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Why Males Are Biology's Riskier Sex

A paper in nature shows that fathers pass down mutations to their babies at a higher rate than mothers, says guest commentator Robert Martin.
Tuan Tran
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Robert D. Martin is emeritus curator of biological anthropology at the Field Museum in Chicago, a member of the Committee on Evolutionary Biology at the University of Chicago, and academic guest at the Institute of Evolutionary Medicine at the University of Zürich. His most recent book is How We Do It: The Evolution and Future of Human Reproduction.

This may be surprising to some: A woman's age is not alone in affecting pregnancy and birth, despite the impression often given.

Reviewing Paul Raeburn's book Do Fathers Matter?, Tabitha Powledge wrote:

"Everybody knows that older mothers run higher risks of a baby with birth defects — Down syndrome being the most common and best-known. By comparison, hardly anybody knows that the older Dad gets, the riskier it is for him to conceive a child."

Partners age together, so a fetus or baby with an older mother will mostly have an older father, too. Logic demands exploration of age effects in both sexes. Though few and far between, such studies do indeed reveal that both men and women contribute.

With Down syndrome, age effects for fathers and mothers are roughly balanced. But new data clearly show that, when it comes to inherited defects, fathers actually carry greater risks than mothers. Random changes in DNA — mutations — accumulate four times faster in sperms than in eggs.

Charles Darwin and Alfred Russel Wallace realized that variety is not just the spice of life; it is the very essence. Inherited differences between individuals are the raw material for natural selection. And the prime source of natural variation in genes is new mutations. These have been studied intensively, notably regarding rates of change. Yet mutation also has a dark side because it can produce adverse effects along with variety. Hence, the mutation rate has fundamental implications for medical genetics as well as for evolutionary biology.

Yet researchers rarely distinguish male and female contributions when calculating mutation rates. One reason for this is that accurate measurement demands large samples. This became feasible with sperms once suitable methods were developed. After all, an average human ejaculate contains 250 million sperms. But a woman can produce only a few hundred eggs over her entire lifetime, so large samples are virtually impossible. On the female side, therefore, analyses have so far relied heavily on indirect evidence.

But a key paper published in Natureby Hákon Jónsson and colleagues, including impressively large samples of both women and men, has dramatically confirmed mounting indications of major differences in mutation rate between the sexes — between sperms and eggs. Analysis of entire nuclear genome sequences from a large database for thousands of Icelanders clearly showed that mutations accumulate at significantly different rates in sperms and eggs.

Comparisons homed in on more than 1,500 "three-generation families," each including a couple, their parents and at least one child, permitting the researchers to tell whether mutations stemmed from either the father or the mother. Across all individuals, they identified more than 100,000 independent mutations, tracing the parent of origin for almost half of them. Estimated mutation rates increased steadily with parental age, but the average yearly increase for fathers was consistently four times greater than for mothers. One clear take-home message is that, genetically speaking, women are the conservative sex, while men are the risk-takers.

As Hákon Jónsson and colleagues noted, their results neatly fit starkly different development patterns for eggs and sperms. Because of DNA copying errors, mutations are far more likely when cells divide. A fourfold higher mutation rate for sperms in fathers than for eggs of mothers, at all ages, matches the fact that in a man's testes sperm starter cells (spermatogonia) divide continuously throughout life. Geneticist James Crow calculated numbers of cell divisions needed to form a sperm at any given age. He estimated that some three dozen divisions occur between conception and puberty, when sperm production begins. For every year after puberty, he counted another two dozen cell divisions, yielding a total of more than 1,000 by age 60.

Eggs, by contrast, develop a few at a time from starter cells (oogonia) in the ovary. Female mammals typically start out with a basic stock that is gradually depleted throughout life. Human ovaries begin to develop in the fetus during the eighth week of pregnancy and halfway through fetal development numbers of starter cells peak at around seven million. But by birth that supply has already shrunk to around two million. Crow estimated that a human egg starter cell is generated by only two dozen cell divisions during fetal life. Numbers of starter cells steadily decline until around 38 years of age, when some 25,000 are left. Loss then accelerates until menopause begins, when only 1,000 remain. Between puberty and menopause only a few hundred starter cells develop into mature eggs for release. The number of sperms in a single human ejaculate is half a million times greater than the total number of mature eggs that a woman's ovaries release during her lifetime!

The bottom line from the findings reported by Jónsson and colleagues is that children inherit many more mutations from their dads than from their moms.

These findings also have far wider implications that will resonate for some time. Take, for example, a long-standing puzzle with mitochondria. These tiny power houses of the cell are derived from once free-living bacteria that became residents in early organisms with a cell nucleus more than 1.5 billion years ago. Reflecting this origin, each mitochondrion carries a few copies of its own genome, a stripped-down circular strand of DNA. Both eggs and sperms have mitochondria, yet surprisingly those borne by sperms are eliminated after fertilization. This is seemingly counterproductive, as it removes a potential source of variability.

Current theory regarding the main genome in the cell nucleus interprets sexual reproduction as a mechanism that evolved to generate much-needed variability. Mitochondria lack sexual reproduction and replicate by simple clonal division. But one might, at the very least, expect mitochondria from both sperm and egg to persist after conception to maximize variation. Now that we know that mutations accumulate more rapidly in the male, we may have an answer to the puzzling elimination of mitochondria carried by sperms. Because the mutation rate is far higher for mitochondrial DNA than for DNA in the nucleus, sperm mitochondria may simply have too many mutations by the time fertilization occurs. The embryo may be far better off with mitochondria exclusively derived from the mother. This could explain why the male himself labels mitochondria in his sperms, marking them for execution after conception. Biologically speaking, it seems that dads have recognized that they are the risky sex.

The new study convincingly demonstrates that sperms pass along more mutations than eggs. Risks of fathers transmitting congenital defects are accordingly greater. Other research has, in fact, revealed that paternal age contributes more than maternal age to the incidence of certain psychiatric disorders, notably schizophrenia and autism. These disorders reportedly have a genetic basis, so the higher load of mutations carried by sperms may be a causal factor.

Regardless of all else, however, one thing is abundantly clear: Age effects must be studied in both sexes, not just in women.

Copyright 2020 NPR. To see more, visit https://www.npr.org.

Robert D. Martin