What makes you unique? Not genes so much as surrounding sequences, says Stanford

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What makes you unique? Not genes so much as surrounding sequences, says Stanford

study

http://www.eurekalert.org/pub_releases/2010-03/sumc-wmy031510.php

STANFORD, Calif. — The key to human individuality may lie not in our genes, but

in the sequences that surround and control them, according to new research by

scientists at the Stanford University School of Medicine and Yale University.

The interaction of those sequences with a class of key proteins, called

transcription factors, can vary significantly between two people and are likely

to affect our appearance, our development and even our predisposition to certain

diseases, the study found.

The discovery suggests that researchers focusing exclusively on genes to learn

what makes people different from one another have been looking in the wrong

place.

" We are rapidly entering a time when nearly anyone can have his or her genome

sequenced, " said Snyder, PhD, professor and chair of genetics at

Stanford. " However, the bulk of the differences among individuals are not found

in the genes themselves, but in regions we know relatively little about. Now we

see that these differences profoundly impact protein binding and gene

expression. "

Snyder is the senior author of two papers — one in Science Express and one in

Nature — exploring these protein-binding differences in humans, chimpanzees and

yeast. Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, came

to Stanford in July 2009 from Yale, where much of the work was conducted.

Genes, which carry the specific instructions necessary to make proteins do the

work of the cell, vary by only about 0.025 percent across all humans. Scientists

have spent decades trying to understand how these tiny differences affect who we

are and what we become. In contrast, non-coding regions of the genome, which

account for approximately 98 percent of our DNA, vary in their sequence by about

1 to 4 percent. But until recently, scientists had little, if any, idea what

these regions do and how they contribute to the " special sauce " that makes me,

me, and you, you.

Now Snyder and his colleagues have found that the unique, specific changes among

individuals in the sequence of DNA affect the ability of " control proteins "

called transcription factors to bind to the regions that control gene

expression. As a result, the subsequent expression of nearby genes can vary

significantly.

" People have done a lot of work over the years to characterize differences in

gene expression among individuals, " said Snyder. " We're the first to look at

differences in transcription-factor binding from person to person. " What's more,

by selectively breeding, or crossing, yeast strains, Snyder and his colleagues

found that many, but not all, of these differences in binding and expression

levels are heritable.

In the Science Express paper, which will be published online March 18, Snyder

and his colleagues compared the binding patterns of two transcription factors in

10 people and one chimpanzee. They identified more than 15,000 binding sites

across the genome for the transcription factor called NF-kB and more than 19,000

sites for another factor called RNA PolII. They then looked to see if every site

was bound equally strongly by the proteins, or if there were variations among

individuals.

They found that about 25 percent of the PolII sites and 7.5 percent of the NF-kB

sites exhibited significant binding differences among individuals — in some

cases greater than two orders of magnitude from one person to another. (For

comparison, the binding differences between the humans and the chimpanzee were

about 32 percent.) Many of these binding differences could be traced to

differences in sequences or structure in the protein binding sites, and several

were directly correlated to changes in gene expression levels.

" These binding regions, or chunks, vary among individuals, " said Snyder, " and

they have a profound impact on gene expression. " In particular, the researchers

found that several of the variable binding regions were near genes involved in

such diseases as type-1 diabetes, lupus, leukemia and schizophrenia.

The researchers confirmed and extended their findings in the Nature paper, which

will be published online March 17. In this study, they used yeast to determine

that many of the binding differences and variations in gene expression levels in

individuals are passed from parent to progeny, and they identify several control

proteins that vary — a study that would have been impossible to perform in

humans.

" We conducted the two studies in parallel, " said Snyder, " and found the same

thing. Many of the binding sites differed. When we mapped the areas of

difference, we found that they were associated with key regulators of variation

in the population. Together these two studies tell us a lot about the so-called

regulatory code that controls variation among individuals. "

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The research in the Science Express study was supported by the National

Institutes of Health, the European Molecular Biology Laboratory and the

Medical Institute's Medical Fellows Program. The research in the Nature

study was supported by the National Institutes of Health. In addition to Snyder,

other Stanford researchers involved in the two studies include postdoctoral

scholars Fabian Grubert, PhD; Minyi Shi, PhD; and Manoj Hariharan, PhD; and

graduate student Konrad Karczewski.

More information about Stanford's Department of Genetics, which supported the

work, is available at http://genetics.stanford.edu/.

The Stanford University School of Medicine consistently ranks among the nation's

top 10 medical schools, integrating research, medical education, patient care

and community service. For more news about the school, please visit

http://mednews.stanford.edu. The medical school is part of Stanford Medicine,

which includes Stanford Hospital & Clinics and Lucile Packard Children's

Hospital. For information about all three, please visit

http://stanfordmedicine.org/about/news.html.