Paternal Influence on Offspring Development: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Vidhu Dhawan.

The paternal impact on fertilization, early embryonic development, and offspring health. The increase in paternal exposure to various pharmaceutical drugs, toxins, xenobiotics, radiations, pesticides, and dietary as well as other lifestyle factors has impacted vulnerable sperm beyond affecting the sperm quality and fertility potential to jeopardizing fetal development and offspring health. While there is substantial evidence in the literature explaining the paternal impact on offspring health, the evolution of these paternal effects is being brought to the surface. The paternal effect refers to a biological phenomenon in which the genotype or phenotype of the father exerts an influence on the phenotype of the offspring without altering its genotype. This effect can manifest in two primary forms: an adaptive manifestation, potentially conferring a survival advantage to the offspring, or a non-adaptive manifestation, which may have detrimental consequences or represent a neutral by-product of underlying biological processes.

  • genetic infertility
  • epigenetic changes
  • transgenerational effects

1. Non-Adaptive Paternal Effects

The paternal influence may not invariably confer advantages; it could manifest as a secondary outcome of other processes or even have harmful effects. For instance, fathers of an advanced age may transmit epigenetic modifications through spermatozoa that negatively impact the progeny’s developmental processes. Such alterations could be associated with pathological conditions or senescence in the paternal figure, and they may not necessarily provide any adaptive benefit to the offspring [25][1]. The mechanisms behind this transgenerational inheritance have remained enigmatic. A recent review elaborated on advancing age in men leading to decreased fertility, lower testosterone, and reproductive pathologies, alongside increased sperm DNA damage and genetic mutations in offspring, contributing to diseases like Apert syndrome and schizophrenia [25][1]. These effects are linked to mutant stem cell expansion and oxidative stress (OS) impacting sperm and hormonal cells. Antioxidants could be a therapeutic strategy, pending clinical trial validation [25][1].
The initial skepticism about the paternal influence on offspring stemmed from the lack of clear mechanisms explaining how environmental influences could modify the genomic DNA that is passed on to the offspring [26,27][2][3]. The exposure of the sperm to environmental insults, psychological stressors, and adverse events predisposes the sperm genome to impending oxidative attack, increasing the activity of repetitive elements and thus inducing nuclear and mitochondrial DNA damage, the accumulation of mutagenic base adducts, changes in gene expression, and epigenetic changes that are transmitted to the oocyte at fertilization [28,29][4][5]. These non-adaptive factors are detrimental to the health of the offspring. They are protected in the sperm genome by various chromatin modifications, the methylation of sperm DNA, and a repertoire of sperm non-coding RNAs (sRNA, piRNA, miRNA, etc.) [27,30,31][3][6][7]. The paternal lineage is thus responsible for transmitting more than just its DNA. Epigenetic marks are delivered by sperm to the zygote, with evidence pointing toward the involvement of DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) [32][8].

2. Paternal Effects as Beneficial Adaptive Responses for Offspring

Parental effects on the phenotype of the offspring can be influenced by the effect of the environment or phenotype of both the mother and father [33][9]. This implies that the paternal effect might have evolved as a beneficial adaptation, allowing fathers to pass on certain environmental or conditional information to their offspring without changing their genetic code [33][9]. It can allow the offspring to be better suited to their environment or the current circumstances. For example, if a father has experienced a particular environmental condition, this might affect the sperm in a way that primes the offspring for similar conditions, giving them a potential survival advantage [33][9]. This “phenotypic plasticity”, also described as “transgenerational plasticity”, is due to the effects of the parental environment and not the offspring environment on the phenotype of offspring [33][9].
The impacts of paternal exposure on the offspring phenotype have been the subject of much speculation, but it is not clear whether these effects are “adaptive”. One explanation for this was given as the “thrifty phenotype” hypothesis [34][10], where it was stated that a compromised in utero environment might program the offspring for a similar environment after birth and increase their predisposition to metabolic disorders. The transmission of paternal environmental effects increases susceptibility to diseases after birth [35][11].
The transmission of information on the environmental effects faced by the parents may provide an adaptive advantage to the offspring [36][12]. Such adaptive effects can be termed “anticipatory parental effects (APEs)”, where the parents modify the phenotype of the offspring with environmental changes to increase the fitness of both the parents and offspring [37][13]. However, the adaptive paternal effects may not only be APEs: the response to environmental stimuli may also decrease offspring fitness in order to achieve long-term fitness benefits by the parents, described as “selfish parental effects”, in order to achieve long-term fitness [38][14]. Another type of adaptive effect is described as “bet-hedging parental effects”, which occur in parents who may randomly adapt to a varying environment by creating phenotypic diversity in the offspring [38][14]. This evolutionary learning of the adaptation to varying environments has been described as “positive transgenerational feedback”, where the parental phenotype is progressively reinforced in successive generations [39][15]. The above two effects thus highlight that parental effects may not always increase offspring fitness [37][13]. The variation seen in the offspring phenotype exerts a greater influence on the population structure than the variation in offspring number [40][16].
The ability of females to affect the phenotype of the offspring by adaptive maternal effects is well documented, but the contribution of non-genetic adaptive paternal effects has been brought to the surface [27,41][3][17]. The literature has highlighted the role of transgenerational epigenetic effects in the male germ line that are transmitted via the male germ line to the offspring. Males can adjust the sperm phenotype in response to local conditions, but the transgenerational consequences of this plasticity are unknown. Increasing speculation arose on how males adjust the sperm phenotype in response to the environment, and the existence of “adaptive” paternal effects was proposed as the “thrifty telomere hypothesis” [42][18].

