I was overwhelmed with joy when my Ph.D. student told me that a quarter of our baby mice displayed waddling gaits last Monday. It was our dream two years ago but it seemed like a nightmare three months ago. As the deadline of the project was drawing nearer my heart sank deeper. We had screened more than three thousands mice and seven pedigrees were found with multiple mice displaying abnormal behavior, though, some of the pedigrees had been proved to have non-Mendelian inheritance and in some we didn’t have confidence. While I was scratching my head to draft the final report of the project about why I failed to come up with the results that I had optimistically expected two years ago, the call from my Ph.D. student was absolutely the biggest gift in my life recently. The findings of the waddling mice in their offspring coming out of our intellectual screening carries great significance. It indicates that our strategy works. Our methods were able to pin down a gene that was alone responsible for a pattern of behavior which has always been thought to be too complicated to be controlled by a single gene. If a single point mutation on a single gene will result in unstable gaits of a mouse, why not in an unstable mood? If a person’s depression is usually expressed as social withdrawal, motor retardation, then why can’t we speculate that a mouse displaying social withdrawal or motor retardation has a depressed mood? If our speculation is right, we have a chance to find a gene that is responsible for the stability of a mood.

All animal, including human, are controlled or created by two sets of dozens of thousands of genes. One set is from his father and the other is from his mother. If a character, or a pattern of behavior, of an animal, is controlled by a single gene, then the animal’s father and mother should each share exactly one half of the characters. However, it seems not the case in the real world. We frequently find a person’s nose is more like that of his father than his mother or a person’s temper is more like that of his mother than his father. We call this phenomenon dominant or recessive inheritance. If the shape of nose is controlled by a gene which has a long form and a short form, and a person with two long forms (one from his father and one from his mother) will have a long nose, two short forms of a short nose and one long form and one short form of a long nose, then we call the long form a dominant gene, and the short form a recessive gene. The waddling mice in our study seem to have two recessive waddling genes (one from his father and one from his mother). A mouse with one stable-gait gene and one waddling gene will have absolutely normal gaits. That’s why we had the following findings. The ancestral male mouse with waddling gaits was mated with a normal female mouse. They gave birth to the first generation of seven normal mice. None of the first-generation offspring displayed any sign of waddling or abnormal gaits. The only and most important thing to prove a character inheritable is to make a connection to the same character in the animal’s offspring. We had waited for months to get the baby mice of the waddling mouse and waited another week to see the baby mice grow to maturity. When we found all of the first generation (seven mice) walked perfectly well, we were desperately disheartened. Why? If it was a recessive inheritance then we shouldn’t lose our heart. All of the first-generation mice have a waddling gene from the waddling ancestor and a normal-gait gene from the normal female mouse. If waddling is a recessive trait, only two waddling genes will result in a waddling mouse. We nerved ourselves and let the seven first-generation mice intercrossed. If our hypothesis was right then a quarter of the second generation would have two normal-gait genes, a quarter two waddling genes and one half one normal gene as well as one waddling gene. We had waited for two months to get the 53 second-generation mice delivered and another one month to let them grow to maturity. When I got the call from my Ph.D. student and learned that a quarter of the second generation waddled, though they were too young to display the waddling gaits as obvious as their grandfather, I jumped up and shouted bingo loudly. As soon as I hung up the phone I sang victory and danced joyfully alone in my office. We are going to find a gene that controls the gaits of a mouse!

When I was asked by one of my co-workers, ‘From a psychiatrist point of view, what’s the connection between psychiatric disorders and waddling gaits?’ I gave him the following answers. First, I would rather be a scientist as well as a physician than a pure psychiatrist. I won’t let myself be constrained to the psychiatric field and let go of those medical or scientific issues, which I am interested in and able to handle, slip away. Second, psychiatry is actually a medicine of behavior. Behavior is the result of the integration and coordination of perception, neuromuscular activity, cognition, thought and emotion. So, pinning down any gene that is clearly responsible for one of the key components of behavior will also contribute to analyzing the mystery of abnormal behavior, of which some are named as psychiatric disorders. Third, evidence has shown that some genes that were originally taken as genes of hepatoma, muscular atrophy, ataxia, chorea, or immunodeficiency were later found significantly related to the regulation of emotion and development of psychosis. Fourth, pinning down a gene from behavioral observation, behavioral measurement, data analysis, breeding, genetic probability calculations, hypothesis testing, sperm and embryonic preservations, rough gene mapping, fine gene mapping, intellectual guess and gambling, sequencing to fix the real etiology of waddling is a long sequence of huge work. We really need a real case to test our results.

Hong CJ