NONMENDELIAN INHERITANCE

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NON-MENDELIAN INHERITANCE

• Chapter 7

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NON-MENDELIAN INHERITANCE

• Mendelian inheritance patterns
• Involve genes directly influencing traits
• Obey Mendels laws
• Law of segregation
• Law of independent assortment
• Include
• Dominant / recessive relationships
• Gene interactions
• Phenotype-influencing roles of sex and
  environment
• Most genes of eukaryotes follow a Mendelian
  inheritance pattern

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NON-MENDELIAN INHERITANCE

• Many genes do not follow a Mendelian inheritance
  pattern
• e.g., Closely linked genes do not follow Mendels
  law of independent assortment
• This chapter will discuss additional and more
  bizarre non-Mendelian inheritance patterns
• Maternal effect
• Epigenetic inheritance
• Extranuclear inheritance

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MATERNAL EFFECT

• Maternal effect
• Inheritance pattern for certain nuclear genes
• Genotype of mother directly determines phenotype
  of offspring
• Genotype of father and offspring are irrelevant
• Explained by the accumulation of gene products
  mother provides to developing eggs

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MATERNAL EFFECT

• A. E. Boycott (1920s)
• First to study an example of maternal effect
• Involved morphological features of water snail
• Limnea peregra
• Shell and internal organs can be either right- or
  left-handed
• Dextral or sinistral, respectively
• Determined by cleavage pattern of egg after
  fertilization
• Dextral orientation is more common and dominant

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MATERNAL EFFECT

• A. E. Boycott (1920s)
• Began with two different true-breeding strains
• One dextral, one sinistral
• Dextral ? x sinistral ? ? dextral offspring
• Reciprocal cross ? sinistral offspring
• Contradict a Mendelian pattern of inheritance

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MATERNAL EFFECT

• A. E. Boycott (1920s) Alfred Sturtevant (1923)
• Sturtevant proposed that Boycotts results could
  be explained by a maternal effect gene
• Conclusions drawn from F2 and F3 generations
• Dextral (D) is dominant to sinistral (d)
• Phenotype of offspring is determined by genotype
  of mother

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MATERNAL EFFECT

• Oogenesis in female animals
• Oocyte is formed
• Will ultimately become haploid
• Nourished by surrounding diploid maternal nurse
  cells

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MATERNAL EFFECT

• Oogenesis in female animals
• Oocyte is formed
• Will ultimately become haploid
• Nourished by surrounding diploid maternal nurse
  cells
• Receives gene products from nurse cells
• Genotype of nurse cells determines gene products
  in oocyte

Oocyte receives gene products of D and d alleles
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MATERNAL EFFECT

• Maternal effect genes
• Encode RNA and proteins that play important roles
  in early steps of embryogenesis
• e.g., Cell division, cleavage pattern, body axis
  orientation
• Defective alleles tend to have dramatic
  phenotypic effects

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MATERNAL EFFECT

• Maternal effect genes
• Identified in Drosophila melanogaster (and other
  organisms)
• Profound effects on early stages of development
• Gene products important in proper development
  along axes
• Anterio-posterior axis
• Dorso-ventral axis
• Discussed further in chapter 23

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EPIGENETIC INHERITANCE

• Epigenetic inheritance
• Modification occurs to a nuclear gene or
  chromosome
• Occur during spermatogenesis, oogenesis, and
  early stages of embryogenesis
• Gene expression is altered
• May be fixed during an individuals lifetime
• Expression is not permanently changed over
  multiple generations
• DNA sequence is not altered

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EPIGENETIC INHERITANCE

• Two types of epigenetic inheritance will be
  discussed
• Dosage compensation
• Offsets differences in the number of sex
  chromosomes
• One sex chromosome is altered
• Genomic imprinting
• Occurs during gamete formation
• Involves a single gene or chromosome
• Governs whether offspring express maternally- or
  paternally-derived gene

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DOSAGE COMPENSATION

• Males and females of many species have different
  numbers of certain sex chromosomes
• e.g., X chromosomes
• The level of expression of many genes on sex
  chromosomes is similar in both sexes

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DOSAGE COMPENSATION

• Apricot eye color in Drosophila
• Conferred by an X-linked gene
• Homozygous females resemble hemizygous males
• Females heterozygous for the apricot allele and a
  deletion have paler eye color
• Two copies of the allele in a female produce a
  phenotype similar to one copy in a male
• The difference in gene dosage is being
  compensated at the level of gene expression

