Inbred strain

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Inbred strains (also called inbred lines, or rarely for animals linear animals) are individuals of a particular species which are nearly identical to each other in genotype due to long inbreeding. A strain is inbred when it has undergone at least 20 generations of brother x sister or offspring x parent mating, at which point at least 98.6% of the loci in an individual of the strain will be homozygous, and each individual can be treated effectively as clones. Some inbred strains have been bred for over 150 generations, leaving individuals in the population to be isogenic in nature. [1] Inbred strains of animals are frequently used in laboratories for experiments where for the reproducibility of conclusions all the test animals should be as similar as possible. However, for some experiments, genetic diversity in the test population may be desired. Thus outbred strains of most laboratory animals are also available, where an outbred strain is a strain of an organism that is effectively wildtype in nature, where there is as little inbreeding as possible. [2]

Contents

Certain plants including the genetic model organism Arabidopsis thaliana naturally self-pollinate, which makes it quite easy to create inbred strains in the laboratory (other plants, including important genetic models such as maize require transfer of pollen from one flower to another). [3] [4]

In the lab

Inbred strains have been extensively used in research. Several Nobel Prizes have been awarded for work that probably could not have been done without inbred strains. This work includes Medawar's research on immune tolerance, Kohler and Milstein's development of monoclonal antibodies, and Doherty and Zinkernagel's studies of the major histocompatibility complex (MHC). [1]

Isogenic organisms have identical, or near identical genotypes. [5] which is true of inbred strains, since they normally have at least 98.6% similarity by generation 20. [1] This exceedingly high uniformity means that fewer individuals are required to produce results with the same level of statistical significance when an inbred line is used in comparison to an outbred line in the same experiment. [6]

Breeding of inbred strains is often towards specific phenotypes of interest such as behavioural traits like alcohol preference or physical traits like aging, or they can be selected for traits that make them easier to use in experiments like being easy to use in transgenic experiments. [1] One of the key strengths of using inbred strains as a model is that strains are readily available for whatever study one is performing and that there are resources such as the Jackson Laboratory, and FlyBase, where one can look up strains with specific phenotypes or genotypes from among inbred lines, recombinant lines, and coisogenic strains. The embryos of lines that are of little interest currently can be frozen and preserved until there is an interest in their unique genotypical or phenotypical traits. [7]

Recombinant inbred lines

QTL mapping using inbred strains QTL mapping using inbred strains.pdf
QTL mapping using inbred strains

For the analysis of the linkage of quantitative traits, recombinant lines are useful because of their isogenic nature, because the genetic similarity of individuals allows for the replication of a quantitative trait locus analysis. The replication increases the precision of the results from the mapping experiment, and is required for traits such as aging where minor changes in the environment can influence the longevity of an organism, leading to variation in results. [8]

Coisogenic strain

One type of inbred strain that either has been altered, or naturally mutated so that it is different at a single locus. [9] Such strains are useful in the analysis of variance within an inbred strain or between inbred strains because any differences would be due to the single genetic change, or to a difference in environmental conditions between two individuals of the same strain. [8]

Gal4 lines

One of the more specific uses of Drosophila inbred strains is the use of Gal4/UAS lines in research. [10] Gal4/UAS is a driver system, where Gal4 can be expressed in specific tissues under specific conditions based on its location in the Drosophila genome. Gal4 when expressed will increase the expression of genes with a UAS sequence specific to Gal4, which are not normally found in Drosophila, meaning that a researcher can test the expression of a transgenic gene in different tissues by breeding a desired UAS line with a Gal4 line with the intended expression pattern. Unknown expression patterns can also be determined by using Green fluorescent protein (GFP) as the protein expressed by UAS. Drosophila in particular has thousands of Gal4 lines with unique and specific expression patterns, making it possible to test most expression patterns within the organism. [10]

