October 28, 2005
Evidence For More Genetic Large Structural Variations Between Humans

A comparison of human and chimpanzee DNA sequences for large structural variations such as inversions (flips) has led to the discovery of more genetic variations between humans than were previously known.

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.


The researchers published their findings in the October 28, 2005, issue of the journal Public Library of Science Genetics (PLoS Genetics).

That previous link is free access.

This paper provides yet more evidence that the early focus on single point mutations (Single Nucleotide Polymorphisms or SNPs) as a measure of genetic variation between humans has understated the extent to which humans differ from each other genetically.

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.

The genetic sequence inversions found in humans are not found uniformly across all humans.

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 Williams-Beuren syndrome, a disease caused by DNA micro-deletions, identified a significantly higher incidence of inversions among the parents of afflicted patients.

Because of the small human population used for comparison by these researchers many more structural variation polymorphisms in humans were probably missed in this report.

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.

We need DNA testing methods for easily and cheaply detecting large copy variations, inversions, and other large structural variations. It is obviously not enough just to compare single point mutations as the HapMap project is doing. Lots of important genetic variations exist as larger structural differences. While most of the SNP differences have been identified most of the large structural variations probably still wait discovery.

Also see my recent posts "Human Genetic HapMap Phase I Published" and "Genetic Analysis Shows Signs Of Selective Pressure In Human Evolution".

Share |      Randall Parker, 2005 October 28 12:30 PM  Trends, Human Evolution

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