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[Lazarus Long]

Scientists Map Largest Chromosome to Date
Wed Jan 1, 2:31 PM ET Add Science - AP to My Yahoo!

By RICK CALLAHAN, Associated Press Writer

French and American scientists have mapped chromosome 14, the longest sequenced to date and the site of more than 60 disease genes, including one linked to early onset Alzheimer's.

The feat enlisting nearly 100 researchers marks the fourth of the 24 human chromosomes mapped so far as part of an international effort.

Scientists at Genoscope, the French national sequencing center, said the chromosome is comprised of more than 87 million pairs of DNA, all of which have been sequenced so that the chromosome's map includes no gaps.

"At the present time, this is the longest piece of contiguous DNA that has been sequenced. We made an effort to close all the gaps," said Genoscope's director, Jean Weissenbach.

The researchers describe chromosome 14 and its 87,410,661 pairs of DNA — a fraction of the total 3 billion pairs found in human genome (news - web sites) — in a paper to be published online Thursday by the journal Nature.

The project was led by Genoscope, with contributions from scientists at Seattle's Institute for Systems Biology and the Washington University School of Medicine in St. Louis.

The scientists identified 1,050 genes and gene fragments, among them more than 60 disease genes. Those include genes linked to early onset Alzheimer's, spastic paraplegia, NiemannPick disease and a severe form of Usher syndrome.

Although the accomplishment is noteworthy, it does not mean science is any closer to conquering Alzheimer's, said Bill Thies, vice president for medical and scientific affairs for the Alzheimer's Association in Chicago.

He said the chromosome 14 gene linked to early onset Alzheimer's accounts for only a fraction of cases of the degenerative brain disease. Several genes, as well as environmental factors, are known to play a role in a person's risk of developing Alzheimer's, Thies said.

During the last three years, nearly complete sequences of chromosomes 22, 21, 20 — and now chromosome 14 — have been published.

By April, researchers around the globe hope to complete the sequencing of the remaining 20 chromosomes, said Mark Guyer, director of the division of extramural research at the National Human Genome Research Institute.

April is also the 50th anniversary of the publication of James D. Watson and Francis H.C. Crick's 1953 paper in Nature describing DNA's double-helix structure.

Guyer said the institute, one of the National Institutes of Health (news - web sites), intends to mark the occasions by publishing a paper outlining its vision of the future human genetics studies.

"Once we've sequenced the chromosomes, that is essentially just the basic set of instructions. We still need to learn how to read the instructions and understand what they mean," he said.

Related Web Sites
• A History of the Human Genome Project
• Human Genome Organisation (HUGO)
• TIGR Database (TDB)


___

On the Net:


Nature: http://www.nature.com


Genoscope: http://www.genoscope.cns.fr/externe

National Human Genome Research Institute: http://www.genome.gov/

Edited by XxDoubleHelixX, 27 May 2003 - 10:48 PM.

[Lazarus Long]

Our Not-So-Distant Cousin
By LISA BROOKS


BETHESDA, Md. — Humans and mice both have hair, five toes on each foot and an affinity for cheese. This month's publication of a draft of the mouse genome shows that genetically, too, we have much in common: 99 percent of our genes are also in mice. We have long known that all living organisms are related to one another genetically, but what does this newfound genetic similarity between humans and mice say about the similarities between any two humans — who are, after all, 99.9 percent the same at the DNA level?

Comparing the genome of humans to that of mice gives us a glimpse into the history of both of our genomes over the 75 million years since we last shared a common ancestor, a species that was a small mammal. One lineage that descended from that species became rodents, and eventually mice, and another became primates — and eventually humans.

During that time, mutations occurred randomly in the DNA sequence of organisms in both lineages. A few mutations had beneficial effects, making the individuals who had them more resistant to disease or better at doing monkey or mousy things. Many such mutations increased in frequency by natural selection until all members of the species had them. Mutations that had detrimental effects were lost from the species, and most of the mutations that lasted probably had only small effects on how individuals functioned. Over time, differences accumulated in parts of the genomes where the exact sequence of DNA is not critical, while far fewer differences accumulated in parts of the genome important for function.

Any individual's genome is composed of long molecules of DNA. Humans have about 3 billion of the units that form our DNA sequence; mice have about 2.6 billion. Most genes are stretches of DNA with the information to make proteins. Looking at entire genomes shows that genes — which transmit the information for hereditary traits — make up only 2 percent of the genome. The rest of the genome is made of DNA, some of which regulates how genes work. Since 99 percent of human genes have a counterpart in mice, it is clear that most gene functions have been conserved in these two mammals, and that very few new gene functions have been added.

