[edit] Mutation

Main article: Mutation

DNA replication is for the most part extremely accurate, with an error rate per site of around 10^-6 to 10^-10 in eukaryotes.^[16] Rare, spontaneous alterations in the base sequence of a particular gene arise from a number of sources, such as errors in DNA replication and the aftermath of DNA damage. These errors are called mutations. The cell contains many DNA repair mechanisms for preventing mutations and maintaining the integrity of the genome; however, in some cases—such as breaks in both DNA strands of a chromosome — repairing the physical damage to the molecule is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of the protein for which they code; for example, the codons UCU and UUC both code for serine, so the U↔C mutation has no effect on the protein. Mutations that do have phenotypic effects are most often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's fitness.

Mutations propagated to the next generation lead to variations within a species' population. Variants of a single gene are known as alleles, and differences in alleles may give rise to differences in traits. Although it is rare for the variants in a single gene to have clearly distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants. However, this does not imply that the wild-type allele is the ancestor from which the mutants are descended.

[edit] Genome

[edit] Chromosomal organization

The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes called chromosomes. Genes that appear together on one chromosomes of one species may appear on separate chromosomes in another species. Many species carry more than one copy of their genome within each of their somatic cells. Cells or organisms with only one copy of each chromosome are called haploid; those with two copies are called diploid; and those with more than two copies are called polyploid. The copies of genes on the chromosomes are not necessarily identical. In sexually reproducing organisms, one copy is normally inherited from each parent.

[edit] Number of genes

Early estimates of the number of human genes that used expressed sequence tag data put it at 50 000–100 000.^[17] Following the sequencing of the human genome and other genomes, it has been found that rather few genes (~20 000 in human, mouse and fly, ~13 000 in roundworm, >46 000 in rice) encode all the proteins in an organism.^[18] These protein-coding sequences make up 1–2% of the human genome.^[19] Most of the genome gives rise to RNA products however, but not much is known about the function of these non-coding RNAs.^[18][19]

[edit] Genetic and genomic nomenclature

Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation). All approved symbols are stored in the HGNC Database. Each symbol is unique and each gene is only given one approved gene symbol. It is necessary to provide a unique symbol for each gene so that people can talk about them. This also facilitates electronic data retrieval from publications. In preference each symbol maintains parallel construction in different members of a gene family and can be used in other species, especially the mouse.

[edit] Evolutionary concept of a gene

George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when we are talking about natural selection favoring some genes. The definition is: "that which segregates and recombines with appreciable frequency." According to this definition, even an asexual genome could be considered a gene, insofar that it have an appreciable permanency through many generations.

The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit.

Richard Dawkins' books The Selfish Gene (1976) and The Extended Phenotype (1982) defended the idea that the gene is the only replicator in living systems. This means that only genes transmit their structure largely intact and are potentially immortal in the form of copies. So, genes should be the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection by describing life as a river of compatible genes flowing through geological time. Scoop up a bucket of genes from the river of genes, and we have an organism serving as temporary bodies or survival machines. A river of genes may fork into two branches representing two non-interbreeding species as a result of geographical separation.

[edit] Gene targeting and implications

Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and provides the mouse models for studying the roles of individual genes in embryonic development, human disorders, aging and diseases. The mouse models, where one or more of its genes are deactivated or made inoperable, are called knockout mice. Since the first reports in which homologous recombination in embryonic stem cells was used to generate gene-targeted mice,^[20] gene targeting has proven to be a powerful means of precisely manipulating the mammalian genome, producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.^[21][22]

Gene targeting strategies have been expanded to all kinds of modifications, including point mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It is predicted that the ability to generate mouse models with predictable phenotypes will have a major impact on studies of all phases of development, immunology, neurobiology, oncology, physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species from which totipotent embryonic stem cells can be established, and therefore may offer a potential to the improvement of domestic animals and plants.^[22][23]

[edit] Changing concept

The concept of the gene has changed considerably (see history section). From the original definition of a "unit of inheritance", the term evolved to mean a DNA-based unit that can exert its effects on the organism through RNA or protein products. It was also previously believed that one gene makes one protein; this concept was overthrown by the discovery of alternative splicing and trans-splicing.^[6]

The definition of a gene is still changing. The first cases of RNA-based inheritance have been discovered in mammals.^[11] Evidence is also accumulating that the control regions of a gene do not necessarily have to be close to the coding sequence on the linear molecule or even on the same chromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.^[24]

The concept that genes are clearly delimited is also being eroded. There is evidence for fused proteins stemming from two adjacent genes that can produce two separate protein products. While it is not clear whether these fusion proteins are functional, the phenomena is more frequent than previously thought.^[25] Even more ground-breaking than the discovery of fused genes is the observation that some proteins can be composed of exons from far away regions and even different chromosomes.^[26][2] This new data has led to an updated, and probably tentative, definition of a gene as "a union of genomic sequences encoding a coherent set of potentially overlapping functional products."^[6] This new definition categorizes genes by functional products, whether they be proteins or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as gene-associated regions.^[6]

[edit] See also

[edit] References

[edit] Further reading

• Dawkins, Richard (1990). The Selfish Gene. Oxford University Press. ISBN 0-19-286092-5.  Google Book Search; first published 1976.
• Dawkins, Richard (1995). River Out of Eden. Basic Books. ISBN 0-465-06990-8. 
• Ridley, Matt (1999). Genome: The Autobiography of a Species in 23 Chapters. Fourth Estate. ISBN 0-00-763573-7. 

[edit] External links

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• Comparative Toxicogenomics Database
• DNA From The Beginning - a primer on genes and DNA
• Entrez Gene - a searchable database of genes
• IDconverter - converts gene IDs between public databases
• iHOP - Information Hyperlinked over Proteins