with this condition have an abnormal number of a particular chromosome • a monosomic zygote has only one copy of a particular chromosome • e.g. XO = Turner’s syndrome • a trisomic zygote has three copies of a particular chromosome • e.g. 3 chromosome 21 = Down’s syndrome • Polyploidy is a condition in which an organism has more than two complete sets of chromosomes • Triploidy (3n) is three sets of chromosomes • Tetraploidy (4n) is four sets of chromosomes • polyploidy is common in plants - but not animals • polyploids are more normal in appearance than aneuploids • large-scale chromosomal alterations in humans and other mammals often lead to spontaneous abortions (miscarriages) or cause a variety of developmental disorders • plants tolerate such genetic changes better than animals do

  31. Aneuploidy of Autosomal Chromosomes Down Syndrome (Trisomy 21) • alterations of chromosome number and structure are associated with some serious disorders • some types of aneuploidy appear to upset the genetic balance less than others - resulting in individuals surviving to birth and beyond • Down syndrome is an aneuploid condition that results from three copies of chromosome 21 • it affects about one out of every 700 children born in the United States • the frequency of Down syndrome increases with the age of the mother, a correlation that has not been explained

  32. Aneuploidy of Autosomal Chromosomes • cri du chat (“cry of the cat”) - results from a specific deletion in chromosome 5 • a child born with this syndrome is mentally retarded and has a catlike cry • individuals usually die in infancy or early childhood

  33. Aneuploidy of Sex Chromosomes • Nondisjunction of sex chromosomes produces a variety of aneuploid conditions • Klinefelter syndromeis the result of an extra chromosome in a male, producing XXY individuals – most common aneuploidy • also known as 47,XXY • 1:500  1:1000 live births • non-disjunction between X and Y chromosomes during meiosis I in spermatogenesis • most are asymptomatic • hypogonadism (decreased endocrine function NOT size)and sterility • gynecomastia • reduced muscle mass, coordination and strength as kids • taller than average • higher incidence (vs. normal males) of breast cancer, autoimmune diseases and osteoporosis

  34. Aneuploidy of Sex Chromosomes • Monosomy X, called Turner syndrome - produces X0 females • also known as 45, X • all of part of the second X chromosome is absent (e.g. deletion of the p arm) • 1 in 2,000 to 5,000 births • sterile – non-working ovaries • short stature, webbing in the neck, low hairline, low wet • congenital heart disease, hypothyroidism, diabetes, visual problems, many autoimmune diseases, specific cognitive problems • it is the only known viable monosomy in humans

  35. Aneuploidy of Sex Chromosomes • 48,XXYY and 48,XXXY – 1 in 18,000 to 50,000 live births • 49,XXXXY 1 in 85,000 to 100,000 births

  36. A B C D E F G H A B C E F G H A B C D E F G H A B C B C D E F G H A B C D E F G H A D C B E F G H A B C D E F G M N O P Q R A B P Q R M N O C D E F H (a) Deletion Alterations of Chromosome Structure A deletion removes a chromosomal segment. (b) Duplication • breakage of a chromosome can lead to four types of changes in chromosome structure • Deletion removes a chromosomal segment • Duplication repeats a segment • Inversion reverses orientation of a segment within a chromosome • Translocation moves a segment from one chromosome to another A duplication repeats a segment. (c) Inversion An inversion reverses a segment within a chromosome. (d) Translocation H A translocation moves a segment from onechromosome to a nonhomologous chromosome. G

  37. Gene Duplications and Deletions both can arise from unequal crossing over during meiosis often results between repetitive sequences shared between them duplication can also result from replicationslippage DNA polymerase dissociates and reattaches at an incorrect position – copies the same strand of DNA again these are not necessarily bad things

  38. Normal chromosome 9 Normal chromosome 22 Reciprocal translocation Translocated chromosome 9 Translocated chromosome 22(Philadelphia chromosome) Translocation • reciprocal translocations involve the exchange of material between non-homologous chromosomes • crossing over between non-homologous chromosomes • 1 to 625 newborns • usually harmless • some may be associated with increased chances of cancer • Philadelphia chromosome • associated with Chronic Myelogenous Leukemia • creates two fused gene  BCR-Abl fusion protein • speeds up the cell cycle • but increased miscarriages can result in affected individuals • can occur due to errors in mitosis in somatic cells • limited to the affected cell type • e.g. CML and Philadelphia chr • can also occur in germline cells during meiosis • all cellular progeny affected

  39. Some inheritance patterns are exceptions to standard Mendelian inheritance • there are two normal exceptions to Mendelian genetics • one exception involves genes located in the nucleus • the other exception involves genes located outside the nucleus • in both cases, the sex of the parent contributing an allele is a factor in the pattern of inheritance • Genetic Imprinting • Organelle Genes

  40. Normal Igf2 alleleis expressed. Paternalchromosome Genomic Imprinting Maternalchromosome Normal-sized mouse(wild type) Normal Igf2 alleleis not expressed. • for a few mammalian traits, the phenotype depends on which parent passed along the alleles for those traits • such variation in phenotype is called genomic imprinting • genomic imprinting involves the silencing of certain genes that are “stamped” with an imprint during gamete production (a) Homozygote Mutant Igf2 alleleinherited from mother Mutant Igf2 alleleinherited from father Dwarf mouse (mutant) Normal-sized mouse (wild type) Normal Igf2 alleleis expressed. Mutant Igf2 alleleis expressed. Mutant Igf2 alleleis not expressed. Normal Igf2 alleleis not expressed. (b) Heterozygotes

  41. Genomic Imprinting • it appears that imprinting is the result of the methylation (addition of —CH3) of the DNA • addition of CH3 to cysteine nucleotides • can result in transcriptional inactivation • the methylation pattern is passed on to progeny through meiosis • genomic imprinting is thought to affect only a small fraction of mammalian genes • most imprinted genes are critical for embryonic development

  42. Inheritance of Organelle Genes • extranuclear genes (or cytoplasmicgenes)are found in organelles in the cytoplasm • mitochondria, chloroplasts, and other plant plastids carry small circular DNA molecules • extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg • the first evidence of extranuclear genes came from studies on the inheritance of yellow or white patches on leaves of an otherwise green plant

  43. Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems • inheritance pattern is non-Mendelian – Maternal • only the egg contributes mitochondria to the embryo • e.g. mitochondrial myopathy • type of myopathy associated with abnormal mitochondria • muscle tissue shows “ragged red” fibers with mild accumulations of glycogen • muscle weakness results • numerous types of MMs known • e.g. Leber’s hereditary optic neuropathy • mitochondrial dysfunction results in the degeneration of retinal ganglion cells (neurons in the retina) • loss of central vision

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