Beyond Mendel

1
Beyond Mendel

• Since Mendels work was rediscovered in the early
  1900s
• Researchers have studied the many ways genes
  influence an individuals phenotype
• These investigations are called neo-Mendelian
  genetics (neo from Greek for new)
• Chapter 4 examines types of inheritance observed
  by researchers that did not conform to the
  expected Mendelian ratios

2
Extensions of Mendelian Genetics

• How alleles affect phenotype
• Not always simple dominant/recessive issue
• Gene interaction
• Phenotype controlled by more than one gene
• Sex-linked genes (X-linkage in X/Y organisms)
• Phenotype can depend on more than genotype
• Environmental effects

3
Alleles

• Alleles are alternate forms of the same gene
• The allele occurring most frequently in a
  population (the normal allele) is called the
  wild-type (wt) allele
• Wt allele is usually dominant and is expressed as
  the wild-type phenotype
• Wt allele used as standard for comparison of
  all mutations (alternative alleles) of the
  gene/locus

4
Mutations

• Mutation
• Ultimate source of new alleles
• Genetic information is modified
• often (not always) produces altered gene product
• New phenotypes result from changes in functional
  activity of gene product
• Eliminating enzyme function
• Changing relative enzyme efficiency
• Changing overall enzyme function
• E.g. enzyme specificity

5
Allele Symbols

• For simple Mendelian traits
• 1st letter of recessive form
• Lowercase recessive allele
• Uppercase dominant allele
• Other systems Drosophila
• Use 1st letter of mutant allele (or combination
  of 2 or 3 letters) to name all alleles at this
  locus
• If trait is recessive, use lowercase uppercase
  if dominant
• Wild-type is indicated by the same letter (s),
  but with a superscript (e.g. Wr and Wr for
  wrinkled and wt wing alleles), or when using /,
  Wr/ for heterozygote

6
Drosophila Conventions (cont.)

• Example body color
• Ebony mutant phenotype is indicated by e
• Normal gray (wild-type) is indicated by e
• Three possible genotypes
• e/e gray homozygote (wild type)
• e/e gray heterozygote (wild type)
• e /e ebony homozygote (mutant)
• Or the above could be simple / /e and e/e

7
More Conventions

• The Drosophila system can be applied to other
  organisms as well
• When no allelic dominance, uppercase letters and
  superscripts designate alternate alleles
• R1 and R2, LM and LN
• There are other systems of genetic nomenclature
• leu - for bacteria with mutation blocking leucine
  biosynthesis
• BRCA1 for a human gene associated with inheritied
  risk of breast cancer

8
Incomplete Dominance

• Cross between two parents with contrasting traits
  
• Offspring with an intermediate phenotype
• incomplete or partial dominance
• Example red snapdragon crossed with white
  snapdragon
• F1 offspring have pink flowers
• F2 generation (Fig. 4.1), ¼ are red, ½ are pink,
  and ¼ are white
• Note phenotypic and genotypic ratios are the
  same
• Each genotype has its own phenotype

9
Incomplete Dominance

• red x white P1 generation
• pink F1
• 0.25/0.50/0.25 ratio of red/pink/white in the F2
  generation

10
Incomplete Dominance

• Clear-cut visual examples of incomplete
  dominance are relatively rare
• However, heterozygotes exhibiting wild-type
  phenotype may have intermediate level of gene
  expression
• Example Tay-Sachs disease
• Homozygous recessives die from fatal
  lipid-storage disorder, hexosaminidase activity
  absent
• Heterozygotes appear normal, but have ½ wt enzyme
  activity when compared to homozygous normal
  non-carriers
• Threshold effect

11
Codominance

• Codominance
• two alleles at a locus produce different and
  detectable gene products in heterozygote
• No dominance or recessiveness
• No blended phenotype (not incomplete dominance)
• Example MN blood group in humans
• Red blood cell glycoprotein surface antigen has
  two forms (M and N)
• An individual may exhibit either or both

12
Multiple Alleles

• Individuals can have up to two alleles for a
  single gene (diploid, homologous chromosomes)
• Multiple alleles applies when there are three or
  more alleles of the same gene in a population
• Any gene can be modified in multiple places/ways,
• each unique change produce a different allele
  (but not necessarily different phenotype)
• NOTE multiple alleles studied in populations,
  not individuals
• Classic example is human ABO blood groups

13
ABO Blood Groups

• Human ABO blood groups provide example of a
  multiple allele situation
• A and B antigens present on surface of blood
  cells (similar to MN blood group antigens)
• A and B antigens controlled by gene on chromosome
  9
• By 1924, studies of blood types of many families
  suggested that 3 alleles of a single gene were
  responsible for ABO phenotypes

