RESUMO
Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders1. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2-20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)2,3 and population control individuals4. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.
Assuntos
Transtorno do Espectro Autista/genética , Expansão das Repetições de DNA/genética , Genoma Humano/genética , Genômica , Sequências de Repetição em Tandem/genética , Feminino , Fatores de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença , Humanos , Inteligência/genética , Proteínas de Ligação ao Ferro/genética , Masculino , Miotonina Proteína Quinase/genética , Motivos de Nucleotídeos , Polimorfismo Genético , FrataxinaRESUMO
BACKGROUND: Commonly used approaches for genomic investigation of bacterial outbreaks, including SNP and gene-by-gene approaches, are limited by the requirement for background genomes and curated allele schemes, respectively. As a result, they only work on a select subset of known organisms, and fail on novel or less studied pathogens. We introduce refMLST, a gene-by-gene approach using the reference genome of a bacterium to form a scalable, reproducible and robust method to perform outbreak investigation. RESULTS: When applied to multiple outbreak causing bacteria including 1263 Salmonella enterica, 331 Yersinia enterocolitica and 6526 Campylobacter jejuni genomes, refMLST enabled consistent clustering, improved resolution, and faster processing in comparison to commonly used tools like chewieSnake. CONCLUSIONS: refMLST is a novel multilocus sequence typing approach that is applicable to any bacterial species with a public reference genome, does not require a curated scheme, and automatically accounts for genetic recombination. AVAILABILITY AND IMPLEMENTATION: refMLST is freely available for academic use at https://bugseq.com/academic .
Assuntos
Técnicas de Tipagem Bacteriana , Tipagem de Sequências Multilocus , Tipagem de Sequências Multilocus/métodos , Técnicas de Tipagem Bacteriana/métodos , Genoma Bacteriano/genética , Salmonella enterica/genética , Salmonella enterica/classificação , Campylobacter jejuni/genética , Campylobacter jejuni/classificação , Surtos de Doenças , Yersinia enterocolitica/genética , Yersinia enterocolitica/classificação , SoftwareRESUMO
A large gap remains between sequencing a microbial community and characterizing all of the organisms inside of it. Here we develop a novel method to taxonomically bin metagenomic assemblies through alignment of contigs against a reference database. We show that this workflow, BugSplit, bins metagenome-assembled contigs to species with a 33% absolute improvement in F1-score when compared to alternative tools. We perform nanopore mNGS on patients with COVID-19, and using a reference database predating COVID-19, demonstrate that BugSplit's taxonomic binning enables sensitive and specific detection of a novel coronavirus not possible with other approaches. When applied to nanopore mNGS data from cases of Klebsiella pneumoniae and Neisseria gonorrhoeae infection, BugSplit's taxonomic binning accurately separates pathogen sequences from those of the host and microbiota, and unlocks the possibility of sequence typing, in silico serotyping, and antimicrobial resistance prediction of each organism within a sample. BugSplit is available at https://bugseq.com/academic .