Why is a Dolphin Not a Cat?

How repurposing non-coding elements in the genome gave rise to the great 'mammalian radiation'

Friday, 30 January 2015

Exploring gene regulation in 20 mammals

provides insights into the mammalian radiation

that occurred over 100 million years ago. Credit:

Spencer Phillips, EMBL-EBI.

New research shows how evolution has given rise to a rich diversity of species by repurposing functional elements shared by all mammals. Published in Cell by scientists at the European Bioinformatics Institute (EMBL-EBI) and the University of Cambridge Cancer Research UK-Cambridge Institute (CRUK CI), the study demonstrates how methods for understanding human biology can be used to understand a broad range of species.

Mammals all share a common ancestor, and they share a lot of the same genes. So what exactly makes a dolphin not a cat, and how did we all start to diverge from one another millions of years ago? Part of the answer lies in how - and when - genes are regulated. This latest research explores the evolution of gene regulation in 20 mammalian species, and provides deep insights into the 'mammalian radiation', a time of rapid morphological evolution that occurred shortly after the asteroid impact that caused the extinction of the dinosaurs.

Leveraging findings from a study comparing the genome sequences of 29 mammals, and with the help of conservation organisations such as the UK Cetacean Strandings Investigation Programme and the Copenhagen Zoo, the team were able to study and compare gene regulation in liver cells from 20 key species including the naked mole rat, human, Tasmanian devil, dolphin and Sei whale.

"What we've shown is that evolution repurposes things that exist in all species, to make each species unique," explains Paul Flicek, head of Vertebrate Genomics at EMBL-EBI.

"By looking at gene promoters and enhancers in many different mammals, we demonstrated that species-specific enhancers come from ancient DNA - that evolution captures DNA that's been around for a long time, and uses it for gene regulation in specific tissues."

Evolution has two ways to turn changes in the genome into differences between species: it can change a protein sequence, or it can change the way promoters or enhancers control that protein's expression. Today's study also shows that in some cases evolution uses both strategies at once. When amino acid sequences evolve very quickly, important regulation changes occur at the same time: the protein-coding sequence and the corresponding regulatory sequence change synergistically.

Gathering the samples - the experimental efforts were led by Diego Villar of CRUK CI - took well over two years, and the experiments themselves produced a staggering volume of data. Analysing the results brought the team to a new frontier in bioinformatics.

"People spend a lot of time and money trying to understand human biology, so most of the tools we have are designed to study human genomes," explains Camille Berthelot of EMBL-EBI, who led the computational work.

"The reference data we have for the less studied species, like the Sei whale or Tasmanian devil, are nothing like the pored-over datasets we have for the human genome. A lot of what we did involved benchmarking, and making sure the methods and algorithms were fit for this kind of comparison."

"What inspired this work was a desire to get on top of the mountain, look out and see what is going on in the landscape of molecular evolution across the breadth of mammalian space," says Duncan Odom of CRUK CI and Wellcome Trust Sanger Institute.

"What's exciting about this study is that we now know we can start to answer questions about the functional genetics of many under-explored species - questions we usually can ask only of humans and mice. We can use tools developed to study humans to understand the biology of all kinds of animals, whether they're blackbirds or elephants, and explore their relationship with one another. This research has given us new insights into mammalian evolution, and proven how powerful these methods can be."

Source: EMBL

Contact: Mary Todd Bergman

Reference:

Enhancer Evolution across 20 Mammalian Species

Diego Villar, Camille Berthelot, Sarah Aldridge, Tim F. Rayner, Margus Lukk, Miguel Pignatelli, Thomas J. Park, Robert Deaville, Jonathan T. Erichsen, Anna J. Jasinska, James M.A. Turner, Mads F. Bertelsen, Elizabeth P. Murchison, Paul Flicek, Duncan T. Odom

Cell, Volume 160, Issue 3, p554–566, 29 January 2015, DOI: http://dx.doi.org/10.1016/j.cell.2015.01.006

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ZenMaster

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Is A Universal Bird Flu Vaccine Achievable?

