Dataset Information

Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing.

ABSTRACT: Sexual reproduction often leads to selection that favors the evolution of sex-limited traits or sex-specific variation for shared traits. These sexual dimorphisms manifest due to sex-specific genetic architectures and sex-biased gene expression across development, yet the molecular mechanisms underlying these patterns are largely unknown. The first step is to understand how sexual dimorphisms arise across the genotype-phenotype-fitness map. The emergence of "4D genome technologies" allows for efficient, high-throughput, and cost-effective manipulation and observations of this process. Studies of sexual dimorphism will benefit from combining these technological advances (e.g., precision genome editing, inducible transgenic systems, and single-cell RNA sequencing) with clever experiments inspired by classic designs (e.g., bulked segregant analysis, experimental evolution, and pedigree tracing). This perspective poses a synthetic view of how manipulative approaches coupled with cutting-edge observational methods and evolutionary theory are poised to uncover the molecular genetic basis of sexual dimorphism with unprecedented resolution. We outline hypothesis-driven experimental paradigms for identifying genetic mechanisms of sexual dimorphism among tissues, across development, and over evolutionary time.

SUBMITTER: Kasimatis KR

PROVIDER: S-EPMC7883666 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing.

Kasimatis Katja R KR Sánchez-Ramírez Santiago S Stevenson Zachary C ZC

Genome biology and evolution 20210201 2

Sexual reproduction often leads to selection that favors the evolution of sex-limited traits or sex-specific variation for shared traits. These sexual dimorphisms manifest due to sex-specific genetic architectures and sex-biased gene expression across development, yet the molecular mechanisms underlying these patterns are largely unknown. The first step is to understand how sexual dimorphisms arise across the genotype-phenotype-fitness map. The emergence of "4D genome technologies" allows for ef ...[more]

PMID: 33587127

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Project description:Targeted genomic enrichment followed by next-generation sequencing dramatically increased the efficiency of mutation discovery in human genomes. Here we demonstrate that these techniques also revolutionize traditional genetic approaches in model systems. We developed a two-step protocol utilizing a traditional bulk-segregant analysis (BSA) approach for positional cloning mutants in phenotype-driven forward genetic screens. First, BSA pools are 'light' sequenced for rough mapping, followed by targeted enrichment and deep-sequencing of the mutant BSA pool for the linked genomic region to fine-map and discover candidate mutations. We applied this method successfully to three Arabidopsis mutants and show that it can be scaled by multiplexing. Similarly, we applied these techniques to a gene-driven reverse genetics method (chemical driven target-selected mutagenesis or TILLING) that is used for generating gene knockouts in a wide range of organisms, including plants, invertebrates and vertebrates. We developed an efficient multiplexed genomic enrichment protocol for pre-barcoded samples. As a proof-of-principle, 770 genes were screened for induced mutations in 30 rats, which identified all but one known variants (30) as well as a large series of novel knockout and missense alleles. Mutations were retrieved at the expected frequency with a the false-positive rate of less than 1 in 6 million basepairs, which is much lower as compared to traditional mutation discovery approaches. Both methods are largely independent of the genome size due to the targeted enrichment and can thus be applied to any genetic model system of interest. Targeted genomic enrichment followed by next-generation sequencing dramatically increased the efficiency of mutation discovery in human genomes. Here we demonstrate that these techniques also revolutionize traditional genetic approaches in model systems. We developed a two-step protocol utilizing a traditional bulk-segregant analysis (BSA) approach for positional cloning mutants in phenotype-driven forward genetic screens. First, BSA pools are 'light' sequenced for rough mapping, followed by targeted enrichment and deep-sequencing of the mutant BSA pool for the linked genomic region to fine-map and discover candidate mutations. We applied this method successfully to three Arabidopsis mutants and show that it can be scaled by multiplexing. Similarly, we applied these techniques to a gene-driven reverse genetics method (chemical driven target-selected mutagenesis or TILLING) that is used for generating gene knockouts in a wide range of organisms, including plants, invertebrates and vertebrates. We developed an efficient multiplexed genomic enrichment protocol for pre-barcoded samples. As a proof-of-principle, 770 genes were screened for induced mutations in 30 rats, which identified all but one known variants (30) as well as a large series of novel knockout and missense alleles. Mutations were retrieved at the expected frequency with a the false-positive rate of less than 1 in 6 million basepairs, which is much lower as compared to traditional mutation discovery approaches. Both methods are largely independent of the genome size due to the targeted enrichment and can thus be applied to any genetic model system of interest.

Dataset Information

Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing.

Publications

Sexual Dimorphism through the Lens of Genome Manipulation, Forward Genetics, and Spatiotemporal Sequencing.

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