14
Review of ABO blood groups

• Phenotype of individual determined by mixing
  blood sample with antiserum containing type A or
  type B antibodies
• Four possible phenotypes
• Person has A antigen only (A phenotype)
• Person has B antigen only (B phenotype)
• Person has both antigens (AB phenotype)
• Person has neither antigen (O phenotype)
• Sample crosses in Table 4.1
• Note that a cross of a type A person with a type
  B person can give offspring of all 4 possibilities

15
ABO Antigens

• H substance is possessed by all and is the
  precursor for both the A and B antigens
• A antigen has an added
• N-acetylgalactosamine
• B antigen has an added galactose

16
The Bombay Phenotype

• Woman typed as type O, but
• One parent has type AB blood and
• She is an obvious IB allele donor to two
  children
• Woman subsequently found to be homozygous FUT1 at
  the fucosyl transferase locus
• No fucose on H substance, no substrate to make A
  or B antigens
• Example of epistasis (more later)

17
Bombay Pedigree

• Family pedigree showing inheritance of Bombay
  allele

18
Multiple Alleles

• Although ABO blood types in humans is considered
  a classic example of multiple alleles, most all
  loci exhibit this phenomenon
• Eye color locus for Drosophila (Morgans famous
  white-eyed mutant) has over 100 known alleles

19
Lethal Alleles

• Many gene products are essential to survival of
  an organism
• Lethal alleles represent essential genes,
  lethal in homozygous state
• Time of death is dependent upon when the gene
  product is essential to development
• Loss of function alleles can be recessive lethal
  (often are)
• Heterozygotes may tolerate a non-functional
  mutant allele if wt allele produces sufficient
  product for organism survival
• Sometimes recessive lethal are still dominant
  with respect to phenotype

20
Lethal Alleles

• Example agouti (coat color) in mice
• agouti x agouti ? all agouti
• yellow x yellow ? 2/3 yellow, 1/3 agouti
• agouti x yellow ? ½ yellow, ½ agouti
• Explanation mutant yellow dominant over wt
  agouti and homozygous agouti lethal. Mutant
  allele always on (gain of function), deletion
  actually affects neighboring essential gene

21
Agouti Allele
22
Lethal Dominant Mutations

• Both homozygous and heterozygous states are
  lethal
• Generally very rare
• Example Huntington disease (humans)
• Nervous and motor system degeneration
• Commonly begins to be exhibited after age forty
  (but can be much earlier)
• Children already born
• Afflicted persons are heterozygous (Hh)

23
Crosses of Two Gene Pairs with Different Modes of
Inheritance

• E.g. autosomal recessive locus with a codominance
  locus
• Remember although the 9331 ratio will be
  altered, all unlinked loci will still follow
  Mendels principle of independent assortment
• Regular Punnett square and determine phenotypes
  individually or forked method

24
Dihybrid cross with two loci having different
patterns of inheritance
25
Epigenesis

• Many phenotypes affected/controlled by more than
  one gene
• gene interaction (occurs at many levels for
  many reasons)
• Epigenesis
• Development is a cascade of events
• Each ensuing step of development increases the
  complexity of the organ and is under the
  control/influence of many genes

26
Epistasis

• Epistasis
• The effect of one gene pair (locus) masks or
  modifies the effect of another gene pair
• Examples
• Recessive alleles at one locus override
  expression of alleles at another locus. Alleles
  at 1st locus are said to be epistatic to the
  masked hypostatic alleles at the 2nd locus
• Allele(s) at one locus may require specific
  allele at another locus, these pairs are said to
  complement each other
• The FUTI allele and ABO phenotype is an example
  of epistasis

27
FUTI and ABO Phenotype
28
Analyzing Other Unique Inheritance Patterns

• Assumptions/conventions
• In each case distinct phenotypes are produced
  (discontinuous variation)
• Genes are not linked
• Complete dominance at any locus, unknown
  genotypes of dominant phenotypes recorded as A-
  or B- (AA or Aa, BB or Bb)
• All P1 crosses involve homozygous individuals
• F2 phenotypes are 9/16 A-B-, 3/16 A-bb, 3/16aaB-
  and 1/16 aabb (dominance makes genotypes in group
  phenotypically equivalent)

29
Coat Color in Mice

• Agouti (A) is wt and caused by alternating bands
  of pigment on each hair
• Black (a) is recessive to agouti
• B locus mutation (recessive, b) can eliminate all
  color
• Albino (bb) and A locus doesnt count

30
Coat Color in Mice

• Cross agouti (AABB) and albino (aabb) mice
• F1 are all agouti (AaBb)
• F2 progeny have 9331 ratio but
• 9/16 have genotype of A-B- and are agouti
• 3/16 are A-bb and are albino (make pigment, no
  B)
• 3/16 are aaB- and are black
• 1/16 are aabb and are albino (no pigment, no B)
• Final phenotypic ratio is 943
• Explanation.