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DOSAGE COMPENSATION

• Dosage compensation does not occur for all eye
  color alleles in Drosophila
• e.g., Eosin eye color
• Conferred by an X-linked gene
• Homozygous eosin females have darker eye color
  than hemizygous eosin males
• Dark eosin and light eosin
• Females heterozygous for the eosin allele and the
  while allele have light eosin eye color
• Two copies of the allele in a female produce a
  phenotype different than one copy in a male

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DOSAGE COMPENSATION

• Most X-linked genes show dosage compensation
• Some X-linked genes do not
• Reasons for the difference are not understood

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DOSAGE COMPENSATION

• Mechanisms of dosage compensation
• Mammals
• One X chromosome is inactivated in females
• X inactivation
• Paternally derived in marsupial mammals
• Paternal or random, depending on species of
  placental mammal
• Drosophila melanogaster
• Twofold increase in expression of genes on the X
  chromosome of males
• The nematode Caenorhabditis elegans
• 50 reduction in expression of X-linked genes in
  XX individuals

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DOSAGE COMPENSATION
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DOSAGE COMPENSATION

• Dosage compensation is poorly understood in
  certain species
• e.g., Birds and fish

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DOSAGE COMPENSATION

• Sex in birds is determined by Z and W sex
  chromosomes
• Males are ZZ, females are ZW
• The Z chromosome is large
• Contains most sex-linked genes
• The W chromosome is a smaller microchromosome
• Contains a large amount of non-coding repetitive
  DNA
• Dosage compensation usually occurs, but not for
  all genes
• Molecular mechanism is not understood
• Highly compacted chromosomes are not seen in
  males
• Perhaps genes on both Zs are downregulated
• Perhaps genes on females Z are upregulated

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DOSAGE COMPENSATION

• Murray Barr and Ewart Bertram (1949)
• Identified a highly condensed structure in
  interphase nuclei of somatic cells of female cats
• This structure was absent in male cats
• Barr body
• Later identified as a highly condensed X
  chromosome

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DOSAGE COMPENSATION

• Mary Lyon (1961)
• Aware of Barr and Bertram cytological evidence
• Also aware of mammalian mutations producing a
  variegated coat color pattern
• e.g., Calico cats are heterozygous for X-linked
  alleles determining coat color
• Possess randomly distributed patches of black and
  orange
• White underside due to dominant mutation of
  another gene
• Lyon hypothesis A single X chromosome was
  inactivated in the cells of females

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DOSAGE COMPENSATION

• X chromosome inactivation
• Both coat color alleles are originally active
• One X chromosome is randomly inactivated in each
  cell during early embryonic development
• X inactivation is passed along to all future
  somatic cells during cell division
• Patches of cells with different coloration result

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DOSAGE COMPENSATION

• X chromosome inactivation
• DNA in inactivated X chromosomes becomes highly
  compacted
• A Barr body is formed
• Most genes cannot be expressed

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DOSAGE COMPENSATION

• Davidson, Nitowsky, and Childs (1963)
• Tested the Lyon hypothesis at the cellular level
• Analyzed expression of a human X-linked gene
• Encoded the enzyme glucose-6-phosphate
  dehydrogenase (G-6-PD)
• Individuals vary with respect to this enzyme
• Different alleles produce different yet
  functional enzymes

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DOSAGE COMPENSATION

• Davidson, Nitowsky, and Childs (1963)
• Variation in G-6-PD can be detected via gel
  electrophoresis
• Electric current forces proteins through a gel
• Different proteins ? different movement rates
• Can discriminate between fast enzyme and slow
  enzyme

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DOSAGE COMPENSATION

• Davidson, Nitowsky, and Childs (1963)
• Hypothesis
• Heterozygous adult females should express only
  one enzyme in any particular somatic cell and its
  descendents

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DOSAGE COMPENSATION

• Davidson, et al. (1963)
• Experimental design
• Isolate tissue from adult heterozygote
• Separate individual cells
• Grow these cells in culture
• Isolate proteins from various clones
• Subject proteins to electrophoresis

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DOSAGE COMPENSATION

• Davidson, et al. (1963)
• The data
• A single form of the enzyme was detected in each
  clone
• Some clones produced the fast enzyme
• Some clones produced the slow enzyme

