Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 54

Inbreeding is well known to concentrate deleterious mutations. Most commonly inbreeding depression is due to the creation of homozygous recessive pathogenic or maladaptive genotypes but also loss of the fitness advantage of heterozygosity due to overdominance.

Most people are familiar with the “Royal disease,” hemophilia B, that affected males of European royalty (https://www.sciencemag.org/news/2009/10/case‐closed‐famous‐royals‐suffered‐hemophilia#:~:text=Now%2C%20new%20DNA%20analysis%20on,subtype%20known%20as%20hemophilia%20B.&text=Such%20was%20the%20case%20with,heir%20to%20the%20Russian%20throne). The same thing happens with laboratory mice. However, with a uniform genetic background combined with strict environmental controls and pathogen free status it is possible to minimize variables to test very specific parameters in a statistically efficient way. It is easier to identify a genetic component to a trait when the population under investigation is effectively one of 150 identical twins rather than 150 unrelated individuals. This comes at a cost (Table 3.3); many lines are lost during inbreeding as they can be hard to maintain due to poor breeding efficiency and impacted by strain‐specific genetic diseases, all of which lead to increased expense compared to use of outbred mice. For example, the commonly used C3H/HeJ inbred strain has a short breeding time (around five months of age) due to the females having a high frequency of ovarian cysts and tumors [6]. There are, however, some advantages of specifically outbred populations such as the Collaborative Cross discussed below.

Figure 3.1 Top, searching p53 SNPs reveals “The gene you selected is not in the database.” An MGI search (bottom) reveals the current, correct symbol is Trp53 which does yield data in the Sanger database. Source: Wellcome Sanger Institute.

Inbred strains are developed by first mating a female (note that in mouse genetics, the female information is usually listed first) and male of disparate or even unknown backgrounds. From their progeny, one breeding pair is selected for breeding, and again one breeding pair is selected from their offspring. This is repeated for 20 generations (written F20 for filial generation 20) at which point the genome is mathematically about 99% homogeneous at all loci. At this point, the mice produced are considered to be an incipient inbred strain, and at F60, a fully inbred strain. In the process, many sublines will not reproduce, produce nonviable progeny, or develop other phenotypic problems making them difficult to maintain.

The first inbred strain, the DBA, was begun in 1909 by C.C. Little, the founder of The Jackson Laboratory (http://www.informatics.jax.org/morsebook/chapters/russell.shtml). These mice were produced by crosses with a stock of mice that carried three different coat colors, dilute (d), brown (b), and non‐agouti (a), the letters of which designated the genes for these different colors [7]. This provides insight into the inbred strain names. The names are always in capital letters and not italicized and can represent coat color (C57BL where BL stands for black), origin of the strain or the person who created it (SJL: Swiss, Jim Lambert), or the phenotype (NOD: non‐obese diabetic or NON: non‐obese non‐diabetic). The line numbers were designated by the creator of the line. For example, C.C. Little mated female 57 and female 58 to male 52 (line C descended from Lathrop's stock) resulting in the C57 and C58 lines (http://www.informatics.jax.org/morsebook/chapters/russell.shtml). A laboratory (lab) code is a 1–5 letters long symbol representing an investigator or institution that is registered with the Institute for Laboratory Animal Research (ILAR). Lab codes are assigned to alleles and strains to designate who made them (Table 3.4).

While the full‐inbred strain designation is important, many of the most commonly used inbred strain names have been assigned official abbreviations (Figure 3.4), to incorporate in derivative strains as described below. Many investigators use abbreviations, often incorrectly, in their publications. Some of the most common mistakes are to use B for BALB/cJ (correct is C) or B6 for any undefined C57BL substrain. Thus, it is often best for investigators to use official strain designations in the methods section of a publication.