Flipped genetic sequences illuminate human evolution and disease

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Flipped genetic sequences illuminate human evolution and disease

http://www.medicalnewstoday.com/medicalnews.php?newsid=32706

By comparing the human genome with that of the chimpanzee, man's

closest living relative, researchers have discovered that chunks of

similar DNA that have been flipped in orientation and reinserted into

chromosomes are hundreds of times more common in primates than

previously thought. These large structural changes in the genome,

called inversions, may account for much of the evolutionary

difference between the two species. They may also shed light on

genetic changes that lead to human diseases.

Although humans and chimpanzees diverged from one another genetically

about six million years ago, the DNA sequences of the two species are

approximately 98 percent identical. Given the 2005 publication of the

draft chimpanzee genome sequence, researchers can now readily

identify the differences between the human and chimp genomes. These

differences lend insight into how primates evolved, including traits

specific to humans.

The researchers published their findings in the October 28, 2005,

issue of the journal Public Library of Science Genetics (PLoS

Genetics). The paper was published early online. Senior author

W. Scherer is a HHMI international research scholar, a senior

scientist in the Genetics and Genomic Biology Program at the Hospital

for Sick Children in Toronto, Canada, and an associate professor of

molecular and medical genetics at the University of Toronto.

This research expands on a Nature paper published on September 1,

2005, by HHMI investigator Evan E. Eichler at the University of

Washington. Eichler's group determined that novel duplications of

genetic material within humans also significantly contribute to

differences between the species.

Instead of identifying sequence changes between the two genomes at

the base-pair level, Scherer focused his research on large structural

variations in chromosomes between humans and chimps, specifically

genetic inversions. Inversions can disrupt the expression of genes at

the point where the chromosome breaks, as well as genes adjacent to

breakpoints. " From a medical genetics perspective, there are probably

hundreds of disease genes that have not yet been characterized, " said

Scherer. " The vast majority of disease gene discovery has been based

on gene sequencing, but this is not a comprehensive view of

chromosomes. We are using an evolutionary approach to identify

mutations that may predispose people to disease. "

According to Scherer, prior to this research, only nine inversions

between humans and chimps had been identified. Using a computational

approach, Scherer's group identified 1,576 presumed inversions

between the two species, 33 of which span regions larger than 100,000

base pairs--a sizeable chunk of DNA. The average human gene is

smaller, only about 60,000 bases in length.

Scherer's team experimentally confirmed 23 out of 27 inversions

tested so far. Moreover, by comparing the chimp genome with its

ancestor, the gorilla genome, they determined that more than half of

the validated inversions flipped sometime during human evolution.

Perhaps even more interesting than the abundance of inversions that

Scherer's group unveiled was their discovery that a subset of the

inversions are polymorphic--taking different forms--within humans,

meaning that the human genome is still evolving. When the 23

experimentally confirmed inversions were tested against a panel of

human samples, the scientists found three inversions with two alleles

or pairs of genes displaying the human inversion in some people,

whereas others had one allele of the human inverted sequence and one

allele of the normal sequence in chimps.

Having one allele with an inversion and one allele without represents

a ticking time bomb in genetic terms, Scherer said, since these

alleles may improperly align and recombine during replication,

ultimately causing DNA deletions or a loss of DNA that subsequent

generations inherit. Scherer's prior research on -Beuren

syndrome, a disease caused by DNA micro-deletions, identified a

significantly higher incidence of inversions among the parents of

afflicted patients.

Interestingly, one of the inversions that Scherer identified as

polymorphic in his current paper includes a gene known to be involved

in colorectal cancer. Whether individuals polymorphic for this

inversion are at increased risk for the development of colorectal

cancer is not yet known.

Scherer said that his group looked at only a very small subset of the

human population when assessing the prevalence of polymorphisms. He

suspects that polymorphisms, and structural variations in general,

may be much more common than his preliminary analyses suggest.

" These findings may cause people to rethink their ideas about how

species evolved, " Scherer said. " They also highlight how the

mechanisms of evolution may be associated with disease. "

Scherer determined that about 10 percent of the presumed inversions

either contain a complete gene within the flipped region, constitute

a flipped region within a gene, or cause a breakpoint somewhere

within a gene. These inversions represent prime targets for disease

gene discovery, which Scherer's team is exploring further.