C4 genes of the chimpanzee,gorilla, and orang-utan: evidence for extensive homogenization

The human complement component 4 is encoded in two genes, C4A and C4B, residing between the class I and class II genes of the major histocompatibility complex. The C4A and C4B molecules differ in their biological activity, the former binding more efficiently to proteins than to carbohydrates while for the latter, the opposite holds true. To shed light on the origin of the C4 genes we isolated cosmid clones bearing the C4 genes of a chimpanzee, a gorilla, and an orang-utan. From the clones, we isolated the fragments coding for the C4d part of the gene (exons and introns) and sequenced them. Altogether we sequenced eight gene fragments: three chimpanzee (Patr-C4-1 ^*01, Patr-C4-1 ^*02, Patr-C4-2 ^*01), two gorilla (Gogo-C4-1 ^*01, Gogo-C4-2 ^*01), and three orang-utan (Popy-C4-1 ^*01, Popy-C4-2 ^*01, Popy-C4-3 ^*01). Comparison of the sequences with each other and with human C4 sequences revealed that in the region believed to be responsible for the functional difference between the C4A and C4B proteins the C4A genes of the different species fell into one group and the C4B genes fell into another. In the rest of the sequence, however, the C4A and C4B genes of each species resembled each other more than they did C4 genes of other species. These results are interpreted as suggesting extensive homogenization (concerted evolution) of the C4 genes in each species, most likely by repeated unequal, homologous, intragenic crossing-over. Address correspondence and offprint requests to: J. Klein.     

The effect of psychosis associated CACNA1C,and its epistasis with ZNF804A,on brain function

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)—to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions—PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis—which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.     

The Dentin Matrix Protein 1 Gene of Prototherian and Metatherian Mammals

Mineralization of tooth dentin (the deposition of hydroxyapatite crystals in and around collagen type I fibers of the extracellular matrix) requires the involvement of several genes, among them the gene coding for the dentin matrix protein 1, DMP1. We determined the exon–intron organization of the cattle DMP1 gene and used this information to amplify by the polymerase chain reaction homologous gene fragments from the genomic DNA of two species of metatherian (marsupial) mammals and one prototherian (monotreme) species. The translated proto- and metatherian protein sequences are highly divergent from the eutherian sequences but retain the general characteristics of the DMP1 (high acidity, serine-richness, multiple glycosylation sites, and the presence of the RGD cell attachment tripeptide). They therefore appear to be functional even though, evolutionarily, teeth are in a regression phase in prototherians. It is possible, therefore, that DMP1 is also involved in other functions besides dentinogenesis. The DMP1 gene appears to evolve rapidly and apparently tolerates non-frame-shifting insertions/deletions throughout the coding sequence. Received: 22 February 1998 / Accepted: 11 July 1998     

Peroxidase activity in the brown alga Laminaria digitata

Cell-free extracts of the brown alga Laminaria digitata catalyse the oxidation of o-dianisidine and of iodide, as well as the formation of iodoamino acids. The enzyme(s) requires hydrogen peroxide for these activities, which are strongly inhibited by cyanide and azide. It is suggested that the activity may be due to a haem-containing peroxidase which, in extracts, is strongly bound, possibly to alginate.