Telegony, the Sire Effect and non‐Mendelian Inheritance Mediated

Review Article Telegony, the Sire Effect and non-Mendelian Inheritance Mediated by Spermatozoa: A Historical Overview and Modern Mechanistic Speculations YS Liu Henan Institute of Science and Technology, Xinxiang, China Contents Telegony is the belief that the sire first mated to a female will have an influence upon some of that female’s later offspring by another male. Although the reality of telegony was acknowl- edged by such authorities as Darwin, Spencer, Romanes and many experienced breeders, it has been met with scepticism because of Weismann’s unfavourable comments and negative results obtained in several test experiments. In this article, alleged cases of telegony are provided. A search of the literature of cell biology and biochemistry reveals several plausible mechanisms that may form the basis for telegony. These involve the penetration of spermatozoa into the somatic tissues of the female genital tract, the incorporation of the DNA released by spermatozoa into maternal somatic cells, the presence of foetal DNA in maternal blood, as well as sperm RNA-mediated non-Mendelian inheritance of epigenetic changes. Introduction The subject of telegony is an exceptional, alleged phenomenon that enjoyed a remarkable career in the nineteenth century (Burkhardt 1979). Its principle is that females are impregnated by the first males to which they are mated, so that some of their subsequent offspring, regardless of their actual father, will show influence of the first male (Rabaud 1914). In modern parlance, the term ‘sire effect’ would cover such a phenomenon. Although the story of the son who resembles his mother’s former husband has circulated among the people in China for generations, Charles Darwin was the first to summarize this phenomenon in biological science. In Chapter 11 of his book The Variation of Animals and Plants under Domestication, Darwin (1868) collected many alleged examples of ‘the direct action of the male element on the female form’. He mentioned the case of Lord Morton’s famous hybrid, from a chestnut mare and a male quagga. Not only the hybrid but also the offspring subsequently produced by themare whenmated to a blackArabian sire was more plainly barred across the legs than even the pure quagga. Darwin concluded that ‘there can be no doubt that the quagga affected the character of the offspring subsequently begot by the black Arabian horse’. He considered it to be of special importance for understanding the mechanisms of heredity and develop- ment and advanced this case as one of several in support of his hypothesis of Pangenesis – a developmental theory of heredity (Darwin 1868; Liu 2008). It is a historical fact that in the nineteenth century, the phenomenon of telegony commanded considerable respect, guided the practice of many animal breeders and played an important role in pre-1900 discussions of heredity. The reality of Morton’s mare was acknow- ledged by such authorities as Louis Agassiz, Claude Bernard, Herbert Spencer, George John Romanes, Francis Galton, William Bernard Tegetmeier and many experienced breeders (Thomson 1908; Burkhardt 1979). Spencer (1893) regarded it as a major weapon in his debate with August Weismann over the reality of the inheritance of acquired characters. Scientists who made any pretence of understanding reproduction and here- dity managed to find ways of explaining it. Unfortu- nately, modern biology has no place for it. Although xenia (pollen effects on seeds and fruits) has been well recognized by most plant biologists and is more alive than ever, telegony, a different case of the same general phenomenon in animals, has been met with scepticism (Burkhardt 1979). A search of the literature of cell biology and biochemistry reveals several plausible mechanisms that may form the basis for telegony. Over the past several decades, convincing evidence has accumulated for the penetration of somatic cells by spermatozoa. The successful achievements in mammalian cell transfection by foreign DNA and the new findings of foetal DNA in maternal blood and sperm RNA-mediated non-Mende- lian inheritance of epigenetic changes furnish a basis for telegony. Thus, it is timely to reconsider the case of telegony. Reasons Why Telegony has been met with Scepticism It was August Weismann who coined the term ‘tele- gony’. Weismann (1912) was confident that if telegony was a genuine phenomenon, he could explain it without sacrificing his theory of the germ plasm. He suggested the possibility that ‘spermatozoa had reached the ovary after the first sexual union had occurred and had penetrated into certain ova which were still immature.’ When these ova mature, amphimixis might occur and coincide in time with the second coitus to which the subsequent offspring would be ascribed. But were this the explanation, one should sometimes find that off- spring were produced without any second sire at all. No such phenomenon is known among higher animals. Thus, he was sceptical that the phenomenon was real. In his book The Germ-Plasm, he placed telegony under the heading ‘doubtful phenomena of heredity’. He thought Reprod Dom Anim 46, 338–343 (2011); doi: 10.1111/j.1439-0531.2010.01672.x ISSN 0936-6768 � 2010 Blackwell Verlag GmbH that the recorded instances of telegony were based on a ‘misconception’ and suggested that experiments be conducted to test this question (Weismann 1912). We now know that some animals have sperm that live for years and the classic example is attine ants. But for most animals, the sperm has a relatively short life in the female genital tract. It is admitted that the life of the spermatozoa is limited to a few hours or days at the longest, and that their powers of fertilizing exist only during their life. None could possibly live to fertilize an egg secreted 1 or 10 years later. Thus, most people think that there is not a theoretical basis for telegony. Realizing that ‘no problem … claims wider attention at the present time than what is now generally known as telegony’, Ewart (1899) conducted a series of experi- ments that were designed ‘to repeat as exactly as possible Lord Morton’s experiment’. He had no illu- sions that his work constituted a formal disproof of telegony but concluded that the striping of Morton’s hybrid was best explained as a case of reversion. In addition, Daniel (1959) carried out a controlled breeding experiment with rats and with Drosophila to re-deter- mine the validity of telegony. No evidence was obtained to support the view that previous matings can have any genetic effect on the offspring of later matings. Possible Data in Respect of the Existence of Telegony Many people thought that Morton’s mare was a coincidence and not a causal connection. As a matter of fact, Darwin (1868) cited nine sources beside Lord Morton with respect to the idea of the influence of a previous sire on the offspring of a female’s later matings. He gave a number of references to other cases, not only in horses but also in pigs, dogs and sheep. For example, a sow of Lord Western’s black and white Essex breed was mated with a wild boar of a deep chestnut colour; and the ‘pigs produced partook in appearance of both boar and sow, but in some the chestnut colour of the boar strongly prevailed.’ After the boar had long been dead, the sow was mated to a boar of her own black and white breed – a kind that is well known to breed very true and never to show any chestnut colour – yet from this union the sow produced some young pigs that were plainly marked with the same chestnut tint as in the first litter. After Darwin’s death, there appeared other examples of telegony in dogs, sheep, birds and human (see Table 1). It should be noted that some dog and sheep breeders, as a rule, still adhere to the idea, and several sheep breeders’ associations even refuse to register lambs whose mother were ever ‘impregnated’ by mating with a common ram (Rabaud 1914; Mole 2006). Zhelnin (1964) observed the phenomenon of telegony in rabbits and argued that telegony did not occur rarely as was previously thought. Interestingly, a telegony phenomenon, or sire effect, has also been observed in the immune system of mice. When normal females that had borne at least three litters to males made tolerant neonatally were subsequently mated to normal, non-immune males, the offspring showed a hyporesponsive phenotype that did not differ from that of the progeny of fathers made tolerant neonatally. The response of this offspring was signif- icantly lower than the response of mice born to normal females mated only to normal mates (Gorczynski et al. 1983). This type of observation has also been reported by Cooper-Willis et al. (1985). In addition, Sobey and Conolly (1986) demonstrated that male domestic rab- bits, mating after recovering from myxomatosis, may transmit immunity to progeny born to the female in the next 7 months, including progeny sired by other males lacking immunity. This has been confirmed by later researches (Williams and Moore 1991; Parer et al. 1995). Although always largely an animal breeders’ issue, telegony is also invoked in ideas about human inheri- tance (Bynum 2002). A remarkable illustration of telegony in humans has been observed and recoded by Lingard (1884), in which a hypospadian, whose father and paternal grandfather were similarly malformed, contracted a marriage with a woman not related to him, who bore him three sons, hypospadians. He died a few years after the birth of his three sons. His widow within 18 months after his death contracted a second marriage, the husband in this instance not being a hypospadian and having no history of any such deformity in his family. By this marriage, she had four sons, all hypo- spadians. Sedgwick (1896) believed that this case might help to overcome some of the objections that have been urged against the influence of a previous marriage on the subsequent offspring by a second or even by a third