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DOSAGE COMPENSATION

• Davidson, Nitowsky, and Childs (1963)
• Interpreting the data
• Lane 1 contains a mixture of cells from a
  heterozygous woman
• Each clone produced only a single form of the
  enzyme
• The allele encoding the other form resides upon
  the inactivated X chromosome
• Consistent with the hypothesis

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DOSAGE COMPENSATION

• Genetic control of X inactivation
• Human cells (and those of other mammals) possess
  the ability to count their X chromosomes
• Only one is allowed to remain active
• XX females ? 1 Barr body
• XY males ? 0 Barr bodies
• XO females ? 0 Barr bodies (Turner
  syndrome)
• XXX females ? 2 Barr bodies (Triple X
  syndrome)
• XXY males ? 1 Barr body (Kleinfelter
  syndrome)

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DOSAGE COMPENSATION

• Genetic control of X inactivation
• Not entirely understood
• X-inactivation center (Xic) is involved
• Short region of the X chromosome
• Skip details

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DOSAGE COMPENSATION

• Genomic imprinting involves the physical marking
  of a segment of DNA
• Mark is retained and recognized throughout the
  life of the organism inheriting the marked DNA
• Resulting phenotypes display non-Mendelian
  inheritance patterns
• Offspring expresses one allele, not both
• Monoallelic expression

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DOSAGE COMPENSATION

• Genomic imprinting
• The Igf-2 gene encodes an insulin-like growth
  factor
• Functional allele required for normal size
• Igf-2m allele encodes a non-functional protein
• Imprinting results in the expression of the
  paternal allele only
• Paternal allele is transcribed
• Maternal allele is transcriptionally silent

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DOSAGE COMPENSATION

• Genomic imprinting
• The Igf-2 gene encodes an insulin-like growth
  factor
• Functional allele required for normal size
• Igf-2m allele encodes a non-functional protein
• Igf-2m Igf-2m ? x Igf-2 Igf-2 ?
• Normal offspring
• Igf-2m Igf-2m ? x Igf-2 Igf-2 ?
• Dwarf offspring
• Different results in reciprocal crosses generally
  indicate sex-linked traits
• In this case, it indicates genomic imprinting of
  autosomal alleles

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DOSAGE COMPENSATION

• Genomic imprinting
• The imprint of the Igf-2 gene is erased during
  gametogenesis
• A new imprint is then imparted
• Oocytes possess an imprinted gene that is
  silenced
• Sperm possess a gene that is not silenced
• The phenotypes of offspring are determined by the
  paternally derived allele

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DOSAGE COMPENSATION

• Genomic imprinting
• Permanent in the somatic cells of an animal
• Can be altered from generation to generation

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DOSAGE COMPENSATION

• Genomic imprinting
• Occurs in several species
• Numerous insects, plants, and mammals
• Effects can include
• A single gene
• A part of a chromosome
• An entire chromosome
• All the chromosomes from one parent

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DOSAGE COMPENSATION

• Genomic imprinting
• First discovered in the housefly Sciara
  coprophilia
• These flies normally inherit three sex
  chromosomes
• One X chromosome from the female
• Two X chromosomes from the male
• Male flies lose both paternal X chromosomes
  during embryogenesis
• Female flies lose one paternal X chromosome
  during embryogenesis

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DOSAGE COMPENSATION

• Genomic imprinting
• First discovered in the housefly Sciara
  coprophilia
• The maternal X chromosome is never lost
• The maternal X chromosome is marked to promote
  its retention, or
• The paternal X chromosome is marked to promote
  its loss

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DOSAGE COMPENSATION

• Genomic imprinting
• Can also be correlated with the process of X
  inactivation
• In some species, imprinting determines which X
  chromosome will be inactivated
• e.g., The paternal X chromosome is always
  inactivated in marsupials
• e.g., The paternal X chromosome is inactivated in
  extraembryonic tissue (e.g., the placenta) of
  placental mammals
• X inactivation is random in the placental embryo
  itself

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DOSAGE COMPENSATION

• Genomic imprinting
• Involves the physical marking of DNA
• Involves differentially methylated regions (DMRs)
  located near imprinted genes
• Maternal or paternal copy is methylated, not both

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DOSAGE COMPENSATION

• Genomic imprinting
• Methylation occurs during gametogenesis
• Methylated in oocyte or sperm, not both
• This pattern of imprinting is maintained in the
  somatic cells of the offspring
• Imprinting is erased during gametogenesis in
  these offspring
• New imprinting established

