Tiny Gene Variations Can Even Alter Effect Of the Pills We Take

Modern genetics produced a paradox: The more we learn how much DNA we share, the more we are intrigued by the minor biochemical variations that set us each apart -- and with good reason.

Tiny differences in genes we have in common make some of us more vulnerable to breast cancer, alcoholism or infections, researchers recently reported. Other variations in genes we share make some of us more resistant to chemotherapy or treatments for heart disease and hypertension.

Any one of 11 variations in a single gene, for another example, can make it harder for commonly prescribed antidepressants to temper our moods, researchers at Munich's Max Planck Institute of Psychiatry reported in January in Neuron. Any one of nine variations in another gene may double the risk of lupus, University of Alabama scientists said.

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Many of these fractional hereditary distinctions are random effects of chance at play. (Any two people are more than 99% the same at the genetic level.) Broadly speaking, they also arise from the ancient history recorded in the genetic autobiography that we carry in our cells, coded there in billions of characters of DNA. The human genome is a biomedical narrative of migration, disease, conquest and trade. It has been accumulating plot twists and changes since small clans first moved out of East Africa to settle the world tens of thousands of years ago.

In the most detailed look yet at global human variation, two independent research teams -- one led by scientists at Stanford University and the other by scientists at the University of Michigan -- recently analyzed more than half a million genetic markers across hundreds of people from 51 ethnic groups on five continents. Melding medical genetics and population genomics, they probed kinship, diversity and the underpinnings of disease. "We are tying together what we know about human history with what we see in the human genome," said University of Utah anthropologist Henry Harpending.

New research in that effort reveals, for example, that Americans of European descent carry more potentially harmful genetic variations than do African-Americans, Cornell University computational biologist Carlos Bustamante and his colleagues reported last month in Nature.

The researchers concluded that this pattern of variation was the legacy of humanity's first forays into prehistoric Europe, when the venturesome probably numbered a few thousand or less. The hereditary flaws carried by these forebears then became widespread as their descendants expanded into a population of millions.

Recommended Reading

This year, new studies of human genetic variation around the world have produced genome data nearly 100 times more detailed than previous global assessments, yielding insights into how humanity's early migrations out of Africa affect us all today.

In Nature, researchers at the University of Michigan last month reported their analysis of more than 500,000 DNA markers occurring across 29 populations on five continents.

In Science, scientists at the Stanford University School of Medicine reported last month on 650,000 genetic markers measured across 51 population groups worldwide.

The effect of migration from Africa to Europe can still be seen in the genes of Europeans today, Cornell University researchers reported last month in Nature.

Differences in gene expression between Europeans and Africans affects responses to medications and to infections, University of Chicago researchers reported earlier this month in the American Journal of Human Genetics.

In January, scientists in England, China and the U.S. launched the 1,000 Genomes Project to seek more detailed information about human genetic variation by sequencing the genomes of at least 1,000 people around the world.

Dr. Bustamante compared 10,000 genes shared by 15 African-Americans and 20 European-Americans and found nearly 40,000 individual differences in which a gene's smallest structural unit -- a single DNA base pair -- had been altered. Half of them had no measurable effect. Everyone harbors some potentially harmful variations, but, overall, the European-Americans had a higher percentage of those that could be deleterious.

"You cannot say anything at the individual level on the basis of this data," Dr. Bustamante cautioned. "No one person's genome is any healthier or better or more fit in an evolutionary sense than any other individual's."

Hundreds of genes also behave slightly differently in families of European descent than they do in families of African ancestry, especially those genes involved in producing antibodies and other fundamental cell functions, University of Chicago medical researchers reported this month in the American Journal of Human Genetics.

The Chicago scientists analyzed gene variations to learn why some people are more sensitive than others to the toxic side effects of chemotherapy. They compared 9,156 genes in 30 Caucasian families in Utah with those in 30 Yoruban families from Ibadan, Nigeria.

All told, they found that 156 shared genes were more active among those of European heritage, while 254 other shared genes were more active among those of African ancestry. No one knows yet what, if anything, the minor variations in levels of gene activity mean medically or if they affect chemotherapy, said Chicago pharmaco-genomics expert Eileen Dolan.

In each instance, "we are comparing the same exact gene in both populations," she said. "The differences are subtle, not dramatic."

To delve even more deeply into human variation, scientists in the U.S., England and China in January launched a $50 million effort to catalog in exhaustive detail the DNA of at least a thousand people from around the world. They expect the 1000 Genomes Project, as they call it, to produce 60 times as much genetic sequence data in three years than has been released in all of the last quarter century.

Researchers hope it may help them tailor more effective medical treatments.

Human variation, however, may be more than medicine can easily master. Researchers at Brigham and Women's Hospital in Boston reported last month in the Proceedings of the National Academy of Sciences that even crucial genetic mutations in cancer cells, for example, may be different in every patient.

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