Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. CONCLUSION: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Exponential sensitivity of noise-driven switching in genetic networks

Cells are known to utilize biochemical noise to probabilistically switch between distinct gene expression states. We demonstrate that such noise-driven switching is dominated by tails of probability distributions and is therefore exponentially sensitive to changes in physiological parameters such as transcription and translation rates. However, provided mRNA lifetimes are short, switching can still be accurately simulated using protein-only models of gene expression. Exponential sensitivity limits the robustness of noise-driven switching, suggesting cells may use other mechanisms in order to switch reliably.

How Good are Genetic Algorithms at Finding Large Cliques: An Experimental Study

This paper investigates the power of genetic algorithms at solving the MAX-CLIQUE problem. We measure the performance of a standard genetic algorithm on an elementary set of problem instances consisting of embedded cliques in random graphs. We indicate the need for improvement, and introduce a new genetic algorithm, the multi-phase annealed GA, which exhibits superior performance on the same problem set. As we scale up the problem size and test on \hard" benchmark instances, we notice a degraded performance in the algorithm caused by premature convergence to local minima. To alleviate this problem, a sequence of modi cations are implemented ranging from changes in input representation to systematic local search. The most recent version, called union GA, incorporates the features of union cross-over, greedy replacement, and diversity enhancement. It shows a marked speed-up in the number of iterations required to find a given solution, as well as some improvement in the clique size found. We discuss issues related to the SIMD implementation of the genetic algorithms on a Thinking Machines CM-5, which was necessitated by the intrinsically high time complexity (O(n3)) of the serial algorithm for computing one iteration. Our preliminary conclusions are: (1) a genetic algorithm needs to be heavily customized to work "well" for the clique problem; (2) a GA is computationally very expensive, and its use is only recommended if it is known to find larger cliques than other algorithms; (3) although our customization e ort is bringing forth continued improvements, there is no clear evidence, at this time, that a GA will have better success in circumventing local minima.

A Lower-Bound Result on the Power of a Genetic Algorithm

This paper presents a lower-bound result on the computational power of a genetic algorithm in the context of combinatorial optimization. We describe a new genetic algorithm, the merged genetic algorithm, and prove that for the class of monotonic functions, the algorithm finds the optimal solution, and does so with an exponential convergence rate. The analysis pertains to the ideal behavior of the algorithm where the main task reduces to showing convergence of probability distributions over the search space of combinatorial structures to the optimal one. We take exponential convergence to be indicative of efficient solvability for the sample-bounded algorithm, although a sampling theory is needed to better relate the limit behavior to actual behavior. The paper concludes with a discussion of some immediate problems that lie ahead.

On the Effectiveness of Genetic Search in Combinatorial Optimization

In this paper, we study the efficacy of genetic algorithms in the context of combinatorial optimization. In particular, we isolate the effects of cross-over, treated as the central component of genetic search. We show that for problems of nontrivial size and difficulty, the contribution of cross-over search is marginal, both synergistically when run in conjunction with mutation and selection, or when run with selection alone, the reference point being the search procedure consisting of just mutation and selection. The latter can be viewed as another manifestation of the Metropolis process. Considering the high computational cost of maintaining a population to facilitate cross-over search, its marginal benefit renders genetic search inferior to its singleton-population counterpart, the Metropolis process, and by extension, simulated annealing. This is further compounded by the fact that many problems arising in practice may inherently require a large number of state transitions for a near-optimal solution to be found, making genetic search infeasible given the high cost of computing a single iteration in the enlarged state-space.