31
One Explanation for Epistasis

• Colorless precursor converted to back pigment by
  wt B gene product
• Black pigment deposited to hair in agouti pattern
  by gene A product
• Since a recessive allele at one locus (b)
  masks/supresses the expression of the dominant
  allele at another locus this is called recessive
  epistasis

32
Dominant Epistasis

• Dominant allele at one locus suppresses/masks
  expression of alleles at another locus
• Example fruit color in summer squash
• Allele A is dominant and gives white fruit
• If aa, Bb/BB gives yellow, bb gives green
• Cross AABB with aabb, F2 is AaBb, cross F2
• Final phenotypic ration is 12 white, 3 yellow and
  1 green (see figure 4-7 and analyze to see why)

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34
White-flowered Sweet Peas

• Complementary gene interaction
• Must have at least one dominant allele at each
  locus (A-B-) to have the phenotype
• Cross two white-flowered peas
• all F1 are purple
• F2 was 9/16 purple, 7/16 white
• Explanation multiple enzyme pathway
• Precursor converted to intermediate by Gene A
  product
• Intermediate converted to purple pigment by Gene
  B product

35
Fruit Shape in Summer Squash

• Disk-shaped fruit (AABB) crossed with long fruit
  (aabb)
• F1 is all disc-shaped fruit
• F2 includes both parental phenotypes plus
  spherical variants in 961 ratio
• 9/16 A-B- disc
• 3/16 A-bb sphere, 3/16 aaB- sphere
• 1/16 aabb long
• Disc requires dominant alleles at both loci,
  sphere requires a dominant allele at one/either
  locus and no dominant alleles at either locus
  give long

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Eye Color in Drosophila

• Wt color is brick red
• Cross two autosomal recessive mutants (brown and
  scarlet)
• F1 is wt color
• F2 has wild scarlet brown and white in a 9331
  ratio
• Mendelian ratio but only one character involved
  (eye color)
• Explanation
• Wt is two pigments deposited into compound eye
• Brown mutant and scarlet mutant are blocked in
  respective pigment pathways
• Both pathways blocked yields white eyes

38
Epistasis and Drosophila Eye Color
39
Modified Dihybrid F2 Ratios
40
Modified Ratios

• Note that although many ratios are possible for
  the dihybrid crosses, in all cases segregation
  and independent assortment rules are not violated
• Genotypic ratios remain the same and therefore
  phenotypic ratios expressed in 1/16ths as before
• What changes is how you convert genotypes to
  phenotypes

41
Pleiotrophy

• One gene has effect(s) on multiple phenotypes
• Many examples
• Cystic fibrosis
• Marfan syndrome
• Porphyria variegata
• Cannot metabolize porphyrin, deep red urine
• Becomes toxic to brain (also abdominal pain
  muscular weakness fever insomnia headaches vision
  problems, delerium, etc.)
• King George III of England (U.S. Revolution) may
  have suffered from condition

42
Chromosome-based Sex Determination

• X,Y system used for sex determination by many
  animal and plant species
• X is a large chromosome and encodes many genes
• Y is a small chromosome with few genes (not
  homologous to X in the traditional sense but has
  pairing region for synapsis)
• Males therefore have a single copy of genes
  encoded by the X chromosome, hemizygous
• These genes have unique inheritance/expression
  properties resulting from their X-linkage

43
X-linkage in Drosophila

• First documented by Thomas Morgan, 1910
• White-eyed mutant
• Inheritance pattern clearly related to sex of
  parent carrying allele and offspring
• See figure 4-11

44
Inheritance of White-eyed Trait

• Results depend of sex of red and white-eyed
  members of P generation
• In each case ½ of F1 is red and ½ is white (but
  all red are female and white are male)
• F2 results also sex-dependent

45
X-linkage and Chromosomes
46
X-linkage and Humans

• Many traits controlled by X chromosome-linked
  traits
• Red/green color blindness is classic example
• Numerous significant genetic-based diseases
• Only females are carriers of recessive alleles
• Males are hemizygous

