Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Background: Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results: This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC.Conclusion: This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

Genetic studies of the Roma (Gypsies): a review

Background: Data provided by the social sciences as well as genetic research suggest that the 8-10 million Roma (Gypsies) who live in Europe today are best described as a conglomerate of genetically isolated founder populations. The relationship between the traditional social structure observed by the Roma, where the Group is the primary unit, and the boundaries, demographic history and biological relatedness of the diverse founder populations appears complex and has not been addressed by population genetic studies. Results: Recent medical genetic research has identified a number of novel, or previously known but rare conditions, caused by private founder mutations. A summary of the findings, provided in this review, should assist diagnosis and counselling in affected families, and promote future collaborative research. The available incomplete epidemiological data suggest a non-random distribution of disease-causing mutations among Romani groups.Conclusion: Although far from systematic, the published information indicates that medical genetics has an important role to play in improving the health of this underprivileged and forgotten people of Europe. Reported carrier rates for some Mendelian disorders are in the range of 5 -15%, sufficient to justify newborn screening and early treatment, or community-based education and carrier testing programs for disorders where no therapy is currently available. To be most productive, future studies of the epidemiology of single gene disorders should take social organisation and cultural anthropology into consideration, thus allowing the targeting of public health programs and contributing to the understanding of population structure and demographic history of the Roma.

The capital gains from trade are not enough: Evidence from the environmental accounts of Venezuela and Mexico

In principle, a country can not endure negative genuine savings for longperiods of time without experiencing declining consumption. Nevertheless,theoreticians envisage two alternatives to explain how an exporter ofnon-renewable natural resources could experience permanent negativegenuine savings and still ensure sustainability. The first one allegesthat the capital gains arising from the expected improvement in theterms of trade would suffice to compensate for the negative savings ofthe resource exporter. The second alternative points at technologicalchange as a way to avoid economic collapse. This paper uses the dataof Venezuela and Mexico to empirically test the first of these twohypotheses. The results presented here prove that the terms oftrade do not suffice to compensate the depletion of oil reservesin these two open economies.

Spinning welfare: The gains from process innovation in cotton and car production

Economists and economic historians want to know how much better life is today than in the past.Fifty years ago economic historians found surprisingly small gains from 19th century US railroads,while more recently economists have found relatively large gains from electricity, computers and cellphones. In each case the implicit or explicit assumption is that researchers were measuring the valueof a new good to society. In this paper we use the same techniques to find the value to society ofmaking existing goods cheaper. Henry Ford did not invent the car, and the inventors of mechanisedcotton spinning in the industrial revolution invented no new product. But both made existing productsdramatically cheaper, bringing them into the reach of many more consumers. That in turn haspotentially large welfare effects. We find that the consumer surplus of Henry Ford s production linewas around 2% by 1923, 15 years after Ford began to implement the moving assembly line, while themechanisation of cotton spinning was worth around 6% by 1820, 34 years after its initial invention.Both are large: of the same order of magnitude as consumer expenditure on these items, and as largeor larger than the value of the internet to consumers. On the social savings measure traditionally usedby economic historians, these process innovations were worth 15% and 18% respectively, makingthem more important than railroads. Our results remind us that process innovations can be at least asimportant for welfare and productivity as the invention of new products.

Full insurance, asymmetric information and genetic testing

This paper extends previous resuls on optimal insurance trading in the presence of a stock market that allows continuous asset trading and substantial personal heterogeneity, and applies those results in a context of asymmetric informationwith references to the role of genetic testing in insurance markets.We find a novel and surprising result under symmetric information:agents may optimally prefer to purchase full insurance despitethe presence of unfairly priced insurance contracts, and other assets which are correlated with insurance.Asymmetric information has a Hirschleifer-type effect whichcan be solved by suspending insurance trading. Nevertheless,agents can attain their first best allocations, which suggeststhat the practice of restricting insurance not to be contingenton genetic tests can be efficient.

Reflections on gains and losses: A 2x2x7 experiment

We test whether risk attitudes change when losses instead of gains areinvolved. The study of gain-loss asymmetries has been largely confinedto reflected choices, where all the money amounts of a positiveprospect are multiplied by minus one. We define the decomposition reflection = translation + probability switch, and experimentally findboth a translation effect (risk attraction becomes more frequent whengains are translated into losses) and a probability switch effect (riskattraction becomes more frequent when the probability of the best outcomedecreases). Surprisingly, the switch effect is somewhat stronger than thetranslation effect, negating a conventional reflection effect when onestarts with choices between gains with a low probability of the bestoutcome. We conclude by arguing that, while both the translation effectand the switch effect contradict the expected utility hypothesis, thetranslation effect implies a deeper violation of standard preference theory.

Solving a concrete sleepers production scheduling by genetic algorithms

PRECON S.A is a manufacturing company dedicated to produce prefabricatedconcrete parts to several industries as rail transportation andagricultural industries.Recently, PRECON signed a contract with RENFE,the Spanish Nnational Rail Transportation Company to manufacturepre-stressed concrete sleepers for siding of the new railways of the highspeed train AVE. The scheduling problem associated with the manufacturingprocess of the sleepers is very complex since it involves severalconstraints and objectives. The constraints are related with productioncapacity, the quantity of available moulds, satisfying demand and otheroperational constraints. The two main objectives are related withmaximizing the usage of the manufacturing resources and minimizing themoulds movements. We developed a deterministic crowding genetic algorithmfor this multiobjective problem. The algorithm has proved to be a powerfuland flexible tool to solve the large-scale instance of this complex realscheduling problem.

