Between puberty and the natural end of a long life, ahealthy man manufactures anywhere from 1 trillion to 10trillion spermatozoa. If shared out equitably, that wouldbe enough to impregnate every fertile woman on earth athousand to 10 thousand times over.

Yet, not all mature human males make any sperm at all intheir semen. About 10 percent of all infertile men owetheir disease to azoospermia _ severe defects inspermatogenesis. Most of them are otherwise quitehealthy.

Since Biblical times, and until recently, being "barren"was regarded as a female disease, and grounds forunilateral divorce. Nowadays, it's recognized thatinfertility cuts about equally across both genders; that it'sa major disease of young adults.

But the cause or causes of azoospermia _ let alone itscure _ remain uncertain. "In general," said moleculargeneticist David Page, of the Whitehead Institute inBoston, "male infertility has been ascribed to chemicalinsults, infections, anatomical malformations, varicoseveins around the testes, all sorts of things of this sort. Inreality," he adds, "in very few cases is a specific etiologyidentified with confidence in a given individual. As aresult, therapy has been haphazard at best."

Now Page, who heads the Whitehead Institute's Centerfor Genome Research, has taken a first step in exploring apossibly inherited, genetic, component in male infertility.His paper in the August issue of Nature Genetics bearsthe title: "Diverse spermatogenic defects in humanscaused by Y chromosome deletions encompassing anovel RNA-binding protein gene."

"It's the first explanation for the basis of the severe spermproduction defects in any men," Page told BioWorldToday. Never before have those men had a concretemolecular explanation for their infertility."

For the general public, he defines the significance of hisjust-published finding as offering "one in sevenazoospermic men the prospect of a definitive diagnosis oftheir infertility.

Gene Therapy _ No Time Soon

As for the prospect of some day reversing azoospermiatherapeutically, he said, "We certainly can't be worse offbecause we have that understanding." But he added,"There's the possibility that that understanding isultimately going to suggest new therapeutic directions,but I think it would be very misleading if I were tosuggest that those are just around the corner."

Page and his co-authors compared the Y-chromosomeDNA of 89 azoospermic patients in Finland and in St.Louis, Mo. with similar sequences from their fathers, andfrom 90 fertile males.

Unique among the 46 chromosomes in the humangenome, Y _ by definition, as it confers maleness _passes down from fathers to all sons, but no daughters.Therefore, Page pointed out, it's the only chromosome onwhich geneticists can't do linkage analysis, "which is themost commonly used tool to map disease genes onautosomes and the X chromosome.

"The reason we can't do linkage analysis on the Y," heexplained, "is because it requires that each parent havetwo of every chromosome. Y is present on only one of theparents, and only in one copy."

Instead, Page said, "We asked the question: Was the Yinherited intact, or only in part? We were essentiallylooking for fresh lightning strikes, that is, new mutationsthat may have arisen. And that's what we found."

Actually, he and his co-authors found that "a sizablechunk of the Y chromosome was missing in 12 of 89patients with azoospermia, one in seven, but not in theirfathers' Y." Page estimates the size of this deletion, at"one half-million base pairs, which would make it about1 percent of the Y chromosome."

He and his colleagues are now exploring "the possibilitythat some of the 77 men in whom we did not detectdeletions _ six in seven _ might have more subtlemutations in the gene, within the deleted region, thatmight lead us to a more confident and precisebiochemical explanation."

The group "has so far identified one candidate genewithin that region. We don't know how much of those500,000 bp it takes up. And we don't yet know its fullstructure."

Absence of the gene lost in this deletion correlates withazoospermia. How it functions in fertile men is one of theblack boxes that Page et al. are trying to pry open.

Null Mutation On Y `Fantastically' Frequent

"Each individual in whom we detected this deletioncarries a new mutation, which won't be passed on. Wesuspect," he continued, "that these de novo null mutationsare arising at a fantastically high frequency. Perhaps onein 8,000 newborn boys have a Y chromosome deleted inthis manner."

Page and his co-authors don't know what triggers thesesporadic mutations. "One suspicion is the monotonousrepetitive nature of the DNA sequences in this portion ofthe Y. It may sometimes lead to confusion duringreplication of the chromosome."

They've raised one corner of the black-box lid: "Thatcandidate gene," he said, "encodes what appears to be anRNA-binding protein." His only evidence for this "is byanalogy _ the similarity of the protein's 366-amino-acidsequence, in part, to that of other proteins known tofunction in binding messenger RNA." But he does not yetknow if this gene is the "azoospermic factor" required tomake sperm.

He has a take-home message for the biotechnologycommunity: "I think we should begin to turn the geneticspotlight on infertility as much as it has been turned onother common adult diseases, such as heart disease,cancer and so on. Fertility should no longer remain in thedarkness, with regard to genetic studies." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.