Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia
MOLECULAR PSYCHIATRY
Authors: Piton, A.; Gauthier, J.; Hamdan, F. F.; Lafreniere, R. G.; Yang, Y.; Henrion, E.; Laurent, S.; Noreau, A.; Thibodeau, P.; Karemera, L.; Spiegelman, D.; Kuku, F.; Duguay, J.; Destroismaisons, L.; Jolivet, P.; Cote, M.; Lachapelle, K.; Diallo, O.; Raymond, A.; Marineau, C.; Champagne, N.; Xiong, L.; Gaspar, C.; Riviere, J-B; Tarabeux, J.; Cossette, P.; Krebs, M-O; Rapoport, J. L.; Addington, A.; DeLisi, L. E.; Mottron, L.; Joober, R.; Fombonne, E.; Drapeau, P.; Rouleau, G. A.
Abstract
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified > 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1). Molecular Psychiatry (2011) 16, 867-880; doi:10.1038/mp.2010.54; published online 18 May 2010
GENE-MAPPING STUDIES CONFIRM THE HOMOLOGY BETWEEN THE PLATYPUS-X AND ECHIDNA X(1)-CHROMOSOMES AND IDENTIFY A CONSERVED ANCESTRAL MONOTREME X-CHROMOSOME
CHROMOSOMA
Authors: WATSON, JM; RIGGS, A; GRAVES, JAM
Abstract
The identification of the sex chromosomes in the three extant species of Prototherian mammals (the monotremes) is complicated by their involvement in a multivalent translocation chain at the first division of male meiosis. The platypus X chromosome, identified by the presence of two copies in females and one in males, has been found to possess a suite of genes that have been mapped to the X chromosomes of all eutherian and metatherian mammals. We have extended gene mapping studies to a member of the only other extant monotreme family, the echidna, which has a G-band equivalent X1 chromosome, as well as a smaller X2. We find that the five human X-linked genes (G6PD, GDX, F9, AR and MCF2) map to the echidna X1 chromosome in locations equivalent to those on the platypus X. These results confirm that the echidna X1 is the original X chromosome in this species, and identify a conserved ancestral monotreme X chromosome.
COA
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