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GENETIC PRINCIPLES
The birth and evolution of modern genetics
Dana King 1-22-14
Genetic Principles
•  Part I: Readings & Questions
•  Chapter 2: Mendel
•  Chapter 11: Mutation
•  The Chromosomes in Heredity (Sutton)
•  Part II: Genetics Refresher
•  Definitions
•  Meiosis
•  Pea crosses
Why are we talking about these guys?
q  I’ve taken one or two genetics courses. I’m down with the
chromosomes but I don’t expect my research to involve much
“classical” genetics.
My research has already involved some genetics. I like
cloning genes or knocking things out or knocking things
down. Genetics is cool.
q 
q  I could do forward/reverse screens in my sleep… with one
hand tied behind my back. Genetics is the BEST.
Part I: Mendel, Mutations, & Heredity
•  Mendel: The father of genetics
•  Model organism: Pisum et al.
•  Principles of segregation and recombination
•  Fisher’s criticisms: too good to be statistically true?
•  Muller: Mutation
•  Model organism: Drosophila
•  Determination of mutation rates using sex-linked lethals
•  A “one-hit” phenomenon
•  Sulston: Chromosomal theory of inheritance
•  Meiosis: unifying inheritance and chromosomes since 1903
•  Principle of independent assortment
Chapter 2: Mendel
•  Goal: To understand the principles of segregation and
independent assortment, as they were discovered by
Mendel.
•  Key points:
•  The scientific process isn’t perfect; Mendel tried several model
systems before defining heredity in Pisum.
•  Mendel’s insights were likely in part due to his excellent record
keeping.
•  Understanding the assumptions made in analyses is important (and
so is thinking about statistics)
1. Other model systems: the good, the
bad, & the ugly
A.  Hieracium: a poor choice because the seed is purely
maternal in origin so impossible to study segregation or
recombination
Mom x Dad = Kid always looks like mom
A.  Mirabilis: a poor choice because the flowers had too
many shades of color to separate (likely a complex trait)
For complex traits like human height, still don’t know all
the genes/loci that contribute to height.
2. Mendel: The groundbreaker
A.  Mendel employed three new procedures:
A.  Determined the number of forms of hybrid progeny
B.  Arranged these forms according to their generations
C.  Determined their statistical relations
B.  His approach was effective because:
A.  Developed a simple interpretation of the ratios obtained
B.  Carried out direct experiments to test this interpretation
3. Fisher’s criticisms
A.  Fisher criticizes Mendel’s ratios for being too close to
expectation.
B.  Fisher calculates that, according to sampling theory, the
chance of getting as close of a fit as reported by Mendel
for all of the data is only 1 out of 14,000 (.00007).
4. Future scientists to the rescue!
A.  Replications of Mendel’s experiments are in agreement with
expectation.
B.  The overall impression is that the results fit neither too well
nor too too poorly with expectation.
QUESTIONS?
Before we move on to the next sub-section…
Chapter 11: Mutation
•  Goal: To understand the contributions of early geneticists
to developing key genetic tools.
•  Key points:
•  One source of novel genetic variability are mutations.
•  Experimental design is key, especially for screens.
•  Early researchers demonstrate the power of quantitation.
•  Also: Muller à Muller’s morphs.
5. The origins of genes
A.  The first question in regards to the origins of genes was
if new genes arise (de novo mutations) or if all genetic
variability is pre-existing.
B.  The “presence & absence” hypothesis explained newly
arisen forms (phenotypes) as merely the result of gene
loss.
6. Pedigree and “class”
A.  The two classes of mutations that can be most easily
studied in diploid organisms are Dominant & Sex-linked.
B.  The detailed analysis of pedigreed material revealed
that mutation occurs in one gene, in one cell, and it can
occur at any stage of development.
7. Muller’s experimental design
A.  Muller’s experimental design established a quantitative
study of mutation with 1) an objective index and 2) a
class of mutations frequent enough to give statistically
significant values.
B.  The “ClB” chromosome made it possible to detect new
sex-linked lethals without counting or anesthetizing flies,
which meant more chromosomes could be tested and
adequate data on the frequency of the lethal
phenotypes could be collected.
Balancer Chromosomes
From Kile et al. 2003
8. Ionization vs. mutation rates
A.  The relationship between ionization and mutation rates
were determined to be direct and simple due to the
superimposability of the rate curves.
B.  This conclusion was reached by using lead shields of
different thicknesses and recording the ionization in
each treatment in the induction of lethal mutations in
Drosophila.
QUESTIONS?
Before we move on…
The Chromosomes in Heredity (1903)
•  Goal: To understand the connection between heritable
traits (ie: Mendel) and the physical vectors of these traits,
the chromosome, as discussed by Sutton himself.
•  Key points:
•  Physically of inheritance: connecting Mendel with meiosis
•  Logical deduction can get you a long way
•  Meiosis explains independent assortment and segregation, even
without defining a gene.
Remember Meiosis?
•  Synapsis: close
pairing of homologous
chromosomes to form
a bivalent; during
prophase I when
crossing over occurs.
