John T. Mulligan

Positional Cloning of the Werner's Syndrome Gene

Werners syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.

Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing Protein

Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed SOST. Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.

Of Monkeys and Men: Vervets and the Genetics of Human-Like Behaviors

pendence and social learning is unique to primates. Patterns and rates of cortical and limbic brain development Caribbean population is under no predator pressure and also are similar in humans and the Old World primates. carries none of the known African pathogenic viruses These generalizations apply across many species of pri- (McGuire 1974). mates, but characteristic and stable patterns of social The basic troop structure is matrifocal and matrilinorganization and individual behavior vary from species eal, with multiple males and a juvenile:adult ratio of C2 to species. Because of the idiosyncracies of different spe- (Struhsaker 1967a; Gartlan and Brain 1968; McGuire cies of primates, not every human behavior of interest 1974). Field studies reveal a readily defined dominant to geneticists will have a parallel in every nonhuman (alpha) male and a less easily recognized alpha female, primate species. Our own experience with the African which may or may not accept the alpha male as a congreen, or vervet, monkey (Cercopithecus aethiops), sort. Young males leave the troop around the time of which arose through a fortuitous combination of acci- sexual maturity (5–6 years of age) and work their way dent and intent, has revealed complex physiological and into neighboring troops. Territory is well defined and is behavioral phenotypes—such as, hypertension, alcohol maintained by scent markings and active defense. consumption, and anxiety, among others—that reflect Breeding in the wild is seasonal, with summer being features seen in human populations. As increasingly the peak birth season, after 6 mo of gestation. The fepowerful tools for the study of the genetics of these traits male is sexually mature by C3 years of age, and the in the vervet become available, this species promises successful rearing of her own infants requires social exnovel insights into the roles of genes that influence be- perience and learning within the group context. Mothers haviors shared by our two species. and aunts thus overtly teach the adolescent female how to hold and to carry a new infant, and, in naturalistic