Susan M.G. Hoffman

OBJECTIVES: Completion of both the mouse and human genome sequences in the private and public sectors has prompted comparison between the two species at multiple levels. This review summarizes the cytochrome P450 (CYP) gene superfamily. For the first time, we have the ability to compare complete sets of CYP genes from two mammals. Use of the mouse as a model mammal, and as a surrogate for human biology, assumes reasonable similarity between the two. It is therefore of interest to catalog the genetic similarities and differences, and to clarify the limits of extrapolation from mouse to human. METHODS: Data-mining methods have been used to find all the mouse and human CYP sequences; this includes 102 putatively functional genes and 88 pseudogenes in the mouse, and 57 putatively functional genes and 58 pseudogenes in the human. Comparison is made between all these genes, especially the seven main CYP gene clusters. RESULTS AND CONCLUSIONS: The seven CYP clusters are greatly expanded in the mouse with 72 functional genes versus only 27 in the human, while many pseudogenes are present; presumably this phenomenon will be seen in many other gene superfamily clusters. Complete identification of all pseudogene sequences is likely to be clinically important, because some of these highly similar exons can interfere with PCR-based genotyping assays. A naming procedure for each of four categories of CYP pseudogenes is proposed, and we encourage various gene nomenclature committees to consider seriously the adoption and application of this pseudogene nomenclature system.

A group of human cytochrome P450 genes encompassing the CYP2A, CYP2B, and CYP2F subfamilies were cloned and assembled into a 350-kb contig localized on the long arm of chromosome 19. Three complete CYP2A genes--CYP2A6, CYP2A7, and CYP2A13--plus two pseudogenes truncated after exon 5, were identified and sequenced. A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6v2. Sequence differences in the CYP2A6v2 gene are restricted to regions encompassing exons 3, 6, and 8, which bear sequence relatedness with the corresponding exons of the CYP2A7 gene, located downstream and centromeric of CYP2A6v2, suggesting recent gene-conversion events. The sequencing of all the CYP2A genes allowed the design of a PCR diagnostic test for the normal CYP2A6 allele, the CYP2A6v2 allele, and a variant--designated CYP2A6v1--that encodes an enzyme with a single inactivating amino acid change. These variant alleles were found in individuals who were deficient in their ability to metabolize the CYP2A6 probe drug coumarin. The allelic frequencies of CYP2A6v1 and CYP2A6v2 differed significantly between Caucasian, Asian, and African-American populations. These studies establish the existence of a new cytochrome P450 genetic polymorphism.

Abstract We use museum and other collection records to document large and extraordinarily rapid changes in the ranges and relative abundance of nine species of mammals in the northern Great Lakes region (white‐footed mice, woodland deer mice, southern red‐backed voles, woodland jumping mice, eastern chipmunks, least chipmunks, southern flying squirrels, northern flying squirrels, common opossums). These species reach either the southern or the northern limit of their distributions in this region. Changes consistently reflect increases in species of primarily southern distribution (white‐footed mice, eastern chipmunks, southern flying squirrels, common opossums) and declines by northern species (woodland deer mice, southern red‐backed voles, woodland jumping mice, least chipmunks, northern flying squirrels). White‐footed mice and southern flying squirrels have extended their ranges over 225 km since 1980, and at particularly well‐studied sites in Michigan's Upper Peninsula, small mammal assemblages have shifted from numerical domination by northern species to domination by southern species. Repeated resampling at some sites suggests that southern species are replacing northern ones rather than simply being added to the fauna. Observed changes are consistent with predictions from climatic warming but not with predictions based on recovery from logging or changes in human populations. Because of the abundance of these focal species (the eight rodent species make up 96.5% of capture records of all forest‐dwelling rodents in the region and 70% of capture records of all forest‐dwelling small mammals) and the dominating ecological roles they play, these changes substantially affect the composition and structure of forest communities. They also provide an unusually clear example of change that is likely to be the result of climatic warming in communities that are experienced by large numbers of people.