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3
The Chromosomal Basis
of Heredity
Human Chromosomes
• Humans have 46 chromosomes organized
as 23 pairs which are homologous
because each pair contains the same
genes
• Humans are genetically diploid = 2 copies
of each chromosome , except for the sex
chromosomes (X+Y) which are nonidentical
Mammalian Cell Cycle
• Cell division cycles occur in stages:
- G1 = pre-DNA synthesis
- S = DNA synthesis
- G2 = post-DNA synthesis
- M = mitosis:
cell division occurs
by precise steps
which distribute
one set of
chromosomes to
each of two cells
Stages of Mitosis
• Occurs in dividing
somatic cells
• Chromosome replication:
exact duplicates = sister
chromatids attached at
centromere
• Prophase- chromosomes
are visible, spindle fibers
organize and attach to
chromosomes at kinetochore
Stages of Mitosis
• Metaphase- chromosomes line up in
center of cell = metaphase plate
• Anaphase - sister chromatids separate:
one member of each pair is pulled to
either pole of the cell
• Telophase - nuclei of two new cells
reorganize; the cells are diploid = each
contains both members of every pair of
chromosomes
• Mitosis is usually accompanied by
cytokinesis = cytoplasmic division
Meiosis
• Meiosis is a specialized type
of cell division which occurs
only in reproductive cells =
germ cells
• Two rounds of cell division
result in the formation of
gametes which are genetically
haploid = contain only one
copy of each pair of
homologous chromosomes
Meiosis: First Division
Meiosis occurs in specialized cells called
meiocytes in stages and requires two cell
division events:
First Meiotic Division:
- chromosomes duplicate in S phase
- homologous chromosomes pair
- homologous chromosomes separate and
are pulled to either pole of the cell at
anaphase
Meiosis: Second Division
• Each daughter cell contains only one
member of each homologous pair of
chromosomes after meiosis I
• Second Meiotic Division:
- cell division occurs in the absence of
chromosome duplication
- sister chromatids separate at anaphase
as in mitotic division
Meiotic vs. Mitotic Division
• Meiosis produces four cells, each of
which contains one copy of each pair of
homologous chromosomes = genetically
haploid
• Mitosis produces two cells which contain
both members of each pair of homologous
chromosomes = genetically diploid
Meiosis I: Stages
• Prophase - unique process of genetic
recombination occurs
- homologous chromosomes pair = synapsis
- physical
exchange of
genetic material
occurs between
homologous
chromosomes
- chiasmata =
linkage points
Prophase I: Meiosis
• Leptotene - chromosome condensation
• Zygotene - pairing (synapsis) of
homologous chromosomes=bivalent
• Pachytene - crossing-over between
homologous chromosomes occurs
• Diplotene - chromosome repulsion
• Diakinesis- maximum chromosome
contraction
Independent Assortment
• Random alignment of homologous
chromosomes during metaphase I results
in independent assortment of nonhomologous chromosomes
• This occurs because
the genetic elements
on non-homologous
chromosomes are
unlinked = inherited
as separate physical
units
Meiosis I
• Metaphase I - homologous chromosomes
line up at metaphase plate; random
alignment of non-homologous
chromosomes is basis of Law of
Independent Assortment
• Anaphase I - physical separation of
homologous chromosomes to opposite
poles of spindle-demonstrates Law of
Segregation;
Meiosis I and II
• Telophase I - spindle breaks down, nuclear
reorganization; one homolog from each
bivalent is at each pole
• Second Meiotic Division occurs in
absence of chromosome replication
• Meiosis II = equational division as the
number of chromosomes in each cell
remains constant
Meiosis II
• Meiosis II consists of prophase II,
metaphase II, anaphase II and telophase II
which are identical to the stages of
mitosis
• Anaphase II - sister chromatids of each
chromosome separate
• Telophase II - each cell contains haploid
chromosome number, one member of
each homologous pair
Chromosome Structure
• Eukaryotic chromosomes are highly
coiled complexes of DNA and protein
• Chromosome size is measured in kb=
kilobase pairs; 1 kb=1,000 base pairs; 1
Mb (megabase) = 1 million bp
• Chromosome-sized DNA molecules can be
separated by electrophoresis in which
DNA molecules move in response to
electric field
Chromatin Structure
• Chromatin is a stable,
ordered complex of DNA
and protein
• Histones = major class
of basic proteins in
chromatin fibers
• Five major types of histones are found in
chromatin:
H1, H2A, H2B, H3 and H4
• Histones of different species are similar =