Effects

Inbreeding animals will sometimes lead to genetic drift. The continuous overlaying of like genetics exposes recessive gene patterns that often lead to changes in reproduction performance, fitness, and ability to survive. A decrease in these areas is known as inbreeding depression. A hybrid between two inbred strains can be used to cancel out deleterious recessive genes resulting in an increase in the mentioned areas. This is known as heterosis. [11]

Inbred strains, because they are small populations of homozygous individuals, are susceptible to the fixation of new mutations through genetic drift. Jackson Laboratory, in an information session on the genetic drift in mice, calculated a quick estimate of the rate of mutation based on observed traits to be 1 phenotypic mutation every 1.8 generations, though they caution that this is likely an under-representation because the data they used was for visible phenotypic changes and not phenotype changes inside of mice strains. They further add that statistically every 6-9 generations, a mutation in the coding sequence is fixed, leading to the creation of a new substrain. Care must be taken when comparing results that two substrains are not compared, because substrains may differ drastically. [12]

Notable species

Rats and mice

"The period before World War I led to the initiation of inbreeding in rats by Dr Helen King in about 1909 and in mice by Dr C. C. Little in 1909. The latter project led to the development of the DBA strain of mice, now widely distributed as the two major sub-strains DBA/1 and DBA/2, which were separated in 1929-1930. DBA mice were nearly lost in 1918, when the main stocks were wiped out by murine paratyphoid, and only three un-pedigreed mice remained alive. Soon after World War I, inbreeding in mice was started on a much larger scale by Dr L. C. Strong, leading in particular to the development of strains C3H and CBA, and by Dr C. C. Little, leading to the C57 family of strains (C57BL, C57BR and C57L). Many of the most popular strains of mice were developed during the next decade, and some are closely related. Evidence from the uniformity of mitochondrian DNA suggests that most of the common inbred mouse strains were probably derived from a single breeding female about 150–200 years ago."

"Many of the most widely used inbred strains of rats were also developed during this period, several of them by Curtis and Dunning at the Columbia University Institute for Cancer Research. Strains dating back to this time include F344, M520 and Z61 and later ACI, ACH, A7322 and COP. Tryon's classic work on selection for maze-bright and dull rats led to the development of the TMB and TMD inbred strains, and later to the common use of inbred rats by experimental psychologists." [7]

Rats

  • Wistar as a generic name for inbred strains such as Wistar-Kyoto, developed from the Wistar outbred strains.
  • The Rat Genome Database maintains the current list of inbred rat lines and their characteristics.

Mice

The numerous inbred strains of mice have been mapped extensively. [1] A genealogical chart building on those relationships is actively maintained by the Jackson Laboratory, [7] and can be found on their website. [13]

Guinea pigs

G. M. Rommel first started conducting inbreeding experiments on guinea pigs in 1906. Strain 2 and 13 guinea pigs, were derived from these experiments and are still in use today. Sewall Wright took over the experiment in 1915. He was faced with the task of analyzing all of the accumulated data produced by Rommel. Wright became seriously interested in constructing a general mathematical theory of inbreeding. By 1920 Wright had developed his method of path coefficients, which he then used to develop his mathematical theory of inbreeding. Wright introduced the inbreeding coefficient F as the correlation between uniting gametes in 1922, and most of the subsequent theory of inbreeding has been developed from his work. The definition of the inbreeding coefficient now most widely used is mathematically equivalent to that of Wright. [7]

Medaka

The Japanese Medaka fish has a high tolerance for inbreeding, one line having been bred brother-sister for as many as 100 generations without evidence of inbreeding depression, providing a ready tool for laboratory research and genetic manipulations. Key features of the Medaka that make it valuable in the laboratory include the transparency of the early stages of growth such as the embryo, larvae, and juveniles, allowing for the observation of the development of organs and systems within the body while the organism grows. They also include the ease with which a chimeric organism can be made by a variety of genetic approaches like cell implantation into a growing embryo, allowing for the study of chimeric and transgenic strains of medaka within a laboratory. [14]

Zebrafish

Though there are many traits about zebrafish that are worthwhile to study including their regeneration, there are relatively few inbred strains of zebrafish possibly because they experience greater effects from inbreeding depression than mice or Medaka fish, but it is unclear if the effects of inbreeding can be overcome so an isogenic strain can be created for laboratory use. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Model organism</span> Organisms used to study biology across species

A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Model organisms are widely used to research human disease when human experimentation would be unfeasible or unethical. This strategy is made possible by the common descent of all living organisms, and the conservation of metabolic and developmental pathways and genetic material over the course of evolution.

