Other pieces of genetic material incorporated in them–DNA transposons and insertion
Other pieces of genetic material incorporated in them–DNA transposons and insertion sequences with the help of the enzyme transposase (with or without maintaining a copy at the source), and retroelements with the help of the enzyme reverse transcriptase and integration into the DNA (always maintaining a copy at the source) [17,148]. As will be discussed later, one school of thought, associated with the traditional framework, has held that TEs are “selfish elements”–parasites of the genome–and that occasionally they are coopted by chance for other functions [5,6,149]. But we will see later how TEs can have PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27107493 the appearance of selfish elements yet be an inherent part of the mutational mechanisms that serve the evolution of the organism. Indeed, they donate every kind of functional element, including promoters, enhancers, splice sites, coding sequences and sequence motifs, and have an extraordinarily wide and deep range of evolutionary influences [15,17,148,150,151]. TE movement is not random. They have a wide range of preferences for target sites, some showing affinity to MG-132 cost certain chromosomes, others to loci distinguished by certain sequences, others to loci of a particular nucleotide composition, etc. [17,148]. It is also thought that TEs are involved in the formation of SDs/LCRs discussed before. Alus have been observed at the end-points of nearly 30 of the LCRs/SDs in humans [152,153], implying Alu-based homology is involved in their proliferation. Korbel et al. [146] and Kidd et al. [154] systematically analyzed structural (rearrangement) variation breakpoints in the human genome, and have found that almost all breakpoints analyzed have signatures of one of the four mechanisms above. As previous authors already noted [123,124], this means that the vast majority of rearrangements in humans are due to biological mechanisms whoseaction is directed by DNA sequence and structure and are therefore not random. We need only to add that this sequence and structure is itself evolving.Point mutation is nonrandomWe discussed rearrangement mutation above. The other general category of mutation is point mutation, nowadays referring to a single nucleotide change from one of the four kinds of nucleotide to another. Naturally, we used to think that these changes are random, but cutting edge research in molecular biology is showing that, as in the case of rearrangement mutation, a great deal of point mutation is nonrandom. Point mutations are not uniformly distributed at random across the genome, but instead the mutation rate per locus varies across the genome on all scales, from the single-base resolution through the gene scale and mega-base scale to the chromosome scale [155]. Many point mutations in humans are due to a change in the cytosine of CpG dinucleotides (dinucleotides where cytosine is adjacent to guanine in the 5′-CpG-3′ orientation) [156] that are spread out over the genome outside of the relatively narrow CpG-rich regions (themselves not experiencing this high rate of mutation; [157-159]). This change is due to methylation of the cytosine, which, in this CpG context, is the predominant target of DNA methylation in vertebrates [159,160]. The methylation is enzymatic and controlled by evolved machinery, and following deamination it leads to a CT mutation at a very high rate (reviewed in [155]). This high rate of transition is either because of chemical instability of the methylated cytosine, or due to an enzymatic process yet to be discov.
