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CHAPTER 19THE ORGANIZATION AND CONTROL OF

EUKARYOTIC GENOMES

• The estimated 35,000 genes in the human genome includes an enormous amount of DNA that does not program the synthesis of RNA or protein.

• Non-coding DNA is elaborately organized.• The DNA associated with protein to form chromatin, and

the chromatin is organized into higher organizational levels.

• Level of packing is one way that gene expression is regulated.• Densely packed areas are inactivated.

• Loosely packed areas are being actively transcribed.

Introduction

• Bacteria- single circular chromosome is coiled and looped

• Eukaryotic chromatin is far more complex. The DNA is precisely combined with large amounts of protein.

• Eukaryotic chromosomes contain an enormous amount of DNA relative to their condensed length.• Each human chromosome averages about 2 x 108

nucleotide pairs. If extended, each DNA molecule would be about 6 cm long, thousands of times longer than the cell diameter.

Chromatin structure is based on successive levels of DNA packing

• Japanese canopy plant (Paris japonica), native to the mountains surrounding Nagano

• Largest genome found• 150 billion base pairs—50 times as many as

human DNA• If the DNA in a human cell were unraveled, it

would stretch to two meters. A strand of DNA in the canopy plant would span 100 meters

• Histone proteins are responsible for the first level of DNA packaging.

• Their positively charged amino acids bind tightly to negatively charged DNA.

• The five types of histones are very similar from one eukaryote to another and are even present in bacteria.

• Nucleosome- DNA winds around a core of histone proteins

• In prokaryotes, most of the DNA in a genome codes for protein (or tRNA and rRNA), with a small amount of noncoding DNA, primarily regulators.

• In eukaryotes, most of the DNA (about 97% in humans) does not code for protein or RNA.• Some noncoding regions are regulatory sequences.

• Other are introns.

• Finally, even more of it consists of repetitive DNA, present in many copies in the genome.

Genome Organization at the DNA Level: Repetitive DNA and other noncoding sequences account for much of a eukaryotic genome

• In mammals about 10 -15% of the genome is tandemly repetitive DNA, or satellite DNA.

• These sequences (up to 10 base pairs) are repeated up to several hundred thousand times in series.

• There are three types of satellite DNA, differentiated by the total length of DNAat each site.

• Much of the satellite DNA appears to play a structural role at telomeres and centromeres.

Mutations because of extra repeats• A number of genetic disorders are caused by

abnormally long stretches of tandemly repeated nucleotide triplets within the affected gene.• Fragile X syndrome is caused by hundreds to thousands

of repeats of CGG in the leader sequence of the fragile X gene. Problems at this site lead to mental retardation.

• Huntington’s disease, another neurological syndrome, occurs due to repeats of CAG that are translated into a proteins with a long string of glutamines.

• The severity of the disease and the age of onset of these diseases are correlated with the number of repeats.

• About 25-40% of most mammalian genomes consists of interspersed repetitive DNA.

• Sequences hundreds to thousands of base pairs long appear at multiple sites in the genome.• The “dispersed” copies are similar but usually not

identical to each other.• One common family of interspersed repetitive

sequences, Alu elements, is transcribed into RNA molecules with unknown roles in the cell role.

• While most genes are present as a single copy per haploid set of chromosomes, multigene families exist as a collection of identical or very similar genes.

Gene families have evolved by duplication of ancestral genes

• Identical genes are multigene families that are clustered tandemly.

• These usually consist of the genes for RNA products or those for histone proteins.• For example, the three largest rRNA molecules are

encoded in a single transcription unit that is repeated tandemly hundreds to thousands of times.

Nonidentical genes have diverged since their initial duplication event.

Pseudogenes- DNA segments that have sequences similar to real genes but that do not yield functional proteins.

• In gene amplification, certain genes are replicated as a way to increase expression of these genes.• In amphibians, the genes for rRNA not only have a

normal complement of multiple copies but millions of additional copies are synthesized in a developing ovum.

• This assists the cell in producing enormous numbers of ribosomes for protein synthesis after fertilization.

• These extra copies exist as separate circles of DNA in nucleoli and are degraded when no longer needed.

Gene amplification, loss, or rearrangement can alter a cell’s genome during an organism’s lifetime

• Transposon are genes that can move from one location to another within the genome.• Up to 50% of the corn genome and 10% of the human

genome are transposons.

Retrotransposons- transcribed RNA includes the code for an enzyme that catalyzes the insertion of the retrotransposon and may include a gene for reverse transcriptase.

• Gene expression must be controlled on a long-term basis during cellular differentiation, the divergence in form and function as cells specialize.• Highly specialized cells, like nerves or muscles, express

only a tiny fraction of their genes.

The Control of Gene Expression: Each cell of a multicellular eukarote expresses only a small fraction of its genes

• In addition to its role in packing DNA inside the nucleus, chromatin organization impacts regulation.

• DNA methylation is the attachment by specific enzymes of methyl groups (-CH3) to DNA bases after DNA synthesis.

• Inactive DNA is generally highly methylated compared to DNA that is actively transcribed.

Chromatin modifications affect the availability of genes for transcription

• Histone acetylation (addition of an acetyl group -COCH3) and deacetylation appear to play a direct role in the regulation of gene transcription.• Acetylated histones grip DNA less tightly, providing

easier access for transcription proteins in this region.

• Distant control elements, enhancers, may be thousands of nucleotides away from the promoter or even downstream of the gene or within an intron.

• Bending of DNA enables transcription factors, activators, bound to enhancers to contact the protein initiation complex at the promoter.

• Eukaryotic genes also have repressor proteins that bind to DNA control elements called silencers.

Transcription initiation is controlled by proteins that interact with DNA and with each other

• In alternative RNA splicing, different mRNA molecules are produced from the same primary transcript, depending on which RNA segments aretreated as exons and which as introns.

Post-transcriptional mechanisms pay supporting roles in the control of gene expression

• Cancer-causing genes, oncogenes, were initially discovered in retroviruses, but close counterparts, proto-oncogenes were found in other organisms.

The Molecular Biology of Cancer: Cancer results from genetic changes that affect the cell cycle

• Mutations to genes whose normal products inhibit cell division, tumor-suppressor genes, also contribute to cancer.

• Any decrease in the normal activity of a tumor-suppressor protein may contribute to cancer.

• Mutations in the products of two key genes, the ras proto-oncogene, and the p53 tumor suppressor gene occur in 30% and 50% of human cancers respectively.

Oncogene proteins and faulty tumor-suppressor proteins interfere with normal signaling pathways

• Ras, the product of the ras gene, is a G protein that relays a growth signal from a growth factor receptor to a cascade of protein kinases.• At the end of the pathway is the synthesis of a protein

that stimulates the cell cycle.

• Many ras oncogenes have a point mutation that leads to a hyperactive version of the Ras protein that can issue signals on its own, resulting in excessive cell division.

• The tumor-suppressor protein encoded by the normal p53 gene is a transcription factor that promotes synthesis of growth-inhibiting proteins.• A mutation that knocks out the p53 gene can lead to

excessive cell growth and cancer.

• More than one somatic mutation is generally needed to produce the changes characteristic of a full-fledged cancer cell.

• If cancer results from an accumulation of mutations, and if mutations occur throughout life, then the longer we live, the more likely we are to develop cancer.

Multiple mutations underlie the development of cancer