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Whitehead Researchers Map Y Chromosome

By Bill Jackson
Opinion Editor

Researchers at the Whitehead Institute for Biomedical Research have mapped the entire functional region of the Y chromosome, which controls sex determination in humans. The maps are considered a major early step in the U.S. Human Genome Project, an effort to assemble physical maps of all human chromosomes.

The research, led by David Page, an associate professor in the Department of Biology and assistant investigator for the Howard Hughes Medical Institute, actually involved the completion of two separate maps. One used 196 overlapping pieces of DNA and a set of pre-determined "islands" of previously known Y chromosome sequences. By determining which pieces of DNA contained which of these known sequences, the map order was constructed.

In the October 2 issue of Science, the team explained that they used Yeast Artificial Chromosomes (YACs), or pieces of human DNA carried in yeast, in order to complete the map. The investigators compared 196 of these YACs and used the common, overlapping regions to determine the correct order of the DNA and to locate a series of markers along the chromosome.

The second map was constructed by analyzing data from patients with partial deletions of their Y chromosome and determining which phenotypes, or measurable traits, they were missing as a result of those deletions. Each phenotype corresponds to a gene or genes in the DNA, and comparing the relative locations of the missing genes allowed the researchers to map 43 intervals along the Y chromosome.

Researchers compared this first map to crude maps of unknown territory made by earlier researchers. With these maps, Page said that if a gene were already cloned and known to be on the Y chromosome, "within one day it could be localized to about 1% of Y chromosome and placed within 1 of 127 bins along the length of the chromosome."

"The physical maps of the Y chromosome that we've made should make it much easier to explore the biology of the chromosome that to this time has been one of the most mysterious," said Page. "The Y chromosome is particularly mysterious" because it is difficult to investigate through family inheritance studies, he said. "I think the biology of the Y chromosome can only be explored from the DNA level up."

Page said that the work has set the stage for constructing a more detailed map, either by extending the methods already used, or by using the known islands of sequence as a starting point for determining the exact order of the remaining bases in the DNA.

"Since this map is anchored in the sequence itself," Page said, "It can melt away into the sequence of the chromosome." The ultimate goal of the Genome Project is an actual DNA sequence that lists each individual chemical base on the chromosomes.

Page said that the work's pioneering aspects are important as well. "If one can make such maps for the Y chromosome, then the same can be done for the rest of the genome. People in human genetics are excited about this work because perhaps in a few years we will have similar maps of the other chromosomes."