Joubert syndrome is an autosomal recessive brain disorder. Affected individuals show weakness, abnormal breathing and eye movements, clumsiness, cognitive difficulties and autistic behaviors. Joubert syndrome is defined by the absence of the cerebellar vermis (Fig. 1e,f) and by the 'molar tooth sign', formed by an abnormal configuration of the superior cerebellar peduncles (SCPs) that connect the cerebellum to the midbrain and thalamus (Ferland et al. 2004:1008).
The paper identified three amino acid variants in three disease pedigrees, each apparently a novel mutation. Aside from its involvement in Joubert syndrome, it is highly brain-expressed:
Ahi1 mRNA is also highly expressed in other brain regions that are not directly implicated in the Joubert syndrome phenotype, such as the cerebral cortex, hippocampus, basal ganglia and hypothalamus and weakly expressed in the thalamus (from E16.5 to adulthood; Fig. 4cf). If the expression pattern in humans parallels that in mice, then some of the behavioral phenotypes associated with Joubert syndrome may be mediated by structures that are not usually malformed, such as the cerebral cortex (Ferland et al. 2004:1010).
The interesting part is that the gene appears to have undergone repeated adaptive substitutions on the human lineage. The ratio of nonsynonymous to synonymous mutations is significantly high for the gene, and 12 amino acid substitutions have occurred in the human lineage, a rate higher than in other hominoid lineages for the gene (although some of them are also elevated for this gene compared to other loci). They find that none of the 12 apparent substitutions are polymorphic in "several diverse individuals".
The "several diverse individuals is actually 10 individuals from five populations, so I doubt we have a conclusive answer about the present allelic variability of the gene.
The authors conclude this:
Although they are not definitive, these results suggest that positive darwinian selection occurred in AHI1 in the direct ancestors of humans and has been particularly pronounced in the first half of the gene. Key directional selection on AHI1 probably occurred after the common ancestor of human and chimpanzee, 67 million years ago, and before the common ancestor of modern humans, 200,000 years ago.
Chalk up another candidate for brain evolution.
Ferland RJ, et al. 2004. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36:1008-1013. Full text (subscription required)