Chromosomal Basis of Inheritance
Genes can be tagged with a fluorescent marker and visualized on chromosomes
• Evidence that genes are on chromosomes
• Fruit flies were studied because
• A generation can be bred every two weeks
• Produce hundreds of offspring
• Only 4 pairs of chromosomes; 3 pairs of autosomes and 1 pair of sex chromosomes
• In Morgan’s experiment, reciprocal crosses gave different outcomes
• Only the males were affected by the trait
• Mated male flies with white eyes (mutant) with female flies with red eyes (wild type)
• The F 1eneration all had red eyes
• The F 2eneration showed the 3:1 red:white eye ratio, but only males had white eyes
→ The gene for eye color must be located on the X chromosome with no corresponding gene on the Y
→ This finding supported the chromosome theory of inheritance
• X and Y chromosomes:
– Differ in size, shape and gene content
– Contains genes for many characters unrelated to sex
– Synapse during meiosis (behave as homologous chromosomes) and segregate in
Sex-linked Gene – A gene located on either sex chromosome
- In humans, sex-linked usually refers to a gene on the larger X chromosome (also called X-linked
- Males only inherit one X chromosome from their mother
- Both dominant and recessive alleles located on X chromosome will be expressed in males!
- Sex-linked recessive disorders are more common in males than in females
- Color blindness
- Duchenne muscular dystrophy
X-Linked Vs. Autosomal Inheritance
• X-linked inheritance
– Males tend to be more affected than women.
– Mother-to-sons transmission can occur.
– Father-to-sons transmission cannot occur.
– Father-to-daughters transmission will occur.
• Autosomal inheritance (from genes located on autosomal chromosomes)
– Both male and female are affected by the trait.
– Parents and/or grand-parents must carry or be affected by the trait Sex-linked genes exhibit unique patterns of inheritance
• SRY gene (sex-determining region of Y) activation in mammal embryo (2 month old), lead to
development of male characteristics
• In absence of SRY, embryo develops into a female
X Inactivation in Female Mammals
• In mammalian females, one of the two X chromosomes in each cell is randomly inactivated
• The inactive X condenses into a Barr body
• If a female is heterozygous for a particular gene located on the X chromosome, she will be a
mosaic for that character.
– Some cells will express the trait while some other will not
• Inactivation of X involves DNA modification (methylation of bases)
Linked genes tend to be inherited together because they are located near each other on the same
• Morgan crossed Drosophila that differed in traits of body color and wing size (these 2 are linked)
• He noted that these genes do not assort independently, and reasoned that they must be on the
• Linked genes - genes on the same chromosome that tend to be inherited together
• When genes are on the same chromosome
• Genes are linked and tend to be inherited together
Recombination of Linked Genes: Crossing Over
• Incomplete linkages are possible; evident from the ratio of recombinant phenotypes
• Crossing over during meiosis I explains these phenotypes
• The closer the genes on the chromosome the less likely they are to be separated by a crossover
event in meiosis I
Linkage map (Sturtevant)
• Genetic map: Location of genes on a chromosome
• Linkage map: Genetic map based on recombination frequencies
• One map unit (centimorgan) = 1% recombination frequency. They indicate relative distance and
order, not precise locations of genes
• The further apart the genes, the higher the recombination frequency.
• Genes that are physically linked (on the same chromosome), but genetically unlinked
(recombination frequency near 50%) behave as if they are found on different chromosomes.
• Frequency of cross-over is not uniform along the chromosome.
Cytogenetic map: indicate the positions of genes with respect to chromosomal features (e.g. stained
Physical maps: determined by nucleotide sequences Genetic recombination and linkage (summary)
• Genes on different chromosomes:
– Recombination occurs due to independent assortment of chromosomes; Follow
– 50% of the offspring will have a recombinant genotype due to random orientation of the
homologous chromosomes at metaphase I.
• Genes on the same chromosome:
– Recombination will occur if crossing over between linked genes occurs during prophase
– The recombination frequency is proportional to the distance between the two genes.
