DNA, chromosomes and genomes Notes based on molecular biology of the cell. Biology Elite: biologyelite.weebly.com, please use together with the presentation

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Part II Chapter 4 DNA, Chromosomes and genomes
Base pairing:
• purines: adenine and guanine (heavier and longer, two rings)
• pyrimidines: thyme and cytosine (lighter and shorter, one ring)
• each base pairing is in similar width, holding the sugar backbones a constant distance
• two hydrogen bonds forming between A and T
• three hydrogen bonds forming between C and G
• Each turn of DNA contains 10 base pairs
Packaging of DNA:
• prevent form unmanageable tangle of DNA
• remain accessible for some section of DNA
• Chromosomes: a single, enormously long linear DNA molecule along with the proteins that fold
and pack the one DNA thread into a more compact structure
• each human cell (except gametes) contains two copies of each chromosome, one from mother
and one form father, called “homologous chromosomes (homologs)”
• nonhomologous chromosome pairs are sex chromosomes (Y-father, X-mother, XY-male, XX-
female)
• each human cell contains 46 chromosomes, 22 pairs of homologs and 1 pair of sex chromosome
• distinguish of chromosomes: DNA hybridisation (colour painting using fluorescent dyes); stain
them with dyes (showing patterns of bands)
• display of the 46 chromosomes at mitosis is called human karyotype
• abnormalities of chromosome can be detected by banding patterns or chromosome painting
• gene: a segment of DNA that contains the instructions for making a particular protein
Specialised nucleotide sequence:
• Replication origins: the location where the duplication of DNA begins
• Centromere: allow one copy of each duplicated and condensed chromosome to be pulled into
each daughter cells when a cell divide. Kinetochore (protein complex) forms at the centromere,
making the chromosomes apart
• Telomeres: the end of the chromosomes, protect the end of chromosomes from being mistaken
by the cell for a broken DNA molecule in need of repair
• Each chromosome has multiple origins of replication, one centromere and two telomere
Basic unit of eukaryotic chromosomes:
• Chromatin: complex of both classes of protein (histone & non-histone chromosomal protein)
with the nuclear DNA of eukaryotic cells
• Nucleosome: a protein-DNA complex, with two molecules each of histone H2A, H2B, H3 and
H4, and double stranded DNA that is 147 pairs long
• A histone octamer is the eight protein complex found at the center of a nucleosome core
particle. It consists of two copies of each of the four core histone proteins (H2A, H2B, H3 and
H4).
• Linker DNA between each nucleosome core can vary in length from a few pairs up to 80
• On average, nucleosome repeats at intervals of about 200 nucleotides
• All four histone protein are small (102-135 amino acids), and have the same structural motif
called histone fold, formed from three alpha helices connected by two loops
• N-tail is subjected to several forms of covalent modification

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• H2A and H2B form a dimer through an interaction called handshake and H3 and H4 forms a
dimer through the same type of interaction
• Two H3-H4 dimer then further combines to form a tetramer.
• An H3-H4 tetramer then combines with two H2A-H2B dimer to form the histone octamer core
where DNA is wound.
• 142 hydrogen bonds are formed between the histone core and the DNA, along with numerous
hydrophobic interactions and salt linkages.
• Nucleosome has a dynamic structure, it will unwrap from each end and recloses thus leaving 10
to 50 milliseconds of free DNA for protein to bind in.
• ATP-Dependent Chromatin remodelling complexes: the arrangement of the nucleosomes on
DNA can be highly dynamic, changing rapidly according to cells’ need.
• By using the energy from ATP hydrolysis, the complexes can reposition nucleosome cores,
remove either all or part of the nucleosome core, make less DNA winding looser
• Packed of nucleosome: Histone tails and histone H1 proteins
• Histone H1 protein presents 1-to-1 ratio with nucleosome cores, and it contacts both the DNA
and nucleosome core. H1 proteins change the path of the DNA as it exits from the nucleosome.

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Chromatin structure and function:
• Heterochromatin: compact chromatin region that share the common feature of being unusually
resistant to gene expression
• Euchromatin: less condense region of chromatin
• Position effect: euchromatin translocated into the neighbourhood of heterochromatin, which
always causes silencing, inactivation of genes.
• Position effect variegation: once the heterochromatic condition is establish on a piece of
chromatin, it tends to be stably inherited by all of that cell’s progeny
Covalently modified of core histones:
• acetylation of lysines, the mono-, di-, and trimethylation of lysins and the phosphorylation of
serines.
• most of the modification occur on N-terminals of histone tails
• Specific enzymes are responsible for the modification: histone acetyl transferases (HATs) are
responsible for adding of acetyl group and histone deactylase complexes (HDACs) are for
removing acetyl group
• Acetylation of lysine on the N-terminal tails loosens chromatin structure
• Histone modification can also recruit proteins: trimethylation of one specific lysine on the histone
H3 tail attracts the heterochromatin-specific protein HP1 and contributes to the establishment
and spread of heterochromatin
Variants of histone proteins
• those proteins are synthesised and instead into a already formed chromatin, which requires a
histone-exchange process catalysed by the ATP-dependent chromatin remodelling complexes.

