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Evolvable hardware is a recently proposed technology in which reconfigurable hardware under the control of and evolutionary (genetic) algorithm can automatically self-reconfigure into sonfigurations with the desired behavior.
The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.
Abstract Objective Supplementation of naturally spawning populations by the addition of hatchery-spawned individuals is commonly conducted for recovery of threatened and endangered populations and to support harvest opportunities. Our objective was to evaluate whether the use of a juvenile captive broodstock and an integrated paradigm could increase returns of steelhead, the anadromous form of Rainbow Trout Oncorhynchus mykiss, while avoiding negative genetic impacts commonly associated with hatchery propagation. Methods We analyzed 291 genetic markers in adult steelhead returning to an integrated population in southwest Washington over the course of 15 years. Reproductive success (RS) of fish spawning in the natural environment was evaluated by origin (hatchery versus natural) and return year. Data were then pooled over years to maximize sample sizes for comparing RS estimates among groups (i.e., estimation of relative reproductive success [RRS]). Result We observed a weak relationship between RS and origin (male p = 0.347; female p = 0.066), but a significant relationship between RS and return year (male p < 0.001, η2 = 0.896; female p ⟨ 0.001, η2 = 0.867) (i.e., hatchery- and natural-origin fish did well or poorly together each year). Estimates of RRS for fish spawned in the hatchery ranged from 2.4 to 6.4, indicating that fish spawned in the hatchery produced more returning adult progeny than did fish allowed to spawn in the natural environment. Estimates of RRS were ⟨1.0 for hatchery-origin fish spawning in the natural environment, but the difference was nonsignificant for males and marginally significant for females. Hatchery-origin fish exhibited reduced genetic diversity as well as evidence of increased temporal population structure. Conclusion We conclude that the program was successful in achieving an increase in adult returns but not in avoiding negative genetic effects on the population and that any lasting impacts of supplementation remain to be determined.
A computer program was used to test Wong's coevolution theory of the genetic code. The codon correlations between the codons of biosynthetically related amino acids in the universal genetic code and in randomly generated genetic codes were compared. It was determined that many codon correlations are also present within random genetic codes and that among the random codes there are always several which have many more correlations than that found in the universal code. Although the number of correlations depends on the choice of biosynthetically related amino acids, the probability of choosing a random genetic code with the same or greater number of codon correlations as the universal genetic code was found to vary from 0.1% to 34% (with respect to a fairly complete listing of related amino acids). Thus, Wong's theory that the genetic code arose by coevolution with the biosynthetic pathways of amino acids, based on codon correlations between biosynthetically related amino acids, is statistical in nature.
One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.
The opportunistic fungal pathogen Candida albicans undergoes an unusual parasexual cycle wherein diploid cells mate to form tetraploid cells that can generate genetically diverse progeny via a nonmeiotic program of chromosome loss. The genetic diversity afforded by parasex impacts clinically relevant features including drug resistance and virulence, and yet the factors influencing genome instability in C. albicans are not well defined. To understand how environmental cues impact genome instability, we monitored ploidy change following tetraploid cell growth in a panel of different carbon sources. We found that growth in one carbon source, D-tagatose, led to high levels of genomic instability and chromosome loss in tetraploid cells. This sugar is a stereoisomer of L-sorbose which was previously shown to promote karyotypic changes in C. albicans. However, while expression of the SOU1 gene enabled utilization of L-sorbose, overexpression of this gene did not promote growth in D-tagatose, indicating differences in assimilation of the two sugars. In addition, genome sequencing of multiple progenies recovered from D-tagatose cultures revealed increased relative copy numbers of chromosome 4, suggestive of chromosome-level regulation of D-tagatose metabolism. Together, these studies identify a novel environmental cue that induces genome instability in C. albicans, and further implicate chromosomal changes in supporting metabolic adaptation in this species.
OBJECTIVE To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011–2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and their characteristics resembled those of individuals with T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low-risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low GRS 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble those of people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.
