Researchers Study Evolutionary Factors of Genome-Wide Nucleotide Composition

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA.

The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people.

The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences.

DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix.

And one of the long-standing mysteries of evolutionary genomics is the source of the wide phylogenetic diversity in genome nucleotide composition (G + C versus

A + T), which must be a consequence of interspecific differences in mutation bias, the efficiency of selection for different nucleotides or a combination of the two.

Scientists at the Arizona State University’s Biodesign Institute led by  Michael Lynch, have now demonstrated that G+C composition is generally strongly favored, whereas this is often opposed by a mutational pressure of various strengths in the opposite direction.

On average, natural selection or some other factor (possibly associated with recombinational forces)  favors G+C content, regardless of the class of DNA, size of a species’ genome, or where the species is found on the evolutionary tree of life,” said Lynch.

We started with knowledge of the mutational spectrum that occurs at the genome level in about 40 species examined in my lab,” said Lynch. “You can use such information to calculate what the GC composition would be in the absence of selection. And then we can compare this null expectation with the actual genome content, the difference being due to selection.

This particular experiment, is the largest survey to date, as the team examined every single DNA mutation across different species, sequencing billions of DNA chemical bases. “This represented a very substantial workload, effort and cost that was necessary to test different evolutionary models with high statistical power,” said Hongan Long, a postdoctoral researcher who led the experiments.

Additionally, they also took advantage of an analysis of 25 current datasets of mutations and 12 new mutation-accumulation (MA) experiments (many from their own lab), including bacteria and a menagerie of multicellular organisms including yeast, worms, fruit flies, chimpanzees and humans.

During each MA experiment, they performed complete genome sequencing of about 50 different bacterial lines that had been passaged through severe, single-cell bottlenecks for thousands of cell divisions.

This single-cell passage of each line acts like a filter, eliminating the ability of natural selection to modify the accumulation of all but the most severe and deleterious mutations, giving us an effectively unbiased view of the mutation process,” said Long.

After much data crunching the team obtained a striking pattern between G+C content and the expectations based on DNA mutations. “It turns out, they are correlated,” said Lynch. “The G+C composition is always higher than you expect, based on neutrality. That tells us that there is pervasive selection. So mutation drives the overall pattern, but selection for G’s and C’s over A’s and T’s boosts the genome content above the neutral mutational expectation. This seems to be almost universally true.

One question is, ‘why does the mutation spectrum change so dramatically across species’”? asked Lynch. “Species don’t have the same mutation spectrum. There are species whose mutation profiles are more AT-rich and others more GC rich. We still don’t know the mechanisms behind such divergence in the mutational spectrum.

Now, with their experimental setup in place, Lynch’s team is poised to further explore the mechanisms of evolution and fundamental forces behind this great mystery.

Disha Padmanabha
In search of the perfect burger. Serial eater. In her spare time, practises her "Vader Voice". Passionate about dance. Real Weird.