Recombination affects accumulation of damaging and disease-associated mutations in human populations. Journal: Nature Genetics| Pages: 400-404 |Date: April 2015 | Authors: Julie G Hussin, Alan Hodgkinson, Youssef Idaghdour, Jean-Christophe Grenier, Jean-Philippe Goulet, Elias Gbeha, Elodie Hip-Ki, Philip Awadalla Many decades of theory have demonstrated that, in non-recombining systems, slightly deleterious mutations accumulate non-reversibly, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion; however, it is not clear the extent to which damaging mutations accumulate along chromosomes with highly variable rates of crossing over. Using high-coverage sequencing data from over 1,400 individuals in the 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the distribution of putatively deleterious variants across the entire human genome. Exons in regions of low recombination are significantly enriched for deleterious and disease-associated variants, a signature varying in strength across worldwide human populations with different demographic histories. Regions with low recombination rates are enriched for highly conserved genes with essential cellular functions and show an excess of mutations with demonstrated effects on health, a phenomenon likely affecting disease susceptibility in humans. http://www.ncbi.nlm.nih.gov/pubmed/25685891 Last Updated on April 20, 2015

Cohorts and consortia conference: a summary report (Banff, Canada, June 17-19, 2009) Journal: Cancer Causes Control | Pages: 463-468 | Date: March 2011 | Authors: Boffetta P, Colditz GA, Potter JD, Kolonel L, Robson PJ, Malekzadeh R, Seminara D, Goode EL, Yoo KY, Demers P, Gallagher R, Prentice R, Yasui Y, O’Doherty K, Petersen GM, Ulrich CM, Csizmadi I, Amankwah EK, Brockton NT, Kopciuk K, McGregor SE, Kelemen LE. Epidemiologic studies have adapted to the genomics era by forming large international consortia to overcome issues of large data volume and small sample size. Whereas both cohort and well-conducted case-control studies can inform disease risk from genetic susceptibility, cohort studies offer the additional advantages of assessing lifestyle and environmental exposure-disease time sequences often over a life course. Consortium involvement poses several logistical and ethical issues to investigators, some of which are unique to cohort studies, including the challenge to harmonize prospectively collected lifestyle and environmental exposures validly across individual studies. An open forum to discuss the opportunities and challenges of large-scale cohorts and their consortia was held in June 2009 in Banff, Canada, and is summarized in this report.   http://www.ncbi.nlm.nih.gov/pubmed/21203821 Last Updated on April 16, 2015

Quality, quantity and harmony: the DataSHaPER approach to integrating data across bioclinical studies. Journal: Int J Epidemiol | Pages: 1383-1393 | Date: September 2012 | Authors: Fortier I, Burton PR, Robson PJ, Ferretti V, Little J, L’Heureux F, Deschênes M, Knoppers BM, Doiron D, Keers JC, Linksted P, Harris JR, Lachance G, Boileau C, Pedersen NL, Hamilton CM, Hveem K, Borugian MJ, Gallagher RP, McLaughlin J, Parker L, Potter JD, Gallacher J, Kaaks R, Liu B, Sprosen T, Vilain A, Atkinson SA, Rengifo A, Morton R, Metspalu A, Wichmann HE, Tremblay M, Chisholm RL, Garcia-Montero A, Hillege H, Litton JE, Palmer LJ, Perola M, Wolffenbuttel BH, Peltonen L, Hudson TJ. BACKGROUND: Vast sample sizes are often essential in the quest to disentangle the complex interplay of the genetic, lifestyle, environmental and social factors that determine the aetiology and progression of chronic diseases. The pooling of information between studies is therefore of central importance to contemporary bioscience. However, there are many technical, ethico-legal and scientific challenges to be overcome if an effective, valid, pooled analysis is to be achieved. Perhaps most critically, any data that are to be analysed in this way must be adequately ‘harmonized’. This implies that the collection and recording of information and data must be done in a manner that is sufficiently similar in the different studies to allow valid synthesis to take place. METHODS: This conceptual article describes the origins, purpose and scientific foundations of the DataSHaPER (DataSchema and Harmonization Platform for Epidemiological Research; http://www.datashaper.org), which has been created by a multidisciplinary consortium of experts that was pulled together and coordinated by three international organizations: P³G (Public Population Project in Genomics), PHOEBE (Promoting Harmonization of Epidemiological Biobanks in Europe) and CPT (Canadian Partnership for Tomorrow Project). RESULTS: The DataSHaPER provides a flexible, structured approach to the harmonization and pooling of information between studies. Its two primary components, the ‘DataSchema’ and ‘Harmonization Platforms’, together support the preparation of effective data-collection protocols and provide a central reference to facilitate harmonization. The DataSHaPER supports both ‘prospective’ and ‘retrospective’ harmonization. CONCLUSIONS: It is hoped that this article will encourage readers to investigate the project further: the more the research groups and studies are actively involved, the more effective the DataSHaPER programme will ultimately be. http://www.ncbi.nlm.nih.gov/pubmed/20813861 Last Updated on April 16, 2015

The Canadian Partnership for Tomorrow Project: building a pan-Canadian research platform for disease prevention. Journal: CMAJ | Pages: 1197-1201 | Date: August 2010 | Authors: Borugian MJ, Robson P, Fortier I, Parker L, McLaughlin J, Knoppers BM, Bédard K, Gallagher RP, Sinclair S, Ferretti V, Whelan H, Hoskin D, Potter JD. As the proportion of the population over age 65 increases in Western countries, the burden of cancer 1 and other chronic diseases is also increasing. If advances in preventing these diseases are to be realized, better information is needed about their causes and the antecedents of the causes. For example, although it is known that many sporadic cancers are caused by a combination of lifestyle factors, exposure to environmental carcinogens and individual genetic makeup, 2,3 detailed knowledge about the interplay among these factors is lacking. Much of our current knowledge about the causes of cancer and most relatively rare chronic diseases has come from retrospective case–control studies, in which the characteristics of patients (cases) are compared with those of age- and sex-matched people who do not have the disease (controls). This design has strengths but also a number of weakneses, including potential recall bias and selection bias 4 (Table 1). To address some of these weaknesses, in particular recall bias and the temporal relation between risk factors and outcomes, prospective cohorts are helpful because participants are enrolled before the onset of disease. In studies with a prospective cohort design, large numbers of participants, who generally have not had cancer or any other significant diagnosis, are recruited and followed over a long time, periodically providing updated health and lifestyle information and biologic samples. Layers of data and samples accumulate over time, allowing an exploration of why cancer develops in some people within the cohort but not others. 6 The disadvantages of such a design (Table 1) are cost and time, as it may be a decade or more before major results are obtained. Fortunately, many shorter-term results are also available, such as information on screening attendance and information on the frequency of major risk factors and health states, as well as environmental and individual determinants of these risk factors, all of which are useful for planning various health services. Furthermore, because many diseases can be studied simultaneously, the cost over time per health outcome studied is substantially lower than the cost of case–control studies for a comparable number of participants. http://www.ncbi.nlm.nih.gov/pubmed/20421354 Last Updated on April 16, 2015