<span class="mw-page-title-main">Inbreeding</span> Reproduction by closely related organisms

Inbreeding is the production of offspring from the mating or breeding of individuals or organisms that are closely related genetically. By analogy, the term is used in human reproduction, but more commonly refers to the genetic disorders and other consequences that may arise from expression of deleterious recessive traits resulting from incestuous sexual relationships and consanguinity. Animals avoid inbreeding only rarely.

<span class="mw-page-title-main">ENU</span> Chemical compound

ENU, also known as N-ethyl-N-nitrosourea (chemical formula C3H7N3O2), is a highly potent mutagen. For a given gene in mice, ENU can induce 1 new mutation in every 700 loci. It is also toxic at high doses.

Heterosis, hybrid vigor, or outbreeding enhancement is the improved or increased function of any biological quality in a hybrid offspring. An offspring is heterotic if its traits are enhanced as a result of mixing the genetic contributions of its parents. The heterotic offspring often has traits that are more than the simple addition of the parents' traits, and can be explained by Mendelian or non-Mendelian inheritance. Typical heterotic/hybrid traits of interest in agriculture are higher yield, quicker maturity, stability, drought tolerance etc.

Backcrossing is a crossing of a hybrid with one of its parents or an individual genetically similar to its parent, to achieve offspring with a genetic identity closer to that of the parent. It is used in horticulture, animal breeding, and production of gene knockout organisms.

<span class="mw-page-title-main">Laboratory mouse</span> Mouse used for scientific research

The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory mice are usually of the species Mus musculus. They are the most commonly used mammalian research model and are used for research in genetics, physiology, psychology, medicine and other scientific disciplines. Mice belong to the Euarchontoglires clade, which includes humans. This close relationship, the associated high homology with humans, their ease of maintenance and handling, and their high reproduction rate, make mice particularly suitable models for human-oriented research. The laboratory mouse genome has been sequenced and many mouse genes have human homologues. Lab mice are sold at pet stores for snake food and can also be kept as pets.

<span class="mw-page-title-main">Laboratory rat</span> Rat used for scientific research

Laboratory rats or lab rats are strains of the rat subspecies Rattus norvegicus domestica which are bred and kept for scientific research. While less commonly used for research than laboratory mice, rats have served as an important animal model for research in psychology and biomedical science.

Ectopic is a word used with a prefix ecto-, meaning “out of”, and the suffix -topic, meaning "place." Ectopic expression is an abnormal gene expression in a cell type, tissue type, or developmental stage in which the gene is not usually expressed. The term ectopic expression is predominantly used in studies using metazoans, especially in Drosophila melanogaster for research purposes.

<span class="mw-page-title-main">Japanese rice fish</span> Species of fish

The Japanese rice fish, also known as the medaka, is a member of genus Oryzias (ricefish), the only genus in the subfamily Oryziinae. This small native of Japan is a denizen of rice paddies, marshes, ponds, slow-moving streams and tide pools. It is euryhaline, occurring in both brackish and freshwater. It became popular as an aquarium fish because of its hardiness and pleasant coloration: its coloration varies from creamy-white to yellowish in the wild to white, creamy-yellow, or orange in aquarium-bred individuals. Bright yellow, red or green transgenic populations, similar to GloFish, have also been developed, but are banned from sale in the EU. The medaka has been a popular pet since the 17th century in Japan. After fertilization, the female carries her eggs attached anterior to the anal fin for a period before depositing them on plants or similar things.

