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The Human Genome and Chromosomal
Basis of Heredity and Chromosomal
Disorders
Chromosomes were found to be the bearer
of genetic factor
Ömer Faruk Bayrak
WHAT IS GENE?
2005
2003
DNA Double Helix,
Watson & Crick
Nature, 1953
Human genome Proj
ect
Inactivation of different X genes
• The physical and functional unit of here
dity that carries information from one
generation to the next
• DNA sequence necessary for the synthe
sis of a functional protein or RNA molec
ule.
GENE
• Gene were first detected and analyzed by Mendel and
subsequently by many other scientist (Mendel stated
that physical traits are inherited as “particles”)
 Mendel did not know that the “particles” were actually
Chromosomes & DNA
• Subsequent studies shows the correlation between
transmission of genes from one generation to
generation (Segregation and independent assortment)
and the
behavior of chromosomes during sexual
reproduction, specifically the reduction division of
meiosis and fertilization.
• These and related expt. provided a strong early eviden
ce that genes are usually located on chromosomes.
What are the requirements to fulfill as a gen
etic material?
• 1. The genotype function or replication:
• The genetic material must be capable of storing
genetic
information
and
transmitting
this
information faithfully from parents to progeny,
generation after generation.
• 2. The phenotype function or gene expression
• The genetic material must control the development
•
of phenotype of the organism, be it a virus, a
bacterium, a plant or animal.
That is, the genetic material must dictate the growt
h and differentiation of the organism from single c
elled zygote to the mature adult.
6
DNA STRUCTURE
Nucleic acids first called “nuclein” because they
were isolated from cell nuclei by F. Miescher in
1869
• Each nucleotide is
composed of
(1) a Phosphate group
(2) a five – carbon sugar (
or Pentose), and
(3) a cyclic nitrogen
containing compound
called a base.
In DNA, the sugar is 2-deoxyribose (thus the
name deoxyribonucleic acid)
In RNA, the sugar is ribose (thus ribonucleic
acid).
Adenine and Guanine are double ring base called Purines
6-aminopurine
2-amino-6-oxypurine
Cytosine, thymine, and uracil are single-ring base called
Pyrimidines.
4-amino-2-oxypyri
midine
2,4-oxypyrimidine
2,4-oxy-5-pyrimidine
16.6 Base pairing in DNA
Chargaff’s rule
• The composition of DNA from many different organisms
was analyzed by E.Chargaff and his colleagues.
• It was observed that concentration of thymine was
always equal to the concentration of adenine (A = T)
• And the concentration of cytosine was equal to the
concentration of guanine (G = C).
• This strongly suggest that thymine and adenine as well
as cytosine and guanine were present in DNA with fixed
interrelationship.
• Also the total concentration of purines (A +G) always
equal to the total concentration of pyrimidine (T +C).
However, the (T+ A)/ (G+C) ratio was found to vary
widely in DNAs of different species.
Did you know?
• Each cell has about 2 m
of DNA.
• The average human has
75 trillion cells.
• The average human has
enough DNA to go from
the earth to the sun
more than 400 times.
• DNA has a diameter of
only 0.000000002 m.
The earth is 150 billion m
or 93 million miles from
the sun.
DNA replication
After publishing their model, W&C made a hypothesis for
the replication of DNA.
a. Hydrogen bonds break, and the two strands separate.
b. Each strand now serves as a template for a new
complimentary strand.
c. Nucleotides are connected and the daughter DNA
molecules are formed.
16.8 Three alternative models of DNA replication
16.13 Synthesis of leading and lagging strands during DNA replication
- Once hydrogen bonds begin to break, replication bubbl
es begin to form at points along the DNA strand.
- Bubbles form at sites called origins of replication.
- DNA replication proceeds in both directions from the or
igin of replication.
Human Chromosomes
• Humans have 46 chromosomes organized as 23
•
•
pairs that are homologous because each pair
contains the homologous genes
Humans are genetically diploid = 2 copies of each
chromosome, except for the sex chromosomes (X+Y)
that are non-identical
Each species has a characteristic set of
chromosomes.
