XLinkage in Drosophila

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Chapter 4

• Part 2

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X-Linkage in Drosophila

• White mutation in eyes
• linked to sex of the parent carrying the mutation
• Wild-type red is dominant to white
• Reciprocal crosses did not show the same results
• F1 and F2 would have the same ratio regardless of
  who had the mutation
• white locus is on the X chromosome gene and
  trait are called X-linked
• females have 2 alleles because 2 Xs and no locus
  on the Y, will have only one X

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X-Linked Inheritance

• In males with no corresponding gene on Y means
  that gene on X chromosome leads directly to
  phenotype
• cannot be homo- or heterozygous for X-linked
  rather hemizygous
• X-linkage results in criss-cross pattern of
  inheritance
• Recessive X-linked genes are passed from
  homozygous mom to all sons sons are hemizygous
• all sons have the recessive allele

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Color Blindness

• Mom pass to all sons but not daughters
• Generation II marry normal vision person and
  have no color blind children
• Normal vision daughter will have normal vision
  daughters as well as normal and color blind sons

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Unusual Circumstances

• If X-linked disorder debilitates or is lethal to
  the affected individual prior to maturation
  occurs exclusively in males
• Females are carriers if heterozygous but dont
  express the disorder
• pass on to ½ sons and ½ daughters who are also
  carriers such as in Duchene Muscular Dystrophy
• occurs only in males

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Sex-Limited and Sex-Influenced Inheritance

• Individuals sex influences the phenotype
• Inheritance patterns affected by the sex of
  individual although not necessarily by the genes
  on the X chromosomes
• Sex limited specific phenotype is absolutely
  limited to one sex
• Sex influenced sex of an individual influences
  the expression of phenotype that is not limited
  to one sex or the other

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Neck and Tail Feathers in Fowl

• Different in males and females sex-limited
• Single pair of autosomal alleles is modified by
  sex hormones
• Hen feathers is due to dominant H allele, even hh
  homozygous females have short feathers but hh
  males have cock-feathering
• Some fowl have only HH alleles and have no visual
  difference in feathers between the sexes
• Also see in autosomal genes responsible for milk
  yield in dairy cattle , genes expressed only in
  females

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Sex-Influenced Inheritance

• Pattern baldness, horn formation in certain
  breeds of sheep and coat-color patterns in cattle
• Autosomal genes responsible for contrasting
  phenotype displayed by males and females
• expression of gene dependent on hormonal
  constitution of individuals
• heterozygous genotype has 1 phenotype in one sex
  and contrasting one in the other
• Pattern baldness hair thinning on the top of
  head
• BB bald in both sexes but more prevalent in
  males even if female BB, baldness is less
  prominent and later in life
• Bb no bald females, bald in males
• bb neither sex is bald

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Genetic Background and Environment

• Gene expression and resultant phenotype are often
  modified thru the interaction between the
  genotype of individual and external environment
• Penetrance and expressivity degree of
  expression of a particular trait can be studied
  quantitatively by determining penetrance/expressiv
  ity of the genotype under investigation

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Penetrance

• of individual show at least some degree of
  expression of a mutant genotype
• expression of mutant alleles in Drosophila can
  overlap wild-type
• 15 of mutations look like wild-type so gene has
  penetrance of 85

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Expressivity

• Reflects range of expression of mutant genotype
• Flies with recessive mutant eyeless gene range
  from normal eyes to small to absence of 1 or both
  eyes
• may be both genetics and environmental
  contributing to eyes in homozygous recessive
  eyeless flies

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Suppression and Position Effects

• Expression of other genes in genome may affect
  phenotype of gene under consideration
• genetic suppression mutant genes such as
  suppressor of sable, forked or hairy wing will
  completely or partially restore the normal
  phenotype in sable, forked or hairy, wing homo-
  or hemizygous mutations
• suppressor genes genetic background modifying
  primary gene effects
• position effect location of gene to other
  material may influence its expression
• portion of chromosomes relocated or rearranged
  normal expression of genes may change, especially
  if moved from normal area to an area of
  heterochromatin tightly coiled and inactive