<span class="mw-page-title-main">C57BL/6</span> Common strain of laboratory mouse

C57BL/6, often referred to as "C57 black 6", "B6", "C57" or "black 6", is a common inbred strain of laboratory mouse.

In genetics, two organisms that differ in only one locus and a linked segment of chromosome are defined as congenic. Similarly, organisms that are coisogenic differ in one locus only and not in the surrounding chromosome. Unlike congenic organisms, coisogenic organisms cannot be bred and only occur through spontaneous or targeted mutation at the locus.

<span class="mw-page-title-main">BALB/c</span> Laboratory-bred strain of the house mouse

BALB/c is an albino, laboratory-bred strain of the house mouse from which a number of common substrains are derived. Now over 200 generations from New York in 1920, BALB/c mice are distributed globally, and are among the most widely used inbred strains used in animal experimentation.

<span class="mw-page-title-main">History of model organisms</span>

The history of model organisms began with the idea that certain organisms can be studied and used to gain knowledge of other organisms or as a control (ideal) for other organisms of the same species. Model organisms offer standards that serve as the authorized basis for comparison of other organisms. Model organisms are made standard by limiting genetic variance, creating, hopefully, this broad applicability to other organisms.

<span class="mw-page-title-main">GAL4/UAS system</span> Biochemical method

The GAL4-UAS system is a biochemical method used to study gene expression and function in organisms such as the fruit fly. It is based on the finding by Hitoshi Kakidani and Mark Ptashne, and Nicholas Webster and Pierre Chambon in 1988 that Gal4 binding to UAS sequences activates gene expression. The method was introduced into flies by Andrea Brand and Norbert Perrimon in 1993 and is considered a powerful technique for studying the expression of genes. The system has two parts: the Gal4 gene, encoding the yeast transcription activator protein Gal4, and the UAS, an enhancer to which GAL4 specifically binds to activate gene transcription.

<span class="mw-page-title-main">Neurogenetics</span> Study of role of genetics in the nervous system

Neurogenetics studies the role of genetics in the development and function of the nervous system. It considers neural characteristics as phenotypes, and is mainly based on the observation that the nervous systems of individuals, even of those belonging to the same species, may not be identical. As the name implies, it draws aspects from both the studies of neuroscience and genetics, focusing in particular how the genetic code an organism carries affects its expressed traits. Mutations in this genetic sequence can have a wide range of effects on the quality of life of the individual. Neurological diseases, behavior and personality are all studied in the context of neurogenetics. The field of neurogenetics emerged in the mid to late 20th century with advances closely following advancements made in available technology. Currently, neurogenetics is the center of much research utilizing cutting edge techniques.

A recombinant inbred strain or recombinant inbred line (RIL) is an organism with chromosomes that incorporate an essentially permanent set of recombination events between chromosomes inherited from two or more inbred strains. F1 and F2 generations are produced by intercrossing the inbred strains; pairs of the F2 progeny are then mated to establish inbred strains through long-term inbreeding.

Genetic ablation occurs when a gene is deemed “null” through the homologous genetic recombination of a gene. It is utilized in the selective suppression of a specific cell line or cell type. This genetic engineering technique does not limit growth suppression to just the activity of an individual gene. Specific cell ablation enables the examination of the in vivo activity of cells. An example of this method in action can be seen through the production of a knockout mouse. This is accomplished through the administration of one or more transgenes into a fertilized mouse oocyte’s pronucleus. Afterwards, it is reimplanted into a host mother, who then births a transgenic mouse. The transgenic mouse carries one copy of the transgene3 out of several hundred. From these mice, a homozygous colony can be created through breeding.

A behaviour mutation is a genetic mutation that alters genes that control the way in which an organism behaves, causing their behavioural patterns to change.

