Transmission (Classical, Mendelian) Genetics Ch 11

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Transmission (Classical, Mendelian) Genetics Ch
11

• Gregor Mendel
• Experiments in Plant Hybridization, 1865
• Simple, controlled, data collection, mathematical
  analysis

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Pisum sativum, the garden pea

• What makes this a good model organism?
• easy to grow
• hundreds of offspring per cross
• short generation time
• can self fertilize or cross
• Paint pollen (sperm) from one plant onto the
  female parts of another (emasculated)
• parental plants true breeding strains

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Genes and alleles of Pisum sativum

• Gene Alleles
• Pea color ?
• Flower color white, purple
• Pod shape constricted, inflated
• Pea surface ?
• Stem height tall, dwarf

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I. Monohybrid cross
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Mendels results from the monohybrid cross

• F2 787 long 277short PHENOTYPES
• Ratio tall/dwarf
• 4 Conclusions
• Genes discrete units passed on from parent to
  offspring
• A dominant allele masks expression of recessive
  allele
• Unit factors in pairs- each gene has 2 alleles
• why?

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Genotypes

• Homozygous dominant
• Heterozygous
• Homozygous recessive

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• 4. Random segregation
• gamete receives ONE allele per gene
• random segregation of alleles 50/50
• Humans

• Sperm egg fertilized egg
• 23 chromosomes ?
• 1 set alleles 1 set ?
• haploid haploid ?

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Summing it up

• Sperm and egg (gametes) are haploid.
• Each contains half the genes, or one allele for
  each gene
• When sperm and egg unite, organism formed is
  diploid
• 2 alleles per gene

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More results of Mendels monohybrid crosses

• Parental Strains F2 progeny Ratio
• Tall X dwarf 787 tall, 277 dwarf
• Round seeds X wrinkled 5474 round, 1850 wrinkled
• Yellow seeds X green 6022 yellow, 2001 green
• Violet flowers X white 705 violet, 224 white
• Inflated pods X constricted 882 inflated, 299
  constricted
• Green pods X yellow 428 green, 152 yellow
• Axial flowers X terminal 651 axial, 207 terminal
• gene ?
• alleles ?

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II. Test cross (one gene)

• mouse Z has black fur, what are its 2 possible
  genotypes?
• Test cross mouse Z to homozygous recessive
  mouse
• Z was test crossed and 6 offspring were black 2
  were white. What is Zs genotype?

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Autosomal recessive inheritance (bb)

• unaffected parents can have affected offspring
• affected progeny male, female
• May skip a generation
• Two affected parents cannot have an unaffected
  child

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Phenylketonuria pp (Ch. 4 pg 73)

• PKU (1/12,000) Mutation in gene encoding
  phenylalanine hydroxylase enzyme needed for phe
  metabolism

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missing phenylalanine hydroxylase enzyme
If plasma phe level is too high, phe is
converted into a phenylpyruvate toxic to brain
tissue
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Pleiotropic effects no tyrosine (little
melanin) slow growth retardation blue
eyes low adrenaline
) No nutrasweet low phe diet (5K/yr
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Page 68
1902 Archibald Garrod One gene one
enzyme Inborn errors of metabolism PKU Albinism
Alkaptonuria Tyrosinemia
Black urine arthritis
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One gene/one enzyme

• Garrods work on alkaptonuria
• Inborn Errors of Metabolism 1902
• Autosomal recessive metabolic disease

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All people have harmful recessive alleles, small
chance That 2 people with same rare alleles will
mate Consanguinous marriage increases the chance
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Fill in genotypes. If II,1 and II, 4 mate, what
is the chance of offspring having PKU?
How do we know this is autosomal recessive?

• II, 1 X II, 4 p(aa)
• p(aa AND a girl)?

