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Communications Biology Sep 2021Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the...
Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52-67% of cases of autism arising from low risk families, and 30-39% of cases of all autism.
Topics: Adult; Autism Spectrum Disorder; Autistic Disorder; Female; Genetic Predisposition to Disease; Humans; Incidence; Male; Middle Aged; Mutation; New York; Risk Factors; Young Adult
PubMed: 34471188
DOI: 10.1038/s42003-021-02533-z -
Molecules (Basel, Switzerland) Dec 2022Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of... (Review)
Review
Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of approaches for constructing these skeletons have been developed. Among them, de novo synthesis, due to its highly convergent and superior atom economy, serves as a promising strategy to access these challenging scaffolds including C-N, C-C, and N-N chiral axes. So far, several elegant reviews on the synthesis of axially chiral heterobiaryl skeletons have been disclosed, however, atroposelective construction of the heterobiaryl subunits by de novo synthesis was rarely covered. Herein, we summarized the recent advances in the catalytic asymmetric synthesis of the axially chiral heterobiaryl scaffold via de novo synthetic strategies. The related mechanism, scope, and applications were also included.
Topics: Biological Products; Catalysis; Skeleton
PubMed: 36500610
DOI: 10.3390/molecules27238517 -
Trends in Genetics : TIG Nov 2019Human germline de novo mutations (DNMs) are both a driver of evolution and an important cause of genetic diseases. In the past few years, whole-genome sequencing (WGS)... (Review)
Review
Human germline de novo mutations (DNMs) are both a driver of evolution and an important cause of genetic diseases. In the past few years, whole-genome sequencing (WGS) of parent-offspring trios has facilitated the large-scale detection and study of human DNMs, which has led to exciting discoveries. The overarching theme of all of these studies is that the DNMs of an individual are a complex mixture of mutations that arise through different biological processes acting at different times during human development and life.
Topics: Humans; Aging; Alleles; DNA Replication; Embryonic Development; Genome, Human; Genomics; Germ Cells; Germ-Line Mutation; Maternal Age; Mosaicism; Mutation; Male; Female; Human Development
PubMed: 31610893
DOI: 10.1016/j.tig.2019.08.005 -
Molecular Biology and Evolution May 2023The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they...
The formation of new genes during evolution is an important motor of functional innovation, but the rate at which new genes originate and the likelihood that they persist over longer evolutionary periods are still poorly understood questions. Two important mechanisms by which new genes arise are gene duplication and de novo formation from a previously noncoding sequence. Does the mechanism of formation influence the evolutionary trajectories of the genes? Proteins arisen by gene duplication retain the sequence and structural properties of the parental protein, and thus they may be relatively stable. Instead, de novo originated proteins are often species specific and thought to be more evolutionary labile. Despite these differences, here we show that both types of genes share a number of similarities, including low sequence constraints in their initial evolutionary phases, high turnover rates at the species level, and comparable persistence rates in deeper branchers, in both yeast and flies. In addition, we show that putative de novo proteins have an excess of substitutions between charged amino acids compared with the neutral expectation, which is reflected in the rapid loss of their initial highly basic character. The study supports high evolutionary dynamics of different kinds of new genes at the species level, in sharp contrast with the stability observed at later stages.
Topics: Evolution, Molecular; Proteins; Gene Duplication; Saccharomyces cerevisiae; Phylogeny
PubMed: 37139943
DOI: 10.1093/molbev/msad098 -
Journal of Neurology, Neurosurgery, and... Feb 2022The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations...
OBJECTIVE
The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in as a cause of ALS.
METHODS
We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.
RESULTS
We identified four sporadic ALS cases with de novo mutations in . They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in . We also encountered familial cases where de novo mutational events in recent generations may have been involved.
CONCLUSIONS
De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy.
Topics: Adult; Amyotrophic Lateral Sclerosis; Female; Genetic Association Studies; Genetic Testing; Germany; Humans; Longitudinal Studies; Male; Mutation; Phenotype; RNA-Binding Protein FUS; Republic of Korea; Superoxide Dismutase-1; Sweden; Young Adult
PubMed: 34518333
DOI: 10.1136/jnnp-2021-327520 -
Current Opinion in Chemical Biology Jun 2020Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use... (Review)
Review
Engineered proteins are revolutionizing immunotherapy, but advances are still needed to harness their full potential. Traditional protein engineering methods use naturally existing proteins as a starting point, and therefore, are intrinsically limited to small alterations of a protein's natural structure and function. Conversely, computational de novo protein design is free of such limitation, and can produce a virtually infinite number of novel protein sequences, folds, and functions. Recently, we used de novo protein engineering to create Neoleukin-2/15 (Neo-2/15), a protein mimetic of the function of both interleukin-2 (IL-2) and interleukin-15 (IL-15). To our knowledge, Neo-2/15 is the first de novo protein with immunotherapeutic activity, and in murine cancer models, it has demonstrated enhanced therapeutic potency and reduced toxicity compared to IL-2. De novo protein design is already showcasing its tremendous potential for driving the next wave of protein-based therapeutics that are explicitly engineered to treat disease.
