Natural History of House Mice

by on February 2nd, 2011
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Mus musculus is the Linnean name for the domesticated mouse, which is comprised of four subspecies originally broken off from the group Rattus rattus. The fossil record is sparse with regards to the domestic mouse, and in 1970, it was estimated the mouse diverged about 0.23 mya due to insufficient records. This split is now estimated to occur in East Asia about 800,000 years ago. (Berry 1970). The original ancestors of the mouse began in Pakistan after the Permian-Triassic extinction event, with several regions of overlap in the Persian Gulf (Prager et al. 1998).

The domesticated mouse is represented by four subspecies based on their locale, with recent genetic analysis indicating possibly up to 12 substrains. Before genetic identification became prevalent in molecular biology in the early 1980s, 114 genus and species of mice were used in the literature (Silver 1995). For the purposes of this paper, the mouse is referred to as M. domesticus or M. musculus.

The house mouse fits well within Rodentia, and is a small tail-possessing mammal similar to a vole. It can be distinguished from the vole using an indentation on its jaw, and has longer teeth (Berry 1970). This differentiates the family Muridae from other Rodentia. The average weight of the house mouse is roughly 15 grams, with variance depending on climate and access to the indoors. Most domesticated mice have tails as long as their bodies, usually under 10 centimeters for each (Reeder and Wilson 2012). They have a male-dominated social hierarchy, and tend to live in small groups (Berry 1970).

Domestication of the mouse could have evolved based on their original

impudence: they became domesticated around the time agriculture developed in the Fertile Crescent. It could also simply have been coincidence, and an author uses the term “no good evidence” (Berry 1970). Western literature did not disclose evidence of mouse domestication, and they were generally viewed as pests. The mouse appeared in Egyptian paintings and hieroglyphic findings as domesticated around 1100 BC. Luckily for grain stores and the citizens that depended on them, the cat was domesticated around the same time (Silver 1995).

It wasn’t until three millenia after domestication that the mouse was used and bred in a research capacity. This occurred at the turn of the twentieth century, mostly due to the renaissance of Mendel’s work. Mendel attempted to use mice originally as a model but was opposed by his boss, who believed that having mice breeding in a place of God was unsavory (Paigen 2003). Prior to Mendel’s foray into mouse genetics, a 19 thcentury pharmacist named Coladon was able to mix both white and grey mice and produce new coat colors with reasonable success. This coat color was dependent on heterozygotic and homozygotic alleles, pre-dating Mendel’s work with peas (Pennisi 2000).

Mice were largely believed to be obligate commensalists with humans, however; many tracts have been found in Ireland independent of human contact, possibly due to settlements long disbanded. Mice have also been found on remote Pacific islands without evidence of human interference (Berry 1970).

The mouse has the benefit of a short pre-natal period and roughly six weeks until full maturation. M. domesticus has a large litter size with the average of ten pups per

mating. Humans wait roughly 15% of their lifespan before coming sexually mature, while the laboratory mouse spends 1/3 of that before efficient reproduction (Berry 1970). Generally speaking, 20 selected inbed crosses between mice results in a new sub-strain, while 40 causes a new strain to develop (Hilgers et al. 1985).

Research on breeding was vociferous by the 1920s, with Mendelian genetics highly regarded due to the excellent results breeders retained. The work relies on four basic tenets: backcross, intercross, outcross and intercrosses (Green 1966).

An outcross is the mating of two unrelated mice, while an incross is the normal mating of inbred mice. The backcross requires a heterozygous and homozygous reservoir, and for practical purposes this may require a parental mate. Intercrosses are doubly heterozygous (Silver 1995).

As a perfunctory explanation mice are inbred, outbred, congenic, mutated or hybrid, but many more exist (e.g. conplastic [mitochondria/nuclear hybrids]). Inbred mice are placed mated brother-sister, while outbred mice have multiple indiscriminate mates (Silver 1995). It’s unclear why mice tolerate inbreeding depression more so than humans, but it may be due to their tendency towards close-quarters living in small places, with most venturing only within a 50-60 square foot radius (Berry 1970).

