Females do most of the heavy lifting in sexual reproduction _pregnancy and nursing. Yet mothers donate only half of their genes totheir offspring. Their male partners contribute the other half.This unequal opportunity is most often explained as nature's way ofcutting the risk of bad mutation in half. But it turns out that mammalianmales generate more than half of these deleterious genes.So why then did evolution impose sex on us two-legged eukaryotes,and our four-legged fellow mammals, in order to be fruitful andmultiply?A bacterial geneticist at the University of British Columbia inVancouver, Rosemary J. Redfield, took a first pass at tackling thisquestion in the current issue (May 12) of Nature. Her paper, titled"Male mutation rates and the cost of sex for females," appliesprobability statistics and computer simulation to show that "the cost ofmale mutations can easily exceed the benefits of recombination,causing females to produce fitter progeny by [no-sex] parthenogenesisthan by mating.""How did evolution get us into this fix?" she asked BioWorld Today,rhetorically. "The female does all the work, throws away half hergenes, while the male's genes get a free ride into the next generation."One of the big questions this inequity poses, Redfield adds, is "Whydon't females just say no to sex?" She quickly continues, "Not inhumans of course; in other species they can; why don't they?"Her answer to this evolutionary puzzle: "It must be that the progenyturn out twice as fit as if she had said, `Hell no, I'll make my own,alone.' Now our challenge is to understand where this two-foldadvantage of sex could have come from, to pay back the mother for herlabor and lost genes."She said, "Rather than helping to solve this riddle, my paper points outthat the problem is worse than we had thought."Redfield notes, sexual reproduction increases fitness (fertility plusviability) both when male to female rates of mutation are equal, or eventwo to one, but reduces it at six or 10 to one.Given the female's unshared burden of reproduction, with only half thegenetic input, Redfield's computer algorithm required that each sexualpopulation's fitness be twice that of its parthenogenetic counterpart.She cites research by others supporting the hypothesis that germlinemutations arise during DNA replication when cells divide.A mammalian female's ovaries produce a finite number of eggs duringher reproductive lifetime _ 300 to 400 in a human's childbearingyears. A sexually mature male Homo sapien, by contrast, generatesspermatozoa nonstop through life; a cubic millimeter of seminal fluidmay contain 60,000 sperm cells.As Redfield pointed out, "The problem is that most mutations arisewhen sperm is being made, allowing copying errors to accumulate."Chromosomal defects, such as Down's syndrome, increase statisticallywith a woman's age. In men, DNA point mutations occur more often intheir proliferating sperm."The obvious solution," Redfield suggested conceptually: would be"increasing the fidelity of germ-line-specific DNA polymerases andpathways," that promote DNA repair of mutated genes. Her computermodel draws the logical conclusion: Female mammals, by definitionunequipped to switch to parthenogenesis, might reduce the contributionfrom male mutations by mating with the youngest males available, astheir gametes will have undergone the fewest rounds of DNAreplication.That's where she and her current simulated model part company. Shemakes the non-genetic point that "human males contribute far more totheir children than just chromosomes, so women don't have to changehow they seek their mates."As for the computer, "The naive and simple model [of her Naturepaper] had to pretend that dealing with very large homogeneouspopulations, we could ignore random effects entirely. We didn't haveto worry about the odd individual who got eaten by a bear."Next she would like to refine her construct, "making it more realistic,by extending it to a smaller, mixed population, which could worryabout random effects."Redfield points out that "one of the most important benefits of sexapplies only in small populations." Sexual recombination betweencouples with a variety of heterozygous mutations produces aMendelian distribution of offspring, some of whom may be mutation-free."Basically," Redfield said, "sex randomizes combination," so humanshave evolved to fight off parasites and pathogens. These tookevolutionary counter-measures, and we fought back, evolving again tofight them off, and so on. That's the kind of selection whererandomizing is good."Mutations: The Good, The Bad, The NeutralAlexey Kondrashov is a noted Russian population geneticist, recentlytransplanted from Moscow's Institute of Mathematical Problems ofBiology to Cornell University's Ecology and Systematics section. Hewrote Nature's commentary on Redfield's paper, titled "Sex anddeleterious mutations."For BioWorld Today, Kondrashov described the "culturalmisunderstanding between population/evolutionary geneticists andthose doing molecular and human genetics."When the latter think mutations, they picture some drastic mutationthat leads to syndromes. That's reasonable, because the doctor doesn'tcare about you until you are half dead, then tries to save you."Such severely deleterious mutations appear at a rate no more than 10percent, closer to 1 percent or less, of a genome's total deleteriousmutations. A dominant, lethal point mutation can change onenucleotide in our genome, and you are dead. But in many cases whenyou replace one nucleotide, the result is not completely neutral, but notthat devastating."These mild, deleterious mutations cannot be individually detected. Amolecular human geneticist wouldn't notice them at all. He isconcerned with `genes that cause diseases' _ one gene, one disease,such as cystic fibrosis."I believe that in the long run, tens of generations, these mildlydeleterious mutations can be much more important. Quantitatively, theamount of human suffering caused by slightly deleterious mutationscan be 100 times greater than by the far fewer severely deleteriousones."I don't want to talk about beneficial mutations, because these arecertainly rare."Kondrashov multiplies the genomic mutation rate _ 2 X 10-8 pernucleotide per generation _ by the total size of the diploid genome _7 billion haploid sites -- and comes up with "a striking number: Eachzygote carries more than 100 new mutations."We cannot measure the genomic deleterious mutation rate directly, sowe measure fitness in populations. As mutations accumulate, fitnessdeclines."What Redfield did in Nature is really great. She combined molecularand populational evidence as to the difference between the male andfemale mutation rates, and this data is widely known and appreciated inthe population community."
-- By David N. Leff Science Editor
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