Topics: Amino Acid Sequence; Animals; Immunotherapy; Interleukin-15; Interleukin-2; Mice; Models, Molecular; Neoplasms; Neoplasms, Experimental; Protein Binding; Protein Conformation; Protein Engineering; Structure-Activity Relationship
PubMed: 32371023
DOI: 10.1016/j.cbpa.2020.02.002 -
Genes Sep 2021The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number... (Review)
Review
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of variants in CDH. This review gives an overview of the known disease-causing variants in CDH patients.
Topics: Aneuploidy; Chromosome Aberrations; DNA Copy Number Variations; Hernias, Diaphragmatic, Congenital; Humans; Mutation
PubMed: 34573387
DOI: 10.3390/genes12091405 -
Current Opinion in Structural Biology Apr 2023Generative deep learning is accelerating de novo drug design, by allowing the generation of molecules with desired properties on demand. Chemical language models - which... (Review)
Review
Generative deep learning is accelerating de novo drug design, by allowing the generation of molecules with desired properties on demand. Chemical language models - which generate new molecules in the form of strings using deep learning - have been particularly successful in this endeavour. Thanks to advances in natural language processing methods and interdisciplinary collaborations, chemical language models are expected to become increasingly relevant in drug discovery. This minireview provides an overview of the current state-of-the-art of chemical language models for de novo design, and analyses current limitations, challenges, and advantages. Finally, a perspective on future opportunities is provided.
Topics: Drug Design; Drug Discovery; Models, Chemical
PubMed: 36738564
DOI: 10.1016/j.sbi.2023.102527 -
ArXiv Mar 2023The high-throughput short-reads RNA-seq protocols often produce paired-end reads, with the middle portion of the fragments being unsequenced. We explore if the...
The high-throughput short-reads RNA-seq protocols often produce paired-end reads, with the middle portion of the fragments being unsequenced. We explore if the full-length fragments can be computationally reconstructed from the sequenced two ends in the absence of the reference genome - a problem here we refer to as de novo bridging. Solving this problem provides longer, more informative RNA-seq reads, and benefits downstream RNA-seq analysis such as transcript assembly, expression quantification, and splicing differential analysis. However, de novo bridging is a challenging and complicated task owing to alternative splicing, transcript noises, and sequencing errors. It remains unclear if the data provides sufficient information for accurate bridging, let alone efficient algorithms that determine the true bridges. Methods have been proposed to bridge paired-end reads in the presence of reference genome (called reference-based bridging), but the algorithms are far away from scaling for de novo bridging as the underlying compacted de Bruijn graph(cdBG) used in the latter task often contains millions of vertices and edges. We designed a new truncated Dijkstra's algorithm for this problem, and proposed a novel algorithm that reuses the shortest path tree to avoid running the truncated Dijkstra's algorithm from scratch for all vertices for further speeding up. These innovative techniques result in scalable algorithms that can bridge all paired-end reads in a cdBG with millions of vertices. Our experiments showed that paired-end RNA-seq reads can be accurately bridged to a large extent. The resulting tool is freely available at https://github.com/Shao-Group/rnabridge-denovo.
PubMed: 37033458
DOI: No ID Found -
Microbiome Research Reports 2023Comparative metagenomic analysis requires measuring a pairwise similarity between metagenomes in the dataset. Reference-based methods that compute a beta-diversity...
Comparative metagenomic analysis requires measuring a pairwise similarity between metagenomes in the dataset. Reference-based methods that compute a beta-diversity distance between two metagenomes are highly dependent on the quality and completeness of the reference database, and their application on less studied microbiota can be challenging. On the other hand, comparative metagenomic methods only rely on the sequence composition of metagenomes to compare datasets. While each one of these approaches has its strengths and limitations, their comparison is currently limited. We developed sets of simulated short-reads metagenomes to (1) compare k-mer-based and taxonomy-based distances and evaluate the impact of technical and biological variables on these metrics and (2) evaluate the effect of k-mer sketching and filtering. We used a real-world metagenomic dataset to provide an overview of the currently available tools for metagenomic comparative analysis. Using simulated metagenomes of known composition and controlled error rate, we showed that k-mer-based distance metrics were well correlated to the taxonomic distance metric for quantitative Beta-diversity metrics, but the correlation was low for presence/absence distances. The community complexity in terms of taxa richness and the sequencing depth significantly affected the quality of the k-mer-based distances, while the impact of low amounts of sequence contamination and sequencing error was limited. Finally, we benchmarked currently available comparative metagenomic tools and compared their output on two datasets of fecal metagenomes and showed that most k-mer-based tools were able to recapitulate the data structure observed using taxonomic approaches. This study expands our understanding of the strength and limitations of k-mer-based comparative metagenomic approaches and aims to provide concrete guidelines for researchers interested in applying these approaches to their metagenomic datasets.
PubMed: 38058765
DOI: 10.20517/mrr.2023.26