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International Journal of Epidemiology, 2016, Vol. 45, No. 1 23 24. Dias BG, Maddox SA, Klengel T, Ressler KJ. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci 2014:1–12. 25. Meaney MJ, Szyf M, Seckl JR. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med 2007;13:269–77. 26. Weaver ICG, Cervoni N, Champagne FA et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7:847–54. 27. Weaver ICG, Meaney MJ, Szyf M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci U S A 2006;103:3480–85. 28. Dietz DM, Laplant Q, Watts EL et al. Paternal Transmission of Stress-Induced Pathologies. BPS 2011;70:408–14. 29. Lazic SE, Essioux L. Improving basic and translational science by accounting for litter-to-litter variation in animal models. BMC Neurosci 2013;14:37. 30. Dias BG, Ressler KJ. Experimental evidence needed to demon- Commentary: Lamarckian inheritance and epigenetics: is there a connection? International Journal of Epidemiology, 2016, 23–25 doi: 10.1093/ije/dyw003 strate inter- and trans-generational effects of ancestral experiences in mammals. Bioessays 2014;36:919–23. 31. Darwin C. Pangenesis. Nature 1871:502–03. 32. Galton F. Pangenesis. Nature 1871:5–6. 33. Gapp K, Jawaid A, Sarkies P et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 2014;17:667–69. 34. Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 2006;441:469–74. 35. Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG, Bing XY, et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 2015, Dec 31. pii: aad6780. [Epub ahead of print.] David J Galton Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected] Accepted 11 January 2016 Francis Galton is mainly remembered for his work on eugenics (a word he coined) which he unfortunately referred to on occasion as Race Improvement—naturally raising much opprobrium today. His other major contribution is in statistics to analyse results of studies of inheritance of quantitative traits such as height of parents related to height of offspring. He originated correlation analysis to determine if one variable has any relation to another and, after modification by people like Pearson, Spearman, Kendall and others, the method has found its way into school textbooks. In some ways Galton’s mental energy was his own worst enemy. Some would say he worked on too many topics, including meteorology with the invention of isobars and weather maps, fingerprints to identify an individual (which is still in use), African exploration (opening up parts of Namibia in South West Africa) and problems of heredity. The latter was a major field of interest and he gained the reputation of a Victorian polymath.1 The date of this present paper—1889—is long after his work on eugenics started with his book on Human Faculty,2 which he pursued with almost religious zeal until his death in 1911. So it is interesting that he is still pondering ideas of heredity in 1889. His work on heredity started in about 1865, culminating in his two major books: Heredity Genius3 and Natural Inheritance.4 He had studied with Charles Darwin the possible change of fur colour in rabbits after blood transfusions, to determine if there were any blood-borne particles that may be involved in inheritance. The results were negative and, going against Darwin’s wishes, Galton published them in the Proceedings of the Royal Society of 1871. Darwin was not a co-author. Galton also studied the inheritance of coat colour of Basset hounds and the occurrence of diseases in identical and non-identical twins; and came very close to Mendel’s experiments, studying the inheritance in the sweet pea (not the edible pea that Mendel studied). He measured how the seed size and weight related between parents and progeny. If only he had measured the shape of pollen grains of the sweet pea (either oblong or round—a Mendelian trait) he might have replicated the results of Mendel only 5 years after Mendel’s great publication of C The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association V 24 1866.5 Galton preferred quantitative rather than qualitative measurements. He advanced the study of quantitative inheritance but based it wrongly on the transmission of Darwin’s theoretical particles (gemmules), not discrete elements as Mendel had discovered. Galton’s statistics have been of lasting value, as mentioned above. Mendel on the other hand concentrated on just one problem in heredity, working steadily on it for 8 years and revealing some fundamental Laws or Principles of Heredity. He is rightly regarded as the founding father of modern genetics. Galton, an exact contemporary of Mendel (both born in 1822), lived to see Mendel’s triumph after three botanists replicated Mendel’s data in the early 1900s. He must have been disappointed to see how close he had got to Mendel’s ideas. He generously acknowledged in his Memories of My Life of 1908 that: ‘I must stop for a moment to pay tribute to Mendel . . . Mendel clearly showed that there were such things as alternative atomic characters in equal potency in descent . . . ’ He writes for a further one and a half pages on his work with his Basset hound supporting Mendel’s ideas of discrete rather than blending inheritance.6 Galton’s short note of 1889 raises the question of inheritance of acquired characters. For Lamarck (1744–1829) this was the driving force behind his theory of evolution, or transformation as he called it, of animal species changing into new forms. It has been an idea that many biologists from Darwin’s time onwards have strongly decried but it never seems to die, unlike the deaths of false ideas like phlogiston or vitalism. There might be some truth in this idea of the inheritance of acquired characters, especially as the topic of Lamarckian epigenetics is alive and debated today. Galton’s experimental suggestions of 1889 show some of his ways of tackling a problem. He often chooses to get hold of an issue from the complex rather than the simpler end. He chooses as experimental material the vague and variable features of animal behaviour, rather than the more stable features of animal anatomy. He mentions the discovery of August Weismann that inherited traits must pass through the sex or germ cells, in Weismann’s nomenclature; so that acquired features of animal behaviour, such as the trout being conditioned not to attack the minnows, must somehow affect the hereditary material in the germline to affect the behaviour of the progeny. This is a clear anticipation of an epigenetic type of inheritance. Epigenetics can mean epi (above, or in addition to) genetics as though it is in some way beyond and more important than germline genetics. Methylation, histone phosphorylation, non-coding RNAs etc. are just the ways the genome organizes its components. Epigenetics is no International Journal of Epidemiology, 2016, Vol. 45, No. 1 more nor less important than crossing-over of chromosomes, transcription factors, transposable elements or the variety of non-coding RNA species and other regulatory molecules that occur. Long non-coding RNAs can silence genes. The whole of the X chromosome in the female zygote is silenced by an X-inactivating specific RNA transcript (Xist) which coats the X-chromosome to inactivate it. The transcription of the Xist gene is in turn regulated by a DNA methyltransferase, showing the close inter relationships of genomic regulation.7 Some biologists have taken up Lamarckian epigeneticswith enthusiasm. A study of the foraging behaviour in chickens as a function of stress (an echo of Galton’s suggestion) concluded that the transmission of acquired behavioural traits across generations did not involve changes in DNA sequence, but could possibly be due to DNA methylation.8 Another study in mice suggested that fathers can transfer the liability to obesity to their daughters as a result of the father’s food intake even before the delivery of the daughter and is not due to their genetics.9 Of course, as is usual with vaguely defined hypotheses, there are plenty of opponents to the idea of Lamarckian epigenetics. As a contribution to Francis Galton’s original paper, a feasible experiment that may help to validate Lamarckian epigenetics would be to take a simple inherited structural trait (not behavioural) that codes for a simple protein (A), such as a lipid transport peptide, that can be shown to be silenced to produce phenotype (a). The study would then be to genotype grand-parents, parents and children and select those pedigrees where the grand-parents are both A.A (the default setting), find a parent who is A.a (acquired by DNA methylation as revealed by methylome analysis of the specific gene region) and then find children genotyping as A.A or A.a, thus demonstrating transmission of the acquired structural feature of (a) from parent to child. This to me would be very convincing evidence that epigenetic inheritance occurs; the Lamarckian part of it affecting evolution would perhaps come later. If this experiment has been done, please send me the reference. Conflict of interest: None declared. References 1. Gillham NW. A Life of Sir Francis Galton. New York, NY: Oxford University Press, 2001. 2. Galton F. Inquiries into Human Faculty & Its Development. London: J. M. Dent, 1883. 3. Galton F. Hereditary Genius. 1st edn. London: Macmillan, 1869. 4. Galton F. Natural Inheritance. London: Macmillan, 1889. International Journal of Epidemiology, 2016, Vol. 45, No. 1 5. Mendel GJ. Versucheuber Pflanzen-Hybriden. Verknaturf.Ver in Brunn; band iv 1866. English translation in: J R Hort Soc 1901;xxvi. 6. Galton DJ. Man of Science, Man of God. Mendel: Discovering the Gene. London: Timaeus Press, 2015 (in press). 7. Sharon F. Briggs, Renee A. Pera. Chromosome inactivation: recent advances and a look forward. Curr Opin Genet Dev 2014;28:78–82. 25 8. Natt D, Lindqvist N, Stranneheim H, Lundeberg J, Torjesen PA, Jensen P. Inheritance of acquired behaviour adaptation and brain gene expression in chickens. PloS One 2009;4:e6405. 9. Ng S-F, Lin RC, Laybutt D, et al. Chronic high fat diet in fathers programs B-cell dysfunction in female rat off spring. Nature 2010;467:963–66.