H9N2 virus ‘core’ bird flu vaccine protects both people and pets Monday, 20 October 2008 A single vaccine could be used to protect chickens, cats and humans against deadly flu pandemics, according to an article published in the November issue of the Journal of General Virology. The vaccine protects birds and mammals against different flu strains and can even be given to birds while they are still in their eggs, allowing the mass vaccination of wild birds. The emergence of bird flu has posed a major challenge to scientists designing vaccines as it can infect a number of different animals, including birds, pets and people. Now, researchers in the USA have discovered that a vaccine based on a bird flu virus could be used to protect several species against different influenza viruses. "The world is experiencing a pandemic of influenza in birds caused by an H5N1 virus. Although it has been restricted to Eurasia and some countries in Africa, there is a risk that this virus may spread worldwide," said Professor Daniel Perez from the University of Maryland, USA. "The H5N1 virus also has an unusual expanded host range: not only birds and humans have been infected but also cats, which are usually resistant to influenza. To prepare for a pandemic, it would be ideal to have a vaccine that could be used in multiple animal species." The researchers found that the central genes or 'backbone' of the H9N2 virus that infects guinea fowl can protect birds and mice against highly pathogenic strains of influenza. They modified the virus to make it less pathogenic and then used it to vaccinate mice. Three weeks after being vaccinated, the mice were infected with the potentially lethal H1N1 virus – the same virus that caused the 1918 Spanish flu pandemic. All the vaccinated mice survived with no signs of disease. Vaccinated mice also survived infection with the deadly H5N1 bird flu virus, again showing no signs of disease. "Our results show that the H9N2 backbone vaccine can be used to protect mice against two different, highly pathogenic strains of influenza. We chose genes from H9N2 influenza for the vaccine because the virus can infect many different animals, including chickens, mice and pigs," said Professor Perez. "A very important limitation in the current design of flu vaccines is that they are usually species specific. Our approach involves a universal backbone that can be used in several different species, including humans." More importantly, this live attenuated virus provided effective protection when it was administered to birds before they had hatched. By vaccinating eggs against influenza, we could protect wild bird species as well as domestic chickens against pandemic flu strains, limiting the spread of disease to humans. "If an emerging strain of bird flu spreads among a broad range of animal species, we should expect major health, economic and ecological consequences," said Professor Perez. "It is unrealistic to consider preparing different vaccines specifically tailored to different animal species in this situation. An influenza vaccine that could protect different species would save valuable time during a pandemic." ......... ZenMaster

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Cat Genome Sequenced

Domestic cat genome sequenced Wednesday, 31 October 2007 A report that appears in the scientific journal Genome Research details the first assembly, annotation, and comparative analysis of the domestic cat genome (Felis catus). The DNA of a 4-year-old Abyssinian cat named Cinnamon, whose well-documented lineage can be traced back several generations to Sweden, has been sequenced. Cinnamon is one of several mammals that are currently being analyzed using “light” (two-fold) genome sequence coverage. To make sense of Cinnamon’s raw sequence data, a multi-centre collaboration of scientists leveraged information from previously sequenced mammalian genomes as well as previous gene-mapping studies in the cat. In doing so, they found that Cinnamon’s sequences spanned about 65% of the euchromatic (gene-containing) regions of the feline genome. Cinnamon DNA was sequenced about 1.9 times the length of her 2.7 billion base-pair genome. For comparison, the human genome was sequenced seven times over, and the dog’s seven and a half times. The data is presnted at the Garfield Project. The similarity between the cat genome and six recently completed mammalian genomes (human, chimpanzee, mouse, rat, dog, and cow) allowed the scientists to identify 20,285 putative genes in the cat genome. The comparison also revealed hundreds of chromosomal rearrangements that have occurred among the different lineages of mammals since they diverged from a diminutive ancestor that roamed the earth among the dinosaurs some 100 million years ago. The genome sequence analysis is certainly expected to lead to health benefits for domestic cats. But the domestic cat also serves as an excellent model for human disease, which is one reason why the National Human Genome Research Institute (NHGRI) initially authorized the Cat Genome Sequencing Project three years ago. Domestic cats possess over 250 naturally occurring hereditary disorders, many of which are similar to genetic pathologies in humans. Cats areoften used as a model to study conditions such as heart disease, blindness or HIV. For example, Cinnamon’s pedigree carries a genetic mutation that causes retinitis pigmentosa, a degenerative eye disease that can lead to blindness. In humans, retinitis pigmentosa affects 1 in 3,500 Americans. The domestic cat also serves as an excellent model for human infectious diseases, including HIV/AIDS. Feline immunodeficiency virus (FIV) is a genetic relative of human immunodeficiency virus (HIV), which causes AIDS. Using the cat genome sequence data, the researchers identified 327,000 single letter differences (known as SNPs, DIPs, and STRs), which can be used to determine the genetic basis for common hereditary diseases. The scientists have already used these variants to identify the causative gene for Cinnamon’s retinitis pigmentosa (they published a paper describing this study in the May/June, 2007 issue of the Journal of Heredity). These variants will also be useful for parentage testing, forensic analysis, and studies of evolution, including the reconstruction of domestication processes, fancy breed development, and ecological adaptation among the great roaring cats. The researchers also analyzed the feline genome for interesting features such as microRNAs, Numts (pronounced “new mights” — nuclear genomic fragments that migrated to cat chromosomes from mitochondria), and a vast sea of selfish DNA-like repetitive elements. The repetitive elements included scores of genomic stretches from historic retroviruses, some with known links to cancer. References Pontius, J. U. et al . Genome Res. 17, 1675–1689 (2007). ......... ZenMaster

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