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Infant born in Gambia. Image credit: Felicia Webb Chromosomes (blue) in their compressed state showing allele areas marked in the colors light blue and green. An allele is one member of a pair located in a specific area of a gene on a specific chromosome. Image credit: The National Cancer Institute

You are what your mother eats, really

A mother's diet just before she gets pregnant can permanently affect how her child developes.

A mother's diet before conception can permanently affect how her child's genes function, according to a study published in Nature Communications. This is the first clear evidence of such an environmental influence on humans and opens up the possibility that a mother's diet before pregnancy could permanently affect many aspects of her children's lifelong health.

Researchers from the MRC International Nutrition Group, based at the London School of Hygiene & Tropical Medicine and MRC Unit, The Gambia, devised a unique 'experiment of nature' in rural Gambia. In Gambia, the population depends on growing their own food and seasonal climate changes between rainy and dry seasons creates large difference in people's diets.

Through a selection process involving over 2,000 women, researchers enrolled 84 women who conceived at the peak of the rainy season and 83 women who conceived at the peak of the dry season.

By measuring the concentrations of nutrients in their blood, and later analysing blood and hair follicle samples from their 2-8 month old infants, the researchers found a mother's diet before conception had a significant effect on her child's DNA.

A child's genes are inherited directly from their parents, but whether these genes function, called 'expressed,' is controlled through influences from the environment outside of the gene blueprint, these are epigentic influences. In this particular study, the mother's DNA is functioning or not functioning in response to the epigenetic influence of her diet.

One gene modification was seen when a mother's gene was tagged with chemical compounds called methyl groups. This tag results in the silencing, or turning off, of that area of the gene. Methylated chemical compounds influenced key nutrients including folate, vitamins B2, B6 and B12, choline and methionine.

Experiments in animals have already shown that environmental influences before conception can lead to epigenetic changes that affect their offspring.

A 2003 study found that a female mouse's diet can change her offspring's coat colour by permanently modifying DNA methylation.(1)

But until this latest research, funded by the Wellcome Trust and the MRC, it was unknown whether such effects also occur in humans.

Senior author Dr Branwen Hennig, Senior Investigator Scientist at the MRC Gambia Unit and the London School of Hygiene & Tropical Medicine, says: "Our results represent the first demonstration in humans that a mother's nutritional well-being at the time of conception can change how her child's genes will be interpreted, with a life-long impact."

The researchers found that infants from rainy season conceptions had consistently higher rates of methyl groups present on all six genes under study in the mothers. These six genes are linked to various nutrient levels in the mother's blood. Strong associations were found with two genes in particular, homocysteine and cysteine.

The mothers' body mass index (BMI) also had an additional influence. The heavier the mother, the less methylation.

"There were no overweight women in this group. Even then, we found a strong link between the mother's BMI and methylation patterns," added professor Andrew Prentice. For years scientists have observed a similar phenomenon in mice. Diet and weight, at the time of conception, alter a mouse pup's DNA methylation affects on its genes.

However, although epigenetic effects were observed on these six genes, their functional outcomes remain unknown.

Professor Andrew Prentice, Professor of International Nutrition at the London School of Hygiene & Tropical Medicine, and head of the Nutrition Theme at the MRC Unit, The Gambia, says: "Our on-going research is yielding strong indications that methylation machinery can be disrupted by nutrient deficiencies - and that this can lead to disease.

"Our ultimate goal is to define an optimal diet for mothers-to-be to prevent defects in the methylation process. Taking folic acid pre-conception is already used to prevent [spina-bifida] defects in embryos. Now our research is pointing towards the need for a cocktail of nutrients, which could come from either diet or supplements."

Dr Rob Waterland of Baylor College of Medicine in Houston, who conducted the epigenetic analyses adds: "We selected these gene regions because our earlier studies in mice had shown us that establishment of DNA methylation at metastable epialleles(2) is particularly sensitive to maternal nutrition in early pregnancy."

The authors note that their study was limited by including only one blood sampling point during early pregnancy, but estimates of pre-conception nutrient concentrations were calculated compared to results from non-pregnant women sampled throughout a whole calendar year. The authors also plan to increase the sample size in future studies.

(1) Study by Robert A. Waterland and Randy L. Jirtle, Duke University Medical Center. Published in Molecular and Cellular Biology, August 2003

(2) Metastable epialleles are alleles that are turned on or off independent of the other pair of the allele.

An allele is one member of a pair of alleles in a specific area of a gene located on a specific chromosome.

If the pair of alleles are the same, the organism is said to be homozygous for the trait expressed by that gene; if each is different, the organism is heterozygous.

A dominant allele overrides the traits of a recessive allele in a heterozygous pair. In some traits, however, alleles may be codominant—i.e., neither acts as dominant or recessive. An example is the human ABO blood system; persons with type AB blood have one allele for A and one for B. (Persons with neither are type O.)

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Abstract
In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles.

This study was funded by the Wellcome Trust, UK; the Medical Research Council (MRC); the UK Department for International Development (DFID); the NIH/National Institute of Diabetes and Digestive and Kidney Diseases, USA; and the USDA, USA. Additional institutions involved in the study included the University of North Carolina, USA; University of British Columbia, Canada; and SRI International, USA.

About the London School of Hygiene & Tropical Medicine
The London School of Hygiene & Tropical Medicine is a world-leading centre for research and postgraduate education in public and global health, with 3,900 students and more than 1,000 staff working in over 100 countries. The School is one of the highest-rated research institutions in the UK, and was recently cited as the world's leading research-focused graduate school. Our mission is to improve health and health equity in the UK and worldwide; working in partnership to achieve excellence in public and global health research, education and translation of knowledge into policy and practice. http://www.lshtm.ac.uk

About the MRC International Nutrition Group
On 1 April 2014, the MRC International Nutrition Group (MRC ING seehttp://www.ing.mrc.ac.uk) became fully integrated into the MRC Unit, The Gambia. Nutrition will become a fourth theme within The Gambia Unit and will be led by Professor Andrew Prentice. The MRC's unit in The Gambia has an international reputation for ground-breaking research into some of the leading causes of morbidity and mortality in the tropics, and its research has led to some of the most outstanding successes in tropical medicine. http://www.mrc.gm/

About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.http://www.wellcome.ac.uk

About the Baylor College of Medicine
Baylor College of Medicine in Houston is recognized as a premier academic health sciences center and is known for excellence in education, research and patient care. It is the only private medical school in the greater southwest and is ranked 21st among medical schools for research and 12th for primary care by U.S. News & World Report. Baylor is listed 19th among all U.S. medical schools for National Institutes of Health funding and number one in Texas. Located in the Texas Medical Center, Baylor has affiliations with seven teaching hospitals and jointly owns and operates CHI St. Luke's Baylor St. Luke's Medical Center. Currently, Baylor trains more than 3,000 medical, graduate, nurse anesthesia, physician assistant and orthotics students, as well as residents and post-doctoral fellows.http://www.bcm.edu

About the Medical Research Council
The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers' money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. http://www.mrc.ac.uk

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