Eukaryotic Chromosome Structure
• Genetic material in eukaryotes is organized to
form linear chromosomes
(one chromosome = one molecule)
• Pulsed-field gel electrophoresis is used to
separate individual chromosomes that migrate
as distinct bands on a gel
(visible evidence for chromosomes)
Chromatin Fiber Organization
• Dark field electron microscopy shows fiber
structure of chromosomes as beads on a string
• Nucleosome = the fundamental unit of
organization of the chromatin fiber
• Each nucleosome contains a core particle of
basic proteins = histones surrounded by 1.75
turns of DNA helix = 145 bp of DNA
Chromatin Fiber Structure
• Core particle histone octamer contains two
molecules each of:
- histone H2A
- histone H2B
- histone H3
- histone H4
• Linker region connecting nucleosomes contains
histone H1
Chromatin Fiber Structure
• Primary Structure of DNA = double helix = 2nm duplex
DNA
• Duplex DNA winds around histone octamers to form
nucleosomes = 11 nm histone fiber
• Nucleosome fibers form left-handed helix with 6
nucleosomes per turn = 30 nm chromatin fiber (solenoid
structure)
Organization of Nucleosomes
The DNA molecule is
wound one and three
fourths turns around a
histone octamer.
Various Stages of Chromosome Condensation
Solenoidal
Model of
Chromatin
Chromosome Structure
• 30 nm chromatin fiber condenses to metaphase
chromatid = 1400 nm
• Nonhistone protein complexes = scaffold:
Required for the attachment of loops of
chromatin fibers
(confirmed by DNase digestion)
Chromosome Structure
• Euchromatin = comprises most of the genome,
•
•
•
transcriptionally active parts
Heterochromatin = highly condensed inactive
chromatin located at centromeres and telomeres
Centromere = attachment point for sister
chromatids and spindle fibers
Telomere = end of chromosome
Schematic Drawing of
Metaphase Chromosome
Centromeres
(Essential for chromosome segregation)
• Centromeres = chromosome regions that
contain the site of attachment for microtubules =
kinetochore
• Centromeres contain heterochromatin,
condensed chromatin
• In situ hybridization of metaphase chromosomes
shows satellite DNA at centromeres
Telomeres
(Essential for the stability of the chromosomal tip)
• Telomeres are specialized regions of DNA at the ends of
chromosomes
• Telomeres contain short tandem DNA repeats that are
added to ends by the enzyme = telomerase
• Telomerase contains RNA primer complementary to
telomere repeat
Function of Telomere Repeat and
Telomerase
Sex Chromosomes
• X and Y chromosomes = sex chromsomes
which are non-identical but share some
genes for pairing
• Males are genetically haploid for most genes
on the X chromosome which results in unique
patterns of X-linked inheritance
• Autosomes = non-sex chromosomes
Cell Division – Chromosome Division:
Cell Cycle (Mammalian)
• Cell division cycles occur in stages:
- G1 = pre-DNA synthesis
Interphase
- 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 daughter cells
• Cell cycle takes about 18-24 hours in higher eukaryotes.
• Mitosis takes about 1-2 hours.
Mitosis: Meiosis:
The Cell Cycle of a Typical Mammalian Cell
Mitosis
• Chromosome replication: exact duplicates are made
during the S period = sister chromatids formed
(interphase).
•
•
-Stages of MitosisProphase - individual chromosomes become visible,
spindle fibers organize and attach to centromeres of
chromosomes
Metaphase - chromosomes line up in center of cell:
alignment of chromosomes along the metaphase plate
is a checkpoint to proceed to the next phase.
• Anaphase- sister chromatids separate after
centromere division: 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
*Chromosomes decondense until they are no longer visible.
*Cytokinesis follows.
Mitosis
Diploidity is
maintained
after mitosis.
Meiosis
• Meiosis is a specialized type of cell division
that occurs only in reproductive cells (e.g.
eggs or sperms)
• Two rounds of cell division result in the
formation of gametes that are genetically
haploid = contain only one copy of each pair
of homologous chromosomes
Meiosis
<Simplified overview of meiosis>
*The behavior of a single pair of
homologous chromosomes.
*Each chromosomes already
consists of two chromatids,
joined at a single centromere.
Meiosis
• Meiosis occurs in stages and requires two cell division
events
• Meiosis I:
- Chromosomes duplicate in S phase
- Homologous chromosomes pair: 4 strands of
chromatids align
- Homologous chromosomes are pulled to either pole of
the cell at anaphase
• Meiosis II:
- Cell division occurs in the absence of chromosome
duplication
- Sister chromatids separate at anaphase as in mitotic
division
Major Stages of Meiosis with
Two Pairs of Homologous Chromosomes
Crossing-over (Chiasmasis) between
Homologous Chromosomes
* No cross-over between sister chromatids.
