Rationale Environmental factors can influence the role of genes in human traits via both natural selection (a long-term, multi-generational response) and epigenetic changes (shorter-term intra-individual or trans-generational response). Extensive literature provides examples of both of these mechanisms (reviewed in 1&2). However, for the first time, the availability of high-density genetic data in multiple populations and high-density genome-wide methylation in large-scale cohorts enables detailed analysis of both mechanisms in parallel to determine the relationship between these two environmental response mechanisms.
The ALSPAC resource of over 10,000 mothers and their children includes genome-wide methylation data, extensive clinic and questionnaire data, genome-wide SNP arrays, expression data, whole genome sequencing and metabolomics. This unique collection of data provides an opportunity to examine the relationship between environmental/lifestyle factors, molecular mechanisms and health.
Aims & Objectives 1. Systematically review literature for selection, and perform additional analyses to identify loci with strong evidence of natural selection 2. Analyse relationship between exposures, methylation and genotype to investigate how methylation interacts with or provides an alternative to selection in facilitating adaptation to different exposures 3. Analyse trans-generational methylation patterns in relation to exposures to assess influence of short-term selective pressures on methylation.
Methods 1. Methods to assess natural selection – eg Cross Population Extended Haplotype Homozogysity 2. Bioinformatics/biostatistical approaches to integrate and analyse datasets 3. Epigenome-wide association study (EWAS) using, for example, CpGassoc 4. Statistical analyses of natural selection and methylation changes
1. Alegría-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics. 2011 Jun;3(3):267-77. doi: 10.2217/epi.11.22. 2. Bamshad M, Wooding SP. Signatures of natural selection in the human genome. Nature Reviews Genetics 4, 99-111