– If the genes are close to one another
→Do not follow Mendel’s law of independent assortment
– If the genes are far away and recombination frequency is ≥ 50% due to high frequency
of crossing over, the genes will behave as if they are not linked!
→Follow Mendel’s law of independent assortment
Alterations of chromosome number or structure cause some genetic disorders
• Large-scale chromosomal alterations often lead to spontaneous abortions (miscarriages) or
cause a variety of developmental disorders
• Abnormal Chromosome Number is caused by nondisjunction:
– Pairs of homologous chromosomes do not separate normally during meiosis I or II.
– One gamete receives two of the same type of chromosome, and another gamete
receives no copy
– results from the fertilization of gametes in which nondisjunction occurred
– Offspring have an abnormal number of a particular chromosome
• A monosomic zygote has only one copy of a particular chromosome (2n -1
• A trisomic zygote has three copies of a particular chromosome (2n +1
– Mitosis will transmit the anomaly to all embryonic cells.
– Nondisjunction can also occur during mitosis; harmful effect if it happens early in
Human disorders caused by aneuploidy
• Down syndrome (Trisomy 21):
– Facial features; short stature; heart defects; susceptibility to respiratory infections;
mental retardation; sterile
– Incidence increases with the age of the mother
– Trisomy or monosomy of sex chromosomes
– Not as detrimental as aneuploidy in autosomes
Klinefelter syndrome: extra chromosome in a male, producing XXY individuals; usually sterile;
develop some female body characteristics.
Turner syndrome: Monosomy X, produces X0 females, who are sterile; it is the only known viable
monosomy in humans Polyploidy
• Condition in which an organism has more than two complete sets of chromosomes
– Triploidy (3n) is three sets of chromosomes
– Tetraploidy (4n) is four sets of chromosomes
– Polyploidy is common in plants, but not animals (in fishes and amphibians)
• Polyploids are more normal in appearance than aneuploids
Alterations of Chromosome Structure
• Due to meiosis error and/or radiation damages
Disorders Caused by Structurally Altered Chromosomes
• The syndrome cri du chat (“cry of the cat”), results from a specific deletion in chromosome 5
– A child born with this syndrome is mentally retarded and has a catlike cry; individuals
usually die in infancy or early childhood
– Certain cancers, including chronic myelogenous leukemia (CML), are caused by
translocations of chromosomes
Some inheritance patterns are exceptions to the standard chromosome theory
• For a few mammalian traits (mainly on autosomes), the phenotype depends on which parent
passes along the alleles for those traits
• Involves the silencing of certain alleles during gamete production. Allele are “stamped”
with an imprint (CH 3n cytosine); This causes inactivation/activation of the allele.
→ In the zygote, only the male or female allele is expressed
→ All the cells will behave the same way.
• In a given species, imprinted genes are always imprinted the same way.
• Aberrant imprinting leads to abnormal development and certain cancers.
Inheritance of Organelle Genes
• Mitochondria, chloroplasts, and other plant plastids carry small circular DNA molecules
• Extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg
• Some defects in mitochondrial genes prevent cells from making enough ATP and result in
diseases that affect the muscular and nervous systems
– Mitochondrial myopathy
– Leber’s hereditary optic neuropathy
Molecular Basis of Inheritance
DNA is the genetic material
• Used in information storage and transfer.
• Nucleic acid - Polymer of nucleotide monomers consisting of
• A pentose sugar: deoxyribose
• Phosphate group (on carbon 5’)
• Nitrogenous bases (on carbon 1’)
• Purine (ring:5 + 6): Adenine and Guanine
• Pyrimidine (ring: 6); Cytosine and Thymine • Made of nucleodide monomers attached via covalent phosphodiester bond between the 3’-
OH and the 5’-OH of the deoxyribose.
• Sugar-phosphate make up the backbone of the structure.
• The polymer is directional; 5’-phosphate and 3’-OH
Structure of DNA
• Erwin Chargaff (1950):
– DNA composition varies from one species to the next.
