Gene duplication in the context of Genetic mutations

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA (such as pyrimidine dimers caused by exposure to ultraviolet radiation), which then may undergo error-prone repair (especially microhomology-mediated end joining), cause an error during other forms of repair, or cause an error during replication (translesion synthesis). Mutations may also result from substitution, insertion or deletion of segments of DNA due to mobile genetic elements.

Mutations may or may not produce detectable changes in the observable characteristics (phenotype) of an organism. Mutations play a part in both normal and abnormal biological processes including: evolution, cancer, and the development of the immune system, including junctional diversity. Mutation is the ultimate source of all genetic variation, providing the raw material on which evolutionary forces such as natural selection can act.

Divergent evolution or divergent selection is the accumulation of differences between closely related populations within a species, sometimes leading to speciation. Divergent evolution is typically exhibited when two populations become separated by a geographic barrier (such as in allopatric or peripatric speciation) and experience different selective pressures that cause adaptations. After many generations and continual evolution, the populations become less able to interbreed with one another. The American naturalist J. T. Gulick (1832–1923) was the first to use the term "divergent evolution", with its use becoming widespread in modern evolutionary literature. Examples of divergence in nature are the adaptive radiation of the finches of the Galápagos, changes in mobbing behavior of the kittiwake, and the evolution of the modern-day dog from the wolf.

The term can also be applied in molecular evolution, such as to proteins that derive from homologous genes. Both orthologous genes (resulting from a speciation event) and paralogous genes (resulting from gene duplication) can illustrate divergent evolution. Through gene duplication, it is possible for divergent evolution to occur between two genes within a species. Similarities between species that have diverged are due to their common origin, so such similarities are homologies.

Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and the evolution of those cells by natural selection in the body. Only certain mutations lead to cancer whereas the majority of mutations do not.

Variants of inherited genes may predispose individuals to cancer. In addition, environmental factors such as carcinogens and radiation cause mutations that may contribute to the development of cancer. Finally random mistakes in normal DNA replication may result in cancer-causing mutations. A series of several mutations to certain classes of genes is usually required before a normal cell will transform into a cancer cell. Recent comprehensive patient-level classification and quantification of driver events in TCGA cohorts revealed that there are on average 12 driver events per tumor, of which 0.6 are point mutations in oncogenes, 1.5 are amplifications of oncogenes, 1.2 are point mutations in tumor suppressors, 2.1 are deletions of tumor suppressors, 1.5 are driver chromosome losses, 1 is a driver chromosome gain, 2 are driver chromosome arm losses, and 1.5 are driver chromosome arm gains. Mutations in genes that regulate cell division, apoptosis (cell death), and DNA repair may result in uncontrolled cell proliferation and cancer.

Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speciation event (orthologs), or a duplication event (paralogs), or else a horizontal (or lateral) gene transfer event (xenologs).

Homology among DNA, RNA, or proteins is typically inferred from their nucleotide or amino acid sequence similarity. Significant similarity is strong evidence that two sequences are related by evolutionary changes from a common ancestral sequence. Alignments of multiple sequences are used to indicate which regions of each sequence are homologous.

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 (human epidermal growth factor receptor 2) or CD340 (cluster of differentiation 340).

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. But contrary to other members of the ERBB family, HER2 does not directly bind ligand. HER2 activation results from heterodimerization with another ERBB member or by homodimerization when HER2 concentration are high, for instance in cancer. Amplification or over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.

In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like deletions, duplications, inversions, and translocations. Usually, these events are caused by a breakage in the DNA double helices at two different locations, followed by a rejoining of the broken ends to produce a new chromosomal arrangement of genes, different from the gene order of the chromosomes before they were broken. Structural chromosomal abnormalities are estimated to occur in around 0.5% of newborn infants.

Some chromosomal regions are more prone to rearrangement than others and thus are the source of genetic diseases and cancer. This instability is usually due to the propensity of these regions to misalign during DNA repair, exacerbated by defects of the appearance of replication proteins (like FEN1 or Pol δ) that ubiquitously affect the integrity of the genome.Complex chromosomal rearrangements (CCR) are rarely seen in the general population and are defined as structural chromosomal rearrangements with at least three breakpoints with exchange of genetic material between two or more chromosomes. Some forms of campomelic dysplasia, for example, result from CCRs.

Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of functional genes, either directly by gene duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are usually identified when genome sequence analysis finds gene-like sequences that lack regulatory sequences or are incapable of producing a functional product. Pseudogenes are a type of junk DNA.

Most non-bacterial genomes contain many pseudogenes, often as many as functional genes. This is not surprising, since various biological processes are expected to accidentally create pseudogenes, and there are no specialized mechanisms to remove them from genomes. Eventually pseudogenes may be deleted from their genomes by chance of DNA replication or DNA repair errors, or they may accumulate so many mutational changes that they are no longer recognizable as former genes. Analysis of these degeneration events helps clarify the effects of non-selective processes in genomes.