Friday, 30 January 2015

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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Thursday, 29 January 2015

Mitochondrial Donation: How Many Women Could Benefit?

Two and a Half Thousand Women Could Benefit from Mitochondrial Donation in the UK
Thursday, 29 January 2015

Almost 2,500 women of child-bearing age in the UK are at risk of transmitting mitochondrial disease to their children, according to the most recent estimates published today in the New England Journal of Medicine.

The research offers the most recent evidence yet of how many families could potentially be helped by new IVF techniques to prevent mitochondrial disease, which would be permitted by new regulations on which a vote in parliament is imminent.

Mitochondrial diseases are caused by inherited mutations in the DNA contained in mitochondria - tiny structures present in every cell that generate energy. Mitochondrial diseases can be devastating and particularly affect tissues that have high energy demands - brain, muscle (including heart), liver and kidney.

New IVF-based techniques have been developed which have the potential to prevent the transmission of serious mitochondrial disease. Known as 'mitochondrial donation' the techniques involve removing faulty mitochondria inherited from the mother and replacing them with the healthy mitochondria of another woman. The nuclear DNA, containing 99.9% of genetic material from the mother and father, remains unchanged.

Researchers at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, which will be the first to offer mitochondrial donation if parliament agrees to new regulations of the Human Fertilisation and Embryology Act (1990), have now calculated how many women have disease-causing mutations in their mitochondrial DNA in order to estimate how many could potentially benefit. The new regulations only allow for mitochondrial donation to prevent mitochondrial disease and set no precedent for genetic manipulation of nuclear DNA.

They calculate that 2,473 women in the UK, and 12,423 women in the US, aged between 15 and 44 years, are at risk of passing on potentially lethal mitochondrial DNA disease to their children. This equates to an average of 152 births per year in the UK, and 778 births per year in the US.

The estimates were made by identifying the number of women in North East England who are at risk of passing on mitochondrial disease to their children and extrapolating the figure to the rest of the UK, based on the relative number of women of child-bearing age in the North East compared to the UK as a whole. A similar method was used for the US figures. The study did not account for variance due to ethnicity or potentially different fertility rates in different parts of the UK.

Researchers also assessed the fertility of women with mitochondrial DNA mutations. To do this they compared fertility data from their patients' to data about the general population, obtained from the UK Office for National Statistics. They found that mitochondrial mutation has no statistically significant effect on fertility rate.

Dr GrĂ¡inne Gorman from the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, and joint first author of the paper, said:

"Our estimate of how many women could benefit from mitochondrial donation is based on our data from North East England, where we have very detailed insight into how many women are affected. We are confident that there are a similar number of women across the UK at risk of passing on mitochondrial disease to their children."

Professor Doug Turnbull, Director of the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, and an author of the paper, said:

"Our findings have considerable implications for all countries that are considering allowing mitochondrial donation techniques. In the UK we are waiting for parliament to decide whether to support these regulations. This would allow women who carry these mutations greater reproductive choice. "

Source: Wellcome Trust 
Contact: Clare Ryan 

Reference:
Mitochondrial Donation: How many women could benefit? 
GrĂ¡inne S. Gorman, John P. Grady, Yi Ng, Andrew M. Schaefer, Richard J. McNally, Patrick F. Chinnery, Patrick Yu Wai Man, Mary Herbert, Robert W. Taylor, Robert McFarland, and Doug M. Turnbull
New England Journal of Medicine, January 28, 2015 DOI: 10.1056/NEJMc1500960
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New Cells May Help Treat Diabetes

U. Iowa group creates insulin-producing cells that normalize blood-sugar levels in diabetic mice
Thursday, 29 January 2015

University of Iowa researchers reprogrammed
human skin cells to create induced pluripotent
stem cells, which were then differentiated in a
stepwise fashion to create insulin-producing cells.
When these cells were transplanted into diabetic
mice, the cells secreted insulin and reduced the
blood sugar levels of the mice to normal or near-
normal levels. The image shows the insulin-
producing cells (right) and precursor cells (left).
Credit: University of Iowa.
Starting from human skin cells, researchers at the University of Iowa have created human insulin-producing cells that respond to glucose and correct blood-sugar levels in diabetic mice. The findings may represent a first step toward developing patient-specific cell replacement therapy for type 1 diabetes.

In the new study, published Jan. 28 in the journal PLOS ONE, the UI team led by Nicholas Zavazava, MD, PhD, UI professor of internal medicine, reprogrammed human skin cells to create induced pluripotent stem (iPS) cells, which were then coaxed into forming insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels.

Although the cells were not as effective as pancreatic cells in controlling blood sugar levels, Zavazava says that the results are an "encouraging first step" toward the goal of generating effective insulin-producing cells that can be used to potentially cure type 1 diabetes.

"This raises the possibility that we could treat patients with diabetes with their own cells," says Zavazava, who also is a member of the Fraternal Order of Eagles Diabetes Research Center at the UI.

"That would be a major advance, which will accelerate treatment of diabetes."

In type 1 diabetes, a person's immune system attacks and destroys the pancreatic beta cells that produce insulin. Although it is possible to treat type 1 diabetes with pancreas transplants from deceased donors, the demand for transplants far exceeds the availability of donated organs.

Zavazava's team is among several groups aiming to create an alternative source of insulin-producing pancreatic cells that can be transplanted into patients with type 1 diabetes. However, the UI study is the first to use human iPS cells to create the insulin-producing cells. Creating these cells from a patient's own cells would not only eliminate the need to wait for a donor pancreas, but would also mean patients could receive transplants without needing to take immunosuppressive drugs. Using iPS cells rather than embryonic stem cells as a starting point also avoids the ethical concerns some people have with using embryonic stem cells.

In the mouse study, the insulin-producing cells were placed under the kidney capsule - a thin membrane layer that surrounds the kidney - where they developed into an organ-like structure with its own blood supply. This new "organ" secreted insulin and gradually corrected the blood sugar levels in the diabetic mice over a period of several months. In addition, after the mice became normoglycemic, the glucose levels stayed steady.

By developing the cells in a stepwise fashion, the UI team was able to collect and use only those cells that would develop into pancreatic cells. This meant they were able to remove very immature (undifferentiated) cells that could form tumours. None of the mice developed tumours from the transplanted cells.

Contact: Jennifer Brown

Reference:
Human iPS Cell-Derived Insulin Producing Cells Form Vascularized Organoids under the Kidney Capsules of Diabetic Mice
Raikwar SP, Kim E-M, Sivitz WI, Allamargot C, Thedens DR and Nicholas Zavazava
PLoS ONE 10(1): e0116582 (2015), doi:10.1371/journal.pone.0116582
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