An alteration in the sequence of purine and pyrimidine bases in a gene due to a change—a removal or an insertion—of one or more bases may result in an altered gene product or alteration of gene expression if nonprotein coding DNA is involved. Such insertions or deletions are termed indels.

Chromosomal Recombination Is One Way of Rearranging Genetic Material

 Genetic information can be exchanged between similar or homologous chromosomes. The exchange, or recombination event, occurs primarily during meiosis in mammalian cells and requires alignment of homologous metaphase chromosomes, an alignment that almost always occurs with great exactness. A process of chromosome (chromatid) crossing over occurs as shown in Figure 1. This usually results in an equal and reciprocal exchange of genetic information between homologous chromosomes. If the homologous chromosomes possess different alleles (ie, gene/DNA sequence variants) of the same genes, the crossover may produce noticeable and heritable genetic linkage differences. In the rare case where the alignment of homologous chromosomes is not exact, the crossing over, or recombination event, may result in an unequal exchange of information. One chromosome may receive less genetic material and thus a deletion, while the other partner of the chromosome pair receives more genetic material and thus an insertion or duplication. One well-studied example of unequal crossing that occurs in humans involves the genes encoding hemoglobins. Unequal crossing over results in a human hemoglobinopathy designated Lepore and anti-Lepore (Figure 2).

Fig1. The process of crossing over between homologous metaphase chromosomes to generate recombinant chromosomes.

Fig2. The process of unequal crossover in the region of the mammalian genome that harbors the structural genes encoding hemoglobins and the generation of the unequal recombinant products hemoglobin delta-beta Lepore and beta delta anti-Lepore. The examples given show the locations of the crossover regions within amino acid coding regions of the indicated genes (ie, β and δ globin genes). (Modified with permission from Clegg JB, Weatherall DJ: β0 Thalassemia: time for a reappraisal? Lancet 1974;304(7873):133-135.)

The farther apart any two genes are on an individual chromosome, the greater the likelihood of a crossover recombination event. This is the basis for genetic mapping methods. Unequal crossover affects tandem arrays of repeated DNAs whether they are related globin genes, as in Figure 2, or more abundant repetitive DNA. Unequal crossover through slippage in the base pairing can result in expansion or con traction in the copy number of the repeat family and may contribute to the expansion and fixation of variant members throughout the repeat array.

Some Viruses Chromosomally Integrate Their Genomes in Infected Cells

Some bacterial viruses (bacteriophages) are capable of recombining with the DNA of a bacterial host in such a way that the genetic information of the bacteriophage is incorporated in a linear fashion into the genetic information of the host. This integration, which is a form of recombination, occurs by the mechanism illustrated in Figure 3. The backbone of the circularized bacteriophage genome is broken, as is that of the DNA molecule of the host; the appropriate ends are resealed with the proper polarity. The bacteriophage DNA is figuratively straightened out (“linearized”) as it is integrated into the bacterial DNA molecule—frequently a closed circle as well. The site at which the bacteriophage genome integrates or recombines with the bacterial genome is chosen by one of two mechanisms. If the bacteriophage contains a DNA sequence homologous to a sequence in the host DNA molecule, then a recombination event analogous to that occurring between homologous chromosomes can occur. However, some bacteriophages synthesize proteins that bind specific sites on bacterial chromosomes to a nonhomologous site characteristic of the bacteriophage DNA molecule. Integration occurs at the site and is said to be “site specific.”

Fig3. The integration of a circular genome from a virus (with genes A, B, and C) into the DNA molecule of a host (with genes 1 and 2) and the consequent ordering of the genes.

Many animal viruses, particularly the oncogenic viruses— either directly or, in the case of RNA viruses such as HIV that causes AIDS, double-stranded DNA copies generated by the action of the viral RNA-dependent DNA polymerase, or reverse transcriptase—can be integrated into chromosomes of the mammalian cell. Integration of the viral DNA into the genome of the infected cells generally is not “site specific” but does display site preferences. Not surprisingly a subset of such integration events is mutagenic.

