Genetic cause of behavioral diversity

Some mice are easily scared. Others are tame. Some mice are quick and agile… Different mice have different traits and respond differently to stimuli and stress. What genes account for such behavioral diversity? What are they like? These are some of the questions that Prof. Koide is trying to answer from the genetic point of view in his research on animal behavior using wild-derived mice.

Unique wild-derived mouse resource center in the world

NIG’s Genetic Strains Research Center has 10 strains of wild-derived mice. NIG takes pride in this extensive collection of mouse strains, rarely found elsewhere in the world. Prof. Koide has the advantage of easy access to this collection for his research.

“Wild-derived mice show behavioral patterns different from those of lab mice due to phenotypic differences (expressed in traits and behavior by genes). We expect to find something totally unique and interesting by studying them,” says Prof. Koide.

Laboratory mice originate from docile mice that used to be kept as pets about 100 years ago. Wild-derived mice, on the other hand, originate from mice that live in fields and in and around human habitations.

“For genetic experiments, we need large numbers of mice that have the same genetic makeup. For this, we must establish what we call ‘strains.’ Concretely, we perform brother-sister mating, repeat the same procedure with the offspring, and continue generation after generation. With each new generation, genetic divergence dwindles among the mice. We estimate that after more than 20 generations, the genome of all the mice that are born becomes almost wholly identical. These mice constitute an inbred strain.”

“Since I’ve been conducting research for many years using wild-derived mice, whose behavior I find very interesting, I’ve studied various phenotypes of the 10 strains. Our research center is extremely unique and valuable not only because it has this collection but because we also have a wealth of data about the behavioral patterns and phenotypes of the strains.”

Genes responsible for anxiety-related behavior in wild-derived mice

“Compared to lab mice, which originate from docile mice that were developed as pets, wild-derived mice are easily scared. It’s not easy to catch them even when they’re already in a lab cage as they hide and try to get away from humans. They show high levels of anxiety in their behavior.”

To identify genes that may be responsible for anxiety-related behavior in mice, Prof. Koide and his group performed an experiment using consomic strains, i.e., special strains of lab mice and wild-derived mice between which specific chromosomes are systematically exchanged. As a result, they succeeded in specifying a gene.

“This gene carries simple repeats of two bases. In many strains of lab mice, these repeats are short, whereas they are long in wild-derived strains. Longer repeats mean that the gene is expressed more. The shorter two-base repeats in lab mice means that the gene is less expressed. As they were domesticated as pets, less timid individuals were selected. In this process, the short repeats of two bases seem to have been implicated.”

Exhaustively identifying related genes

Prof. Koide identified one gene involved in anxiety-related behavior, but there are still many other genes to be studied. Eager to grasp the whole picture of the process in which animals get accustomed to humans, he and his team are now taking an out-of-the-box approach to research.

 

“We’re interested in the way animals are tamed by humans. Animals that are domesticated as pets don’t run away as humans approach them. Some even come to us if we hold out a hand. In fact, there are two ways of animals’ being tame: not running away when a human approaches, and spontaneously coming to a human. In general, the two are not distinguished. But in research, they are different.”

“To study this difference, we have designed an experiment called ‘Tame Test.’ We put a mouse in a square box. In one series of tests, the experimenter inserts her hand into the box to see if the mouse comes near the hand spontaneously. In the other series of test, the experimenter brings her hand close to the mouse to see if it tolerates the hand and let it touch the mouse. We were able to do this experiment quite successfully.”

In the experiment, all of the many lab mouse strains deriving from domesticated mice did not escape or reject the approaching human hand, whereas wild-derived mouse strains showed aversion to the approaching hand and ran away. Neither lab mice nor wild-derived mice spontaneously came close to the experimenter’s hand.

The experiment results suggest that in the domestication process, individuals not showing excessive aversion to human contact were continuously selected and that individuals that spontaneously approached humans were not selected.

“At the moment, we’re working on genetically heterogeneous crossbreeding of eight wild-derived mouse strains with nearly equal level of contribution. For each generation, we crossbreed individuals that are genetically distant from each other and, from among their offspring, select mice that spontaneously approach humans. We’re hoping to see the genetic types that are involved in the act of approaching humans becoming increasingly predominant in the group after each generation and eventually stabilize in optimal condition. When almost all the individuals of a group spontaneously approach humans with sufficient consistency, we will be able to exhaustively identify the genes related to this act. We are witnessing gradual changes in phenotypes as one generation succeeds to another. We’re very much looking forward to the results.”

Going all the way in search of answers

Talking with Prof. Koide, this interviewer sensed the great importance of perseverance and patience required for his research into mouse behavior, in drawing up meticulous plans, steadily performing experiments and crossbreeding, and carefully managing lab animals. My final question was about his view of his career as a research scientist.

“What is great about being a research scientist is that we can go all the way looking for answers to our questions, without setting limits to what we want to learn. I can’t think of any other work that allows this – can you? Of course, there’re tough times. But I feel great when research goes well and when we finally discover something that we always wanted to know. Experiencing one such success leading to another, I feel a great sense of reward.”

 

（Text translated based on the interview conducted by Yoshiko Tamura in August 2013）

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