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Temperature Effects

• Temperature can influence the phenotype
• Siamese cats and Himalayan rabbits have darker
  fur in areas where the body temperature is cooler
  ears, nose, paws
• pigment production functional in cooler areas but
  not at higher temperatures
• Conditional mutations mutations whose
  expression is affected by temp temperature
  sensitive mutations
• Mutant phenotype at 1st temperature and wild-type
  phenotype at 2nd temperature
• permissive condition gene functional at
  temperature
• restrictive condition gene nonfunctional

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Onset of Genetic Expression

• Different genes are expressed at different times
  prenatal, infant, teen, adult
• Some genetic diseases do not show up until the
  mutant genes are expressed
• Tay-Sachs autosomal recessive, defective lipid
  metabolism, do not see until infant is several
  months old
• Lesch-Nyhan Syndrome X-linked recessive,
  abnormal nucleic acid metabolism uric acid
  builds up, normal for the first 6-8 months
• Duchene muscular dystrophy X-linked recessive,
  muscular wasting, dont see until 3-5 years old,
  fatal by 20
• Huntington disease autosomal dominant, most
  age-variable, onset usually between 30-50 years
• All demonstrate that gene products play more
  essential roles at certain life stages, internal
  physiological environment changes with age

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Genetic Anticipation

• Heritable disorders that exhibit a progressively
  earlier age of onset and an increase of the
  severity of the disorder in each successive
  generation
• myotonic dystrophy (DM) adult muscular
  dystrophy, autosomal dominant, extreme variation
  in symptoms cataracts with no muscular weakness
  to extensive myopathy and mental retardation
  most extreme is death just after birth
• studied 61 parent-child pairs, 60 had worse
  symptoms than parent and earlier onset in
  children
• DM gene has region that repeats variable number
  of times, normal has 5 copies, mildly affected
  has 50 copies, severely affected gt1000 copies
• Not sure the function of the gene but see repeats
  in fragile-X syndrome, Kennedy disease and
  Huntington disease

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Genomic Imprinting

• Phenotype depends on silencing of one or the
  other of the gene pair following fertilization
  depending on parental origin of chromosome that
  contains that allele
• Certain chromosomal regions and genes in this
  region are imprinted dependent on origin either
  expressed or silenced
• Imprinting thought to occur before or during
  gamete formation leading to differentially marked
  genes
• not a mutation as it is reversible in subsequent
  generations mother to son to granddaughter

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Imprinting in Mice

• 3 specific mouse genes undergo imprinting
• Insulin-like growth factor 2
• 2 wt alleles normal size
• 2 mutant alleles dwarf size
• heterozygous mouse size depends on where the wt
  allele originates
• normal if wt from father but dwarf if from mother
• imprinted during egg formation but not during
  sperm formation

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Imprinting in Humans

• Differential imprinting of the same region of
  chromosome 15 deletion of an identical region
• Prader-Willi syndrome (PWS) when inherited thru
  sperm but called Angelman syndrome (AS) is
  inherited thru the egg
• PWS causes mental retardation, over-eating
  disorder marked by uncontrollable appetite,
  obesity and diabetes
• AS mental retardation, involuntary muscle
  contractions and seizures
• Both may be caused by methylation of bases in
  gene which will prevent transcription and
  necessary protein production

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Extranuclear Inheritance

• Important aspect of genetics and can also modify
  Mendelian patterns
• 2 cases of extranuclear genetic information
• DNA of mitochondria or chloroplasts organelle
  heredity
• genetic information expressed in the gamete of 1
  parent, usually mother, after fertilization
  zygote is influenced by gene products of only 1
  parent during development influenced by the
  genotype of the mother maternal effect

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Organelle Hereditary

• Before we knew DNA was in mitochondria not
  clear how transmission happened but it was in the
  cytoplasm
• usually from maternal parent thru ooplasm
  reciprocal cross varies
• Hard to study as requires both nuclear and
  organelle DNA gene products and many mitochondria
  and chloroplasts passed on to each progeny so if
  only 1 or 2 organelles have the mutation you may
  not see the phenotype
• heteroplasmy may lead to normal cells since the
  organelles lacking mutation provide basis of wt
  function

