Gene of Mideast Ancestor May Link 4 Disparate Peoples, The New York Times-1997

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Several thousand years ago, somewhere in the Middle East, there lived a person who bequeathed a particular gene to many present-day descendants. But these millions of now distant relatives could not convincingly be called one big happy family. They include Jews, Arabs, Turks and Armenians.

The gene, a variant of a gene that controls fever, has come to light because it causes an unusual disease called familial Mediterranean fever in people who inherit a copy from both parents. The gene’s presence among a surprising group of populations hints at the rich archeology that lies buried in the human genome, once geneticists and historians have learned how to interpret it.

Two rival teams of scientists in France and the United States have been racing to isolate the gene for a year. The race finished today, with the American team announcing its finding in the journal Cell, the French team in Nature Genetics.

The American team has named the gene pyrin, from the Greek word for fire, after its role in fever; the French team calls it marenostrin after the Latin ”Our Sea,” a Roman phrase for the Mediterranean. The race could be considered a dead heat, although the American team has recovered the whole gene, the French team just a major portion.

People who inherit a single variant copy of the fever gene from one parent and a normal copy from the other parent have no sign of the disease. They are so numerous, constituting up to 20 percent of certain Jewish and Armenian populations, that carrying one copy is assumed to confer some significant benefit, like a greater resistance to disease.

In people with two copies, however, the immune system goes into overdrive at inappropriate moments, causing bouts of severe fever. The scientists who have analyzed the fever gene and its variants say they now understand why.

The normal gene specifies a protein that from its design motifs looks as if it is meant to slip into the nucleus of the cell and switch genes on or off. Since the gene is active only in a special class of white blood cells, its usual duty seems to be to control the cells’ activity and rein them in when the threat of infection has passed. The white blood cells defend against infections and often cause fever in doing so.

The new findings, in portraying the exact genetic anatomy of the normal gene and its variant forms, give a strong clue as to why the variant versions have the effects they do. The variant forms have mutations, or changes of a single DNA letter, in the region of the gene assigned to the switching function. Presumably the mutations make the gene’s protein inefficient in its duty of restraining the white blood cells.

The historical significance of the finding lies in the genetic relationship it implies between populations that have been separate for many hundreds of years. For example, the variant form of the gene found in North African Jews, Iraqi Jews and Armenians is the same, carrying both the same mutation and a pattern of 11 other genetic changes, all harmless. Although single genetic changes can arise independently, the presence of so many together in the same combination points strongly to a ”founder” or single ancestor as the original source of the variant gene.

A second variant form of the gene, according to the American team, is shared by Iraqi Jews, Ashkenazi Jews, the Moslem Druze sect and Armenians. The two variants are similar and probably derive from the same founder.

The Americans write that the mutations are ”very old” and that they suggest ”common origins for several Middle Eastern populations.”

Dr. Daniel L. Kastner, a member of the team, said the original possessor of the variant gene probably lived several thousand years ago and certainly less than 40,000 years ago, according to a formula that relates the average length of a shared genetic segment to the number of generations that have passed. Dr. Kastner said the founder’s gene may have spread through a population in the Middle East that existed before Jews, Armenians and Arabs became distinct peoples.

He also noted that the variant fever gene established a common genetic lineage between Ashkenazi Jews and Iraqi Jews, even though the two communities have been separated since the Babylonian Captivity that began in 597 B.C. Many Jews from the ancient community in Iraq now live in Israel.

The French team has detected the main variant in Jews and Arabs from North Africa and in Turks and Armenians. Dr. Jean Weissenbach of the gene laboratory Genethon, a member of the French team, said that the variant gene was ancient but that an exact date of it origin could not be calculated.

Experts in Middle Eastern history and linguistics said they knew of no historical event to link the four populations in which the variant fever gene has been found, although three – Arabs, Jews and Armenians – are related geographically, having originated in the Middle East. The ancestral Armenian homeland is around Lake Van in Turkey. The Seljuk Turks invaded from Central Asia in the 11th century, and they absorbed many of the local inhabitants.

Familial Mediterranean fever is rare in the United States. Patients often endure years of misdiagnoses. Once the disease is recognized, an effective drug, colchicine, is available. Now that the DNA sequence of the variant gene is known, an accurate test can be made.

”This will really help to diagnose the disease in the very early stages and to start the colchicine treatment as soon as possible,” Dr. Weissenbach said.

The American-led team includes scientists from Israel and Australia. The French team is from Genethon in Evry and two other laboratories.

By Nicholas Wade Aug. 22, 1997 The New York Times

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