•  Meiosis I: reduction
division… separation
of…
•  Meiosis II: separation
of…
9. Sutton’s thesis statement
A.  The stated purpose of the manuscript is devoted to the
detailed discussion of the relationship between study of
chromosomes in Brachystola and the conclusions
drawn from observations of plant hybrids by Mendel.
Brachystola spermatocytes
Pisum flower position
10. Parental purity & alternatives
A.  Parental purity is the concept that all maternal
chromosomes are passed to one pole and all paternal
chromosomes are passed to the other during meiosis,
such that all germ cells are either maternal or paternal
in origin.
B.  It predicts that no amount of cross breeding can
accomplish more than the first cross, that there can be
only four combinations in the offspring of a single set of
parents, and offspring cannot inherit chromosomes
(traits) from both paternal or both maternal
grandparents.
C.  The term is independent assortment; the position of the
chromosomes in the reducing division is purely a matter
of chance.
11. Chromosomes & Allelomorphs
A.  Sutton raises the possibility that allelomorphs
correspond to a part of a chromosome.
B.  He supports his hypothesis by arguing that this must be
true since otherwise the number of distinct
characteristics of an organism could not exceed the
number of chromosomes.
12. Non-Mendelian cases!
A.  The fourth class of non-Mendelian cases is Mosaics.
B.  Sutton hypothesizes that the underlying cause of
mosaicism is that one body of chromatin is active in one
group of cells while its homologue is active in another.
C.  We know that X-inactivation through epigenetic
silencing causes the mosaic fur patterns of calico cats.
QUESTIONS?
Then on to the genetics refresher!!
Part II: Genetics Refresher
•  Key areas covered:
•  Alleles and ploidy
•  Linkage
•  Comparative Genetics
•  Phenotyping
•  Epigenetics
•  Population Genetics
•  Plus:
•  Pea crosses
•  Meiosis
Allele Status & Ploidy:
A.  Homozygous- an
individual with two
identical alleles at a
locus
B.  Heterozygous- an
individual with two
different alleles at a
locus
C.  Aneuploidy- having
an abnormal number
of chromosomes
Genetic Linkage
D.  Linkage: the close
physical proximity
of two or more
genes.
E.  Linkage
disequilibrium:
the tendency for
two (or more)
alleles to be
inherited together.
Genetic Linkage
D.  Linkage: the close
physical proximity
of two or more
genes.
E.  Linkage
disequilibrium:
the tendency for
two (or more)
alleles to be
inherited together.
Comparative Genetics/Genomics
F.  Synteny: conservation of
blocks of order within two
chromosomes that are being
compared, usually between
species.
Characteristics of Phenotypes
Phenotype: a measurable trait.
G.  Expressivity: the degree to which a phenotype
is displayed in individuals of a given genotype.
•  “Hemingway cat”: Polydactyly in
cats has variable expressivity.
H.  Penetrance: the percentage of individuals of a
given genotype that display a phenotype.
•  BRCA1/BRCA2 and breast cancer risk
Characteristics of Phenotypes
I. 
Pleiotrophycontribution by a
single gene to more
than one phenotype.
J.  Epistasis-
interaction/
modification of a
gene by a gene at
another locus.
Epigenetic Inheritance
K.  Epigenetics: changes in gene production or regulation
produced through mechanisms acting independently of
changes in DNA sequence that are heritable (mitotically and/or
meiotically) and whose effects persist even after the
environmental stimulus is removed.
Imprinting: DNA methylation marks
preserved across generations.
Templating: DNA
methylation and
histone marks
preserved across
cell division.
Population Genetics
•  Study of variation in reproductive success
•  Gametic
•  Environmentally
induced
From Novembre et al. 2008
Population Genetics
L.  Inheritance- the
way in which genes
are passed to the
next generation
M.  Heritablity-
proportion of
parental phenotypic
variance passed on
genetically to the
offspring
Hardy-Weinberg Equilibrium
•  In a large population with random mating and no
disruptive circumstances, genotype and allele frequencies
will remain constant since they will remain in equilibrium.
•  Disruptive forces include: non-random mating, mutations, natural
selection, genetic drift, and gene flow between two population.
•  Described mathematically as:
p2 + 2pq + q2 = 1 Population Genetics
O.  Evolution: changes
in frequency of
alleles/characters in
a population over
time.
14. Monogenetic pea crosses
•  If (R) has a dominant
RR
“WT” red phenotype
then ratios would be:
rr
•  F1: all red flowers, (Rr)
Rr
R
R
r
r
genotype
•  F2: phenotypes are 3:1,
red:white flowers with
genotypes of 1(RR):2
(Rr): 1(rr)
14. Monogenetic pea crosses
•  If (R) has an
incomplete dominant
red phenotype then
ratios would be:
RR
rr
•  F1: all pink flowers, (Rr)
genotype
•  F2: phenotypes are
1:2:1, red:pink:white
flowers
Rr
R
R
r
r
QUESTIONS?
Mendelian inheritance & complex
phenotypes
•  Incomplete/semi-
dominance: when the
phenotype of the
heterozygote is
intermediate to the
phenotypes of each
homozygote
•  Snapdragon petal color
•  Codominance:
contributions from both
alleles visible in the
phenotype.
•  E.g. blood type alleles in
human.