First marsupial genome decoded

By Nicole Davis, Communications, May 9th, 2007
Scientists sequence genome of opossum Monodelphis domestica; comparison with human highlights junk DNA as creative force in genome evolution
Photo courtesy of Phil Myers, Museum of Zoology, University of Michigan

The human genome is littered with so-called junk DNA, relics of “jumping genes” that hopped about chromosomes for more than a billion years. Although these jumping genes have been widely regarded as parasites, concerned only with self-propagation, a new study suggests they in fact played a creative role in evolution — spreading key genetic innovations across the genome.

This insight emerges from the work of an international research team led by scientists at the Broad Institute of MIT and Harvard, which announced today the completion of a high-quality genome sequence of the opossum Monodelphis domestica — the first marsupial to have its DNA decoded. Appearing in the May 10 issue of Nature, the findings provide a fresh look at the evolutionary origins of the human genome. They also shed light on the genetic differences between placental mammals (including humans, mouse and dogs) and marsupial mammals, such as opossums and kangaroos.

“Marsupials are the closest living relatives of placental mammals, which include humans,” said senior author Kerstin Lindblad-Toh, the co-director of the Broad Institute’s Genome Sequencing and Analysis Program. “Because of this relationship, the opossum genome offers a unique lens through which to view the evolution of our own genome.”

In the last few years, the functionally important elements of the human genome have been identified through genomic comparisons with other placental mammals. These genetic “working parts” are shared universally across all placental mammals, and therefore must have been present when the creatures arose, about 100 million years ago.

But how did these critical features evolve in the first place?

The scientists knew important clues could be found if they could search the recent past, rather than far-off times in evolutionary history. For this, marsupials held the key. Marsupials are closely related to placental mammals, but the two groups diverged 180 million years ago — well before placental mammals appeared. So, by comparing the opossum and human genomes, the scientists were able to pinpoint the genetic elements that are present in placental mammals but missing from marsupials — that is, the ones that appeared just before the divergence of placental mammals.

Interestingly, about one-fifth of the key functional elements in the human genome arose during this recent evolutionary period. By focusing on these “newer” innovations, the scientists made two remarkable findings:

  • The vast majority (~95%) of recent genetic innovation lies not in protein-coding genes, but rather the regulatory elements that influence genes’ activity. This result implies that mammals have evolved not so much by inventing new kinds of proteins, as by tweaking the molecular controls that dictate when and where proteins are made.
  • Most surprisingly, many of the new DNA instructions are derived from the jumping genes, or “transposons”, which make up our so-called junk DNA. The percentage is at least 16% — and is likely much higher, as many transposon-derived sequences have mutated beyond the point of recognition.

“Transposons have a restless lifestyle, often shuttling themselves from one chromosome to another,” said first author Tarjei Mikkelsen, a Broad Institute researcher and a Harvard-MIT Health Sciences and Technology graduate student. “It is now clear that in their travels, they are disseminating crucial genetic innovations around the genome.”

“Biology depends upon the precise coordination of large sets of genes that are switched on and off together,” said Eric Lander, director of the Broad Institute of MIT and Harvard and an author of the Nature paper. “One of the great mysteries in evolution is how this synchrony arises. These findings suggest a simple answer — genetic controls can evolve in one location in the genome and then be distributed elsewhere by transposons.”

Other important findings to emerge from the analysis of the opossum genome include:

  • the discovery that the opossum has many genes involved in immunity, challenging the notion that marsupials possess only ‘primitive’ immune systems;
  • insights into the evolutionary origins of the random inactivation of one of the two X chromosomes in females, a process unique to placental mammals; and
  • the unusual structure of the opossum genome, which has fewer chromosomes than the human genome (9 pairs versus 23 pairs, respectively) but a longer total length (3.4 billion versus 3 billion bases, respectively). Opossum chromosomes also exhibit distinct genetic compositions from human chromosomes, providing strong support for a recent theory of chromosome evolution.

The sequencing of the M. domestica genome was made possible by a close collaboration with the marsupial research community. In addition to comparative genomics studies, the genome sequence provides a fundamental resource for scientists who study opossums as model organisms, and will help shed light on the unique aspects of marsupial biology. For instance, newborn opossums can repair damage to their spinal cord and thus are the focus of research in regenerative medicine. Opossums are also the only known mammals, other than humans, in which ultraviolet (UV) radiation behaves as a complete carcinogen. Genetic tools may enable deeper insights into the molecular mechanisms of melanoma and other UV-induced cancers, both in opossums and in humans.

Senior author Kerstin Lindblad-Toh led the opossum genome project, working together with first author Tarjei Mikkelsen as well as several other Broad Institute scientists, including Jean Chang, Michele Clamp, April Cook, James Cuff, Manuel Garber, Manfred Grabherr, Michael Kamal, Michael Kleber, Eric Lander, Evan Mauceli, Ted Sharpe, Claire Wade, Xiaohui Xie, Michael Zody, and members of the Genome Sequencing Platform and Whole Genome Assembly team.

Funding and data access

Sequencing of the opossum genome began in 2003, funded by the National Human Genome Research Institute (NHGRI). The Broad Institute is part of NHGRI's Large-Scale Sequencing Research Network. NHGRI is one of 27 institutes and centers at the National Institutes of Health (NIH), an agency of the Department of Health and Human Services. The NHGRI Division of Extramural Research supports grants for research and for training and career development at sites nationwide. Information about NHGRI can be found at: www.genome.gov.

In alignment with the mission of both NHGRI and the Broad Institute, all of these data can be accessed through the following public databases: www.ncbi.nlm.nih.gov, www.ensembl.org, genome.ucsc.edu.

They can also be viewed at the Broad Institute website (www.broad.mit.edu/mammals/opossum/).

Paper cited:

Mikkelsen TS et al. Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences. Nature; DOI:10.1038/nature05805