Dataset Information

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

ABSTRACT: Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schizophrenia cases and 13,791 controls). Single variants, genes, and gene sets were analyzed for association with schizophrenia. No single variant or gene reached genome-wide significance. Among candidate gene sets, we found significant enrichment for rare alleles (minor allele frequency [MAF]??4). We also show risk alleles within this frequency range exist, but confer smaller effects and should be identified by larger studies.

SUBMITTER: Leonenko G

PROVIDER: S-EPMC5669020 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

Leonenko Ganna G Richards Alexander L AL Walters James T JT Pocklington Andrew A Chambert Kimberly K Al Eissa Mariam M MM Sharp Sally I SI O'Brien Niamh L NL Curtis David D Bass Nicholas J NJ McQuillin Andrew A Hultman Christina C Moran Jennifer L JL McCarroll Steven A SA Sklar Pamela P Neale Benjamin M BM Holmans Peter A PA Owen Michael J MJ Sullivan Patrick F PF O'Donovan Michael C MC

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20170718 7

Risk of schizophrenia is conferred by alleles occurring across the full spectrum of frequencies from common SNPs of weak effect through to ultra rare alleles, some of which may be moderately to highly penetrant. Previous studies have suggested that some of the risk of schizophrenia is attributable to uncommon alleles represented on Illumina exome arrays. Here, we present the largest study of exomic variation in schizophrenia to date, using samples from the United Kingdom and Sweden (10,011 schiz ...[more]

PMID: 28719003

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Project description:The ciliate Tetrahymena, a model organism, contains divergent mitochondrial (Mt) genome with unusual properties, where half of its 44 genes still remain without a definitive function. These genes could be categorized into two major groups of KPC (known protein coding) and Ymf (genes without an identified function). To gain insights into the mechanisms underlying gene divergence and molecular evolution of Tetrahymena (T.) Mt genomes, we sequenced three Mt genomes of T.paravorax, T.pigmentosa, and T.malaccensis. These genomes were aligned and the analyses were carried out using several programs that calculate distance, nucleotide substitution (dn/ds), and their rate ratios (omega) on individual codon sites and via a sliding window approach. Comparative genomic analysis indicated a conserved putative transcription control sequence, a GC box, in a region where presumably transcription and replication initiate. We also found distinct features in Mt genome of T.paravorax despite similar genome organization among these approximately 47 kb long linear genomes. Another significant finding was the presence of at least one or more highly variable regions in Ymf genes where majority of substitutions were concentrated. These regions were mutation hotspots where elevated distances and the dn/ds ratios were primarily due to an increase in the number of nonsynonymous substitutions, suggesting relaxed selective constraint. However, in a few Ymf genes, accelerated rates of nonsynonymous substitutions may be due to positive selection. Similarly, on protein level the majority of amino acid replacements occurred in these regions. Ymf genes comprise half of the genes in Tetrahymena Mt genomes, so understanding why they have not been assigned definitive functions is an important aspect of molecular evolution. Importantly, nucleotide substitution types and rates suggest possible reasons for not being able to find homologues for Ymf genes. Additionally, comparative genomic analysis of complete Mt genomes is essential in identifying biologically significant motifs such as control regions.

Dataset Information

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

Publications

Mutation intolerant genes and targets of FMRP are enriched for nonsynonymous alleles in schizophrenia.

Similar Datasets

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