The impact of paternal age and nutrition on offspring fitness

Mothers have long been known to influence their offspring's condition in many ways other than just transmitting genes. Less obvious is that the condition and environment of fathers can affect their sperm and, as a result, the quality of their offspring. Poor paternal diet is now thought to cause metabolic disorders in offspring, and advanced paternal age may harm offspring brain development. However, we still know little about the causes and consequences of such effects. A major barrier to progress is that these effects are challenging to study in humans and other mammals. To overcome this barrier and push the field forward, I plan to make use of one of the major alternative models for understanding animal evolution and physiology, the fruit fly Drosophila melanogaster.

The fruit fly is already a major model system for studies of ageing, diet and neurobiology. It has a short lifespan; it is simple and genetically well characterized. These make the fruit fly ideal for experimental study and the study of both evolutionary (why) and mechanistic (how) questions. With the fruit fly, I will tackle three of the major open questions in the study of paternal effects: 1) Why do they occur? 2) How do they impact offspring? and finally 3) What causes them? At the University of Oxford, I will combine large-scale evolutionary experiments with cutting-edge molecular methods and establish a major new research program to understand all aspects of these important and fascinating effects.

An individual's environment and experiences during a lifetime can strongly impact its descendants. While our understanding of non-genetic inheritance is mostly based on maternal effects, powerful paternal effects have now been discovered across diverse taxa. These include effects of male age on offspring neurodevelopment, and male diet on the risk of metabolic disorders in progeny. However, the evolutionary and mechanistic bases for these effects remain poorly understood.

The aim of this project is to experimentally study the causes, consequences and mechanisms of paternal effects. To do this, I will employ the highly tractable fruit fly, Drosophila melanogaster, which is the ideal model for this project. Paternal effects are known to occur in flies and the fruit fly is already a major model system for studies of ageing, diet and neurobiology, owing to its experimental tractability. Moreover, Drosophila research has been at the forefront of genetics for decades, providing an extensive set of cutting-edge genomic tools to draw upon.

My project will address three main questions: 1) Are paternal effects evolutionarily adaptive? I will explore how paternal age and paternal diet impact offspring survival and reproduction. I will test the hypotheses that the father primes the offspring for the anticipated environment (anticipatory effects), or, alternatively, that the father transfers his condition to the offspring (condition-transfer effects). 2) How does paternal environment affect offspring neurodevelopment? I will focus on offspring neurodevelopment as a major trait known to be affected by paternal effects. I will explore changes in offspring learning ability and brain transcriptome organization as a response to paternal age and paternal diet. 3) What is the mechanistic basis of paternal effects? I will identify the age- and diet-induced changes in sperm small RNAs and proteins, and use transgenic flies to establish causation.

- Reproductive health researchers: A key part of my proposed research is to determine the sperm-mediated epigenetic factors that impact offspring health. I will identify sperm non-coding small RNAs or sperm proteins that are driving adverse offspring effects. My results may initiate research in mammals to establish if similarities exist. In the long run this research may help reproductive health researchers and in vitro fertilization specialists and inform about ways to ameliorate the risks associated with advanced parental age and poor paternal diet.

- Public health researchers: My work will determine whether there is a causal relationship between advanced paternal age, paternal diet and the health of the offspring, with particular emphasis on offspring lifespan, reproductive output and risk of neurodevelopmental disorders. The causal relationship between a father's age and the child's health has been a contentious subject in public health research with equivocal evidence; hence my tractable, experimental approach will be an important contribution to the field. Although the work will be based on a simple organism, the fruit fly, the pathways that regulate ageing and metabolism are conserved between humans and flies. Hence my research may aid in translating the results to vertebrates and may have potential value for the public health sector in the long term.

- The public: My work will address a question that is of great interest to the public, the influence of paternal age and paternal diet on offspring fitness. Given the growing trend for delayed parenthood in developed countries and the rising incidence of obesity this subject will capture the public's interest. I will maximize the reach of my work through press releases of published papers, by designing an accessible website and volunteering at outreach activities.

I will also engage the public in my research by setting up a citizen science project. I will prepare a video detailing the aims of this research and ask the publics' help in counting flies from the pictures that I will upload. These pictures will help me to determine the reproductive output of offspring from young and old males that are fed an array of diets. I will continue to upload videos as I get results to explain my findings and to explain how the citizen science project has helped me to gather the data. This will be beneficial to the public, as they will understand why and how fruit flies are used as a model organism in biology. Overall my project will foster public interest in basic science.