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IS-2.- GENES AND AGGRESSION: FROM MICE TO HUMANS

Organizer: Maxson, Stephen
Department of Psychology, The University of Connecticut, Storrs, CT, USA

Discussant: Blanchard, Caroline
Pacific Biomedical Research Center and Department of Genetics and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa. Honolulu, Hawaii, USA

Symposium Abstract
For more than 60 years, research on the genetics of mammalian aggression has focused on the mouse. It has been hoped that the findings with mice would be relevant to our understanding of the causes of aggression in humans. Since the mid 1990s, more than 15 genes have been identified with effects on offense type aggression in male mice. These genes have homologues in humans with similar effects on molecular and cellular biology. Pierre L. Roubertoux (Attack behavior in mice: implications of the Sts gene mapped on the pairing region of the X-Y chromosomes) will discuss his research program on the genetics of mouse aggression, and he will relate these studies to the genetics of human aggression. Pascale V. Guillot (Genetic determinants of aggressive behavior) will relate research on the role of the Y chromosome in mouse aggression to a program of research on primate and human aggression. The formal discussant for this symposium will be Caroline Blanchard who is concerned with the relevance of findings on animal aggression to those on
human aggression.

IS-2.1.-Attack behavior in mice: implication of the steroid sulfatase gene mapped on the pairing region of the X-Y-chromosomes.

Roubertoux, P.L., Mortaud, S., Nicolas, L., Le Roy, I.  and Tordjma, S.
UPR CNRS 9074, Génétique, Neurogénétique, Comportement, Institut de
Transgénose, Orléans, France.

The sexual dimorphism of aggression has led to a search for its Y- chromosomal correlates. We have previously confirmed that initiation of attack behavior against a conspecific male is Y- dependent in two strains of laboratory mice (NZB and C57BL/6J). We have provided evidence that the pairing region of the Y co-segregates with attack behavior, in these strains. In addition, the genetic correlates of attack behavior are not expressed when borne on the homologous pairing region on the X chromosome but only when carried on the Y chromosome. Only one functional gene (coding for steroid sulfatase or STS) is mapped on this region as of yet, suggesting that it could be a candidate for attack behavior. We estimated the genetic correlation between the concentration of STS protein in the liver and initiation of attack behavior. We have employed also mice in which gene invalidation induced attack behavior. Pharmacological modulations of STS or of its metabolites modifies the frequencies of attack in these male mice, confirming the implication of STS in aggression. Recent investigations have demonstrated the involvement of STS in neurosteroid biochemical pathways, and several lines of evidence indicate that neurosteroids interact with neurotransmitters. These conclusions and our present results support the hypothesis that sulfatation of steroids may be the prime mover of a complex network, including genes shown to be implicated in aggression by mutagenesis. Supported by CNRS (UPR 9074), Ministry for Research and Technology, Région Centre, Préfecture de la Région Centre and Fondation pour la Recherche Médicale (to I.L.R.) UPR 9074 is affiliated with INSERM and University of Orléans.

IS-2.2.-Genetic determinism of aggressive behavior

Guillot, P.V., Kittles, R.A., Long, J.C., Bergen, A.W. , Virkkunen^*, M., Naukarinnen, H., Linnoila, M. and Goldman, D.
Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, USA. *Department of Psychiatry, University of Helsinki, Helsinki, Finland.

In mice, aggression has a genetic component which acts in concert with environmental factors. Furthermore, inter-individual differences for the propensity to attack are partly attributable to allelic variants located on both the non-pseudoautosomal and recombinant regions of the mouse Y chromosome. However, no nucleotide change in a Y chromosome gene has yet been found to account for a behavior difference. Interspecies comparisons of aggressive behavior reveals some similarities between primates and mice, including both the existence of sexual dimorphism (males being more aggressive than females) and inter-male differences. Measures of aggression in primates and rodents are compared. The data supporting Y chromosome-specific factors in murine aggression are principally from reciprocal crosses, in which the strain of origin of the male parent predicts behavior. The human data derive from a Y-haplotype association study conducted in a Finnish population [Kittles et al., 1998, 1999]. Type II alcoholism and antisocial personality disorder (ASDP) are commonly associated in men in Swedish and American populations. Whereas Y-chromosome variations account for individual differences in alcohol dependence in Finnish population, results failed to show an association between a Y-chromosome haplotype and ASDP. Relevance of murine attack behavior to human aggression is discussed. The hypothesis that Y chromosome gene variation is responsible for behavioral variation now requires direct testing at the gene sequence level. The genes located on the Y chromosome are TSPY, RPS4Y, TDF, ZFY, PRKY, AZF1, BPY, DBY, HY, RNM , and it is these genes whose allelic variants could influence inter-individual behavioral variations. Of particular interest for primate behavioral variation may be RPS4Y because this ribosomal protein subunit gene does not have a Y chromosome counterpart in rodents. Both humans and rodents have an RPS4X gene [Bergen et al. 1998]; the RPS4Y gene could be a primate-distinct origin of sexual dimorphism and intermale behavioral variation. Kittles, R.A. et al., Am. J. Hum. Genet. 62:1171-1179, 1998. Kittles, R.A. et al., PNAS, 96:4204-4209, 1999. Bergen, A.W. et al., Mol. Biol. Evol. 15(11)1412-1419, 1998.