Eukaryotic Genome Organization and Evolutionary Genetics
What is a chromosome?
• Each chromosome packages a single long molecule of DNA
• Comprised of DNA and a protein (chromatin)
• Chromatin = 1/3 DNA; 1/3 histone proteins + 1/3 non-histone protein
• DNA content of each chromosome varies
• Larger chromosomes = more DNA
HISTONE PROTEINS
• Small basic, positively charged amino acids (lysine + arginine) + make up +- half of
all chromatin protein
• Negative charge of DNA phosphate backbone is neutralized
• 5 type of histones
o H1, H2A, H2B, H3, H4
§ H1 = linker histone that join histones
§ Overall, histone H1 plays an important role in regulating chromatin
structure and gene expression by stabilizing the nucleosome
structure and modulating the accessibility of DNA to regulatory
proteins.
• 2 x H2A, H2B, H3 and H4 à nucleosome when bound to DNA
• Sequence is largely conserved among diverse organisms
o Therefore cannot study histone functioning through knockout and mutations
because these mutations would be lethal
• Essential in that DNA cannot exist in a naked state because it would not fit in a cell!!
NON HISTONE PROTEINS
• Large variety
• Many functions
o Scaffold – backbone of chromosomes
o DNA replication – DNA pol
o Chromosome segregation – motor proteins of kinetochores
o Transcriptional regulation – largest group + regulate transcription during
gene expression, transcription factors
• Different amounts in different tissues
NUCLEOSOMES
• Condensed DNA form chromatin fibres with beads (nucleosomes)
• Diameter of 100A and chromatin fibres have a diameter of 20A
• Each nucleosome = 160bp of DNA wrapped twice around a core of 8 histones
• Linker DNA (L1) links together nucleosomes & is ~40bp of DNA
• DNA sequence, spacing + structure affect genetic function
MECHANISM OF CHROMOSOMAL COMPACTION
1. Nucleosome à condenses naked DNA 7fold to a 100A fiber
2. Supercoiling à causes additional 6 fold compaction achieving a 40 to 50 fold
condensation relative to naked DNA
3. Radial Loop-Scaffold à through the progressive compaction of 300A fiber
condenses DNA to rodlike mitotic chromosome that is 10 000 times more compact
than naked DNA
,*H1 takes euchromatin to heterochromatin
*all histones and chromosomes are packaged in the same way à hence why a histone
mutation = deleterious and is lethal
RADIAL LOOP SCAFFOLD
• DNA compaction is sequential and progressive
1. Chromatin fibres are wrapped around nucleosomes which are supercoiled
2. Supercoiled chromatin undergoes compaction + forms loops held together by non-
histone scaffold and non-scaffold proteins
3. Chromatin loops form a rosette shape held together by additional non histone
scaffold proteins
4. Rosettes condense into compact bundles to rodlike chromosomes (10 000 times
more compact than naked DNA)
KARYOTYPE
• Metaphase chromosomes stained with Giemsa have alternating bands of light and
dark staining known as G banding
o Giesma stain gives light and dark banding
o Each band contains many DNA loops + ranges from 1 – 10 Mb in length
o Banding will be the same across a species
Karyotype = DNA and its unique pattern of chromosomal packaging
o Made from fully compacted metaphase chromosomes that have unique
reproducible banding patterns
, o Highly reproducible within a species/ individual within its lifetime
o Chromosomes = most visible in metaphase portion of mitosis (most
condensed) vs least visible in G1 phase
• Useful à
o locate genes on a chromosome
§ P and Q arms of a chromosome (long and short arms of a
chromosome)
o reveal cause of genetic diseases
§ eg. Down’s Syndrome à 3 copies of chromosome 21 rather than 2
copies
o analyze chromosomal differences between species
§ barriers to fertilization that allow organisms to live in the same space
without inter-species breeding
SPECIALIZED ELEMENTS OF CHROMOSOMES
à ensure accurate replication and
segregation of chromosomes
1. origins of replication
2. telomeres
3. centromeres
NB!! Cell performs different activities and
functions at different times of the cell cycle
1. ORIGINS OF REPLICATION
o Accessible regions of DNA
with repetitive sections of
DNA w/ fewer nucleosomes à
easier access
o Replication unit (replicon) =
DNA running both ways from one origin to the endpoints (AT rich regions)
§ Easier to form a replication bubble
§ Strong sequence conservation at origins of replication
§ Origins do not bind tightly around nucleosomes because they need to
be accessible
o Many origins of replication!! + active at the same time
o Replicons are scattered throughout chromatin 30-300kb apart
o Rate of DNA synthesis = 50 nucleotides/second
§ Therefore, mammals = 10 000 origins
o If only one origin à would take 800 hours to replicate human genome and
the cell cycle is only 24 hours, therefore, one origin = too slow
2. TELOMERES
o Protective caps on the end of the chromosome
o Preserve the integrity of linear chromosomes + prevent fusion with other
chromosomes
§ As DNA is replicated, primers are removed generating overhangs that
will progressively lead to shorter sequences
o Consist of DNA + proteins
§ Telomerase = NB!!!
o NO GENES PRESENT
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