Transposition Can Produce Processed Genes

In eukaryotic cells, small DNA elements that clearly are not viruses are capable of transposing themselves in and out of the host genome in ways that affect the function of neigh boring DNA sequences. These mobile elements, sometimes called “jumping DNA,” or jumping genes, can carry flanking regions of DNA and, therefore, profoundly affect evolution. As mentioned earlier, the Alu family of moderately repeated DNA sequences has structural characteristics similar to the termini of retroviruses, which would account for the ability of the latter to move into and out of the mammalian genome.

Direct evidence for the transposition of other small DNA elements into the human genome has been provided by the discovery of “processed genes” for immunoglobulin molecules, α-globin molecules, and many others. These processed genes consist of DNA sequences identical or nearly identical to those of the messenger RNA for the appropriate gene product. That is, the 5′-nontranslated region, the coding region without intron representation, and the 3′ poly(A) tail are all present contiguously. This particular DNA sequence arrangement must have resulted from the reverse transcription of an appropriately processed messenger RNA molecule from which the intron regions had been removed and the poly(A) tail added. The only recognized mechanism that this reverse transcript could have used to integrate into the genome would have been a transposition event. In fact, these “processed genes” have short terminal repeats at each end, as do known transposed sequences in other organisms. In the absence of their transcription and thus genetic selection for function, many of the processed genes have been randomly altered through evolution so that they now contain nonsense codons that preclude their ability to encode a functional, intact protein even if they could be transcribed. Thus, such transposed sequences are referred to as “pseudogenes.”

Gene Conversion Produces Rearrangements

Besides unequal crossover and transposition, a third mechanism can effect rapid changes in the genetic material. Similar sequences on homologous or nonhomologous chromosomes may occasionally pair up and eliminate any mismatched sequences between them. This may lead to the accidental fixation of one variant or another throughout a family of repeated sequences and thereby homogenize the sequences of the members of repetitive DNA families. This process is referred to as gene conversion.

Sister Chromatids Exchange

 In diploid eukaryotic organisms such as humans, after cells progress through the DNA synthetic, or S phase of the mitotic cell cycle, they contain a tetraploid content of DNA. This is in the form of sister chromatids of chromo some pairs. Each of these sister chromatids contains identical genetic information since each is a product of the semiconservative replication of the original parent DNA molecule of that chromosome. Crossing over can occur between these genetically identical sister chromatids. Of course, these sister chromatid exchanges (Figure 4) have no genetic consequence as long as the exchange is the result of an equal crossover.

Fig4. Sister chromatid exchanges between human chromosomes. The exchanges are detectable by Giemsa staining of the chromosomes of cells replicated for two cycles in the presence of bromodeoxyuridine (BrdU; 5-Bromo-2′-deoxyuridine with a depiction of 5-Iodo-2′deoxyuridine). The arrows indicate some regions of exchange. DNA synthesized with the thymine analog BrdU appears black in this image. (Reproduced with permission from S Wolff and J Bodycote.)

Immunoglobulin Genes Rearrange

In mammalian cells, some interesting gene rearrangements occur normally during development and differentiation. For example, the VL and CL genes, which encode for the immunoglobulin G (IgG) light-chain variable (VL ) and constant (CL ) portions of the IgG light chain in a single IgG molecule, are widely separated in the germ line DNA. In the DNA of a differentiated IgG-producing (plasma) cell, the same VL and CL genes have been moved physically closer, and linked together in the genome within a single transcription unit. However, even then, this rearrangement of DNA during differentiation does not bring the VL and CL genes into contiguity in the DNA. Instead, the DNA contains an intron of about 1200 bp at or near the junction of the V and C regions. This intron sequence is transcribed into RNA along with the VL and CL exons, and the interspersed, intronic non IgG sequence information is removed from the RNA during its nuclear processing via mRNA splicing.

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مواضيع ذات صلة

Translation and protein production

Epigenetic Regulation of Transcription

Chromatin-Remodeling Complexes Help Activate or Repress Transcription

Activators Can Direct Histone Acetylation at Specific Genes

Repressors Can Direct Histone Deacetylation at Specific Genes

Formation of Heterochromatin Silences Gene Expression at Telomeres, near Centromeres, and in Other Regions

Multiprotein Complexes Form on Enhancers

Transcription Factor Interactions Increase Gene-Control Options

Structurally Diverse Activation and Repression Domains Regulate Transcription

Electrophoresis of Nucleic Acids

Regulation of Transcription Factor Activity

Activators Are Composed of Distinct Functional Domains