Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.

The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.

Phylogeographic evidence of crop neodiversity in sorghum.

Sorghum has shown the adaptability necessary to sustain its improvement during time and geographical extension despite a genetic foundation constricted by domestication bottlenecks. Initially domesticated in the northeastern part of sub-Saharan Africa several millenia ago, sorghum quickly spread throughout Africa, and to Asia. We performed phylogeographic analysis of sequence diversity for six candidate genes for grain quality (Shrunken2, Brittle2, Soluble starch synthaseI, Waxy, Amylose extender1, and Opaque2) in a representative sample of sorghum cultivars. Haplotypes along 1-kb segments appeared little affected by recombination. Sequence similarity enabled clustering of closely related alleles and discrimination of two or three distantly related groups depending on the gene. This scheme indicated that sorghum domestication involved structured founder populations, while confirming a specific status for the guinea margaritiferum subrace. Allele rooted genealogy revealed derivation relationships by mutation or, less frequently, by recombination. Comparison of germplasm compartments revealed contrasts between genes. Sh2, Bt2, and SssI displayed a loss of diversity outside the area of origin of sorghum, whereas O2 and, to some extent, Wx and Ae1 displayed novel variation, derived from postdomestication mutations. These are likely to have been conserved under the effect of human selection, thus releasing valuable neodiversity whose extent will influence germplasm management strategies.