Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

In the first wave of synthetic biology, genetic elements, combined into simple circuits, are used to control individual cellular functions. In the second wave of synthetic biology, the simple circuits, combined into complex circuits, form systems-level functions. However, efforts to construct complex circuits are often impeded by our limited knowledge of the optimal combination of individual circuits. For example, a fundamental question in most metabolic engineering projects is the optimal level of enzymes for maximizing the output. To address this point, combinatorial optimization approaches have been established, allowing automatic optimization without prior knowledge of the best combination of expression levels of individual genes. This review focuses on current combinatorial optimization methods and emerging technologies facilitating their applications.

/pdf/application-of-combinatorial-optimization-strategies-in-237kwthza1.pdf

Application of combinatorial optimization strategies in synthetic biology.

Conventional plasmid-based gene expression tends to introduce genetic instability and gene copy number variations that lead to degenerated production. The limited number of auxotrophic markers in Y...

/pdf/combining-26s-rdna-and-the-cre-loxp-system-for-iterative-1fj57ohjmp.pdf

Combining 26s rDNA and the Cre-loxP System for Iterative Gene Integration and Efficient Marker Curation in Yarrowia lipolytica.

Technological advances in the production of carotenoids and their applications- A critical review.

Wine is an archetypal traditional fermented beverage with strong territorial and socio-cultural connotations. Its 7000 year history is patterned by a tradition of innovation. Every value-adding innovation - whether in the vineyard, winery, supply chain or marketplace - that led to the invention of a new tradition spurred progress and created a brighter future from past developments. In a way, wine traditions can be defined as remembered innovations from the distant past - inherited knowledge and wisdom that withstood the test of time. Therefore, it should not be assumed a priori that tradition and innovation are polar opposites. The relations between the forces driven by the anchors of tradition and the wings of innovation do not necessarily involve displacement, conflict or exclusiveness. Innovation can strengthen wine tradition, and the reinvention of a tradition-bound practice, approach or concept can foster innovation. In cases where a paradigm-shifting innovation disrupts a tradition, the process of such an innovation transitioning into a radically new tradition can become protracted while proponents of divergent opinions duke it out. Sometimes these conflicting opinions are based on fact, and sometimes not. The imperfections of such a debate between the 'ancients' and the 'moderns' can, from time to time, obscure the line between myth and reality. Therefore, finding the right balance between traditions worth keeping and innovations worth implementing can be complex. The intent here is to harness the creative tension between science fiction and science fact when innovation's first-principles challenge the status quo by re-examining the foundational principles about a core traditional concept, such as terroir. Poignant questions are raised about the importance of the terroir (biogeography) of yeasts and the value of the microbiome of grapes to wine quality. This article imagines a metaphorical terroir free from cognitive biases where diverse perspectives can converge to uncork the effervescent power of territorial yeast populations as well as 'nomadic' yeast starter cultures. At the same time, this paper also engages in mental time-travel. A future scenario is imagined, explored, tested and debated where terroir-less yeast avatars are equipped with designer genomes to safely and consistently produce, individually or in combination with region-specific wild yeasts and or other starter cultures, high-quality wine according to the preferences of consumers in a range of markets. The purpose of this review is to look beyond the horizon and to synthesize a link between what we know now and what could be. This article informs readers where to look without suggesting what they must see as a way forward. In the context of one of the world's oldest fermentation industries - steeped in a rich history of tradition and innovation - the mantra here is: respect the past, lead the present and secure the future of wine.

Tasting the terroir of wine yeast innovation.

The power of synthetic biology has enabled the expression of heterologous pathways in cells, as well as genome-scale synthesis projects. The complexity of biological networks makes rational de novo design a grand challenge. Introducing features that confer genetic flexibility is a powerful strategy for downstream engineering. Here we develop an in vitro method of DNA library construction based on structural variation to accomplish this goal. The “in vitro SCRaMbLE system” uses Cre recombinase mixed in a test tube with purified DNA encoding multiple loxPsym sites. Using a β-carotene pathway designed for expression in yeast as an example, we demonstrate top-down and bottom-up in vitro SCRaMbLE, enabling optimization of biosynthetic pathway flux via the rearrangement of relevant transcription units. We show that our system provides a straightforward way to correlate phenotype and genotype and is potentially amenable to biochemical optimization in ways that the in vivo system cannot achieve. SCRaMbLE allows for the rapid and large scale rearrangement of genetic data in yeast carrying synthetic chromosomes. Here the authors demonstrate an in vitro use of the method to generate DNA libraries for optimization of biochemical reactions.

