A recombinant inbred strain (or recombinant inbred line) is an organism with chromosomes that incorporate an essentially permanent set of recombination events between chromosomes inherited from two or more inbred strain

Inbred strain

Inbred strains are individuals of a particular species which are nearly identical to each other in genotype due to long inbreeding. Inbred strains of animals are frequently used in laboratories for experiments where for reproducibility of conclusions all the test animals should be as similar as...

s. Families of recombinant inbred strains numbering from 25 to 5000 are often used to map the locations of DNA sequence differences (quantitative trait loci) that contributed to differences in phenotype

Phenotype

A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

 in model organisms. Recombinant inbred strains or lines were first developed using inbred strains of mice but are now used to study a wide range of organisms – Saccharomyces cerevisiae

Saccharomyces cerevisiae

Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

(yeast), Zea mays (maize), barley

Barley

Barley is a major cereal grain, a member of the grass family. It serves as a major animal fodder, as a base malt for beer and certain distilled beverages, and as a component of various health foods...

, Drosophila melanogaster

Drosophila melanogaster

Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

, C. elegans

Caenorhabditis elegans

Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...

and rat

Rat

Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

.

History

The origins and history of recombinant inbred strains are described by Crow. While the potential utility of recombinant inbred strains is mapping analysis of complex polygenic traits was obvious from the outset, the small number of strains only made it feasible to map quantitative traits with very large effects (quasi-Mendelian loci). One of the initial motivations to use recombinant inbred strains is that expensive genotype data can be accumulated and reused – greatly simplifying mapping studies. Another factor is the precision of mapping that can be achieved using these strains compared to typical F2 intercross progeny.

As genotyping became progressively less expensive and more accurate the main advantage of using recombinant inbred strains and other genetic reference panels shifted to the ability to assemble massive and coherent databases on phenotypes (e.g., the GeneNetwork

Genenetwork

GeneNetwork is a database and open source bioinformatics software resource for systems genetics. This resource is used to study gene regulatory networks that link DNA sequence variants to corresponding differences in gene and protein expression and to differences in traits such as health and...

 web service), and to use these coherent open-source data sets for large-scale collaborative research projects in predictive medicine

Predictive medicine

Predictive medicine is a rapidly emerging field of medicine that entails predicting disease and instituting preventive measures in order to either prevent the disease altogether or significantly decrease its impact upon the patient...

 and plant and animal research.

Use

Recombinant inbred strains are now widely used in systems genetics and to study gene-environmental interactions. . It is possible to accumulate extensive genetic and phenotype

Phenotype

A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

 data for each member of a family of recombinant inbred strains under several different conditions (e.g., baseline environment versus stressful environment). Each strain has a single fixed genome and it is also possible to resample a given genotype multiple times in multiple environments to obtain highly accurate estimates of genetic and environmental effects and their interactions.

Genetics

Chromosomes of recombinant inbred strains typically consist of alternating haplotypes of highly variable length that are inherited intact from the parental strains. In the case of a typical mouse recombinant inbred strain made by crossing maternal strain BALB/cBy (C) with paternal strain C57BL/6By (B) called a CXB recombinant inbred strain, a chromosome will typically incorporate 2 to 5 alternating haplotype

Haplotype

A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...

 blocks with underlying genotypes such as BBBBBCCCCBBBCCCCCCCC, where each letter represents a single genotype

Genotype

The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

 (e.g. a SNP), where series of identical genotypes represent haplotypes, and where a transition between haplotypes represents a recombination event between the parental genomes. Both pairs of each chromosome will have the same alternating pattern of haplotypes, and all markers will be homozygous. Each of the different chromosomes (Chr 1, Chr 2, etc.) will have a different pattern of haplotypes and recombinations. The only exception is that the Y chromosome and the mitochondial genome, both of which are inherited intact from the paternal and maternal strain, respectively. For an RI strain to be useful for mapping purposes, the approximate position of recombinations along each chromosome need to be well defined either in terms of centimorgan or DNA basepair position. The precision with which these recombinations are mapped is a function of the number and position of the genotypes used to type the chromosomes – 20 in the example above.

Mapping

All else being equal, the larger the family of recombinant inbred strains, the greater the power and resolution with which phenotypes can be mapped to chromosomal locations. The first set of eight strains, the CXB family, were generated by Donald Bailey at the Jackson Laboratory from an intercross between a female BALB/cBy mouse (abbreviated C) and a male C57BL/6By mouse in the 1960s. The small panel of 8 CXB strains was originally used to determine if the Major Histocompatibility (MHC) locus on proximal chromosome 17 was a key factor in different immune responses such as tissue rejection. The methods used to determine the locations of recombinations relied on visible markers (coat color phenotypes such as the C and B loci) and the electrophoretic mobility of proteins. Somewhat larger families of recombinant inbred strains were generated concurrently by Benjamin Taylor to map Mendelian and other major effect loci. In the 1990s the utility of recombinant inbred strains for mapping was significantly improved thanks to higher density genotypes made possible by the use of microsatellite markers. Between 2005 and 2007, virtually all extant mouse and rat recombinant inbred strains were regenotyped at many thousands of SNP markers, providing highly accurate maps of recombinations.