Abstract Camelina (Camelina sativa), an allohexaploid species, is an emerging aviation biofuel crop that has been the focus of resurgent interest in recent decades. To guide future breeding and crop improvement efforts, the community requires a deeper comprehension of subgenome dominance, often noted in allopolyploid species, “alongside an understanding of the genetic diversity” and population structure of material present within breeding programs. We conducted population genetic analyses of a C. sativa diversity panel, leveraging a new genome, to estimate nucleotide diversity and population structure, and analyzed for patterns of subgenome expression dominance among different organs. Our analyses confirm that C. sativa has relatively low genetic diversity and show that the SG3 subgenome has substantially lower genetic diversity compared to the other two subgenomes. Despite the low genetic diversity, our analyses identified 13 distinct subpopulations including two distinct wild populations and others putatively representing founders in existing breeding populations. When analyzing for subgenome composition of long non-coding RNAs, which are known to play important roles in (a)biotic stress tolerance, we found that the SG3 subgenome contained significantly more lincRNAs compared to other subgenomes. Similarly, transcriptome analyses revealed that expression dominance of SG3 is not as strong as previously reported and may not be universal across all organ types. From a global analysis, SG3 “was only significant higher expressed” in flower, flower bud, and fruit organs, which is an important discovery given that the crop yield is associated with these organs. Collectively, these results will be valuable for guiding future breeding efforts in camelina.
Molecular characterization of diverse germplasm can contribute to breeding programs by increasing genetic gain for sorghum [ Sorghum bicolor (L.) Moench] improvement. Identifying novel marker-trait associations and candidate genes enriches the existing genomic resources and can improve bioenergy-related traits using genomic-assisted breeding. In the current scenario, identifying the genetic loci underlying biomass and carbon partitioning is vital for ongoing efforts to maximize each carbon sink’s yield for bioenergy production. Here, we have processed a high-density genomic marker (22 466 550) data based on whole-genome sequencing (WGS) using a set of 365 accessions from the bioenergy association panel (BAP), which includes ~19.7 million (19 744 726) single nucleotide polymorphism (SNPs) and 2.7 million (~2 721 824) insertion deletions (indels). A set of high-quality filtered SNP (~5.48 million) derived markers facilitated the assessment of population structure, genetic diversity, and genome-wide association studies (GWAS) for various traits related to biomass and its composition using the BAP. The phenotypic traits for GWAS included seed color (SC), plant height (PH), days to harvest (DTH), fresh weight (FW), dry weight (DW), brix content % (BRX), neutral detergent fiber (NDF), acid detergent fiber (ADF), non-fibrous carbohydrate (NFC), and lignin content. Several novel loci and candidate genes were identified for bioenergy-related traits, and some well-characterized genes for plant height ( Dw1 and Dw2 ) and the YELLOW SEED1 locus ( Y1 ) were validated. We further performed a multi-variate adaptive shrinkage analysis to identify pleiotropic QTL, which resulted in several shared marker-trait associations among bioenergy and compositional traits. Significant marker-trait associations with pleiotropic effects can be used to develop molecular markers for trait improvement using a marker-assisted breeding approach. Significant nucleotide diversity and heterozygosity were observed between photoperiod-sensitive and insensitive individuals of the panel. This diverse bioenergy panel with genomic resources will provide an excellent opportunity for further genetic studies, including selecting parental lines for superior hybrid development to improve biomass-related traits in sorghum.
Abstract Fisheries managers routinely use hatcheries to increase angling opportunity. Many hatcheries operate as segregated programs where hatchery-origin fish are not intended to spawn with natural-origin conspecifics in order to prevent potential negative effects on the natural-origin population. Currently available techniques to monitor the frequency with which hatchery-origin strays successfully spawn in the wild rely on either genetic differentiation between the hatchery- and natural-origin fish or extensive sampling of fish on the spawning grounds. We present a method to infer grandparent–grandchild trios by using only genotypes from two putative grandparents and one putative grandchild. We developed estimators of false-positive and false-negative error rates and showed that genetic panels containing 500–700 single-nucleotide polymorphisms or 200–300 microhaplotypes are expected to allow application of this technique for monitoring segregated hatchery programs. We discuss the ease with which this technique can be implemented by pre-existing parentage-based tagging programs and provide an R package that applies the method.
