Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG)n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine.

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.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are dominantly inherited chondrodysplasias characterized by short stature and early-onset osteoarthrosis. The disease genes in families with PSACH and MED have been localized to an 800 kilobase interval on the short arm of chromosome 19. Recently the gene for cartilage oligomeric matrix protein (COMP) was localized to chromosome 19p13.1. In three patients with these diseases, we identified COMP mutations in a region of the gene that encodes a Ca++ binding motif. Our data demonstrate that PSACH and some forms of MED are allelic and suggest an essential role for Ca++ binding in COMP structure and function.

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.

The cytochrome P450 superfamily of mixed-function oxygenases has been extensively studied due to its many critical metabolic roles, and also because it is a fascinating example of gene family evolution. The cluster of genes on human chromosome 19 from the CYP2A, 2B, and 2F subfamilies has been previously described as having a complex organization and many pseudogenes. We describe the discovery of genes from three more CYP2 subfamilies inside the cluster, and assemble a complete map of the region. We comprehensively review the organization, structure, and expression of genes from all six subfamilies. A general hypothesis for the evolution of this complex gene cluster is also presented.