– Amount of A = amount of T
– Amount of C = amount of G
• Rosalind Franklin:
– produced pictures of the DNA molecule using X-ray crystallography
– concluded that that there were two antiparallel sugar-phosphate backbones, with the
nitrogenous bases paired in the molecule’s interior.
Watson and Crick: using Rosalind X-ray pictures of DNA and what was known about DNA
chemistry determined the structure of DNA as we know it today.
Two polynucleotide chains coiled around a common axis forming a “right-handed” helix.
Two strands run antiparallel.
Strands are held together via hydrogen bonds between bases on opposite chains (weak bonds)
Stabilized by base stacking (hydrophobic)
Helix diameter: Purine pairs with pyrymidine
Complementary Base pairing
• Adenine always pairs with Thymine
– Forms 2 hydrogen bonds
– Guanine always pairs with Cytosine
– Form 3 hydrogen bonds
→ Consistent with Chargaff’s rule
(A=T and G=C)
→Selective base pairing provides basis for DNA replication
Human has 33% of A;
how many T; C and G?
Differences between DNA and RNA
Used in storage and transmission of genetic Involved in protein synthesis
Deoxyribose Sugar Ribose Sugar
Thymine Base Uracil Base
Two anti-parallel Strands Single stranded (can also be double stranded)
• Nucleoside: pentose + base
• Nucleotide: pentose + base + phosphate (up to 3)
• Pentose: ribose (RNA)/deoxyribose (DNA)
– Purine: adenine / guanine – Pyrimidine: thymine (DNA)/ uracyl (RNA)/ cytosine
– Form by condensation of 3’-OH of one nucleotide and 5’-phosphate of the next
nucleotide; 3’-5’-phosphodiester bond.
• Molecule directional: 5’ → 3’
Many proteins work together in DNA replication and repair
• Mechanism of DNA replication:
– DNA is made of two complementary strands.
Replication is semi-conservative: each parental strand serves as a template for synthesis of the new
• DNA unwinds and separates at the origin of replication; Formation of replication bubbles.
– One in prokaryotes
– Hundreds (thousand) in eukaryotes
• Replication proceeds at the replication folks in both directions from each origin.
DNA replication requires:
DNA + dTTP, dATP, dGTP, dCTP
→ 2 x DNA + PPi
– DNA template
– dNTPs (deoxynucleoside triphosphate)
– RNA primer (Primase + NTPs)
A variety of enzymes and proteins
DNA polymerase III
• Catalyze the addition of nucleotides complementary to the template DNA
• Cannot initiate replication
• Require a RNA primer (primase enzyme) to provide 3’OH.
• Formation of phosphodiester
between 3’ OH of the growing chain and the 5’ phosphate of the incoming nucleotide
triphosphate releasing pyrophospate that breaks down into 2 Pi (energy).
• Chain grows in the 5’ to 3’ direction
• DNA gyrase is a topoisomerase: relieve over twisting of the DNA helix ahead of the replication
fork by breaking and reforming phosphodiester bonds.
• Helicase: Converts double-stranded DNA into single-stranded DNA by breaking the hydrogen
bonds between bases at the replication fork.
• SSB: single-strand binding proteins. Bind to the single-stranded created by helicase to prevent
the re-formation of double-stranded DNA.
• Synthesize RNA primer complementary to the DNA template
• Provide the 3’-OH needed for DNA polymerase III to start replicating DNA.
DNA replication – summary (1)
• Helicase and topoisomerase: Unwind the DNA double helix into single-stranded DNA.
• SSB protein: protect and prevent rewinding of single-stranded DNA. • Primase: Synthesize a short RNA primer (5-10 nucleotides) following DNA template (base-
pairing rule) to provide the 3’-OH group for DNA polymerase III to function.
• DNA polymerase III: covalently add nucleotides to the 3’-OH end of the RNA primer or pre-
existing DNA strand, following the DNA template (Base pairing rule).