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Variation in 4-oclocks

• Found variant with white, variegated or green
  leaves
• Inheritance determined by ovule source
• if seeds from green branch all were gene leaves
  regardless of the source of pollen phenotype
  transmitted thru cytoplasm of maternal parent
  because pollen gives little or no cytoplasm to
  the zygote
• white is the mutant form of gene in chloroplasts

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Mitochondrial Mutations

• Transmitted thru the cytoplasm poky in
  Neurospoa (bread mold) and petite in
  Saccharomyces
• poky is a slow growing mutant associated with
  impaired mitochondrial mutations usually in
  cytochromes of the ETC
• extranuclear trait thru cytoplasm

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petite in Yeast - Saccharomyces

• Small colony size all have common
  characteristic deficiency in cellular
  respiration involving abnormal electron transport
  may use anaerobic fermentation to make energy
• small number of mutations caused by nuclear gene
  and follow the Mendelian numbers both nuclear
  and organelle gene products
• majority are cytoplasmic transmission
  mitochondrial DNA

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Mitochondrial Mutations - Human

• mtDNA has 16,569 nucleotides, 13 proteins for
  aerobic respiration, 22 tRNAs and 2 rRNAs
• 2 reasons mtDNA may be vulnerable to mutations
• mtDNA repair mechanisms not as good as nuclear
  DNA
• concentration of highly mutagenic free radicals
  accumulate in mitochondria likely to increase
  DNA mutations
• Usually have a mixture of normal and damaged
  mitochondria - heteroplasmy

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Criteria to Attribute to Mitochondrial Mutation

• Inheritance must exhibit a maternal rather than
  Mendelian pattern
• Disorder must reflect a deficiency in
  bioenergetic function of the organelle
• Must be specific genetic mutation in one or more
  of mitochondrial genes

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Myoclonic Epilepsy and Ragged-Red Fiber Disease
(MERRF)

• Both are maternal transmission only offspring
  of affected mother inherit as offspring of
  affected father are normal
• Ataxia lack of muscular coordination, deafness,
  dementia and epileptic seizures
• Muscle looks ragged-red due to aberrant
  mitochondria
• Heteroplasmy is present which probably keeps
  disease from being lethal

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Lebers Hereditary Optic Neuropathy

• Maternal inheritance, mitochondrial DNA lesions
  that result in sudden bilateral blindness at 27
  years old
• 4 mutations identified all disrupt oxidative
  phosphorylation
• gt50 are in NADH dehydrogenase
• transmitted maternally thru mitochondria
• many cases no family history sporadic (newly
  arising mutation in a population)

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Limnaea Coiling

• Situation where offsprings phenotype for a
  particular trait under control of gene products
  present in egg prior to fertilization
• Nuclear genes transcribed and gene products
  (protein or RNA) accumulate in egg after
  fertilization divided into new cells
  influencing patterns or traits established during
  early development
• Snails influenced by maternal genome
• left or sinistrally coiled shells are dd
• others are right or dextrally coilded and are DD
  or Dd

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Shell Coiling

• Snails are hermaphrodites and may undergo cross-
  or self-fertilization variety of mating
• True breeding snails progeny reveal phenotypes
  depend on genotype of female
• female is DD or Dd only dextrally coiled
  progeny
• female is dd only sinistrally coiled progeny
• Determined by genotype of parent producing the
  egg regardless of the phenotype of that parent

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Spindle Orientation

• Controlled by maternal genes acting on developing
  eggs in the ovary
• D right handed active gene product ooplasm
  from dextral egg injected into uncleaved
  sinistral eggs cleave in dextral pattern
• Sinistral ooplasm has no effect on dextral eggs
• allele results in inactive gene product
• Females either DD or Dd synthesize D gene product
  stored in ooplasm even if oocyte has only d and
  fertilized by d sperm you will still get
  dextrally division because of D product passes to
  gene