So if we have pretty much the same genes as mice, why do we look so different? Part of the answer lies in the mutations that accumulated in the DNA sequences along the lineages of humans and mice: the DNA sequences in genes are about 85 percent the same in humans and mice. Since the gene for, say, collagen in bones does not have exactly the same DNA sequence in humans and mice, the collagen produced is not exactly the same, but it functions similarly. Another part of the answer is in how the genes are regulated. For example, both human and mouse feet have the same number of bones in the same order, but the bones are bigger in humans because they grow for a longer time.

If we think of mice and humans as distant cousins on a family tree, then all humans are brothers and sisters in that family. We all descended from a common set of ancestors who lived in Africa about 10,000 generations ago. The people in our ancestral population had a certain amount of variation among their DNA sequences, and most of the genetic variation in people today derives from this ancestral pool. As their descendants spread around the globe, mutations also occurred, adding to the set of human genetic variation.

As a result, 99.9 percent of the DNA sequence in any two people is the same. Even though the remaining 0.1 percent is a small proportion, in the total human population there are about 10 million places in the genome where differences among people are common. Most of these sequence variants fall in parts of the genome that do not appear to be critical for function. Probably only a few hundred thousand variations in the sequence affect how people function, and only a few hundred, mostly yet to be identified, are likely to be of major medical importance.

A small amount of the variation is associated with particular human ethnic or geographic groups, mostly because of natural selection for resistance to disease. However, most human genetic variation occurs from person to person within any ethnic group. Blood type — A, B, AB or O — is an example. All human ethnic groups have people with various blood types. The proportion of people with any particular blood type varies from one group to another, but no group is uniform. Any two people in the same group have a good chance of differing in their blood type.

Just as comparing the human and mouse genome sequences provides important clues about gene function, so, too, does comparing the DNA sequence among people. Most common human diseases, such as diabetes, cancer, heart disease and depression are affected by multiple genes and environmental factors. Researchers can compare the genomes of people with a disease to those of people without it, to find the genetic variants that contribute to the risk of getting that disease.

The similarity of our genome to that of mice, and the closer similarity among all people, reflects our shared genetic heritage from common ancestors, some distant and some close to us. As we learn about the ways our genomes encode how we each develop into human beings, we need also to remember that our common humanity goes beyond our genetic differences.

isa Brooks directs the genetic variation program at the National Human Genome Research Institute of the National Institutes of Health.

[Cyto]

From Science Now...

Fly Genome Warms to Global Change

Although global warming may not yet have reached catastrophic proportions, its subtle effects can already be seen in the natural world. Butterflies, for example, are shifting their home ranges toward cooler areas (ScienceNOW, 10 June 1999). Now, a new study in this month's Evolutionary Ecology Research shows that fruit flies are also feeling the heat--in their genes.

Back in the 1940s, geneticist Max Levitan of the Mount Sinai School of Medicine in New York City did his Ph.D. on the chromosomes of the eastern North American woods fly Drosophila robusta. Like many organisms, it sometimes has genetic variants called "inversions," where entire chunks of chromosome have been turned back-to-front. This unorthodox orientation means that these parts of the genome cannot be shuffled during the production of egg and sperm, and the genes on them are packages of permanently linked genes. As the young Levitan found out in lab experiments, certain of these gene packs, called 2L-1 and 3R-1, help the flies cope better with high temperatures. Although the exact causes for their heat-resistance are not clear, this feature probably explains why 2L-1 and 3R-1 are more common in the south.

But now all that has changed. Over the past 60 years, Levitan has been regularly putting out fly traps over the United States and parts of Canada, often returning to the same places. But lately he has been noticing something strange. "My first inkling came from the 1995 collections at Philadelphia," he says, when the frequency of the heat-resistant 2L-1 variant came in at 60%, whereas it used to be much rarer in Pennsylvania. Although he has become less mobile (his wife does not let him drive anymore), samples taken last year confirm his suspicions dramatically. In five localities, from St. Louis to Philadelphia, 2L-1 and 3R-1 have doubled or tripled in frequency since the 1970s, reaching levels previously only seen in southern Georgia and Alabama. Even in Central Park in New York City, the only place still easily within Levitan's radius of action, the trend could be detected. "Widespread climate change best explains [this]," Levitan says.

Other evolutionary geneticists are thrilled with the demonstration of a genome responding to global warming. On the other hand, they are also concerned. Bill Etges, who works on Drosophila at the University of Arkansas in Fayetteville, says: "Like canaries in a coal mine, [it is] another warning of the effects of human activities on the rest of the planet's living things."

--MENNO SCHILTHUIZEN