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Paternal Age Effect

Only over the course of the past few decades has the paternal age effect came to light as its own entity. Back at the start of the 20th century the paternal age effect wasn’t its own topic, but rather was part of a vague group of unclassified phenotypic effects that were not directly related to an offspring’s genes or their environment. Over the next 50 years with the development of paternity tests and increased research devoted to these anomalies that didn’t fit elsewhere, paternal and maternal effects became two new classifications. However, even today, there is still debate as to which criteria should be used in order to define each category. With further research at the close of the 20th and beginning of the 21th century, the paternal age effect arose as a sub-classification of the paternal effect. Thus, to be able to explore the paternal age effect the paternal effect must first be understood. By definition a paternal effect “can be said to occur when variation in the paternal genotype or phenotype is causally associated with variation in offspring phenotype, and this effect cannot be accounted for by offspring genotype” (Crean 2014). This can occur in several different manners including effects on the offspring resulting from the paternal genotype, environment, or a combination of the two. This can occur in a variety of different ways and has the possibility to occur in all sexually reproducing species. For example, this can be found in species that exhibit postnatal paternal care as opposed to maternal care such as the mouse Peromyscus californicus. Recent research has also found that sperm can display non-genetic effects on offspring in the womb in the form of lipids and proteins. This can affect an organism’s development in the embryo, postnatal growth, as well as auditory and olfactory development to name a few. However, since most maternal zygotes are larger than paternal zygotes, maternal effects often mediate the actions of the male. This can be accomplished through somatic and epigenetic factors as well as numerous others (Crean 2014). The effects that aren’t mediated by the mother create variation amongst offspring and can play a role in their fitness as well. Although paternal effects have the possibility of resulting in beneficial fitness, there are many more that result in negative fitness. Most of these negative effects fall into the category of paternal age effects, which are paternal effects resulting from an increased age of the father. Paternal age effect research studies the relationship between an increasing age of the father and the effect it can have on that father’s fertility, sperm, and offspring health conditions, as well as many other factors. Over the course of paternal aging, the genetic quality of sperm, along with its motility and quantity decreases on average across sexually reproducing species, which can lead to mutations. Specifically in humans, a father who is 40+ years old is at a 4-5 times greater chance at producing sperm dominant mutations than someone who is in their early 20’s. Another factor that is affected with increasing age is the length of telomeres of sperm being produced. Unlike the quality of sperm being produced, this factor tends to increase with age. Increasing telomere length leads to increased organismal longevity, which can then lead to more problems if it is combined with a negative mutation (Eisenberg 2013). For example, if a mutation occurred an older man who also had increased telomere length, his children would be at a higher risk to express that mutation, as well as pass it on to their offspring. This is because the sperm that he passed on is already damaged and almost always beyond repair. Although the mutation may not have a direct effect on the first offspring, serious consequences have a greater chance of arising further down the given lineage if the mutation becomes displayed. As a result, James Crow a population geneticist has said that older, fertile men are one of the most significant contributors to mutational hazards arising in the human genome (Crow 1997). Although this just applies to humans, this statement can be applied to all older males who reproduce sexually. Recent research has also shown that there is a commonality amongst most mutations caused by the paternal age effect. One common factor is the abnormal regulation of sperm once a mutation arises. It has been seen that once taking place, the mutation will almost always be positively selected for and over time will lead to the mutant sperm replacing all non-mutant sperm. In younger males, this process is corrected and regulated by the growth factor receptor-RAS signal transduction pathway (Goriely 2012). However, it is still unclear as to how or why this pathway is turned off and unable to correct this from happening in older males. There are two specific types of paternal age effects that are known to exist. The first, a direct result of paternal age effect, occurs when autosomal mutations arise that code for a dominant condition. These mutations will thus be present in the next round of offspring produced. Examples of these direct effects include Marfan syndrome, achondroplasia, and Treacher Collins syndrome. The other type of paternal age effect, an indirect effect, arises when mutations occur on the X chromosome. Here, the offspring is not directly affected, but the probability that the mutation is passed on from mother to son is significantly higher. Although the offspring is the grandson of whom the mutation occurred, it is still considered a paternal age effect due to the mutation first occurring in the grandfather. Examples of these indirect effects include hemophilia A and B, muscular dystrophy, and Hunter syndrome (Advanced 2012). Through mutation, increasing paternal age has also been associated with increasing risk for developing complex diseases as well as heritable diseases. Due to paternity tests not being created until the 1970’s, very little research existed prior and therefore many of the mechanisms by which these processes occur are still inadequately understood. There are however, several diseases and conditions that have gotten a significant amount of focus since then. Studies done on diseases and disorders such as autism and schizophrenia have shown a positive correlation to increased paternal age. A significant amount of research has taken place over the last few decades examining autism and in some cases has been linked to the paternal age effect. For example, a study was preformed in Israel on paternal age effect and its potential link to autism spectrum disorder. The study took place in Israel and followed the birth of newborns born over 6 consecutive years. It then followed them until they were 17 years old and assessed certain factors over the duration of the experiment. The study revealed 110 cases of autism and the data from these parents were compared to those who didn’t have autism. What it found was that men who had offspring after 40+ years were 5.75 times more likely to have a child develop autism than fathers under that age of 30 when they had their offspring. As another part of the study, no link was found between maternal age and autism (Croen 2007). This suggests that either no maternal effect exists to counter the paternal effect or that the paternal effect isn’t brought about until later in the development of the offspring. Numerous other studies have also been completed, almost all showing similar results to this one. In fact, it has been proven that increased paternal age doesn’t linearly increase the risk of developing autism, but rather that it increases the likelihood almost exponentially. Although paternal age has been determined to be a significant factor in an offspring’s predisposition for autism, it is certainly not the only factor that is able to contribute to it. Research is still being done to determine exactly how the two are connected and by what mechanisms. Schizophrenia is another disorder that has had significant research completed to determine its potential linkage to increased paternal age. It had been previously found that mutations arising during spermatogenesis, specifically certain point mutations have been linked to an increased risk for schizophrenia. Another factor that has been identified to create a higher risk for the disorder is the absence of the regulation of epigenetic processes in males of higher age. More specifically, error in parental imprinting on the X as well as autosomal chromosome has been hypothesized as a cause (Perrin 2007). A particular case study was performed based on Danish register data in order to try and determine if there is any concrete linkage between the paternal age effect and schizophrenia. The study included nearly 8,000 schizophrenia patients as well as almost 200,000 patients without the disorder. Data collected from registries included a wide variety of information and was controlled specifically for family demographic, socioeconomic, and psychiatric history in order to eliminate any errors that may arise. It discovered that fathers above age 55 were above 3.5 times as likely to have children with schizophrenia and those aged 50-54 were nearly 2.25 times as likely (Byrne 2003). An unexplained result of the study found than female offspring were more likely than males to have this disorder. In conclusion, although it has only been studied heavily since the 1970’s, it can be determined that the paternal age effect plays a significant role in the development of certain disorders and diseases. A paternal effect arises when the paternal genotype or phenotype is associated with variation in the offspring’s phenotype that is unrelated to the genotype of that organism. Although often mediated by maternal effects, paternal effects that do arise are often negative and frequently arise due to increasing paternal age. Increase father age results in longer telomeres and an increased rate of mutation, putting future generations at risk of acquiring the mutation. In certain cases, mutation can lead to the development of diseases and disorders, specifically autism and schizophrenia. Although the exact mechanisms by which these conditions arise are still unknown, research is currently taking place in order to determine them, as well as develop potential ways to prevent them altogether.

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