The elusive costs and the immaterial gains of fiscal contraints

We study whether and how fiscal restrictions alter the business cycle features macrovariables for a sample of 48 US states. We also examine the 'typical' transmission properties of fiscal disturbances and the implied fiscal rules of states with different fiscal restrictions. Fiscal constraints are characterized with a number of indicators. There are similarities in second moments of macrovariables and in the transmission properties of fiscal shocks across states with different fiscal constraints. The cyclical response of expenditure differs in size and sometimes in sign, but heterogeneity within groups makes point estimates statistically insignificant. Creative budget accounting isresponsible for the pattern. Implications for the design of fiscal rules and thereform of the Stability and Growth Pact are discussed.

Genetic homogeneity of dolphinfish (Coryphaena hippurus) in the western Mediterranean and the eastern Atlantic

Dolphinfish (Coryphaena hippurus) is an epipelagic, highly migratory species distributed worldwide in tropical and temperate waters including the Mediterranean Sea. Protein electrophoresis analyses can provide knowledge of the genetic population structure of the species and therefore be used as a tool for fishery management. Areas sampled include the islands of Majorca and Sicily in the western Mediterranean and the Canary Islands in the eastern Atlantic. The results of the protein electrophoresis reveal a level of genetic variability similar to other highly migratory species. No differences were found among locations, and it was not possible to reject the null hypothesis of one panmictic population in the area studied

Childhood adversity and psychosis: examinig whether the association is due to genetic confounding using a monozygotic twin differences approach

Purpose: To test whether the association between childhood adversity and positive and negative psychotic experiences is due to genetic confounding. Method: Childhood adversity and psychotic experiences were assessed in a sample of 226 twins from the general population. A monozygotic (MZ) twin differences approach was used to assess possible genetic confounding. Results: In the whole sample, childhood adversity was significantly associated with positive (β =.45; SE=.16; p=.008) and negative psychotic experiences (β=.77; SE=.18; p<.01). Within-pair MZ twin differences in exposure to childhood adversity were significantly associated with differences in positive (β =.71; SE=.29; p=.016) and negative psychotic experiences (β =.98; SE=.38; p=.014) in a subsample of 86 MZ twin pairs. Conclusions: Individuals exposed to childhood adversity are more likely to report psychotic experiences. Furthermore, our findings indicate that unique environmental effects of childhood adversity contribute to the development of psychotic experiences.

Microsatellite markers reveal shallow genetic differentiation between cohorts of the common sea urchin Paracentrotus lividus (Lamarck) in northwest Mediterranean

Temporal variability was studied in the common sea urchin Paracentrotus lividus through the analysis of the genetic composition of three yearly cohorts sampled over two consecutive springs in a locality in northwestern Mediterranean. Individuals were aged using growth ring patterns observed in tests and samples were genotyped for five microsatellite loci. No reduction of genetic diversity was observed relative to a sample of the adult population from the same location or within cohorts across years. FST and amova results indicated that the differentiation between cohorts is rather shallow and not significant, as most variability is found within cohorts and within individuals. This mild differentiation translated into estimates of effective population size of 90100 individuals. When the observed excess of homozygotes was taken into account, the estimate of the average number of breeders increased to c. 300 individuals. Given our restricted sampling area and the known small-scale heterogeneity in recruitment in this species, our results suggest that at stretches of a few kilometres of shoreline, large numbers of progenitors are likely to contribute to the larval pool at each reproduction event. Intercohort variation in our samples is six times smaller than spatial variation between adults of four localities in the western Mediterranean. Our results indicate that, notwithstanding the stochastic events that take place during the long planktonic phase and during the settlement and recruitment processes, reproductive success in this species is high enough to produce cohorts genetically diverse and with little differentiation between them. Further research is needed before the link between genetic structure and underlying physical and biological processes can be well established.

Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy

Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease. Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3. Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families. Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.

Genetic variants of the FADS gene cluster and ELOVL gene family, colostrums LC-PUFA levels, breastfeeding, and child cognition

Introduction: Breastfeeding effects on cognition are attributed to long-chain polyunsaturated fatty acids (LC-PUFAs), but controversy persists. Genetic variation in fatty acid desaturase (FADS) and elongase (ELOVL) enzymes has been overlooked when studying the effects of LC-PUFAs supply on cognition. We aimed to: 1) to determine whether maternal genetic variants in the FADS cluster and ELOVL genes contribute to differences in LC-PUFA levels in colostrum; 2) to analyze whether these maternal variants are related to child cognition; and 3) to assess whether children's variants modify breastfeeding effects on cognition. Methods: Data come from two population-based birth cohorts (n = 400 mother-child pairs from INMA-Sabadell; and n = 340 children from INMA-Menorca). LC-PUFAs were measured in 270 colostrum samples from INMA-Sabadell. Tag SNPs were genotyped both in mothers and children (13 in the FADS cluster, 6 in ELOVL2, and 7 in ELOVL5). Child cognition was assessed at 14 mo and 4 y using the Bayley Scales of Infant Development and the McCarthy Scales of Children"s Abilities, respectively. Results: Children of mothers carrying genetic variants associated with lower FADS1 activity (regulating AA and EPA synthesis), higher FADS2 activity (regulating DHA synthesis), and with higher EPA/AA and DHA/AA ratios in colostrum showed a significant advantage in cognition at 14 mo (3.5 to 5.3 points). Not being breastfed conferred an 8- to 9-point disadvantage in cognition among children GG homozygote for rs174468 (low FADS1 activity) but not among those with the A allele. Moreover, not being breastfed resulted in a disadvantage in cognition (5 to 8 points) among children CC homozygote for rs2397142 (low ELOVL5 activity), but not among those carrying the G allele. Conclusion: Genetically determined maternal supplies of LC-PUFAs during pregnancy and lactation appear to be crucial for child cognition. Breastfeeding effects on cognition are modified by child genetic variation in fatty acid desaturase and elongase enzymes.