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Covalent modification and histone variants in controlling chromosome functions
• The writer is a enzyme that create a specific modification on one or more of the four nucleosomal
histone
• The writer collaborated with a reader protein to spread its mark from nucleosome to nucleosome
by means of the reader-writer complex
• A similar process is used to remove the histone modification. An eraser protein is recruited to the
complex
• Certain DNA sequences mark the boundaries of chromatin domains and separate one such
domain from another. The sequence is called barrier sequence
• In the case of cells which are destined to give a rise in red-blood cells, a sequence called HS4
normally separate the active chromatin (euchromatin) that contains beta-globin genes. Barrier
sequence in this case contains a cluster of binding sites for histone acetylase enzyme.
Acetylation and methylation of the lysine side chain cannot be performed together and the
methylation are required for the spread of heterochromatin.
• This mechanism stops the spread of reader-writer complex and separate the neighbouring
chromatin
• The chromatin in the centromere contains a centromere-specific variant H3 histone, known as
CENP-A (centromere protein-A)
• In human particularly, centromere also consists of short, repeated DNA sequence called alpha
satellite DNA sequences, but this sequence can be also found in other part of the chromosome,
which indicated they are not sufficient for formation of centromere

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• In some cases, newly formed human centromere called neocentromere cane formed without
alpha satellite DNA sequence
• Centromeres in complex organism are defined by an assembly of proteins, rather than by
specific DNA sequence.
• Cooperative recruitment of proteins, along with the action of reader-writer complexes, can
not only account for the spreading of specific from of chromatin in space along the chromosome,
but also for its propagation across cell generation.
The structure of chromosome
• Chromosome are folded into large loops of chromatin
• Polytene chromosomes are over-sized chromosomes which have developed from standard
chromosomes and are commonly found in the salivary glands of Drosophila melanogaster.
• Polytene chromosome are viewed under light microscope with dark bands and light interbands.
DNA are more condensed in the dark park and may also contain high concentration of proteins.
• Specific set of non-histone proteins assemble on these nucleosomes to affect biological
function in different ways
• Interphase chromosome can be considered as a chromatin structure containing particular
nucleosome modification associated with a particular set of non-histone proteins.
• Classical heterochromatin contains more than six such proteins, including heterochromatin
protein 1 (HP1)
• Chromatin loops decondense when the genes within them are expressed

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How genome evolves:
• Homologous genes: genes that are similar in both their nucleotide sequence and fiction
because of a common ancestry
• Conserved sequences are similar or identical sequences that occur within nucleic acid
sequences, protein sequences, protein structures or polymeric carbohydrates across species or
within different molecules produced by the same organism.
• Non-conserved regions will reflect DNA whose sequence is much less likely to be critical for
function
• The only regions that will have remained closely similar in the two genomes are those in which
mutations would have impaired function and put the animals carrying them at a disadvantage,
resulting in their elimination from the population by natural selection. This region is called
conserved region
• Evolution depends on accidents and mistakes followed by nonrandom survival.
• Errors in DNA replication, DNA recombination, or DNA repair can lead either to simple local
changes in DNA sequence—so-called point mutations such as the substitution of one base pair
for another—or to large-scale genome rearrangements such as deletions, duplications,
inversions, and translocations of DNA from one chromosome to another.
• purifying selection is selection that eliminates individuals carrying mutations that interfere with
important genetic functions
• Evolution has followed a pathway requiring the minimum number of mutations consistent with the
data.
• Small blocks of DNA sequence are being deleted from and added to genomes at a surprisingly
rapid rate. Thus, if we assume that our common ancestor had a genome of human size (about
3.2 billion nucleotide pairs), mice would have lost a total of about 45% of that genome from
accumulated deletions during the past 80 million years, while humans would have lost about
25%. However, substantial sequence gains from many small chromosome duplications and from
the multiplication of transposons have compensated for these deletions.
• DNA is added to genomes both by the spontaneous duplication of chromosomal segments that
are typically tens of thousands of nucleotide pairs long (as will be discussed shortly) and by
insertion of new copies of active transposons.