In any regard, the refined upside of inbred mice is static homozygosity, where a fixed and predictable percentage of homozygosity occurs. This can approach 99%, but a purely inbred mouse has yet to be established. Outbred mice are a rapidly evolving and heterogeneous group, and are ideal for use in hypotheses where human mimicry is not required (Reeder and Wilson 2012).

Hybrid mice are the result of uniting two inbred strains of mice, and have a less hardy F2 generation. Mutated strains add genetic material in the embryo, often using congenic strains. Congenic mice are backcrossed with their parents and then inbred, allowing a fluid transmission of homozygosity (Silver 1995).

From 1900 to 1910, the work with mice was contained to breeding and observation for color traits. It wasn’t until the naughts were complete that mice were specially bred by Tyzzer — for the purpose of studying tumor growth. He and a man named Charles Little contemporaneously inbred (brother-sister) many strains still in use today, including DBA (dilute brown and nonagouti, fur pattern). Note that only about 250 DBA mouse generations of laboratory have existed total (Paigen 2003). Hundreds of strains are available for purchase from Jackson Labs, with the most common being a C57BL/B6 sub-strain (Jackson Laboratory 2013).

C57BL are less-acclimated to confinement than the docile albino BALB/c, but reproduce quicker and more efficiently. Unfortunately, they tend to cannibalize their young. They have the benefit of a relatively homogenous genetic code, with most sub-strains only differing at one locus (Jackson Laboratory 2013). The BALB/c strain is more expensive but can more accurately reflect the human, yet is not recommended for use in cancer research because of its resiliency to tumor proliferation (Hilgers et al. 1985).

The BALB/c mouse is well-attuned to being a model organism for human pharmaceutics, so much so several biologists have commented on it’s ferocity in biochemical equivalence with the term “pocket human” (Silver 1995). Other inbred strains such as A/J and B6 are less hardy than their wild counterparts: they can have lower rates of fecundity and higher rates of mortality due to aggression. The BALB/c immune system is also quite susceptible to stress events to their detriment, and their rapid accumulation of disease is part of what makes them extraordinary models (Reeder and Wilson 2012).

Over 4,000 strains of mice are available from Jackson Laboratories alone, with 1500 being bred actively and the other genetic material retained. The naming conventions for these strains are strict and identify if inbred, congenic, outbred and so on. For instance, two inbred mice combined like DBA and BALB/c would be DBA x BALB/c. Outbred strains are separated with a colon. The first part of the strain name is usually defined as the coat color, yet transgenic strains with longer names begin with the origin source i.e. MCW for Medical College of Wisconsin. Allele additions to mice are signified by a superscript, with trangenic alleles prefaced with a pound sign. If required, an addendum of F(x) for the generation number may be added. Lowercase c infers congenic strains except in the case of BALB/c, like MCWcDBA ( International Committee on Standardized Genetic Nomenclature for Mice 2011).

The mouse as we now know it is isolated to its domestication use in laboratories. It cannot pull a plow or be used for considerable nourishment. The mouse is unique in that can be bred as another animal’s food source, as a laboratory animal and as a pet.

The first research deals with breeding mice for maternal aggression. The two studies discussed now use the relatively rare strain in research, the outbred Hsd-ICR. This subsection relies on the work of Gammie et al. 2006. The main goal of this study was to understand the environments in which maternal aggression flourishes, rather than creating docile maternal mice for better lifespan or external manipulation. Succinctly, unrelated mice were mated and placed in separate cages. A non-mating male intruder entered the cage after the pups were removed. Aggressive female mice were selected for eight generations, and found to retain this behavior. Past studies have implicated arginine vasopressin in maternal aggression, so it’s possible future research should include breeding based on biomarkers instead of observation for better results. Although the data was acceptable, the aggression effect was diminished by the eighth generation.

