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					NON-MENDELIAN
 INHERITANCE

     Chapter 7
                 1
NON-MENDELIAN INHERITANCE
• Mendelian inheritance patterns
  – Involve genes directly influencing traits
  – Obey Mendel’s 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
                                                            2
NON-MENDELIAN INHERITANCE
• Many genes do not follow a Mendelian
  inheritance pattern
  – e.g., Closely linked genes do not follow Mendel’s law
    of independent assortment
  – This chapter will discuss additional and more bizarre
    non-Mendelian inheritance patterns
     • Maternal effect
     • Epigenetic inheritance
     • Extranuclear inheritance



                                                            3
      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




                                                          4
       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
                                                              5
      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




                                                   6
      MATERNAL EFFECT
A. E. Boycott (1920s); Alfred Sturtevant (1923)
• Sturtevant proposed that Boycott’s 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
                                                     7
      MATERNAL EFFECT
• Oogenesis in female animals
  – Oocyte is formed
     • Will ultimately become haploid
  – Nourished by surrounding diploid maternal nurse cells




                                                        8
      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




                                                                    9
      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




                                                                      10
      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




                                                                  11
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 individual’s lifetime
  – Expression is not permanently changed over multiple
    generations
     • DNA sequence is not altered



                                                          12
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


                                                              13
 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




                                                 14
 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


                                                         15
 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
                                                                  16
 DOSAGE COMPENSATION
• Most X-linked genes show dosage compensation
• Some X-linked genes do not
• Reasons for the difference are not understood




                                                  17
 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
                                                                        18
DOSAGE COMPENSATION




                      19
 DOSAGE COMPENSATION
• Dosage compensation is poorly understood in
  certain species
  – e.g., Birds and fish




                                                20
 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
                                                               21
 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




                                                      22
 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                             23
 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
                                           24
 DOSAGE COMPENSATION
• X chromosome inactivation
  – DNA in inactivated X chromosomes becomes highly
    compacted
     • A Barr body is formed
  – Most genes cannot be expressed




                                                      25
 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



                                                         26
 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




                                                     27
 DOSAGE COMPENSATION
Davidson, Nitowsky, and Childs (1963)
• Hypothesis
  – Heterozygous adult females should express only one
    enzyme in any particular somatic cell and its
    descendents




                                                         28
 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

                                          29
 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




                                       30
 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
                                                    31
 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)



                                                              32
 DOSAGE COMPENSATION
• Genetic control of X inactivation
  – Not entirely understood
  – X-inactivation center (Xic) is involved
     • Short region of the X chromosome




           » Skip details                     33
 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”



                                                         34
 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


                                                           35
 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
                                                                    36
 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
                                          37
 DOSAGE COMPENSATION
• Genomic imprinting
  – Permanent in the somatic cells of an animal
  – Can be altered from generation to generation




                                                   38
 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




                                               39
 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


                                                          40
 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




                                                                 41
 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


                                                                    42
 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




                                                           43
 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
                                            44
 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




                                                                    45
 DOSAGE COMPENSATION
• Genomic imprinting
  – Identified in several mammalian genes
  – Biological significance is unclear
  – Plays a role in the inheritance of some human diseases




                                                         46
EXTRANUCLEAR INHERITANCE
• Most genes are found in the cell’s 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”




                                                 47
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




                                                        48
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




                                                                     49
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




                                                        50
EXTRANUCLEAR INHERITANCE
• Most mitochondrial proteins are encoded by
  genes in the cell’s nucleus
  – Proteins are synthesized in the cytosol and transported
    into the mitochondria




                                                          51
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




                                                        52
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




                                                 53
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
                                                        54
EXTRANUCLEAR INHERITANCE
• Pigmentation in Mirabilis jalapa
  – The four-o’clock 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”


                                                                    55
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




                                                          56
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
                                                           57
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




                                                     58
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


                                                                  59
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”
                                                                  60
EXTRANUCLEAR INHERITANCE
• The inheritance pattern
  of mitochondria and
  plastids varies among
  different species




                            61
EXTRANUCLEAR INHERITANCE
• A few rare human diseases are caused by
  mitochondrial mutations
  – Display a strict maternal
    inheritance pattern




                                            62
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




                                                       63
EXTRANUCLEAR INHERITANCE
• Mitochondria and chloroplasts were once free-
  living bacteria
  – Engulfed and retained
    by early eukaryotes
  – Endosymbiosis




                                                  64
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
                                                          65
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




                                             66
EXTRANUCLEAR INHERITANCE
• Mitochondria were likely derived from gram-
  negative nonsulfur purple bacteria
  – Relationship enabled
    eukaryotes to produce
    larger amounts of ATP




                                                67
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




                                                           68
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



                                                                   69
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




                                                      70
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




                                                      71
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

                                                                       72
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



                                                   73
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




                                                                            74

				
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