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If III-3 and II-1 mate p (normal child)
p (affected boy)?
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Autosomal dominant disordersAa and AA are
affectedaa is unaffected

• Tend to show up in every generation
• 2 affected parents can have unaffected child
• 2 unaffected parents cannot have an affected child

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Dominant pedigree
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Achondroplasia -1/20,000 births

• Mutation in one allele of FGFR3 gene Chromosome 4
• Affects cartilage growth needed for bone
  lengthening
• Most affected individuals are Aa why?
• Most cases are spontaneous aa X aa
• Pg. 291

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P(III, 3 and III, 5 have a child of normal height)
P ( II, 3 and III, 7 have a boy with
achondroplasia)
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Fruit fly nomenclature pg 317 box 12.1

• Red eyes is normal phenotype, brown is mutant
• bw wildtype allele
• bw brown allele
• genotype phenotype

red brown
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• Try it
• Wingless is recessive mutant (wg allele)
• Genotype of wildtype, heterozygote, mutant?

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Sex-linked genes Ch 12 pg 314 317, 326 - 328

• Human Female XX
• two alleles for each X-linked gene
• normal application of recessive and dominance
• XHXH
• XHXh
• XhXh

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• Human Male XY
• XHY
• XhY

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Sex-linked genes

• Most on X chromosome
• Hemophilia (recessive) 1/5000 males
• Mutation in gene for clotting factor

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• Mate III 13 with III 1 Probability of a
  hemophiliac son?
• Mate IV 2 with homozygous normal female p
  (hemophilia)?

Criss cross inheritance of X linked traits
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w wildtype allele w white allele X-linked
recessive
The mutant fruit fly discovered by Thomas Hunt
Morgan
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• A white-eyed female is crossed with a red- eyed
  male. An F1 female from this cross is mated with
  her father and an F1 male is mated with his
  mother. What will be the eye color of the
  offspring of these two crosses?

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Dihybrid cross 2 genes

• Mendels Law of Independent assortment - each
  allele for a trait is inherited independently of
  other alleles
• Seeds
• G yellow allele g green allele
  gene?
• W round allele w wrinkled allele gene?

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Parents GGWW X
ggwwphenotype?Gametes?

• F1 genotype ?
• F1 phenotype ?
• F1 Gametes?

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• Forked line method for phenotypes
• GgWw X GgWw

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Probability

• Product rule-
• the probability that two outcomes occur
  simultaneously is product of their individual
  probabilities
• assumes independent assortment of genes
• GgWw X GgWw
• What is the probability of a yellow AND wrinkled?
  
• p(G-ww)
• ¾ X ¼ 3/16

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Trihybrid cross

• AaBbCc X AaBbCc
• p(A-B-cc)
• AabbCcDD X AaBbCcDd
• p(triply recessive)

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Modified Mendelian Ratios

• 1. INCOMPLETE DOMINANCE
• R red flower (snapdragon)
• R white flower
• allele symbols do not connote dominance
• phenotypic ratio genotypic ratio ?
• P CrCr X CwCw
• F1
• F2

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Incomplete dominance
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2. Codominance

• Each allele encodes separate gene
• product distinct in phenotype of heterozygote
• L gene for human blood cell surface protein
• LM M antigen
• LN N antigen

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• A man with the M bloodtype has a child with a
  woman of the MN bloodtype
• Expected ratio of offspring?

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3. Multiple alleles (more than 2 alleles for gene
in population)

• Example Blood Groups Karl Landsteiner 1900s

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• ABO blood system polymorphic I gene
• Blood type genotype
• A IAIA or IAi
• B IBIB or IBi
• AB ?
• O ii
• What is the mechanism of inheritance of A, B, AB,
  O?
• Autosomal or sex chromosome?

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Example

• A child has type O blood. The mother of the child
  has Type B blood. What could the blood types of
  the father be?

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4. Dominance series C series/ rabbits

• c full color
• cch chinchilla (hypomorphic)
• ch himalayan (hypomorphic)
• c albino (apomorphic allele nonfunctional)

Himalayan Albino
Chinchilla
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• Genotype phenotype?
• cch cch
• cch ch
• ch c
• c cch
• c full color
• cch chinchilla (hypomorphic)
• ch himalayan (hypomorphic)
• c albino (apomorphic allele nonfunctional)

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5. Lethal alleles

• MM normal spine
• MM manx cat (no tail)
• MM lethal

Cross two manx, what is ratio of phenotypes in
offspring? How do breeders obtain manx cats?
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6. Epistasis- gene product interactions. Table
13.4 page 355 (look at 4 phenotypic classes and
fewer than 4)

• A product of one gene influences, or masks, the
  expression of another gene(s)
• Modification of dihybrid cross ratio
• AaBb X AaBb 9331

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Epistasis in Cats

• W white w not white
• B black b brown
• Mate 2 heterozygous cats
• What is the expected ratio?