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DOSAGE COMPENSATION

• Genomic imprinting
• Methylation generally inhibits expression
• Can enhance binding of transcription-inhibiting
  proteins and/or inhibit binding of
  transcription-enhancing proteins
• Methylation can increase expression of some genes

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DOSAGE COMPENSATION

• Genomic imprinting
• Identified in several mammalian genes
• Biological significance is unclear
• Plays a role in the inheritance of some human
  diseases

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EXTRANUCLEAR INHERITANCE

• Most genes are found in the cells nucleus
• Some genes are found outside of the nucleus
• Some organelles possess genetic material
• Resulting phenotypes display non-Mendelian
  inheritance patterns
• Extranuclear inheritance
• Cytoplasmic inheritance

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EXTRANUCLEAR INHERITANCE

• Mitochondria and chloroplasts possess DNA
• Circular chromosomes resemble smaller versions of
  bacterial chromosomes
• Located in the nucleoid region of the organelles
• Multiple nucleoids often present
• Each can contain multiple copies of the
  chromosome

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EXTRANUCLEAR INHERITANCE

• Mitochondrial genome size varies greatly among
  different species
• 400-fold variation in mitochondrial chromosome
  size
• Mitochondrial genomes of animals tend to be
  fairly small
• Mitochondrial genomes of fungi, algae, and
  protists tend to be intermediate in size
• Mitochondrial genomes of plants tend to be fairly
  large

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EXTRANUCLEAR INHERITANCE

• Human mitochondrial DNA is called mtDNA
• Circular chromosome 17,000 base pairs in length
• Less than 1 of a typical bacterial chromosome
• Carries relatively few genes
• Genes encoding rRNA and tRNA
• 13 genes encoding proteins functioning in ATP
  generation via oxidative phosphorylation

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EXTRANUCLEAR INHERITANCE

• Most mitochondrial proteins are encoded by genes
  in the cells nucleus
• Proteins are synthesized in the cytosol and
  transported into the mitochondria

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EXTRANUCLEAR INHERITANCE

• Chloroplast genomes tend to be larger than
  mitochondrial genomes
• Correspondingly greater number of genes
• 100,000 200,000 bp in length
• Ten times larger than the mitochondrial genome of
  animal cells

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EXTRANUCLEAR INHERITANCE

• Chloroplast DNA (cpDNA) of the tobacco plant
• 156,000 bp circular DNA molecule
• 110 120 different genes
• rRNAs, tRNAs, and many proteins required for
  photosynthesis
• Many chloroplast proteins are encoded in the
  nucleus

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EXTRANUCLEAR INHERITANCE

• Most nuclear genes in diploid eukaryotes display
  Mendelian inheritance patterns
• Homologous chromosomes segregate during gamete
  production
• Offspring inherit one copy of each gene from each
  parent
• The inheritance pattern of extranuclear genetic
  material displays non-Mendelian inheritance
• Mitochondria and plastids do not segregate into
  gametes as do nuclear chromosomes

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EXTRANUCLEAR INHERITANCE

• Pigmentation in Mirabilis jalapa
• The four-oclock plant
• Pigmentation is determined by chloroplast genes
• Green phenotype is the wild-type condition
• Green pigment is formed
• White phenotype is due to a mutation in a
  chloroplast gene
• Synthesis of green pigment is diminished
• Cells containing both types of chloroplasts
  display green coloration
• Normal chloroplasts produce pigment
• Heterotroplasmy

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EXTRANUCLEAR INHERITANCE

• Pigmentation in Mirabilis jalapa
• Pigmentation in the offspring depends solely on
  the maternal parent
• Maternal inheritance
• Chloroplasts are inherited only through the
  cytoplasm of the egg

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EXTRANUCLEAR INHERITANCE

• Pigmentation in Mirabilis jalapa
• Cells can contain both types of chloroplasts
• Coloration is green because pigment is produced
• Chloroplasts are irregularly distributed to
  daughter cells during cell division
• Some cells may receive only chloroplasts
  defective in pigment synthesis
• The sector of the plant arising from such a cell
  will be white
• Variegated phenotype

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EXTRANUCLEAR INHERITANCE

• Studies in yeast and unicellular algae provided
  genetic evidence for extranuclear inheritance of
  mitochondria and chloroplasts
• e.g., Saccharomyces cerevisiae
• e.g., Chlamydomonas reinhardtii

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EXTRANUCLEAR INHERITANCE

• Many organisms are heterogametic
• Two kinds of gametes are made
• Female gamete tends to be large and provides most
  of the cytoplasm to the zygote
• Male gamete is small and often provides little
  more than a nucleus
• Mitochondria and plastids are most often
  inherited from the maternal parent