husband. Thomson (1908) cited the case of a woman married to a deaf-mute, by whom she had one deaf-mute child. By a second normal husband, she had a deaf-mute child and then others who were normal. There is also evidence for telegony in modern China. For example, two Chinese women gave birth to children after they married their second husband. Interestingly, the appear- ances of their children closely resemble their first husband (Hui 1989; Mei 2000). It should be mentioned that to confirm the existence of telegony, Romanes (1893) pursued investigations on three different lines: (i) He raised discussions on the subject in the principal breeders’ and fanciers’ journal of England and America. (ii) He entered into private correspondence with contributors of the largest experi- ence and also with professional and amateur breeders and fanciers who addressed him directly on the subject. (iii) He started experiments with different animals. He concluded that ‘my evidence is enough to prove the fact of a previous sire asserting his influence on a subsequent progeny, although this fact is one of comparatively rare occurrence.’ Table 1. Cases of telegony in animals and humans Species References Horse Morton (1821); Darwin (1868); Finn (1893) Pig Giles (1821); Darwin (1868); Finn (1893) Sheep Darwin (1868); Cornevin (1891); Finn (1893) Dog Darwin (1868); Cornevin (1891); Spencer (1893); Mole (2006) Bird Darwin (1868); Finn (1893) Human Lingard (1884); Flint (1888); Cornevin (1891); Hui (1989); Redfield (1903); Mei (2000) Mice Gorczynski et al. (1983); Cooper-Willis et al. (1985) Rabbit Zhelnin (1964); Sobey and Conolly (1986); Parer et al. (1995); Williams and Moore (1991) Telegony, the Sire Effect and non-Mendelian Inheritance Mediated by Spermatozoa 339 � 2010 Blackwell Verlag GmbH Previous Explanations for Telegony To explain telegony, xenia, reversion, regeneration, prepotency (Mendelian inheritance), graft hybridization, sex-limited inheritance, the effect of use and disuse, the inheritance of acquired characters and many other facts pertaining to inheritance, variation and development, Darwin (1868) elaborated his ‘provisional hypothesis of Pangenesis.’ Darwin’s Pangenesis had two basic postu- lates: first, that the cells of the body throw off gemmules (the embryonic form of our modern genes), which ‘circulate freely throughout the system’; and second, that these gemmules are not only self-replicating and corpuscular but also able to penetrate other nascent cells and modify their subsequent development. Darwin (1868) maintained: ‘it is certain that [the mother’s] ovaria are sometimes affected by a previous impregna- tion, so that the ovules subsequently fertilized by a distinct male are plainly influenced in character’. He believed that in case of Morton’s mare it was ‘the diffusion, retention, and action of the gemmules included within the spermatozoa of the [first] male’ that left the mare with a ‘quagga taint’ that continued to manifest itself in her later offspring. Darwin was not very explicit about this, but he did say more regarding the effect of pollen on the tissues of the mother plant. Darwin explained that in the case of xenia, ‘the gemmules derived from the foreign pollen do not become developed merely in contact with pre-existing cells, but actually penetrate the nascent cells of the mother plant’ (Darwin 1868). In addition to Darwin’s Pangenesis, there is another explanation, which is that the mother is influenced through the foetus during pregnancy and that the influence manifests on subsequent offspring. That is to say, the first sire impresses his own offspring with certain of his own characteristics; the offspring of this sire impresses the mother through the blood-current; the mother, in turn, transmits the peculiarities of the first sire to her subsequent progeny by means of the blood element she has received from her first offspring (Bell 1896). A New Perspective on the Mechanism of Telegony Penetration of spermatozoa into the somatic tissues of the female genital tract In the early 1910s,Kohlbrugge published reports inwhich he claimed to have identified numerous spermatozoa in the mucosal cells of the uterus and uterine tube in the mouse, rabbit and bat. He maintained that modification of the mucosal cells could mediate a paternal influence upon the embryo, and he suggested that this influence, persisting from one pregnancy to the next, could be the mechanism of telegony (Kohlbrugge 1910, 1913). It should be mentioned that Austin et al. examined sections of uteri of the Great Horseshoe bat and the Common Pipistrelle, and their observations strongly suggest that spermatozoa do in fact enter the mucous membrane of the uterine tube in these animals. These observations are compatible with the possibility that the mucosa of the uterine-tube isthmus may be altered in some way by invading spermatozoa. They concluded that this could conceivably be brought about by transfer of genetic information in a manner analogous to that