19. The Organization and Control of Eukaryotic Genomes

Eukaryotic Chromatin Structure

1. The eukaryotic chromosomes are organized and condensed through the help of proteins known as histones.
2. Histones are proteins that have high proportions of lysine and arginine, which emit a fairly positive charge and allowing it to attach to the DNA molecule, which is negatively charged (because of the phosphate groups).
   • The histone protein can be found even in some bacteria. This means that the gene for histones was conserved for its evolutionary advantages.
   • There are five types of histone protein, H2A, H2B, H3, H4, and H1.
   • The first level of chromatin organization consists of the DNA wrapping around the histone protein several times to form a bead-like structure known as the nucleosome.
3. The histone protein can be found even in some bacteria. This means that the gene for histones was conserved for its evolutionary advantages.
4. There are five types of histone protein, H2A, H2B, H3, H4, and H1.
5. The first level of chromatin organization consists of the DNA wrapping around the histone protein several times to form a bead-like structure known as the nucleosome.
6. Nucleosomes consist of only the first four types of histones, H2A, H2B, H3, and H4. The H1 histone is used to join two
7. adjacent beads by attaching to two strands of DNA.
   • This coiling forms a chromatin fiber about 30-nm in diameter.
   • Throughout most of the cell cycle, the nucleosome structure will remain unchanged. Only during DNA replication will the histones leave the DNA for a brief period of time.
8. This coiling forms a chromatin fiber about 30-nm in diameter.
9. Throughout most of the cell cycle, the nucleosome structure will remain unchanged. Only during DNA replication will the histones leave the DNA for a brief period of time.
10. The chromatin will then further condense into loops known as looped domains. These looped domains are attached to a protein structure known as a scaffold, which serves as a frame for the chromatin to condense even more.

http://cnx.org/content/m11413/latest/histones.jpg

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Genome Organization At The DNA Level

1. Most of the eukaryotic genome consist of introns, or non-coding DNA. Most of the time, the non-coding sequences are repetitive DNA, which are sequences that exist in multiple copies in the genome.
   • Tandemly repetitive DNA are simply short sequences that repeat continuously after another.
     • Satellite DNA are tandemly repetitive DNA- The two terms can be used interchangebly.
       • Satellites can be separated into three categories: Satellite (100,000- 10 million base pairs), Minisatellite (100-100,000 base pairs), and Microsatellite (10-100 base pairs).
     • There are several genetic disorders caused by tandemly repetitive DNA. Such disorders include: fragile X syndrome and Huntington's disease. Almost all genetic disorders linked to the repetitive DNA are linked to the nervous system.
     • Tandemly Repetitive DNA can be found in the centromere and telomere regions of a chromosome. This may be structurally important for a chromosome.
   • Interspersed Repetitive DNA are sequences that are identical, but instead of constantly repeating in one long sequence, they are scattered throughout the genome.
     • Alu elements are interspersed repetitive DNA sequences that actually code for proteins, but as for their actual function, it is unknown.
     • Most interspersed repetitive DNA are transposons.
2. Gene sequences that are highly similar are considered a multigene family.
   • These sequences probably originated from an ancestral gene, in which through replication, mutations generated similar but new sequences.
     • The existence of pseudogenes is proof of an ancestral gene for pseudogenes do not code for any functional product though they resemble functional genes.
   • Examples of multigene families include: rRNA molecules (identical genes) and the globin family (nonidentical genes)
3. The genome can change throughout the course of development.
   • At times, certain genes will require more expression than normal. Gene amplification is the selective replication of certain genes, which means increased expression.
   • During specialization of some cells or tissues in insects, some genes are specifically removed.
   • The genes that can move from one location to another are transposons and retrotransposons.
     • Transposition can regulate the production rate of certain proteins.
     • Retrotransposons move around through reverse transcriptase.
     • Rearrangements in immunoglobulin genes are the source of the many different antibodies produced by the body.

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Control of Gene Expression

*A primary reason for control over gene expression is for the differenciation of cells and allocating specific functions to specific cells in the body during development.

1. The structure of chromatin can control gene expression. Highly condensed chromatin are usually heterochromatin and is hard to transcribe while loosely condensed chromatin are usually euchromatin, which are actively transcribed.
   • DNA methylation by methylation enzymes result in the the deactivation of genes. The methyl group group, -CH3, is normally attached to cytosine. This process can even result in genetic imprinting, or the permanent deactivation of certain genes at the start of development.
   • Histone acetylation is the process in which the acetyl group, -COCH3, is added to histone proteins. This alters their structure to loosen the nucleosome, which allows for more transcription and expression.
2. The control of gene expression occurs before transcription.
   • The existence of control elements, which are segments of noncoding DNA, can increase expression because they bind to transcription factors, which can stimulate transcription. A promoter is considered a control element.
     • A proximal control element is close to the promoter.
     • A distal control element is far from the promoter and is called an enhancer. Enhancers that initiate transcription are called activators.
   • Transcriptional factors have a DNA-binding domain, or region that allows for the binding to DNA, and another region for the binding to other transcription factors.
3. The control of gene expression can also occur after transcription.
   • During RNA processing, alternative RNA splicing can result in different combinations of processed mRNA. It all depends on what will be considered an exon and what will be an intron. This affects the protein produced and the expression of a gene.
   • The length of time in which mRNA continues to exist can affect expression. The longer they exist, the more they are expressed. In eukaryotes, the 5' cap and poly(A) tail prevents rapid degradation or the mRNA.
4. After transcription, translational control, protein degradation and processing account for expression control.
   • Regulatory proteins can render a mRNA molecule untranslatable.
   • After translation, some proteins require cleavage or chemical alterations in order to function.
   • The transport of proteins to their respective areas of function is also important.
   • Lastly, there is protein degradation, in which proteins are marked by ubiquitin and then disassembled by a complex known as a proteasome.

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The Molecular Biology of Cancer

1. In a cell, there are oncogenes that may cause cancer. At their normal state, cellular genes are referred to as proto-oncogenes. But three types of changes can result in the transformation of a normal cell into a malignant cell.
   • Translocation may alter gene expression and resulting proteins.
   • Amplification may result in rapid and excessive expression.
   • A mutation can result in a protein product is less prone to deactivation and degradation, thus being more active.
2. There are tumor-suppressor genes which function to prevent the outbreak of uncontrolled cell growth. However, if such a gene becomes mutated, then its function becomes reversed and tumors are more likely to occur.

*Examples of such occurrences include the ras gene, which participates in cell cycle stimulation, and the p53 gene, which aids in the repairing of damaged regions of DNA. p53 can even trigger apoptosis, or cell suicide.