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Epistasis in labrador retrievers

• B and E color genes (labs)
• B black b brown
• E color e no color (yellow)
• ee is epistatic
• Cross two double heterozygotes
• Phenotypes of parents?
• Phenotypes of offspring? ratio?

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7. Penetrance
Polydactyly, dominant

• individuals that exhibit phenotype
  corresponding to genotype

Pp pp
5,5 6, 5
6, 6
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8. Expressivity (ex. Piebald spotting) the
extent to which a trait is exhibitedosteogenesis
imperfecta pg. 359
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Penetrance AND expressivity

• NF-1 Neurofibromatosis1
• (1/4000, 17q11.2)
• (350 kb gene, 60 exons)
• Autosomal dominant trait N-
• (in many its a spontaneous mutation)
• 50 80 penetrance
• Expressivity
• Pigmented skin to tumors on nerve CT coverings
  (neurofibromas) on skin, eyes, organs, face
• Speech, blood pressure, spine curvature, headaches

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9. Quantitative (multifactorial) traits

• Vary continuously
• Weight, height, IQ

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Gene expression also affected by

• Sex (baldness)
• Temperature (melanin in Siamese cats)
• Chemicals (PKU)
• Diet (height, cancer)
• many other factors!

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Chromosome Theory of Inheritance

• 1902 Sutton and Boveri
• A chromosome is a linkage group of Mendelian
  factors (GENES)
• 1920s Morgan et al.
• Genes are in a linear sequence on the
  chromosomes, they can be mapped

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Chromosomes in most animals

• pairs of autosomes
• 1 pair sex chromosomes
• XY heterogametic
• XX homogametic

Human karyotype -gt
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Do more chromosomes mean more intelligence?

• Human 46
• Chimpanzee 48
• Dog 78
• Cat 72
• Alligator 32
• Goldfish 94
• Mosquito 6
• Potato 48
• Bakers yeast 34

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I. Mammalian sex determination the Y system

• A. Embryo is neither male nor female
• Week 7

How does embryo know to become male?
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XY embryo sex chromosomes

• The Y determines sex. XY male XX female

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B. SRY gene encodes TDF (Testes determining
factor, 1990)

• SRY (sex determining region Y)
• TDF stimulates the growth of testes --gt
• testosterone ---gt sperm ducts, male brain
  sensitization

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XX males If SRY crosses over to the X chromosome
during meiosis (formation of sperm)
Father during meiosis
X from father X from mother
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3. Experiments with transgenic mice
XX males
Add SRY DNA to female mouse embryo
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• A 17 year old female presented with streak
  ovaries, no uterus, no menstrual cycle
• XY female
• Embryo has Y chromosome but does not develop as
  male
• Mutation in SRY ? ?

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II. Other sex determination systems

• A. Drosophila
• Ratio of X to sets of autosomes
• embryo calculates ratio
• X/A 1 or gt1 ------gt female
• X/A 0.5 or lt0.5 --------gt male
• X/A between 0.5 and 1 ---gt intersex

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• What is the sex of an XY fly with 2 sets of
  autosomes?
• 1X/2A 0.5 male
• What is the sex of a fly with with 2 sets of
  autosomes but 1 X chromosome
• 1X/2A 0.5 male
• What is the sex of a triploid fly with 2 X
  chromosomes?
• 2X/3A 0.66 intersex

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B. ZW system - birds

• Females are ZW
• (heterogametic)
• Males are ZZ (homogametic)

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C.Temperature sex determination (TSD)

• In some reptiles sex is not determined
  genetically!
• (Varies widely)
• majority of endangered reptiles use TSD - sea
  turtles, Galapagos tortoises, alligators,
  crocodiles
• sex determined during mid-trimester of
  development by T of incubation

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IV. Dosage Compensation (mammals)

• Females have 2 Xs, males have 1 X. Do females
  have an extra dose of X-linked genes/alleles?