SPLICER computer program used to solve search and optimization problems. Genetic algorithms adaptive search procedures (i.e., problem-solving methods) based loosely on processes of natural selection and Darwinian "survival of fittest." Algorithms apply genetically inspired operators to populations of potential solutions in iterative fashion, creating new populations while searching for optimal or nearly optimal solution to problem at hand. Written in Think C.
COMETBOARDS (Comparative Evaluation Testbed of Optimization and Analysis Routines for Design of Structures) is a design optimization test bed that can evaluate the performance of several different optimization algorithms. A few of these optimization algorithms are the sequence of unconstrained minimization techniques (SUMT), sequential linear programming (SLP) and the sequential quadratic programming techniques (SQP). A genetic algorithm (GA) is a search technique that is based on the principles of natural selection or "survival of the fittest". Instead of using gradient information, the GA uses the objective function directly in the search. The GA searches the solution space by maintaining a population of potential solutions. Then, using evolving operations such as recombination, mutation and selection, the GA creates successive generations of solutions that will evolve and take on the positive characteristics of their parents and thus gradually approach optimal or near-optimal solutions. By using the objective function directly in the search, genetic algorithms can be effectively applied in non-convex, highly nonlinear, complex problems. The genetic algorithm is not guaranteed to find the global optimum, but it is less likely to get trapped at a local optimum than traditional gradient-based search methods when the objective function is not smooth and generally well behaved. The purpose of this research is to assist in the integration of genetic algorithm (GA) into COMETBOARDS. COMETBOARDS cast the design of structures as a constrained nonlinear optimization problem. One method used to solve constrained optimization problem with a GA to convert the constrained optimization problem into an unconstrained optimization problem by developing a penalty function that penalizes infeasible solutions. There have been several suggested penalty function in the literature each with there own strengths and weaknesses. A statistical analysis of some suggested penalty functions is performed in this study. Also, a response surface approach to robust design is used to develop a new penalty function approach. This new penalty function approach is then compared with the other existing penalty functions.
Cells can be programmed to monitor and react to their environment using genetic circuits. Design automation software maps a desired circuit function to a DNA sequence, a process that requires units of gene regulation (gates) that are simple to connect and behave predictably. This poses a challenge for eukaryotes due to their complex mechanisms of transcription and translation. To this end, we have developed gates for yeast (Saccharomyces cerevisiae) that are connected using RNA polymerase flux as the signal carrier and are insulated from each other and host regulation. They are based on minimal constitutive promoters (~120 base pairs), for which rules are developed to insert operators for DNA-binding proteins. Using this approach, in this work we constructed nine NOT/NOR gates with nearly identical response functions and 400-fold dynamic range. In circuits, they are transcriptionally insulated from each other by placing ribozymes downstream of terminators to block nuclear export of messenger RNAs resulting from RNA polymerase readthrough. Based on these gates, Cello 2.0 was used to build circuits with up to 11 regulatory proteins. A simple dynamic model predicts the circuit response over days. Genetic circuit design automation for eukaryotes simplifies the construction of regulatory networks as part of cellular engineering projects, whether it be to stage processes during bioproduction, serve as environmental sentinels or guide living therapeutics.
A diversification of the genetic code based on the number of codons available for the proteinous amino acids is established. Three groups of amino acids during evolution of the code are distinguished. On the basis of their chemical complexity those amino acids emerging later in a translation process are derived. Codon number and chemical complexity indicate that His, Phe, Tyr, Cys and either Lys or Asn were introduced in the second stage, whereas the number of codons alone gives evidence that Trp and Met were introduced in the third stage. The amino acids of stage 1 use purine-rich codons, while all the amino acids introduced in the second stage, in contrast, use pyrimidines in the third position of their codons. A low abundance of pyrimidines during early translation is derived. This assumption is supported by experiments on non-enzymatic replication and interactions of hairpin loops with a complementary strand. A back extrapolation concludes a high purine content of the first nucleic acids, which gradually decreased during their evolution. Amino acids independently available from prebiotic synthesis were thus correlated to purine-rich codons. Implications on the prebiotic replication are discussed also in the light of recent codon usage data.