47
Pedigree
Likely Genotypes
48
Sex-based Influences On Phenotype

• Sex-limited inheritance
• Specific phenotype limited to one sex
• Sex-influenced inheritance
• Sex influences expression of phenotype but not
  limited to one sex or another
• Known examples are autosomally-encoded by
  expression is dependent upon hormone constitution
  of individual (sex)

49
Fowl Feathering

• Cock feathering is longer, more curved and
  pointed
• Hen feathering is shorter and more rounded
• Inheritance of this phenotype is controlled by a
  pair of alleles (H and h) at a single autosomal
  locus
• But actual expression can be modified by the
  individuals sex hormones
• HH male hen feathered HH female hen
  feathered
• Hh male hen feathered Hh female hen
  feathered
• hh male cock feathered hh female hen
  feathered
• H is dominant over h, h only expressed in males,
  some populations fixed for one or the other
  allele,

50
Other Sex-limited and Sex-influenced Inheritance

• Autosomal genes responsible for milk yield in
  dairy cattle are sex limited
• Independent of genotype, bulls give no milk
• Pattern baldness in humans and horn formation in
  Dorsett Horn sheep is sex-influenced
• E.g. in BB women hair loss is reduced and occurs
  later than in BB men, Bb women generally not
  affected

51
Phenotype Is Not Always a Direct Reflection of
Genotype

• Penetrance the percentage of individuals that
  show at least some degree of expression of the
  mutant genotype
• Partial penetrance
• Expressivity the range of expression of the
  mutant phenotype (see Fig. 4-16)
• Can be the result of either or both genetic
  background differences or environmental effects

52
Expressivity

• Eyeless mutation in Drosophila
• Reduces eye size from a partial reduction to
  complete elimination (average 0.25 to 0.50)

53
Genetic Background Effects

• Genetic suppression mutant allele at a locus
  partially or completely restores the wt phenotype
  of another locus homozygous (or hemizygous) for a
  mutant allele
• Position effect the physical location of a gene
  influences its expression (relative position to
  other genetic material
• Translocations or inversions
• Heterochromatin effects

54
Position Effect

• (a) female heterozygote for white eye genotype
  showing normal dominant phenotype
• (b) chromosomal rearrangement leading to
  variegated effect (also female heterozygote for
  white eye)

55
Environmental Effects

• Temperature effects
• Evening primrose produces red flowers at 23C and
  white flowers at 18C
• Siamese cats and Himalayan rabbits have darker
  fur on cooler areas of body (tail, feet, ears)
• Enzymes lose catalytic function at higher
  temperature
• Temperature sensitive mutations
• Mutant allele only expressed (phenotype) at
  generally lower temperature
• ts phage mutants, restrictive and permissive
  temperatures
• Heat-shock genes

56
Nutritional Effects

• Nutritional mutations
• Prevent synthesis of nutrient molecules
• Auxotrophs
• Phenotype expressed or not depending upon the
  diet
• Phenylketonuria
• Loss of enzyme to metabolize phenylalanine
• Severe problems unless low Phe diet
• Galactosemia (very bad again) and lactose
  intolerance (unpleasant)

57
Delayed Onset of Phenotypic Expression

• Tay-Sachs disease
• Autosomal recessive
• Hexosaminidase A, lipid metabolism, baby normal
  for a few months, dies by age 3
• Lesch-Nyhan syndrome
• X-linked recessive
• Purine salvage enzyme defect (HGPRTase)
• Normal for about 6 months, then
• Duchene muscular dystrophy
• X-linked recessive
• Diagnosed 3-5 years old

58
Delayed Onset - Dominant

• Huntington disease
• Autosomal dominant
• Progressive cell death in brain, generally over
  10 year period, ultimately lethal
• Onset commonly between age 30-50 (mean age of 38)

59
Genetic Anticipation

• Genetic anticipation
• Phenotype exhibits a progressively earlier age of
  onset and increased severity with each successive
  generation
• Myotonic dystrophy
• Autosomal Dominant
• Most common type of adult muscular dystrophy
• Trinucleotide expansion, 5-35 copies normal,
  35-150 somewhat affected, 1500 severely affected
• Number of repeats increases with each generation
• Fragile X and Huntington disease also show
  correlation between number of repeats and severity

60
Genetic Imprinting

• Genomic or parental imprinting - phenotypic
  expression depends upon the parental origin of
  the chromosome carrying the particular allele
• Certain chromosomal regions imprinted during
  gametogenesis
• Methylation of CpG or CpG islands (5meC produced)
• Prader-Willi and Angelman syndromes
• Different/unique phenotypes
• Both loci in 15q1 region
• One maternally-imprinted, other
  paternally-imprinted
• Uniparental disomy