3. Paternal Effects to Mediate Sexual Conflict

The inheritance of paternal and maternal genomes creates a conflict between males and females over allele expression at heterozygous loci in the offspring [43][19]. Genomic imprinting, an epigenetic phenomenon, determines the expression of an allele according to its parental origin [44][20]. The difference in the methylation status of gametes generates an inherent asymmetry in the maternal and paternal genomes that drives differential parent-of-origin gene expression. This violates Mendel’s rules at the level of expression. Imprinting is thus a maladaptive phenomenon, as there is a loss of diploidy and the presence of uniparental disomy, and a heterozygote for one defective allele may pose a problem if there is silencing of the active allele.
The evolution of genomic imprinting has been explained by three theories [45][21]: (a) kinship theory [46[22][23],47], (b) sexual antagonism theory [48][24], and (c) maternal–offspring co-adaptation theory [49][25]. The theories proposed above address different fundamentals but rest on one shared feature, which is the presence of asymmetry or conflict in the maternal and paternal alleles over gene expression at heterozygous loci in the offspring [45][21].
Genomic or sexual conflict is not the only mechanism of imprinting: various molecular mechanisms have also been described based on the fact that the maternal and paternal alleles have distinct epigenetic marks [50][26].

4. Paternal Effects to Control Selfish Genetic Elements

Selfish genetic elements, or SGEs, have been referred to by various names, including selfish genes, ultra-selfish genes, selfish DNA, parasitic DNA, and genomic outlaws [51][27]. These are specific segments within a genome that can promote their own survival over other genetic material. They do this by biasing their own transmission, ensuring that they are passed down through successive generations at a higher rate compared to other segments of the genome [51][27]. A notable aspect of SGEs is that they can create a sort of conflict within the genetic material. This happens because while the SGEs are working to increase their own representation, they might be acting against the interests of the genome as a whole. This conflict may or may not have a negative impact on an individual’s health or ability to survive and reproduce. Interestingly, this phenomenon of intragenomic conflict, where parts of the genome are in competition with each other, is also a characteristic of something known as sexually antagonistic (SA) alleles [52][28]. These are specific gene variations that might benefit one sex while being detrimental to the other, leading to a similar type of tension within the genome. Both selfish genetic elements and sexually antagonistic alleles exemplify the complex interactions and competitions that can occur within the genetic material of an individual [52][28].
Replicative mobile elements, or transposable elements (TEs), are the most common SGEs and include DNA sequences that have the potential to move to new locations in the host genome [52,53][28][29]. Other groups of SGEs include segregation distorters (meiotic drivers), which target gametogenesis by killing/modifying maternally inherited endosymbionts (which either kill or feminize females, e.g., mitochondria) [52][28]. Genomic conflicts thus arise, as not all genes are inherited in the same way.
The prime targets of SGEs are gametogenesis and reproduction to facilitate enhanced transmission. They may increase the mutation rate and affect the evolution of genes, genomes, gene expression, sex chromosome formation, and turnover and have also been seen to affect sexual behavior [52,54,55][28][30][31]. Since SGEs are ubiquitous, they also affect sexual selection, including mate preferences and conflict [55][31]. SGE carriers are thus seen to frequently have reduced gamete production [56][32]. Gametogenesis is especially affected in men who have different types of SGEs and have been seen to show reduced sperm production [57][33].
Another well-cited example of SGEs is “selfish mitochondria”, where the conflict is between uniparentally (usually but not always maternally) inherited mitochondria and other biparentally inherited nuclear genes. Uniparental inheritance reduces the ability of selfish mitochondria to spread and is usually maternal, as the mutation rate is lower in female gametes than in male gametes [58,59][34][35].

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