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New sequencing strategy details repetitive structures linked to infertility
Edward R. Winstead

Scientists now know why it has been so difficult to sequence a region of the Y-chromosome linked to infertility. The AZFc region contains six massive and virtually identical stretches of repetitive DNA, according to a new study. The repeat elements were too large and too similar to be distinguished by conventional sequencing techniques.

David C. Page, of the Whitehead Institute in Boston, and colleagues uncovered the region's details using a modified sequencing-mapping strategy. They identified 27 potential genes in the region, all of which are expressed predominantly or exclusively in the testis. Men with low or no sperm production frequently have deletions in the AZFc region, but the deletions do not seem to cause other health problems.

The researchers propose that the repetitive structures in this region cause fertility problems by improperly binding to each other as the Y-chromosome reorganizes over time. DNA is either lost or misplaced. The repetitive elements, or amplicons, can form hairpin-shaped structures called palindromes, the analysis shows. These are associated with diseases involving chromosomal abnormalities, or mosaicism.

"We know of no other genomic region in any organism in which intermingled, hierarchically organized amplicons and palindromes have such scale, copy-to-copy uniformity and elaborate mosaicism," the researchers write in Nature Genetics. The region's most notable landmark is the largest palindrome ever described, whose two 'arms' are 99.97 percent identical in DNA sequence.

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Kuroda-Kawaguchi, T. et al. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet 29, 279-286 (November 2001).

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