Abstract The Natural Resources Research Institute Hybrid Poplar Program breeds and tests genetically improved clones for bio-mass production and environmental services. The testing process progresses from Nursery Progeny Tests (NPT) to Family Field Trials (FFT) to Clone Trials (CT) to Yield Blocks (YB), with limited replication of many clones in FFT and CT and a limited number of highly selected clones set out in monoclonal blocks (YB) to approximate the conditions of commercial plantations. We used correlation vectors, R 2 (coefficient of determination) and r s (Spearman’s Coefficient) for growth (DBH 2 ) and McFadden’s Pseudo R 2 for canker severity score, to determine where testing times could be altered (age – age correlations) and whole testing steps eliminated. FFT can be shortened from 5 years to 4 years. In CT, rank correlations between age 5 (half-rotation) and age 9/10 (full rotation) were significant (R 2 = 0.39 – 0.72), but age 5 selection missed 44 % of the top ten clones at age 9/10. Clone rank in CT at full, but not half, rotation was correlated with rank at full rotation in YB. Choosing clones at 9 years in CT adds 4 years but allows possible elimination of YB for clone selection. Both FFT and CT are necessary. Canker abundance and severity in CT at full rotation cannot be determined at earlier ages. An aggressive strategy saves 6 years of testing.
This project was awarded for understanding the problem and developing a plan for Data Mining tools for use in designing and implementing an Engine Condition Monitoring System. From the total budget of $5,000, Tricia and I studied the problem domain for developing ail Engine Condition Monitoring system using the sparse and non-standardized datasets to be available through a consortium at NASA Lewis Research Center. We visited NASA three times to discuss additional issues related to dataset which was not made available to us. We discussed and developed a general framework of data mining and optimization tools to extract useful information from sparse and non-standard datasets. These discussions lead to the training of Tricia Erhardt to develop Genetic Algorithm based search programs which were written in C++ and used to demonstrate the capability of GA algorithm in searching an optimal solution in noisy datasets. From the study and discussion with NASA LERC personnel, we then prepared a proposal, which is being submitted to NASA for future work for the development of data mining algorithms for engine conditional monitoring. The proposed set of algorithm uses wavelet processing for creating multi-resolution pyramid of the data for GA based multi-resolution optimal search. Wavelet processing is proposed to create a coarse resolution representation of data providing two advantages in GA based search: 1. We will have less data to begin with to make search sub-spaces. 2. It will have robustness against the noise because at every level of wavelet based decomposition, we will be decomposing the signal into low pass and high pass filters.
This project was awarded for understanding the problem and developing a plan for Data Mining tools for use in designing and implementing an Engine Condition Monitoring System. Tricia Erhardt and I studied the problem domain for developing an Engine Condition Monitoring system using the sparse and non-standardized datasets to be available through a consortium at NASA Lewis Research Center. We visited NASA three times to discuss additional issues related to dataset which was not made available to us. We discussed and developed a general framework of data mining and optimization tools to extract useful information from sparse and non-standard datasets. These discussions lead to the training of Tricia Erhardt to develop Genetic Algorithm based search programs which were written in C++ and used to demonstrate the capability of GA algorithm in searching an optimal solution in noisy, datasets. From the study and discussion with NASA LeRC personnel, we then prepared a proposal, which is being submitted to NASA for future work for the development of data mining algorithms for engine conditional monitoring. The proposed set of algorithm uses wavelet processing for creating multi-resolution pyramid of tile data for GA based multi-resolution optimal search.
Robot path planning can refer either to a mobile vehicle such as a Mars Rover, or to an end effector on an arm moving through a cluttered workspace. In both instances there may exist many solutions, some of which are better than others, either in terms of distance traversed, energy expended, or joint angle or reach capabilities. A path planning program has been developed based upon a genetic algorithm. This program assumes global knowledge of the terrain or workspace, and provides a family of good paths between the initial and final points. Initially, a set of valid random paths are constructed. Successive generations of valid paths are obtained using one of several possible reproduction strategies similar to those found in biological communities. A fitness function is defined to describe the goodness of the path, in this case including length, slope, and obstacle avoidance considerations. It was found that with some reproduction strategies, the average value of the fitness function improved for successive generations, and that by saving the best paths of each generation, one could quite rapidly obtain a collection of good candidate solutions.