* Random genotype formation in a gamete
Meiotic vs. Mitotic Division
• Meiosis produces four cells, each of which
contains one copy of each pair of homologous
chromosomes =
genetically haploid (n)
• Mitosis produces two cells that contain both
members of each pair of homologous
chromosomes = genetically diploid (2n)
Fig. 3.
5
48
49
Human Karyotype
Idiogram of Human Karyotype
Cytogenetic disorders are characterized
by an abnormal constitutional karyotype
What mechanisms would result in cytogen
etic abnormalities?
Nondisjunction in Meiosis I & Meiosis
II
Chromosomal Rearrangments
•
•
•
•
Translocation
Deletion
Duplication
Inversion
Chromosomal Rearrangements
What is the diagnosis?
12.2
Chromosome
Accidents
Relate Down syndrome and the nonseparation of chromoso
mes
Describe how chromosomes can be damaged and the cons
equential effects
Explain how a “jumping gene” can affect other genes.
Use a microscope to observe different shapes and lengths
of
chromosomes
Chromosomal Aberrations
• Changes in the numbers of chromoso
mes
– Polyploidy
• Extra complete sets of chromosomes
• 3N, 4N, 5N, etc.
– Aneuploidy
• Extra or missing single chromosomes
• 2N + 1, 2N -1, etc.
Chromosomal Aberrations
• Changes in structure
– Changes in the number of genes
• deletions: genes missing
• duplications: genes added
Chromosomal Aberrations
• Changes in structure
– Changes in the location of genes
• inversions: 180o rotation
• translocations: exchange
• transpositions: gene “hopping”
• Robertsonian changes: fissions or fusions
Polyploidy
• Having extra sets
– 3N, 4N, etc.
• Suffix: “-ploid” or “-ploidy”
– 3N = triploid
– 4N = tetraploid
Polyploidy
N= A
B
C:
2N = AA BB CC:
Polyploidy
N= A
B
C:
3N = AAA BBB CCC
Polyploidy
• Monoploidy (haploidy): rare in animals
– exceptions: Bees: males are haploid - d
evelop from unfertilized eggs; females are
diploid
• More common in plants
– alternation of generations increases occurr
ence of haploidy
Haploidy in Plants
• Occasionally, unfertilized gamete may d
evelop into adult plant
– usually small, with lowered viability
– sterile
3N or More in Animals
• Most common form of polyploidy in a
nimals is triploidy
– arises from two sperm fertilizing the sam
e egg
– if the organism survives, it is sterile
• pairing of homologues in meiosis is disrupte
d
– Survival is extremely rare
3N or More in Plants
• Polyploidy generally improves viability in
plants
– Plants are larger, produce larger flowers, m
ore seeds, hardier, etc.
– Pairing at meiosis is still a problem, especi
ally w/ odd ploidies: 3N, 5N, 7N, etc.
• May reproduce asexually
3N or More
• Autopolypoidy
– Extra sets of chr
omosomes come
from the same s
pecies
– Arise from doubl
e fertilization usu
ally
– All chromosomes
have homologue
s
• Allopolyploidy
– Extra sets of chr
omosomes come
from different sp
ecies
– Arise from hybrid
ization
– New chromosom
es have no hom
ologues
Allopolyploidy or hybridization
Horse + donkey  mule
haploid
+
32
N = 63
Instant Plant Speciation Through Allo- and Auto
polyploidy
• Possible for entirely new species of pla
nt to be created almost instantly
• Hybridization (allopolyploidy) followed b
y autopolyploidy --> plant w/ totally di
fferent chromosomal make up from eith
er parent
• Fertile only w/ itself; NEW SPECIES
Aneuploidy
• Extra single chromosomes or missing
single chromosomes
– 2N + 1
– 2N - 1
• Suffix: “-somy” or “-somic”
– 2N + 1 = trisomy
– 2N - 1 = monosomy
– 2N + 2 = tetrasomy
Aneuploidy
• Generally arise through non-disjunction
at meiosis
– homologues or chromatids do not separate
– gametes contain 2 or no copies of one chr
omosome
Aneuploidies in Humans
• Most aneuploidies in humans lead to su
ch drastic effects, the fetus is spontane
ously aborted early in development
• A few survive ‘til birth; some beyond
• Meiosis occurs repeatedly in a person's lifetime as the teste
s produce sperm or the ovaries complete production of egg
•
s.
Almost always, the meiotic spindle distributes chromosome
s to the daughter cells without error.
• But occasionally an accident occurs that can have serious
Normal Meiosis
Down Syndrome
Genotype
• A normal human karyotype has 46 total chromosom
•
es, or 23 pairs.
