Scientists finish charting genetic sequence for half of human chromosomes

Latest chromosome data yields wealth of information about how humans evolved

Richard Myers

Five years after publicly revealing the official draft of the human genetic sequence, researchers have reached the halfway point in dotting the i’s and crossing the t’s of the genetic sentences describing how to build a human. The newly finalized chromosome 5 is the 12th of 24 chromosomes to be finalized. As the new sequence reveals, this chromosome is a genetic behemoth containing key disease genes and a wealth of information about how humans evolved.

Chromosome 5 is the second of three chromosomes to be finalized through a collaboration between researchers at the School of Medicine and the Department of Energy-funded Joint Genome Institute in Walnut Creek, Calif. The chromosome’s final sequence was published in the Sept. 16 issue of Nature.

Richard Myers, PhD, the Stanford W. Ascherman Professor in Genetics, said the finalized sequences are a powerful tool for researchers to understand the role of genes in disease and other human characteristics.

“Every human chromosome is interesting and unique and chromosome 5 is no exception,” said Myers, chair of the genetics department and director of the Stanford Human Genome Center where the final sequencing was done. “The finished sequence confirmed much of what we know about disease genes, but also contains new information and hints about human biology and evolution.”

Chromosome 5 is made up of 180.9 million genetic letters – the A’s, T’s, G’s and C’s that comprise the genetic alphabet. Those letters spell out the chromosome’s 923 genes, including 66 genes known to be involved in human disease. Another 14 diseases seem to be caused by the chromosome’s genes, but they haven’t yet been linked to a specific gene. Other chromosome 5 genes include a cluster that code for interleukins, molecules that are involved in immune signalling and maturation and are also implicated in asthma.

U.S. Energy Secretary Spencer Abraham, whose agency supported the research through its Office of Science, said the spaces between the genes are as important as the genes themselves. “In addition to such disease genes as those that code for obesity, asthma and colorectal cancer, other important genetic motifs have been gleaned from vast stretches of noncoding sequence,” he said.

These stretches were previously considered “junk DNA” but in recent years those seemingly barren regions have taken on greater importance as researchers learned the areas control the activity of distant genes. Some of the noncoding regions have also stayed remarkably consistent compared with mice or fish rather than accumulating mutations over the course of evolution.

“If you have such a large region that stays conserved, it must be something that’s important,” said Jeremy Schmutz, informatics group leader at the Stanford center. Any mutation that appeared in that region was likely to have either killed the animal or made it less able to reproduce, preventing the mutation from moving to the next generation. So far no one has shown what role the conserved regions play.

“This says that we don’t know as much about this stuff as we think we do,” he added. Schmutz, finishing group leader Jane Grimwood and production sequence group leader Mark Dickson together head Stanford’s chromosome 5 sequencing efforts.

Hidden in the chromosome 5 sequence are clues to how humans evolved after branching away from chimpanzees. On average, the chromosome is more than 99 percent similar between chimpanzees and humans, with the greatest similarity found in genes that cause diseases when mutated.

Despite similarities in the overall sequence, the human and chimpanzee chromosomes have structural differences including one large section that is backward in humans compared to chimps. Such an inversion makes it impossible for the two chromosomes to pair up when the cell divides to create sperm and eggs. Over time, that incompatibility could have driven a reproductive wedge between the evolving populations.

Human chromosome 5 also contains several repeated regions. Although there are fewer total duplicated regions on the chromosome – 3.4 percent compared with 5.3 percent on average for the human genome – the duplications have remained remarkably similar to each other. This suggests the duplications happened recently and haven’t yet accumulated mutations.

Moving evolutionarily further away, about a third of chromosome 5 is similar to a chicken chromosome that determines gender, much like the X and Y chromosomes in humans. This finding backs up previous research suggesting that before mammals and birds split 300 million years ago, the sex chromosomes had not yet evolved. After the split, mammals and birds developed their own methods of creating males and females.

One duplicated region on chromosome 5 could eventually help explain how the disease spinal muscular dystrophy is inherited. Researchers had known that deletions in the gene survival of motor neuron, or SMN, caused the disease, but people with the same eletion can have much more or less severe forms of the disease. It turns out the region contains many duplications and other rearrangements and varies considerably between people. Schmutz said that with the sequence for this region in hand, researchers can study how variations in the number of deletions or repetitions influence the disease severity.

The JGI and Stanford collaborated on finalizing the sequences for chromosomes 19, 5 and 16. The chromosome 19 sequence was published in the April 1, 2004, issue of Nature.