Genetic Variation: We're More Different Than We Thought

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Genetic Variation: We're More Different Than We Thought

http://www.sciencedaily.com/releases/2006/11/061123115741.htm

New research shows that at least 10 percent of genes in the human

population can vary in the number of copies of DNA sequences they

contain--a finding that alters current thinking that the DNA of any

two humans is 99.9 percent similar in content and identity.

This discovery of the extent of genetic variation, by

Medical Institute (HHMI) international research scholar W.

Scherer, and colleagues, is expected to change the way researchers

think about genetic diseases and human evolution.

Genes usually occur in two copies, one inherited from each parent.

Scherer and colleagues found approximately 2,900 genes--more than 10

percent of the genes in the human genome--with variations in the

number of copies of specific DNA segments. These differences in copy

number can influence gene activity and ultimately an organism's

function.

To get a better picture of exactly how important this type of

variation is for human evolution and disease, Scherer's team

compared DNA from 270 people with Asian, African, or European

ancestry that had been compiled in the HapMap collection and

previously used to map the single nucleotide changes in the human

genome. Scherer's team mapped the number of duplicated or deleted

genes, which they call copy number variations (CNVs). They reported

their findings in the November 23, 2006, issue of the journal

Nature.

Scherer, a geneticist at the Hospital for Sick Children and the

University of Toronto, and colleagues searched for CNVs using

microarray-based genome scanning techniques capable of finding

changes at least 1,000 bases (nucleotides) long. A base, or

nucleotide, is the fundamental building block of DNA. They found an

average of 70 CNVs averaging 250,000 nucleotides in size in each DNA

sample. In all, the group identified 1,447 different CNVs that

collectively covered about 12 percent of the human genome and six to

19 percent of any given chromosome--far more widespread than

previously thought.

Not only were the changes common, they also were large. " We'd find

missing pieces of DNA, some a million or so nucleotides long, "

Scherer said. " We used to think that if you had big changes like

this, then they must be involved in disease. But we are showing that

we can all have these changes. "

The group found nearly 16 percent of known disease-related genes in

the CNVs, including genes involved in rare genetic disorders such as

Di, Angelman, -Beuren, and Prader-Willi syndromes, as

well as those linked with schizophrenia, cataracts, spinal muscular

atrophy, and atherosclerosis.

In related research published November 23, 2006, in an advance

online publication in Nature Genetics, Scherer and colleagues also

compared the two human genome maps--one assembled by Celera

Genomics, Inc., and one from the public Human Genome Project. They

found thousands of differences.

" Other people have [compared the two human genome sequences], "

Scherer said, " but they found so many differences that they mostly

attributed the results to error. They couldn't believe the

alterations they found might be variants between the sources of DNA

being analyzed. "

A lot of the differences are indeed real, and they raise a red flag,

he said.

Personalized genome sequencing--for individualized diagnosis,

treatment, and prevention of disease--is not far off, Scherer

pointed out. " The idea [behind comparing the human genome sequences]

was to come up with a good understanding of what we're going to get

when we do [personalized sequencing], " he explained. " This paper

helps us think about how complex it will be. "

In a " News and Views " article in the same issue of Nature, HHMI

professor Huntington F. Willard writes, " the stage is set for global

studies to explore anew...the clinical significance of human

variation. " Willard is director of the Institute for Genome and

Science Policy at Duke University.

To fully extract meaningful data using the human genome maps,

researchers must know what's missing and how much variation exists,

Scherer said. " Our computer algorithms are smart, but it is hard to

find something if it is not there in the reference you are comparing

against. "

In fact, Scherer's group found some 30 million nucleotides that are

seemingly not yet represented at all, or in different copy numbers

or orientations, when comparing the Celera assembly to the public

human genome sequence. The entire human genome is thought to contain

about 3 billion nucleotides.

The discovery of an abundance of DNA variation puts a whole new spin

on the study of genetic disease. Most research has focused on small

alterations, called single nucleotide polymorphisms (SNPs). It may

be, said Scherer, that some diseases are caused by copy number

variations rather than SNPs. In fact, recent research has already

linked such variations to kidney disease, Parkinson's disease,

Alzheimer's disease, and AIDS susceptibility.

The discovery also provides a new outlook on evolution.

" Until now, our focus has been on examining evolution through either

small SNP changes or larger chromosomal alterations you can see

under the microscope, because that's what we could detect, " Scherer

said. " But now there's a whole new class of mid-sized variants

encompassing millions of nucleotides of DNA to consider. "

This change in the way scientists think about human genetics is

exciting, but it is still very early to know what all this means,

said Scherer. " Though it does make you wonder, he added. " If you

have 1 million fewer nucleotides than your buddy, shouldn't you get

a break on your golf handicap? "