Genetic variants influencing human fertility identified - university study

2 March 2023

Fertility is influenced by mechanisms that influence both reproductive biology and human behaviour, according to the largest study to date identifying genetic determinants of the number of children an individual may have. Published today [2 March], the study, led by researchers at the Universities of Cambridge, Oxford, Groningen and Pennsylvania, also identified a region of the human genome that has been influenced by natural selection for thousands of years and continues to affect fertility today.

The findings demonstrate fertility is affected by diverse biological mechanisms, which contribute to variations in fertility, and directly affect puberty timing, sex hormone levels (such as testosterone), endometriosis and age at menopause. There were also links to behaviours such as risk taking.

Professor Melinda Mills, Director of Oxford’s Leverhulme Centre for Demographic Science, comments, ‘This study is of interest to understanding changes in human reproduction over longer periods of time, reproductive biology and potential links to infertility.’
‘It also empirically tests one of the most gripping and fundamental questions asked by scientists across many disciplines and decades: Is there evidence of ongoing natural selection in humans and, if so, what is it and how does it operate?’

The major study, published in Nature Human Behaviour, used data from 785,604 individuals of European ancestry, including individuals in the UK Biobank study, to identify 43 regions of the genome containing genetic variants associated with reproductive success, defined as the number of children ever born to an individual.

Some findings highlight trade-offs across the life-course, for example, the researchers found variations in the gene ARHGAP27 that were associated with having more children, but also with a shorter lifetime window of fertility.

The analysis also suggested a novel role for the red hair colour gene, melanocortin 1 receptor (MC1R) in reproductive biology. But the genetic evidence suggests the influence on number of children is not related to the same genetic mechanisms that affect pigmentation.

Professor John Perry, MRC Epidemiology Unit, University of Cambridge, notes, ‘This study is the largest of its kind and has highlighted new biology that we anticipate will help identify novel therapeutic targets for reproductive diseases such as infertility. It will also help us better understand the biological mechanisms that link reproductive health to broader health outcomes in men and women.’

By integrating their findings from modern genomes with ancient genome data, the researchers were able to identify a region of the genome that has been under selection for thousands of years, and remains under selection today.

The genes in this region - FADS1 and FADS2 - are involved in synthesising specific fats that are important for health and seem to have been important in helping people in Europe to adapt to an agricultural diet. The observation that these genes still affect fertility today suggests that this adaptation may be ongoing.

Dr Iain Mathieson, Department of Genetics, University of Pennsylvania, points out, ‘Independent evidence shows that the FADS region has been under selection in Europe for thousands of years. It represents the clearest example of a genetic variant with evidence of both historical and ongoing natural selection, though the reason for selection remains unclear.'

Notes for Editors

For more information and interviews, please contact the Leverhulme Centre for Demographic Science media team ([email protected]) and Professor Melinda Mills ([email protected]).

About the Leverhulme Centre for Demographic Science
This major new interdisciplinary research centre, funded by the Leverhulme Trust and directed by Professor Melinda Mills, is tackling the most challenging demographic problems of our time. Based at the University of Oxford, the Centre is at the forefront of demographic research that impacts academia, society and policy. Together with academic and industry partners, our researchers use new types of data, methods and unconventional approaches to disrupt conventional thinking across important issues such as COVID-19, climate change, and life expectancy. More information on the Centre can be found here.

About the MRC Epidemiology Unit
The MRC Epidemiology Unit is a department at the University of Cambridge. It is working to improve the health of people in the UK and around the world. Obesity, type 2 diabetes and related metabolic disorders present a major and growing global public health challenge. These disorders result from a complex interplay between genetic, developmental, behavioural and environmental factors that operate throughout life. The mission of the Unit is to investigate the individual and combined effects of these factors and to develop and evaluate strategies to prevent these diseases and their consequences.

About the Medical Research Council
The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation.

About the University of Cambridge
The University of Cambridge is one of the world’s leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence.
Cambridge was second in the influential 2023 QS World University Rankings, the highest rated institution in the UK.
The University comprises 31 autonomous Colleges and over 100 departments, faculties and institutions. Its 20,000 students include around 9,000 international students from 147 countries. In 2022, 72.5% of its new undergraduate students were from state schools and more than 25% from economically disadvantaged backgrounds.
Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. In the Times Higher Education’s rankings based on the UK Research Excellence Framework, the University was rated as the highest scoring institution covering all the major disciplines.
The University sits at the heart of the ‘Cambridge cluster’, in which more than 5,200 knowledge-intensive firms employ more than 71,000 people and generate £19 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK.

About the University of Oxford
Oxford University has been placed number one in the Times Higher Education World University Rankings for the seventh year running, and number two in the QS World Rankings 2022. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer.
Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.
Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 200 new companies since 1988. Over a third of these companies have been created in the past three years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing £15.7 billion to the UK economy in 2018/19, and supports more than 28,000 full time jobs.