DEFB126 and the Evolution of Male Infertility

By Bernard Crespi

Darwin bravely asserted that the discovery of a common trait leading to reduced reproduction would falsify his theory of evolution by natural selection.  A new paper by Tollner et al. (2011) in Science Translational Medicine appears to do precisely that. These authors have discovered a high-frequency allele of a defensin gene, DEFB126, coding for a sperm-surface polypeptide, that is strongly associated with delayed and reduced male fertility in homozygotes.  What’s more, the delayed-fertility allele appears to involve loss of function – a two-nucleotide deletion causing a frameshift that reduces or abrogates the protein’s ability to help deliver sperm to egg.  How, Darwin, might such an apparently-deleterious allele have evolved to high frequency?

Tollner et al. (2011) suggest that the DEFB126 locus is subject to heterozygote advantage. They provide statistical, population-genetic evidence weakly suggestive of this process, but no plausible functional or causal mechanism, indeed pointing out that heterozygote advantage appears inconsistent with loss of function for one of the alleles.

Might the low-fertility DEFB126 allele provide compensatory advantages in some context other than male fertility? Such a mechanism would center on the core evolutionary-genetic principle, first developed by George Williams, of antagonistic pleiotropy, such that common alleles exert multiple effects both positive and negative (Williams 1957).

Defensins are well known as antimicrobial compounds, but it is unclear how a loss-of-function allele, especially for a sperm-surface protein, might benefit its bearer in this regard.  Might the ‘bad’ allele provide benefits against some other diseases, in other tissues? The DEFB126 protein, referred to as HE4, appears to function as a molecular cloak of invisibility, such that protein-coated sperm can temporarily wriggle under the radar of immune molecules within the female reproductive tract.  Benefits to such a cloak are difficult to envision among other tissues, but high HE4 expression serves as a key biomarker for ovarian cancer (Li et al. 2009) suggesting that cancer cell lineages evolve to co-opt expression of this molecule as a means to avoid immunosurveillance.  But it remains dubious to suppose that natural selection is strong enough, in the context of such a rare disease, to maintain delayed male fertility.

There is one natural-selective context, however, in which several-month delays in fertilization can be highly advantageous to the incipient mother, father, and infant.  Hypertensive disorders of pregnancy, which include pre-eclampsia and eclampsia, affect up to 10% of human births, with over 40% of pregnancy-related maternal deaths attributed to eclampsia in some developing countries (Noris et al. 2005).  Risk of pre-eclampsia is strongly reduced by higher duration and frequency of sexual contact between a couple prior to fertilization, because such contact facilitates maternal  immune tolerance to paternal antigens in the later-developing placenta and fetus (Dekker et al. 2011).  But most importantly, longer exposure to paternal antigens in sperm is only part of the answer to pre-eclampsia risk:  males themselves have been demonstrated to vary considerably in how likely their mates are to develop pre-eclampsia (Dekker et al. 2011).  This remarkable finding suggests that some genetically-based factor, in or on male sperm, mediates pre-eclampsia risk. So might males bearing the DEFB126 ‘bad’ allele in homozygous form exhibit not just several-month delayed fertility (perhaps a minor cost, in the long term), but also mates with a much lower risk of this life-threatening condition?

These musings on DEFB126 remain hypothetical, but they epitomize several of the central contributions of evolutionary biology to medical practice.  First, antagonistic pleiotropy, which represents trade-offs at the levels of alleles, genes and proteins, is expected to pervade our genome, and  DEFB126 appears well-launched as a ‘poster gene’ for such effects.  Second, evolution is short-sighted, such that loss of function alleles can apparently arise easily and increase rapidly in frequency due to beneficial effects in one context, even when they impose costs in another (Crespi 2010).  Third, the strange case of DEFB126 highights the usefulness of evolutionary medicine in the development of novel, testable hypotheses, which are grounded in core biological principles but dead-easy to miss without such perspectives.

Finally, the evolution of reduced fertility is perhaps not so unexpected as Darwin might have surmised, especially in our human lineage, which has clearly evolved much lower rates of birth per coital event than our primate ancestors, even for pre-contraception societies (Crespi 2010).  What matters of course is lifetime reproductive success, the summation of survival, fertility and fecundity.  For couples with delayed fertility due to DEFB126, reduced pre-eclampsia risk (or some other benefit) may be cold comfort, but any therapies designed to alleviate reduced fertility may indeed come with unexpected costs, based in the tradeoffs of our evolutionary past.

References

Crespi BJ. The origins and evolution of genetic disease risk in modern humans. Ann N Y Acad Sci. 2010 Sep;1206:80-109.

Dekker G, Robillard PY, Roberts C. The etiology of preeclampsia: the role of the father. J Reprod Immunol. 2011 May;89(2):126-132.

Li J, Dowdy S, Tipton T, Podratz K, Lu WG, Xie X, Jiang SW. HE4 as a biomarker for ovarian and endometrial cancer management. Expert Rev Mol Diagn. 2009 Sep;9(6):555-566.

Noris M, Perico N, Remuzzi G. Mechanisms of disease: Pre-eclampsia.

Nat Clin Pract Nephrol. 2005 Dec;1(2):98-114

Tollner TL, Venners SA, Hollox EJ, Yudin AI, Liu X, Tang G, Xing H, Kays RJ, Lau T, Overstreet JW, Xu X, Bevins CL, Cherr GN. A common mutation in the defensin DEFB126 causes impaired sperm function and subfertility.

Sci Transl Med. 2011 Jul 20;3(92):92ra65.

Williams GC. Pleiotropy, natural selection, and the evolution of senescence. Evolution 1957 11:398–411.