of bacterial transformation (Austin 1959, 1960; Austin and Bishop 1959). Since the first light-microscopic observations of the presence of numerous spermatozoa within the uterine mucosal cells, there have been numerous reports describing the penetration of spermatozoa into tissues, both maternal and embryonic (see Table 2). Recently, Brodsky and Ivanov (2009) proposed that spermatozoids may penetrate somatic cells in vivo, forming viable chimeric cells, which may survive in the body for a long time. The incorporation of exogenous DNA into somatic cells Darwin (1868) supposed that the gemmules derived from the spermatozoa actually penetrate the nascent cells of the mother animal. It has been suggested Darwin’s so-called gemmules could include RNAs (particularly mRNA and small RNAs), circulating DNA, mobile elements, prions or as yet unknown molecules (Steele et al. 1998; Liu 2005). In our modern language, DNA ⁄RNA may penetrate the somatic tissues of female animals. Interestingly, Watson et al. (1983) found that within 24–48 h after artificial insemination with spermatozoa, in which the DNA had been labelled with tritiated thymidine, a minimum of 9% of the radioactivity was transported across the uterine walls. In sperm-treated animals, the ovaries, the adrenals and a mesenteric lymph node exhibited strikingly large accu- mulations of radioactivity. They concluded that the lymphatic system could serve as a route for the dissemination of radioactivity originally associated with spermatozoa deposited in the uterus to maternal tissues. Ledoux and Charles (1972) demonstrated that if mice are killed 1 or 2 h after an I.V. injection of labelled Table 2. Penetration of spermatozoa into somatic tissues and cells of the female genital tract (incomplete statistics) Species Results References Bat Penetration of spermatozoa into uterine mucosa, fallopian-tube mucosa and oviducal epithelial cells Kohlbrugge (1910, 1913); Austin (1959); Austin and Bishop (1959); Uchida et al. (1984) ; Rasweiler (1987) Mouse Penetration of spermatozoa into uterine mucosa, fallopian-tube mucosa and L cells Kohlbrugge (1910, 1913); Lau (1975) Rabbit Penetration of spermatozoa into uterine mucosa and cervical mucosa Kohlbrugge (1910, 1913); Austin (1960); Sievers-Altermann and Engelbrecht (1990) Rat Penetration of spermatozoa into uterine mucosa Stein-Werblowsky (1973) Hamster Penetration of spermatozoa into fibroblast cells and ovary cells Bendich et al. (1974); Lau (1979) Dog Penetration of spermatozoa into uterine tube and uterine glands Doak et al. (1967); England and Pacey (1998); Rijsselaere et al. (2004) 340 YS Liu � 2010 Blackwell Verlag GmbH DNA, this DNA can be recovered in the follicle cells of the ovary, in the vagina, embryos and tumour cells. The exogenous labelled DNA has therefore been transported by the blood and has become absorbed by cells of different tissues of the organism, without important destruction. It has been known for years that naked DNA can be delivered to cells in vivo and result in gene expression, although the efficiency of gene transfer into skeletal or cardiac muscle is relatively low and variable (Wolff et al. 1990). In recent years, it has been demonstrated that naked plasmid DNA can be delivered efficiently into cells in vivo via electroporation, intravascular delivery and tail vein DNA injection (Herweijer andWolff 2003). Bendich et al. (1974) demonstrated that penetration of somatic mammalian cells by spermatozoa occurred after simple admixture in culture. With sperm labelled in vivo, autoradiography revealed incorporation of DNA into nuclei of recipient cells, indicating release of DNA after entrance by sperm. Reid and Blackwell (1967) demon- strated that the pattern of saline elution of DNA prepared from cultured sheep macrophage cells is changed after these cells have been exposed to rat sperm. They believed that this altered pattern is because of the incorporation of intact sperm DNA by the macrophage. Holmgren et al. (1999) raised the question whether DNA can be transferred from one cell to another via the phagocytosis of apoptotic bodies. They demonstrated that genomic DNA from apoptotic bodies is transferred to the nuclear compartment of phagocytosing cells and that this transferred DNA is stable over time. Thus, it is possible that apoptotic bodies, derived from spermato- zoa, might be taken up by phagocytosing cells of the maternal tissues. It is now a well-established notion that mature spermatozoa act as vectors of genetic material, not only for their own genome but also for exogenous DNA molecules. This is called sperm-mediated gene transfer (Spadafora 2007). Although the sperms of the first sire cannot be supposed to persist and fertilize ova discharged long afterwards, it is conceivable that the DNA released by these sperms may persist and influence the ovaries and the ova, which does not amount to fertilization. During coition, millions of DNA-contain- ing spermatozoa are deposited in the body of the fem