Summary: Scientists show that vertebrate-specific globins originated in two rounds of genome duplication.

We vertebrates work for our O2. Whether we’re a fish or antelope, we all have gills and lungs to filter oxygen out of air or water. We also have beating hearts to transport oxygen-rich blood to the most distant corners of our bodies. But not the lancelet. This little fishlike creature breathes directly through its skin. The lancelet does have gills, but it only uses them to filter food particles from the water, not oxygen. It doesn’t even have a heart to direct the flow of its blood.

The way vertebrates and lancelets handle oxygen also differs on a molecular scale. We vertebrates have evolved a whole suite of proteins for carrying and storing oxygen that the lancelets lack. The most well-known member of these proteins is hemoglobin, which makes up 95% our red blood cells. Hemoglobin is a perfect oxygen transporter. It takes up oxygen where its concentration is high (lungs) and releases it where concentrations are low (muscles and other organs). We also have globins that specialize in storing oxygen, such as myoglobin our muscles and cytoglobin in our brains.

The lancelet has neither heart nor hemoglobin.

The origins of all these oxygen-manipulating tools can be traced back to a dramatic event in our evolution. Almost half a billion years ago, not long after the lancelet and vertebrate lineage had parted ways, the entire genome of the vertebrate ancestor was carbon copied by accident. Twice. Our distant ancestor thus had four times as many genes as before. This opened up evolutionary pathways that were closed before. How so? Imagine your Lego collection quadrupled in size. Not only can you now build a larger castle, the extra bricks also bring added flexibility. You can combine them in new ways, while leaving the core of the castle intact. It’s much the same for duplicated genes. Their redundancy allows them to specialize, divide labour and evolve new functions.

In a paper that was published last month, scientists show that our globin genes were born from these two rounds of genome duplication. The team, lead by Jay Storz from the University of Nebraska, first retrieved all the globin sequences of lancelets, sea squirts and fifteen different vertebrates (birds, lizards, fish and mammals) and determined the evolutionary relationships between them.

They found that all vertebrate globins occupied four branches in the globin family tree. They were myoglobin, cytoglobin, hemoglobin and GbY, a globin that has only been found in reptiles and the platypus. These four lineages corresponded to a single lineage of lancelet globins. While such as a 4:1 distribution fits the double genome duplication scenario, the history turned out to be a bit more complex.

The genetic neighbourhoods of the three globins are similar - not identical.

Storz and his colleagues reasoned that if the four globin lineages really arose through genome duplications, their genetic neighbourhoods should look alike. After all, all the genes of our ancestor were copied in one go. As genes tend to retain their relative positions over time, the genetic neighbours of the copied globins families should be similar. Of course they won’t be identical after 500 million years of evolution. Genes are lost, gained and reshuffled all the time time. Nevertheless, the ‘neighborhood signal’ (geneticists call it synteny) is a strong one, and should still be recognizable millions of years later.

The team found three of these globin-containing neighbourhoods, spread out over different chromosomes. They dubbed them Mb (myoglobin), Cygb (cytoglobin) and Hb (hemoglobin). GbY turned out to be a more recent addition to the hemoglobin family rather than the fourth globin type. The researchers discovered that this fourth globin was missing altogether. Its former neighbours are still there, on our nineteenth chromosome, but the globin itself went extinct a long time ago. For want of a globin, the researchers named this region Gb-.

The researchers show how the initial duplication produced the Mb/Cygb and a Hb/Gb- cluster. This is an interesting split, as the proto-hemoglobins (the blood globin) evolved to become oxygen transporters while myo- and cytoglobin (the muscle and brain globin) became oxygen storage proteins. The authors write that “the first round of WGD may have initially set the stage for the physiological division of labor between the evolutionary forerunners of [myoglobin] and [hemoglobin] by permitting divergence in the tissue specificity of gene expression.” In other words, it was the genome duplication that allowed these globins to evolve specific functions in separate tissues.

After 500 million years of evolution, lancelets are small, mud-dwelling filter feeders. We vertebrates have evolved into free-roaming grazers, predators and 180 tonne heavy filter feeders. It’s thanks to the combined evolution of a complex circulatory system (our hearts and gills/lungs) and an elaborate oxygen transport system (the globin family) allowed our ancestors to become larger and live a more active lifestyle than our distant cousins. Hemoglobin is the key to a healthy heartbeat indeed.

Heart by Kris Gabbard.
Genetic neighborhoods from reference.

Hoffmann FG, Opazo JC, & Storz JF (2011). Whole-Genome Duplications Spurred the Functional Diversification of the Globin Gene Superfamily in Vertebrates. Molecular biology and evolution PMID: 21965344