GENEALOGY-DNA-L Archives

From:
Subject: "Inadvertent diagnosis of male infertility"
Date: Fri, 1 Apr 2005 11:10:27 EST

This message is a summary of the article and a call for discussion. Full text
is not available right this moment, but it should be shortly. I'll post a
link when that happens (if someone doesn't beat me to it).

"Inadvertent diagnosis of male infertility through genealogical DNA testing"

Turi E King, Elena Bosch, Susan M Adams, Emma J Parkin, Zoë H Rosser, Mark A
Jobling

J Med Genet 2005;42:366-368

=====

Many of the genes required for sperm production are located on the Y
chromosome. One cause of male infertility is the deletion of a stretch of DNA about 3
million bases long, in a region called AZFc. The frequency of this deletion
has been estimated at about 1 in 4000 men.

King et al were conducting a surname study with Y chromosome markers, and
found three cases in unrelated males where the SNP marker P25 (for R1b) could not
be amplified. When they examined those cases, they found that all of them had
the AZFc deletion. Their sample size was 2574 men, and they pooled their data
with 681 other records that had been typed for P25 (called PN25 in the
article). This gives a rate of 3 in 3255, not significantly different than previous
estimates.

This particular AZFc deletion occurs at a "hot spot." The Y chromosome has
many duplicated segments. It can bend and fold on itself during the copy
process, becoming attached at a "homologous" (similar) stretch of DNA. The URL below
has an animation of how recombination can occur on the Y chromosome. If you
follow the animation, I picture the DNA copying enzymes taking a short-cut
across the base of a loop, "forgetting" to copy the 3 million bases in the loop.

http://www.hhmi.org/biointeractive/animations/y_update/y_update_frames.htm

Side note: I got to wondering if recombination might explain the variable
behavior of the CDY marker. The details about that marker have not been published
yet, but I do see a CDY marker in the AZFc region in Jobling's diagram from
"The Human Y Chromosome: An Evolutionary Marker Comes of Age":

http://www.le.ac.uk/genetics/maj4/JoblingTS.03.NRG.Review.pdf

This same region also contains the DYS464 multi-copy markers. If someone has
the AZFc deletion, he will end up with a "null" result. The authors conclude
"There certainly seems no good reason for continued commercial typing of the
AZFc marker DYS464, which in any case offers problems of interpretation because
of its multilocal nature."

I think that's an overstatement, but it's a situation we should be prepared
to handle when it arises. Perhaps we could integrate a word of warning about
infertility when we forewarn people about the possibility that their DNA results
won't turn out as expected, due to non-paternity or gaps in research (much
more frequent scenarios).

Ann Turner - GENEALOGY-DNA List Administrator
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