Biological inheritance from one generation to the next is generally regarded as transmission of genes and other DNA variation from both parents, plus 'maternal effects' either carried within the egg cytoplasm or through the trans-placental passage of nutrients and metabolic signals. Biological inheritance is supplemented by 'cultural inheritance' (including nurturing behaviour and social patterning) from which it needs to be distinguished.

However, there is growing evidence in mammals (refs 1- 3,9 and references therein) that sperm carry information about the ancestral environment that can influence the development and health of the next generation(s) through enduring alterations in gene expression. How this information is transmitted is unknown, but epigenetic gametic inheritance is one candidate.

There are human epidemiological TGR data (predominantly male-line with mortality, diabetes, coronary heart disease and metabolic syndrome as outcomes) from three populations;Overkalix in Northern Sweden (4-6), ALSPAC (6) and Taiwan (7).A similar phenomenon could occur down the maternal line, complementing the known 'maternal effects', although the latter present a challenge in terms of confounding. Beyond the importance of enlarging our knowledge of human inheritance, understanding the nature and extent of these transgenerational responses is likely to bring medical and public health benefits.

This project will extend our ALSPAC work on TGR to include additional ancestral exposures and further exploration of sex-specific effects.

Background

The initial ALSPAC data (6) showed that paternal onset of smoking before puberty was associated with a greater BMI at 9 years in sons but not daughters. This triggered sex-specific analysis of the Overkalix data with dramatic results. The paternal grandfather's food supply in mid childhood was only linked to the mortality rate of grandsons, whilst paternal grandmother's food supply was only associated with the granddaughters' mortality rate (6). This was true in 2 of 3 independent cohorts and the TGR persists when the grandchild's early life circumstances were also taken into account (8). There are also father to son affects in the Overkalix data. Recent unpublished ALSPAC analysis shows paternal onset of smoking before puberty continues to be associated with greater BMI in (just) sons until age 15.

Since we published 5 years ago, animal studies have paid more attention to sex differences in TGR with varying results from exposed males linked to affected female offspring (2,3) or to affected offspring of both sexes (1) and with curious three generation male-line effects, namely exposed male, his male offspring (unaffected) and that male's male offspring who are affected (2). But some of these studies had altered diet throughout development of the exposed male ancestor. Other studies, e.g. with short term fasting at different ages of the exposed male, found predominantly affected male offspring (9).

Our collaborative work with Lars Olov (Olle) Bygren suggests humans have an exposure sensitive period in mid childhood (both sexes) and in the fetal/infant period (females), but there is no triggering of TGR in puberty in either sex. Thus we can expect to find different outcomes in descendants (analysed by sex) by comparing paternal or ancestral exposures during puberty with exposures at the above specific times before puberty.

The long-term plan is to; a) test the hypothesis that transmission across the generations in TGR is mediated by elements segregating with the Y(non pairing region) and X chromosome by (epi)genomic analysis, and b) to look for the downstream effects on gene expression in the offspring that are relevant to the outcomes using genome wide DNA methylation association studies. However, more epidemiological evidence of triggers of TGR and sex specific effects are needed to inform these future molecular studies. Meanwhile more understanding of the variables in methylome analysis will accumulate (e.g.10).

Planned studies

* Using the established TGR trigger of paternal smoking before puberty, explore outcomes relevant to metabolic syndrome throughout the development of sons and daughters.

* To test the exposure of the study father in utero (via his own mother smoking in pregnancy) on the outcomes as above in his sons and daughters, particularly in fathers who did not smoke themselves.

* To test the exposure of the study mother in utero (via her own mother smoking in pregnancy) on the outcomes as above in her sons and daughters, particularly in mothers who did not smoke themselves.

In line with animal data, explore 'traumatic events' as a TGR trigger for mental health and behavioural outcomes (as well as metabolic syndrome outcomes) in descendants. These will be of two kinds.

* Study fathers and mothers who suffered the death, separation or divorce of a parent before their own puberty.

* Paternal great grandmother's experience of husband being eligible to go to war in 1939-40 whilst the paternal grandmother was a fetus or infant. Outcomes measured in the children of the study fathers who did and did not have this ancestral exposure.

Look for potential TGR by detecting associations with exposures in the parental or grandparental generation for specific outcomes in the study child. [Unpublished analysis with respect to all childhood cancers reveals an association with the study father's early childhood traumatic circumstances.]

References

1. Carone BR et al (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084-1096.

2. Franklin TB et al (2010) Epigenetic transmission of the impact of early stress across generations. Biological Psychiatry 68, 408-415.

3. Ng SF et al (2010). Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963-966.

4. Bygren LO, Kaati G, Edvinsson S (2001) Longevity determined by ancestors' over nutrition during their slow growth period. Acta Biotheoretica 49:53-59.

5. Kaati, G, Bygren LO, Edvinsson S (2002) Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10, 682-88.

6. PembreyME, Bygren, LO, Kaati G, Edvinsson S, Northstone K, Sjostrom M, and Golding J (2006). Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14, 159-166.

7. Tony H-Hsi Chen TH, Yueh-H Chiu YH, Boucher BJ (2006). Transgenerational effects of betel-quid chewing on the development of the metabolic syndrome in the Keelung Community-based Integrated Screening Program. Am J Clin Nutr 83, 688 -92.

8. Kaati G, Bygren LO, Pembrey M, Sjostrom M (2007). Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet 15:784-90.

9. Anderson LM et al (2006). Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition 22, 327-331.

10. Robinson MD et al (2010). Evaluation of affinity-based genome-wide DNA methylation: effects of CpG density, amplification bias and copy number variation. Genome Res 20, 1719-29.