conserved
Chromatin Structure
• Nucleosome = basic
structural unit of chromatin
• Each nucleosome core contains about
200 bps of DNA wrapped around a core of
histone proteins = two each of H2A, H2B,
H3 and H4
• Linker regions with DNA + H1 occur
between adjacent nucleosomes
• Structure termed: beads on a string
Chromatin Structure
• Nucleosomes coil to form
higher order DNA
structure = 30 nm fiber
which is a left-handed
superhelix or solenoidal
supercoil; contains 6
nucleosomes per turn
• 30 nm fiber condenses to compact
metaphase chromosome in which
DNA/histone complex is attached to scaffold
of non-histone proteins
Chromatin Structure
• Heterochromatin = compact, heavily
staining chromosome regions rich in
satellite DNA and low in gene content
• Euchromatin= less condensed
chromosome regions
high in gene content
• Satellite DNA = highly
repeated non-coding
DNA sequences
Chromosomes and Heredity
• Chromosomes consist of linear
sequences of genes = genetic information
which specifies the physical expression of
a phenotypic trait
• Homologous chromosomes contain the
same sequence of genes which may vary
in expression = alleles
Sex Chromosomes
• X and Y chromosomes = sex chromosomes
which are non-identical but share some
genes
• Males are genetically haploid for most genes
on the X chromosome which results in unique
pattern of X-linked inheritance
• Autosomes = non-sex chromosomes
X-Linked Inheritance
• Genes on the X-chromosome are X-linked
• Females = XX; Males = XY
• Sex of progeny is determined by X or Y of
sperm
• Morgan discovered X-linked inheritance
by identifying mutations exclusive to male
fruit flies
Morgan’s Fruit Fly Experiments
• Morgan’s studies of inheritance patterns
in Drosophila melanogaster revealed
important genetic principles
• Fruit flies were excellent tools for research
due to short generation time, large
number of offspring, and ease of
producing and analyzing mutations
Morgan’s Fruit Fly Experiments
Morgan’ s genetic principles:
• X-linked inheritance based on mutations
observed in males
only
• gene linkage based
on the inheritance of
genes as a single unit
• chromosome mapping
based on recombination
frequencies between
linked genes
X-Linked Inheritance in Humans
• Many human genes are on the Xchromosome = X-linked
• Males have XY genotype and only one
copy of X-linked genes
• Mutations = genetic changes in X-linked
genes will be expressed phenotypically in
males even if recessive = X-linked genetic
disorder
• Hemophilia A =X-linked disorder
Meiosis Error: Nondisjunction
• Nondisjunction = chromosomes fail to
separate properly during anaphase of meiosis
I or II
• This results in unbalanced chromosome
segregation, such
that one cell receives
both copies of the
chromosome pair
• Nondisjunction of X
in Drosophila = proof
of Chromosome Theory
Nondisjunction
• Nondisjunction in meiosis I produces
gametes with a pair of homologous
chromosomes
• Nondisjunction in meiosis II produces
gametes with a pair of sister chromatids
• Fertilization produces a zygote with 3
copies of a single chromosome = trisomy
Nondisjunction: Aneuploidies
• Nondisjunction can occur for any human
chromosome resulting in zygotes with an
abnormal number of chromosomes =
aneuploidy
• Trisomy of chromosome 21 is the most
common autosomal aneuploidy = Down’s
Syndrome
• Most aneuploidies are genetic lethals
Mendel’s Ratios: Chi Square Data
Statistical (Chi Square) analysis of Mendel’s
experiments in which phenotypic
frequencies used to derive phenotypic
ratios are the basis for the Law of
Dominance, Law of Segregation and Law
of Independent Assortment show close
correlation between data and predicted
outcome
Did we get the right ratio?
• “Decide” using the Chi-square (c2) test
• Formula:
(Observed-Expected)2
Expected
S
• Example -- is 72:28 a 3:1 ratio ????
– step 1: total is 72 + 28 = 100
– step 2: expected is 3/4 x 100 = 75, 1/4 x 100 =
25
– (observed - expected) = 72-75 = -3, squared is 9
40
– sum over all catagories! (28-25, etc.)_
Chi-square table
41
How we know what to “Expect”
• Statistics
• One tool -- Bionomial Distribution
n! psqt
• Formula:
s!t!
– S + t = n (number of trials)
– p + q = 1 (probability of two alternatives)
– example: probability of 2 boys in 5 sibs
– answer = 10/32
• Find factorial term with Pascal’s Triangle
23
42
Pascals Triangle
43
Chi-Square Analysis
• Goodness of fit = test analyzes whether
observed data agree with theoretical
expectation
• Statistically significant = refers to the
magnitude of the difference between the
observed and expected data
measurements