Environmentally sensitive hotspots in the methylome of the early human embryo
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, United Kingdom
- University of Cambridge, United Kingdom
- CSIR-Centre for Cellular and Molecular Biology, India
- University of Southampton, United Kingdom
- MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Gambia
- King's College London, United Kingdom
- University of Leeds, United Kingdom
- International Agency For Research On Cancer, France
- University of East Anglia, United Kingdom
Abstract
In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin specific methylation and germline DMRs, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 ESCs and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental ‘hotspots’ providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.
Data availability
Illumina 450k methylation array data generated from Gambian 2 year olds from the ENID trial is deposited in GEO (GSE99863). Requests to access and analyse the other Gambian methylation datasets (ENID 5-7yr and EMPHASIS 7-9yr) should be submitted to the corresponding author in the first instance. An application would then need to be made to MRC Unit The Gambia's Scientific Coordinating Committee and the Joint MRC/Gambia Government Ethics Committee.Sources and locations of other publicly available data used in this analysis are described in Methods. Bespoke code used in the analysis is available at https://zenodo.org/record/5801480.
Article and author information
Author details
Funding
Medical Research Council (MC-A760-5QX00)
- Matt J Silver
- Andrew M Prentice
Bill and Melinda Gates Foundation (OPP1 066947)
- Sophie E Moore
- Michael N Routledge
- Zdenko Herceg
Medical Research Council (MR/N006208/1)
- Matt J Silver
- Caroline HD Fall
- Andrew M Prentice
Department of Biotechnology, Ministry of Science and Technology, India (BT/IN/DBT-MRC/DFID/24/GRC/2015-16)
- Gririraj R Chandak
Medical Research Council (MR/M01424X/1)
- Matt J Silver
- Ayden Saffari
- Noah J Kessler
- Andrew M Prentice
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Joris Deelen, Max Planck Institute for Biology of Ageing, Germany
Ethics
Human subjects: Ethics approval for the Gambian ENID and EMPHASIS trials was obtained from the joint Gambia Government/MRC Unit The Gambia's Ethics Committee (ENID: SCC1126v2; EMPHASIS: SCC1441). The ENID study is registered as ISRCTN49285450. The EMPHASIS study is registered as ISRCTN14266771. Signed informed consent for both studies was obtained from parents, and verbal assent was additionally obtained from the older children who participated in the EMPHASIS study.
Version history
- Preprint posted: September 23, 2019 (view preprint)
- Received: July 7, 2021
- Accepted: February 18, 2022
- Accepted Manuscript published: February 21, 2022 (version 1)
- Version of Record published: March 10, 2022 (version 2)
Copyright
© 2022, Silver et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Environmentally sensitive hotspots in the methylome of the early human embryo
eLife 11:e72031.
https://doi.org/10.7554/eLife.72031
Further reading
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Methods: From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.
Results: Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than six months earlier, spike levels fell notably and continuously for the nine months post-vaccination. By contrast, among adults infected within six months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than six months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% CI 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the COVID-19 weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.
Conclusions: Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected dried blood spots are a practicable biological surveillance platform.
Funding: Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
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