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X chromosome inactivation Lyon, 1961

• Observe dense Barr body at edge of nucleus
• in female cells
• Heterochromatic (stains darker)

Male cell female cell cell with 2 Barr bodies
Number of X chromosomes?
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Female mosaics

• All females heterozygous for X-linked traits are
  mosaics for those traits.
• red/green colorblindness XCXc
• phenotype ?
• Look at retina of heterozygous female

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Anhydrotic ectodermal dysplasiaXAXa females
XaY males

• Tooth nail
• abnormalities, life
• threatening hyperthermia,
• sparse hair

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• Most genes on Y are for development and fertility

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Chromosomal Abnormalities

• KARYOTYPE
• Obtain white blood cells from or fetal cells
  from amniotic fluid
• Detects number of chromosomes,
• sex, chromosomal abnormalities

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Amniocentesis usually done week 14
Karyotype and analyze fluid for enzyme defects

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Chorionic villus sample (CVS) usually done week 8
More risk, but earlier results
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• Arrange in pairs according to
• decreasing size
• centromere position
• banding pattern

METACENTRIC
SUBMETACENTRIC
ACROCENTRIC
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metacentric (1) submetacentric (9)
p arm is the upper, shorter arm
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Normalmale
46, XY Which are meta-, submeta- acrocentric?
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Aneuploidy (versus euploidy)

• Trisomy (not triploid)
• 47, 21

21 may be small, but contains 33,546,361 bp of
DNA!
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Down Syndrome (J. Langdon H. Down, 1866)

• effects
• Developmental delays
• Possible heart defects, hearing loss, hypotonia,
  thyroid problems, obesity
• Epicanthic eye folds
• Wide tongues
• Greater risk of Alzheimers

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Trisomy 13 (Patau)

• Fatallt 1 year (usually)
• Deaf, blind, clyclopia, polydactly, cleft palate
• 1/5000 live births

47, XY, 13
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47, XY, 18 (Edwards)

• lt few months1/5000 live births

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Human trisomies of the sex chromosomes (see pg
293)

• 47, XXY Klinefelters
• 47, XXX
• 47, XYY

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Monosomy (only 1 viable in humans!)

• 45 X,
• Turner Syndrome (1/2000 live births)
• Partial monosomy 46, 5p-
• Cri du Chat
• Arises due to a deletion on the short arm of
  chromosome 5

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Cri du Chat 46, 5p-

• pseudodominance for deleted region
• Microcephaly, myotonia, cry of cat, retardation

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Somatic mosaics

• More than one genetically distinct population of
  cells in an individual (like random X
  inactivation)
• Example 46XX embryo, one cell loses an X
• ---? 46,XX/45X mosaic
• Symptoms less severe than the standard Turners
  syndrome

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Polyploidy extra SETS of chromosomes

• in humans
• Triploid, tetraploid
• Octoploid etc..

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• Many plants are polyploid
• Some bees and wasps are monoploid

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Deletions (del)

• can observe large ones by karyotype
• If centromere is lost, then chromosome will be
  lost
• Heat, chemicals, radiation
• Unequal crossing over during meiosis

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46,XX,del(7)(q21.12,q21.2)

• Pseudodominance
• Lethal if both chromosomes

Leads to problems during meiosis
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Duplications

• segment of a chromosome doubles
• May be tandem or reverse
• problems during meiosis

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dup(5)(qter-gtq33.1p15.3-gtqter)

• Sample of cord blood from stillborn male with
  anencephaly

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• Inversions (inv)
• 180o turnaround of segment
• no loss of genetic material
• may change length ratio of p/q arms
• Position effect
• change in gene position with respect to
  centromere
• being near heterochromatic region may influence
  expression

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Translocations - segment moves to other
chromosome - interstitial or reciprocal exchange

• t (1314)
• Individual has all genetic material, but what
  about gametes?

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t(1113) (q21q14.3)

• the parent who has the translocation is
  phenotypically normal as all genetic info is
  present
• The gametes, however, are not as evidence by
  multiple miscarriages