Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.

Joubert syndrome is a congenital brain malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation (crossing in the brain) affecting the corticospinal tract and superior cerebellar peduncles. Individuals with Joubert syndrome have motor and behavioral abnormalities, including an inability to walk due to severe clumsiness and 'mirror' movements, and cognitive and behavioral disturbances. Here we identified a locus associated with Joubert syndrome, JBTS3, on chromosome 6q23.2-q23.3 and found three deleterious mutations in AHI1, the first gene to be associated with Joubert syndrome. AHI1 is most highly expressed in brain, particularly in neurons that give rise to the crossing axons of the corticospinal tract and superior cerebellar peduncles. Comparative genetic analysis of AHI1 indicates that it has undergone positive evolutionary selection along the human lineage. Therefore, changes in AHI1 may have been important in the evolution of human-specific motor behaviors.

Molecular phylogeny and biogeography of langurs and leaf monkeys of South Asia (Primates: Colobinae).

The two recently proposed taxonomies of the langurs and leaf monkeys (Subfamily Colobinae) provide different implications to our understanding of the evolution of Nilgiri and purple-faced langurs. Groves (2001) [Groves, C.P., 2001. Primate Taxonomy. Smithsonian Institute Press, Washington], placed Nilgiri and purple-faced langurs in the genus Trachypithecus, thereby suggesting disjunct distribution of the genus Trachypithecus. [Brandon-Jones, D., Eudey, A.A., Geissmann, T., Groves, C.P., Melnick, D.J., Morales, J.C., Shekelle, M., Stewart, C.-B., 2003. Asian primate classification. Int. J. Primatol. 25, 97-162] placed these langurs in the genus Semnopithecus, which suggests convergence of morphological characters in Nilgiri and purple-faced langurs with Trachypithecus. To test these scenarios, we sequenced and analyzed the mitochondrial cytochrome b gene and two nuclear DNA-encoded genes, lysozyme and protamine P1, from a variety of colobine species. All three markers support the clustering of Nilgiri and purple-faced langurs with Hanuman langur (Semnopithecus), while leaf monkeys of Southeast Asian (Trachypithecus) form a distinct clade. The phylogenetic position of capped and golden leaf monkeys is still unresolved. It is likely that this species group might have evolved due to past hybridization between Semnopithecus and Trachypithecus clades.

Genomic and evolutionary analyses of asymmetrically expressed genes in human fetal left and right cerebral cortex.

In the human brain, the left and right hemispheres are anatomically asymmetric and have distinctive cognitive function, although the molecular basis for this asymmetry has not yet been characterized. We compared gene expression levels in the perisylvian regions of human left-right cortex at fetal weeks 12, 14, and 19 using serial analysis of gene expression (SAGE). We identified dozens of genes with evidence of differential expression by SAGE and confirmed these by quantitative reverse transcriptase-polymerase chain reaction. Most genes with differential levels of expression in the left and right hemispheres function in signal transduction and gene expression regulation during early cortical development. By comparing genes differentially expressed in left and right fetal brains with those previously reported to be differently expressed in human versus chimpanzee adult brains, we identified a subset of genes that shows evidence of asymmetric expression in humans and altered expression levels between chimps and humans. We also compared the coding sequences of genes differentially expressed between left and right hemispheres and found genes that show both asymmetric expression and evidence of positive evolutionary selection in the primate lineage leading to humans. Our results identify candidate genes involved in the evolution of human cerebral cortical asymmetry.