/pdf/in-vitro-dna-scramble-6244rq4ndf.pdf

In vitro DNA SCRaMbLE.

Variations and adaptations of chromosome ends play an important role in eukaryotic karyotype evolution. Traditional experimental studies of the adaptations of chromosome ends mainly rely on the strategy of introducing defects; thus, the adaptation methods of survivors may vary depending on the initial defects. Here, using the SCRaMbLE strategy, we obtained a library of haploid and diploid synthetic strains with variations in chromosome ends. Analysis of the SCRaMbLEd survivors revealed four routes of adaptation: homologous recombination between nonhomologous chromosome arms (haploids) or homologous chromosome arms (diploids), site-specific recombination between intra- or interchromosomal ends, circularization of chromosomes, and loss of whole chromosomes (diploids). We also found that circularization of synthetic chromosomes can be generated by SCRaMbLE. Our study of various adaptation routes of chromosome ends provides insight into eukaryotic karyotype evolution from the viewpoint of synthetic genomics.

Structural Variations and Adaptations of Synthetic Chromosome Ends Driven by SCRaMbLE in Haploid and Diploid Yeasts.

Large DNA transfer technology has been challenged with the rapid development of large DNA assembly technology. The research and application of synthetic yeast chromosomes have been mostly limited in the assembled host itself. The mutant of KAR1 prevents nuclear fusion during yeast mating, and occasionally single chromosome can be transferred from one parental nucleus to another. Using the kar1 mutant method, four synthetic yeast chromosomes of Sc2.0 (synIII, synV, synX, synXII) were transferred to wild-type yeasts separately. SynIII was also transferred into an industrial strain Y12, resulting in an improvement of thermotolerance. Moreover, by combining abortive mating and chromosome elimination by CRISPR-Cas9, which has been reported in our previous study, we developed a strategy for consolidation of multiple synthetic yeast chromosomes. Compared to the previous pyramidal strategy using endoreduplication backcross, our method is a linear process independent of meiosis, providing a convenient path for accelerating consolidation of Sc2.0 chromosomes. Overall, the method of transfer and consolidation of synthetic yeast chromosomes by abortive mating and chromosome elimination enables a novel route that large DNA was assembled in donor yeast and then in vivo directly transferred to receptor yeasts, enriching the manipulation tools for synthetic genomics.

Direct Transfer and Consolidation of Synthetic Yeast Chromosomes by Abortive Mating and Chromosome Elimination.

The invention relates to the field of biological technology, and in particular discloses a method for in-vitro rapid optimization of a strain metabolic pathway. According to the method, on the basis of the property of specific recombination of Cre-loxP site, random insertion of a gene is achieved by introducing an improved loxPsym sequence to a functional gene segment and a receiving vector, so that DNA of random insertion is obtained, and diverse rearrangement plasmid libraries are formed; the random combination of various metabolic pathway functional genes can be achieved; a process of synthesizing long-segment DNA by various functional genes can be avoided; combined analysis of the various functional genes can be efficiently and rapidly achieved; a metabolic pathway can be rapidly optimized; a key gene can be searched, without the limitation of a host; therefore, the method is broad in application fields.

Method for in-vitro rapid optimization of strain metabolic pathway

The invention relates to the technical field of biology and in particular discloses a method for knocking out a saccharomyces cerevisiae chromosome. According to the method, a Vika/vox technology is utilized for removing a complete yeast chromosome, and chromosome centromeres are specifically recombined into a ring by virtue of loci, so that knockout of the whole chromosome is realized. Compared with a method for realizing elimination of the whole chromosome in a reduction mitosis manner, the method disclosed by the invention has the advantages that cutting of the saccharomyces cerevisiae chromosome is more simply, efficiently and rapidly realized, crossing over of sister chromatids is avoided, and a saccharomyces cerevisiae homozygous diploid bacterial strain with the chromosome knocked out is obtained.

Method for knocking out saccharomyces cerevisiae chromosome

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