Due to the standardized nature of modern mouse genetics, M. domesticus is allowed to have controlled experiments with breeding. For example, in Houle-Leroy et al. 2000, several mice were bred selectively over 14 generations for enhanced wheel-running capability. If these mice were to be released instead of immediate cervical dislocation, one would find enhanced predator-escape capability. The mice had the same amount of quantitative muscle mass in their hindlimbs and aerobic capacity, but their biochemistry compared to their ancestor and trained mice not selected for aerobic capacity. Several enzymes were tested compared to sedentary mice, and lactate dehydrogenase (LDH) will be used an example. Humans produce LDH as a byproduct of muscle exertion, and this marker was diminished in just 8 weeks of selection compared to similarly trained mice. It is of note the hypothesis of increased aerobic capacity via artificial selection was not fulfilled. Studies using artificial selection for biochemical endpoints in mice (frequent in rats) are extremely rare according to the

authors. Thus, this study was used here despite wide-ranging implications.

Two additional studies failed to select for wheel-running capability (Brownikowski et al. 2001 and Swallow et al.1998), although this proof was not the sole focus in each. Alternate authors with different methods were able to increase wheel running capability, however. Phenotypic changes in artificially selected mice were discovered in 2012 after meticulous research into the best possible strains (Careau et al.). Intriguingly, human touch was correlated negatively with distance ran and corticosterone levels were a reliable positive indicator of running efficiency.

The applicability of these results are more multi-faceted than face value, as enhanced wheel-running capability is also correlated with increased neurogenesis in both inbred and outbred mice alike, but not in wild types (Hauser et al. 2009 and Schaefer 2013).

It wasn’t until the late 2000s that non-Mendelian artificial selection became more prominent. Some traits are more resistant to artificial selection than others, as in the aforementioned weight selections. Constraints in size breeding are frequently commented upon, with an upward threshold of 30-40 grams. Attempts to breach this limit have been attempted numerous times with little success. Rats are more adept to unrestricted obesity and manipulation of muscle size. Many variables, including temperature and nesting size were selected for in Bult and Lynch (2000) to try to increase the size of the mice. After 46 generations, the size of the mouse had not changed, despite food consumption and litter size increase.

In contrast, robust evidence exists for size variance in domesticated mice and

wild types. Domestic laboratory mice have been artificially selected over generations to have a larger litter size and earlier estrous peak, and have better use of food resources to accomplish this goal (Bronson 1984).

Say one of these domesticated mice in the laboratory were released into the wild. What differences could you expect from its wild-type counterpart? Several studies answer this question in detail, including light variation in laboratory affecting melatonin and consequential gonadotropin secretion and reproduction. A large degree of interbreeding would certainly alter the litter size and nutrient use (Kashahara et al. 2010). Furthermore, artificial selection by researchers breeding for weight induces the same demonstrable change in biochemical pathways as naïve island mice in a phenomenon known as parallel selection (Chan et al. 2012).

Nesting mass could also follow this path. M. domesticus may be selected for an astonishing variation in nest size with just 15 generations: from 5 grams to 40 grams with a mean control group of 15 grams, significant in both groups. The same effector locus is functional in wild types, with bigger nests correlating with offspring survival. Especially in cooler climes, this is an example of natural selection (Goodenough 2009).

In 1975, prior to the introduction of genetic techniques showing changes in alleles (albeit them being hypothetically understood), the domestication of the wild mouse showed negligible influence on their behavior. The main effect was considered to be a trend towards decreased male-male aggression (Connor).

After the era of classical mouse genetics (1902-1980), advances came voluminous and almost simultaneously. Transgenic (viral recombination) of a beta-

globulin gene from a rabbit began the research, with knockout mice implemented shortly after. Knockout mice were originally designed to hamper tumor suppression, specifically p53. Chemically-induced mutagenesis and subsequent breeding increased in frequency in the early 1990s, undeterred by the ubiquity of recombinant technology (Paigen 2003).

Thomas Friedman’s book “The World is Flat” details the emergence of a global economy via improved logistics and communications, and Paigen describes the catapult of this simple breakthrough further. The worldwide shipment of mice has allowed previously isolated geographic strains of mice to be bred, providing better models for human studies. The more phylogenetic data that is uncovered, the more it reveals similarities rather than differences, with over 99.6% of the genome conserved between mice and humans both today and throughout evolutionary history (Paigen 2003).

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