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EXTRANUCLEAR INHERITANCE

• Many organisms are heterogametic
• Two kinds of gametes are made
• Female gamete tends to be large and provides most
  of the cytoplasm to the zygote
• Male gamete is small and often provides little
  more than a nucleus
• Mitochondria and plastids are most often
  inherited from the maternal parent
• Rarely, mitochondria are provided via the sperm
• Paternal leakage

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EXTRANUCLEAR INHERITANCE

• The inheritance pattern of mitochondria and
  plastids varies among different species

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EXTRANUCLEAR INHERITANCE

• A few rare human diseases are caused by
  mitochondrial mutations
• Display a strict maternal inheritance pattern

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EXTRANUCLEAR INHERITANCE

• Symbiosis involves a close relationship between
  two species where at least one member benefits
• Endosymbiosis involves such a relationship where
  one organism lives inside the other

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EXTRANUCLEAR INHERITANCE

• Mitochondria and chloroplasts were once
  free-living bacteria
• Engulfed and retained by early eukaryotes
• Endosymbiosis

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EXTRANUCLEAR INHERITANCE

• Endosymbiosis
• Origin of chloroplasts proposed in 1883
• Origin of mitochondria proposed in 1922
• DNA was discovered in these organelles in the
  1950s
• Hotly debated topic when Lynn Margulis published
  Origin of Eukaryotic Cells in 1970
• Molecular analysis in the 1970s and 1980s
  provided additional evidence
• Endosymbiotic theory is currently virtually
  universally accepted
• Perhaps not among flat-earthers

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EXTRANUCLEAR INHERITANCE

• Plastids were derived from cyanobacteria
• Photosynthetic bacteria
• Relationship allows plants and algae to obtain
  energy from the sun
• Benefit to the bacterium is less clear

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EXTRANUCLEAR INHERITANCE

• Mitochondria were likely derived from
  gram-negative nonsulfur purple bacteria
• Relationship enabled eukaryotes to produce
  larger amounts of ATP

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EXTRANUCLEAR INHERITANCE

• Endosymbiosis
• Most genes originally found in these bacterial
  genomes have been lost of transferred to the
  nucleus
• The DNA sequence of some nuclear genes indicates
  horizontal gene transfer from bacteria
• Biological benefits are unclear

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EXTRANUCLEAR INHERITANCE

• Endosymbiosis
• Transfer of mitochondrial genes to the nucleus
  has apparently ceased in animals
• Gene transfer from mitochondria and chloroplasts
  continues in plants at a low rate
• Transfer from the nucleus to the organelles has
  apparently almost never occurred
• One example in plants of transfer to the
  mitochondrion is known

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EXTRANUCLEAR INHERITANCE

• Endosymbiosis
• Horizontal gene transfer can also occur between
  organelles
• Between mitochondria
• Between chloroplasts
• Between a mitochondrion and a chloroplast
• Biological benefits are unclear

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EXTRANUCLEAR INHERITANCE

• Eukaryotic cells occasionally contain symbiotic
  infective particles
• Some individuals of the protozoan Paramecia
  aurelia possess the killer trait
• Secrete the toxin paramecin
• Many strains of paramecia are killed

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EXTRANUCLEAR INHERITANCE

• Killer strains contain cytoplasmic particles
• Kappa particles
• 0.4 mm long
• Contain their own DNA
• Gene encodes paramecin toxin
• Genes encode resistance to this toxin
• Kappa particles are infectious
• Particles in extract from killer strains can
  infect nonkiller strains
• Converted to killer strains

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EXTRANUCLEAR INHERITANCE

• The protozoan Paramecia aurelia
• Some individuals possess the killer trait
• Secrete the toxin paramecin
• Many strains of paramecia are killed
• Killer strains contain cytoplasmic particles
• Kappa particles
• 0.4 mm long
• Contain their own DNA
• Gene encodes paramecin toxin
• Genes encode resistance to this toxin

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EXTRANUCLEAR INHERITANCE

• Eukaryotic cells occasionally contain symbiotic
  infective particles
• Certain strains of Drosophila possess a trait
  known as sex ratio
• Most of the offspring are female
• Most of the male offspring died
• Surviving males do not transmit the trait to
  their offspring
• Transmitted maternally
• Transmitted infective agent is a symbiotic
  microorganism