Q-system is a genetic tool that allows to express transgenes in a living organism. Originally the Q-system was developed for use in the vinegar fly Drosophila melanogaster, and was rapidly adapted for use in cultured mammalian cells, zebrafish, worms and mosquitoes. The Q-system utilizes genes from the qa cluster of the bread fungus Neurospora crassa, and consists of four components: the transcriptional activator (QF/QF2/QF2w), the enhancer QUAS, the repressor QS, and the chemical de-repressor quinic acid. Similarly to GAL4/UAS and LexA/LexAop, the Q-system is a binary expression system that allows to express reporters or effectors in a defined subpopulation of cells with the purpose of visualising these cells or altering their function. In addition, GAL4/UAS, LexA/LexAop and the Q-system function independently of each other and can be used simultaneously to achieve a desired pattern of reporter expression, or to express several reporters in different subsets of cells.

<span class="mw-page-title-main">Mouse Models of Human Cancer database</span> Database of mouse models of human cancer

The laboratory mouse has been instrumental in investigating the genetics of human disease, including cancer, for over 110 years. The laboratory mouse has physiology and genetic characteristics very similar to humans providing powerful models for investigation of the genetic characteristics of disease.

References

  1. 1 2 3 4 5 Beck, Jon A.; Lloyd, Sarah; Hafezparast, Majid; Lennon-Pierce, Moyha; Eppig, Janan T.; Festing, Michael F. W.; Fisher, Elizabeth M. C. (January 2000). "Genealogies of mouse inbred strains". Nature Genetics. 24 (1): 23–25. doi:10.1038/71641. ISSN   1546-1718. PMID   10615122. S2CID   9173641.
  2. ↑ "Outbred Stocks". Isogenic. Retrieved 28 November 2017.
  3. ↑ Roderick TH, Schlager G (1966). "Multiple Factor Inheritance". In Green EL (ed.). Biology of the Laboratory Mouse. New York: McGraw-Hill. p. 156. LCCN   65-27978.
  4. ↑ Lyon MF (1981). "Rules for Nomenclature of Inbred Strains". In Green, Margaret C. (ed.). Genetic Variants and Strains of the Laboratory Mouse. Stuttgart: Gustav Fischer Verlag. p. 368. ISBN   0-89574-152-0.
  5. ↑ "Isogenic". Merriam-Webster. Retrieved 18 November 2017.
  6. ↑ "Increased statistical power". isogenic.info. Retrieved 2017-11-30.
  7. 1 2 3 4 Michael Festing. "History of inbred strains". isogenic.info. Retrieved 2013-12-19.
  8. 1 2 Dixon LK (1993). "Use of recombinant inbred strains to map genes of aging". Genetica. 91 (1–3): 151–65. doi:10.1007/BF01435995. PMID   8125266. S2CID   6943500.
  9. ↑ Bult CJ, Eppig JT, Blake JA, Kadin JA, Richardson JE (January 2016). "Mouse genome database 2016". Nucleic Acids Research. 44 (D1): D840-7. doi:10.1093/nar/gkv1211. PMC   4702860 . PMID   26578600.
  10. 1 2 Duffy JB (2002-09-01). "GAL4 system in Drosophila: a fly geneticist's Swiss army knife". Genesis. 34 (1–2): 1–15. doi: 10.1002/gene.10150 . PMID   12324939.
  11. ↑ Michael Festing. "Inbreeding & it's[sic] effects" . Retrieved 2013-12-19.
  12. ↑ "Genetic Drift: What It Is and Its Impact on Your Research" (PDF). The Jackson Laboratory. Retrieved 18 November 2017.
  13. ↑ "Genealogies of mouse inbred strains" (PDF). nature genetics.
  14. ↑ Kirchmaier S, Naruse K, Wittbrodt J, Loosli F (April 2015). "The genomic and genetic toolbox of the teleost medaka (Oryzias latipes)". Genetics. 199 (4): 905–18. doi:10.1534/genetics.114.173849. PMC   4391551 . PMID   25855651.
  15. ↑ Shinya M, Sakai N (October 2011). "Generation of highly homogeneous strains of zebrafish through full sib-pair mating". G3. 1 (5): 377–86. doi:10.1534/g3.111.000851. PMC   3276154 . PMID   22384348.
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