X marks the spot for gene hunters

The sequencing, published in the journal Nature today (17 March), involved an international team of more than 250 genomic researchers led by the Wellcome Trust Sanger Institute in the UK.

In humans and other mammals, sexual identity is governed by a pair of chromosomes referred to as X and Y. Females have two X chromosomes, one copy of which is largely inactive, while males have one X chromosome and one Y chromosome.

The new analysis confirmed the existence of 1,098 protein-coding genes on the X chromosome. Only 54 of the 1,098 genes have functional counterparts on the much smaller Y chromosome, which has been described as an "eroded" version of the X chromosome, almost the appendix of the human genome.

Interestingly, almost 10 percent of the genes on the X chromosome are part of a somewhat mysterious family of "cancer-testis antigens," which are normally expressed in the testis but also appear in certain cancers, making them possible targets for immunotherapy.

b"Large numbers of medically related genes happen to fall on the X," said Dr. Steven Scherer, associate professor in the Baylor College of Medicine department of molecular and human genetics and director of mapping in the BCM Human Genome Sequencing Center.

The fact that men have just one copy of the X chromosome makes the mutated genes on that one piece of DNA much easier to find, said Scherer.

The research team compared the human X chromosome to the genome sequences of a variety of other organisms, including dog, rat, mouse and chicken. They found that the gene order of the human and dog X chromosomes were virtually identical. Comparing gene order in the human and rodent sequences showed several segments had reshuffled in the rodent lineage, and an interesting, 9 million base pair region appears to have been deleted from the rodent chromosome after humans and rodents diverged from their common ancestor.

Of particular interest was the comparison of the human X chromosome to the sequence of the chicken. Most of the genes on the short arm of the human X are found on chicken chromosome 1, and most of the genes on the long arm of the human X are found on chicken chromosome 4. These findings support the idea that mammalian X and Y chromosomes evolved from an "ordinary" ancestral pair of identical chromosomes.

Gene activity study​

A second study in the same edition of Nature examined 471 genes on the X chromosomes of 40 women. To the scientists' surprise, they found that each woman's X chromosomes showed a unique pattern of gene expression.

More than 45 years ago, researchers discovered that most genes on one copy of a female's X chromosome are switched off - a modification known as X-inactivation. This mechanism thus reduced the level of female expression of genes on the X chromosome to the same level as that in an XY male. Initially, it was thought the process resulted in a complete inactivation, or "silencing," of all of the genes on that copy of the chromosome in a female. However, in the late 1980s, researchers learned that some fraction of the genes remain active. The new work extends those findings to the complete set of X-linked genes.

Specifically, the researchers determined that due to the incomplete nature of X-inactivation, at least 15 per cent of genes on the X chromosome produced proteins at higher, often variable, levels in females than in males. Furthermore, in some women but not in others, an additional 10 per cent of the X-linked genes are expressed at variable levels.

Much more work is needed to explore the implications of the new findings for human health and disease. But the discovery that up to 25 percent of the X chromosome can be uniquely expressed in one sex relative to the other could explain various sex-specific traits, both in complex disease as well as normal gender differences.

"Papers like this one define the starting gate,"​ commented Scherer. "Now the research community is taking the next step."​