What’s the link between caring grandmas and breast cancer?

Nanas may contribute more than just hugs and kisses. John McNab

A recent study shows that mutations in the “breast cancer genes” BRCA1 and BRCA2 – which increase the risks of breast and ovarian cancers among others – also increase fertility.

This is an extraordinary finding as it links the evolution of disease mutations with the evolution of ageing. It also highlights the fact humans are among very few species whose females live long after menopause.

The research, published by Ken Smith, Heidi Hanson, Geraldine Mineau and Saundra Buys in the journal Proceedings of the Royal Society B, shows women with mutations in BRCA1 or BRCA2 – who have a 40-85% lifetime risk of developing breast cancer and a 16-64% risk of ovarian cancer – also have, on average, almost two more children than women without these mutations.

That makes it one of only a few cases where the frequencies of disease mutations may be predicted from their known effects on survival and reproduction.

Since most breast and ovarian cancers occur after menopause, the mutations that give rise to them could be thought of as having no effects on reproduction. So it could be argued, these mutations are not under any form of natural selection – they are evolutionarily neutral.

If that was the case, the frequency of mutations in populations would be determined by chance events affecting survival and reproduction. These frequencies would be either 100% or 0% in small populations or around 50%, on average, in large populations.

But in reality, these mutations occur at a frequency of only about 1 in 3,000 American women.

Reproduction

This discrepancy has been explained by the fact approximately 25% of breast and ovarian cancer cases occur before the age of 45 – that is, before menopause. So these mutations do affect reproduction because they affect survival during child-bearing years.

With this alone, and assuming no effects on fertility, it has been estimated that mutations in BRCA1 reduce the lifetime number of children a woman has by about 5%. In any reasonably large population this amounts to moderately strong natural selection against these mutations and could explain their observed frequency.

But the new findings of Smith and colleagues throw this tidy picture into disarray. They show women born before 1930 – that is, women who would have had limited access to oral contraception by their mid-30s – produced, on average, 6.22 children if they carried BRCA1/2 mutations and 4.19 children if they didn’t.

That’s a difference in lifetime reproductive output of 48% – an astoundingly large effect in large organisms such as humans. The effect of BRCA1/2 mutations on fertility in women born between 1930 and 1974 is less, but still significant: 4.13 children for carriers and 3.40 children for non-carriers – only a 21% difference, which is explained by greater access to modern birth control methods.

The findings provide the first concrete evidence of mutations that increase fitness (reproductive output) early in life, at a cost of reducing survival later in life. That’s the basis of one of the main theories of the evolution of ageing – the complicated-sounding “antagonistic pleiotropy theory of the evolution of senescence”.

That’s the idea we age because of the inevitable, increased risk of death later in life, due to mutations that help us reproduce when we are young. This explains the otherwise odd fact that we die from old age, when a naïve view of natural selection might predict we should never age.

But now we are left in a quandary. If BRCA1/2 mutations increase lifetime reproductive success, why are they not at a frequency of 100%?

Part of the answer, as mentioned above, is these mutations do cause mortality during the reproductive years. Smith and colleagues did not consider the effect of this mortality because they excluded from their study women who did not survive to the age of 45 (to assess total fertility).

This meant they excluded 12% of women that were carriers of the mutations and 5% of women that were non-carriers. The difference between these percentages is presumably due to the higher rate of mortality caused by BRCA1/2 mutations.

Assuming conservatively that the excluded women produced no children, and subtracting the children that died, we get the following: for women born before 1930 the average number of children produced is 5.13 for carriers and 3.65 for non-carriers – a difference in fertility of 41%. For women born between 1930 and 1974 the difference is 14%.

Grandmother’s helping hands

These lesser increases in fertility due to BRCA1/2 mutations are still substantial and predict such mutations should be ubiquitous. But they’re not, leaving us with only one explanation: the grandmother effect.

The grandmother effect posits that natural selection extends the lifespan of females beyond menopause if they can increase the number of their grandchildren. They may do this by babysitting, feeding or adopting grandchildren. For every ten years of post-menopausal survival, women in farming communities in Finland and Canada in the 18th and 19th centuries could increase their number of grandchildren by two!

This means that the higher post-menopausal mortality due to BRCA1/2 mutations may, by reducing help from grandmothers, reduce numbers of surviving children.

Of course, some of the women in the study by Smith and colleagues would have had living mothers, and so any grandmother effect present would have affected their numbers of children. But judging from similar survival rates for children from carriers and non-carriers, the grandmother effect may have been weak.

More likely, the grandmother effect would have been much stronger in the more distant past when childhood mortality was much higher and opportunities for grandmothers to help much greater.

In fact, if we apply the grandmother effect observed for 18th and 19th century women to the longer survival of non-carriers past the age of 50, we get an interesting result: for women born before 1930, the increase in the lifetime number of children for carriers is only 16%.

If we increase the grandmother effect to five extra grandchildren for every ten years of post-menopausal survival – as may have been the case in hunter-gatherer societies – the difference is reversed, and non-carriers now have a higher reproductive success.

So the low frequencies of BRCA1/2 mutations observed today may be vestiges of a much stronger grandmother effect in the past.

In other words, caring grandmothers may have reduced the frequency of mutations that cause breast and ovarian cancers and other late-onset diseases.

So, here’s to grandmothers.