Identifying genetic variants associated with reproductive success

The genetics of fertility can be demonstrated in most animals, with natural selection limiting the frequency of fertility-limiting alleles¹. However, is the same true for humans?

Now, co-researchers at the University of Pennsylvania, US and the University of Oxford, UK have detected genetic alleles under present-day selection. This provides an insight into the nature of ongoing natural selection in humans. One way of measuring fertility in women in a particular age group is to measure the Number of Children Ever Born (NEB). This is the mean number of children born alive to women in that age group.

Number of Children Ever Born (NEB)

The NEB to a particular woman is a measure of her lifetime fertility experience up to the moment at which the data is collected. Data on NEB can be obtained from censuses or sample surveys from questions regarding the number of children born alive to each woman. The availability of survey and census data depends on the existence of adequate census programmes in a country or area. Censuses are generally conducted every 10 years in western countries.

Since NEB is an epidemiological measure of fertility, the trick is to match it meaningfully to genetic profiles. This has already been accomplished in a broad sense by matching it to genetically determined factors such as age at first sexual intercourse³. This is determined by the genetic factor of onset of puberty and age at first birth⁴. The epidemiological study of the genetics of fertility is a complex arena because fertility-associated loci seem to act through a broad spectrum of mechanisms. They may have direct effects on reproductive biology or act through traits that contribute to partner selection or other aspects of behaviour and personality.

Identified 43 genetic loci

In order to reach their conclusions, the researchers performed genome-wide association studies in up to 785,604 individuals of European ancestry. This allowed them to identify 43 genetic loci associated with a defined NEB or childlessness.

These loci span diverse aspects of reproductive biology across the human lifespan including:

• Puberty timing
• Age at first birth
• Sex hormone levels
• Sexuality
• Age at menopause.

Although not a definitive answer to the genetic basis for infertility, the findings further demonstrate that diverse biological mechanisms, which influence both physiological and behavioural aspects of an individual reproductive life contribute to reproductive success.

Reproductive biology and potential links to infertility

Professor Melinda Mills, Co-Author, University of Oxford said, “This study is of interest in relation to our findings on reproductive biology and potential links to infertility. But 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?”

To test whether NEB-increasing alleles have increased in frequency over time, they integrated their findings with data from three ancient selection scans. The researchers were able to identify a unique allele that was under selection in humanity’s ancient past and which may remain under selection to this day.

Changes in diet

This allele, known as the FADS1/2 locus, expresses the genes FADS1 and FADS2, which encode enzymes that catalyse the -5 and -6 lipid biosynthesis pathways. They synthesize long chain polyunsaturated fatty acids (LC-PUFA) from short chain precursors. It can be linked to NED because modifications to the locus could allow populations to take advantage of changes in diet, which in turn would increase population (NED).

Dr. Ian Mathieson, Lead Researcher, University of Pennsylvania, commented “Independent research has shown that this allele has been under selection for many thousands of years, potentially linked to changes in diet around the time of the transition to agriculture. Therefore, it represents perhaps the only example of a genetic variant with evidence of both historical and ongoing selection.”

He pointed out that knocking out the FADS1 in mice leads to both male and female infertility. With this in mind it could be important to look into why the FADS1/2 locus seems to be under selection in humans. One problem with this study, however, is that is limited by its use of data from only individuals of European ancestry.

Professor Mills concluded, “This is problematic, as we and others have addressed. Future extensions of this work will examine diverse non-European populations.”