When a karyotype includes not two, but three numb
er 21 chromosomes, this condition is called trisom
• Trisomy 21 usually resul
•
•
•
ts from an error during b
ut meiosis I.
In most cases, a human
embryo with an abnorm
al number of chromoso
mes results in a miscarri
age (meaning the embry
o does not survive).
But many embryos with
trisomy 21 do survive.
Trisomy 21 affects abou
t one out of every 700 c
hildren born in the Unite
d States.
Down Syndrome
Down Syndrome
• People with trisomy 21 have a general set of symptoms call
ed Down syndrome, named after John Langdon Down, who
described the syndrome (set of symptoms) in 1866.
• These symptoms include:
–
–
–
–
–
certain characteristic facial features
below-average height
heart defects
an impaired immune system
varying degrees of mental disability.
Though people with Down syndrome have lifetimes that are shorter
than average, they can live to middle age or beyond.
Down Syndrome
Phenotype
Simian Crease
Nondisjunction of Chromosomes
(faulty meiosis)
Nonseparation of Chromosomes
• Trisomy 21 and other err
•
ors in chromosome num
ber are usually caused b
y homologous chromos
omes or sister chromati
ds failing to separate du
ring meiosis, an event c
alled nondisjunction.
Nondisjunction can occ
ur in anaphase of meios
is I or meiosis II, resultin
g in gametes with abnor
mal numbers of chromo
somes.
Nonseparation of
Chromosomes
Nonseparation of Chromosomes
•
•
•
•
•
•
As women gets older, they are
more likely to have offspring with
trisomy 21.
Meiosis begins in the pre-egg c
ells in a girl's ovaries before she
is born but then pauses until yea
rs later.
At puberty, meiosis resumes. Us
ually only 1 egg resumes meiosis
and is released from the ovaries
each month (ovulation) until men
opause.
This means that a cell might rem
ain stopped in the middle of mei
osis for decades!!
It seems that the longer the time
lag, the greater the chance that t
here will be errors such as nondi
sjunction when meiosis is finally
completed.
Some researchers hypothesize th
at damage to the cell during this
lag time contributes to errors in
meiosis.
What causes nondisjunction?
Damaged Chromosomes
•
Even if all chromosomes are present in normal
numbers in a cell, changes in chromosome str
ucture may also cause disorders.
•
1.
2.
3.
4.
There are 4 types of chromosomal change
Duplication
Deletion
Inversion
Translocation
Duplication
• Part of a chromos
•
ome is repeated
Not always fatal, b
ut often results in
developmental abn
ormalities
Deletion
• Chromosome fragme
•
•
nt is lost
If the fragment is par
t of a gene, the gen
e does not work
Potential for very ser
ious effects
• Fragment of original chromosome
’s base sequence is reversed
Inversion
• Fragment of 1 chro
mosome attaches to
a nonhomologous c
hromosome
Translocation
Translocation
Click here for some effects of chro
mosomal translocations…
Spontaneous abortions
Jumping Genes
• Another type of change in chromosomes involves s
ingle genes that can move around. This startling di
scovery was the work of American geneticist Barba
ra McClintock (1902-1992) in the 1940s.
Jumping Genes
• While studying genetic variation in corn, McC
lintock found that certain genetic elements (
genes) had the unusual ability to move from
one location to another in a chromosome. T
hey could even move to an entirely different
chromosome. (Note that this is different from a tr
anslocation, where a whole piece of the chromoso
me moves, not just a gene.)
• McClintock discovered that these "jumping genes" could land in the mid
dle of other genes and disrupt them. For instance, jumping genes could
disrupt pigment genes in corn cells, leading to spotted kernels.
• McClintock's jumping genes are now called transposons.
• Current evidence suggests that all organisms, including humans, have tr
ansposons.
• In 1983, McClintock received a Nobel Prize for her pioneering work.
Jumping Genes - transposons
• The transposon includes a gene that codes for an
•
•
enzyme.
The enzyme catalyzes movement of the gene by att
aching to the ends of the transposon and another
site on the DNA.
The enzyme then cuts the DNA and catalyzes insert
ion of the transposon at the new site, sometimes di
srupting another gene.
Transposons
Some copy themselves
and jump to new locati
ons in our DNA where t
hey affect adjacent ge
nes. In their new locati
on they can disrupt a g
ene completely, or subt
ly change the way it ex
erts its effects in the c
ell. This can have both
positive and negative c
onsequences.
Click here if you want t
o learn more…