Scientists Sequence Male Infertility Region on Y Chromosome

CAMBRIDGE, Mass. — In a tour de force in genomics, researchers led by the Whitehead Institute and the Washington University School of Medicine in St.Louis, Missouri, have sequenced and analyzed one of the most complicated terrains of the human genome. This region on the male sex (Y) chromosome, called AZFc, is important for sperm production and, when lost, causes male infertility.

In the November issue of Nature Genetics, the researchers report that they sequenced—determined the exact order of the DNA letters A, C, T, and G—in the so-called AZFc region of the Y chromosome. Deletions in this region (called azoospermia factor C) are the most common known genetic causes of low sperm counts or no sperm counts. In fact, these deletions arise in roughly one out of every 4,000 newborn boys. Given its biological importance, researchers have been trying for years to fully map, sequence, and analyze this region, but the task seemed virtually impossible because the region contained an enormous amount of repeat DNA sequences. These repeat sequences range in size from 100,000 to 700,000 bases long and are 99.8% identical, making it very difficult to tell them apart.

This month’s Nature Genetics study from the Page lab conquers this tough terrain and reports that the AZFc region is a virtual hall of mirrors—with DNA sequences that read like palindromes nested within palindromes. (Palindromes are words like MADAM that spell the same forwards and backwards; the long sequences of DNA letters in this region are mirror images of each other, reading the same either way).

The palindromic structure of the AZFc region makes it a prime target for a genetic hit, says David Page. Because of its precarious perch within the hall of mirrors, it is more subject to deletion during so-called homologous recombination—substitution of a DNA segment by another near-identical one. This occurs naturally during meiotic recombination, during the formation of sperm (which like an egg is a cell with one copy of each chromosome rather than two).

Such palindromic sequences comprise much of the Y chromosome, according to researchers, and provide a prelude to what the terrain looks like in the entire Y chromosome sequence. That sequence is expected to be announced later this year.