Decoding of DNA may unlock the hidden medical histories of Irish lives

The decoding of the first Irish genome represents a significant advance in the quest to understand the link between genetic variation and disease susceptibility on this island.

This places the Irish genetic code in the public domain for the first time and permits it to be compared with mappings of the codes of other population groups.

This is important as it is only by comparing the genome with other sequences that scientists can hope to isolate a specific “Irish genetic signature”, and to understand the genetic basis of our susceptibility to certain diseases.

A principal reason for sequencing Irish DNA was that it was not represented in any of the large genomic studies under way, explained the Irish project’s originator Prof Brendan Loftus of University College Dublin’s Conway Institute.

“Certain gene variants can become locked in a population due to factors like geography. Irish people’s genes mirror the island’s peripheral location in Europe, which makes it an interesting subgroup to sequence,” Prof Loftus said.

“Some 13 per cent of the variation we uncovered has not been seen before. It’s likely that some of that variation is specific to the individual and some is more diagnostic of him being Irish. We will only find out which is which over time.”

A Mayo-born graduate of Dublin City University, Prof Loftus spent the 1990s working in the US under the well-known Craig Venter, collaborator on the first human genome sequencing project completed in 2003 at a cost of €2.7 billion.

In contrast with the original human genome project, the Irish project was carried out with the resources of a small lab over about 13 months and at a cost of €30,000.

Prof Loftus said the project illustrated how rapidly the accumulation of genomic information on a population level can be generated.

But he acknowledged that while the capacity to generate the sequence data is proceeding at pace, the rate at which the data can be reliably interpreted has lagged behind.

One area where genetic sequencing is likely to play a major role is in patient response to medication.

“The majority of blockbuster drugs, from aspirin to cancer medication, don’t appear to work on significant sections of the population,” said Prof Loftus.

“There is a big thrust in the medical community towards personalising medicine and nutrition because people respond in different ways to the same product.

“And one of the most likely reasons for this is their genetic background. The drug companies are interested to see who these people are, and to find out if they will respond to variations of the existing drug compounds.”

Since the first human sequence was generated in the US in 2003, between 20 and 30 full human genome sequences have been published.

However, the rapid acceleration in DNA sequencing technology in recent years has seen a proliferation of projects, with more than 100 separate projects in progress.With the cost of sequencing dropping all the time, experts maintain it won’t be long before people will be carrying around parts of their genome on a USB key.

US company 23andMe, established by Anne Wojcicki – wife of Google founder Sergey Brin – already offers to sequence portions of the genome using a sample of saliva, for as little as $350.

Dr Gerard Cagney, principal investigator in functional genomics at the Conway Institute, said representative species from all branches of the tree of life – bacteria, fungi and plants, along with animals ranging from worms to insects and from fish to monkeys – are now being sequenced daily.

“Nevertheless, the technical difficulty associated with sequencing a small virus like HIV, containing some 9,000 units of DNA, pales in significance next to the challenge of sequencing a human genome, composed of more than three billion units.

“The problem is compounded by the fact that the entire sequence is assembled from short individual sequence fragments – typically less than 200 units – so the final product is similar to piecing together a huge jigsaw puzzle, and requires the work of computer scientists and statisticians,” Dr Cagney said.

“There are also large regions of repeated sequence in human genomes and their biological significance is still not fully understood.

“The sequencing process therefore relies partly on comparison with other known sequences, and it is for this reason that reading an Irish genome is significant.

“It can be used to place Irish genes in the context of worldwide human genome diversity.”

Genetic factors in breast cancer risk prediction

Breast cancer is now the most common cancer in the UK (see CRUK website). However, thanks to extensive research and improved management, survival rates for breast cancer have been improving for thirty years. Ongoing research is aiming to identify ways of reducing the incidence of breast cancer by improved prevention, as well as to understand the complex biological disease pathways in order to develop new treatments. Sporadic breast cancer is a complex disease associated with both genetic and environmental risk factors. There are now about 20 genetic variants known to be linked to disease susceptibility and more are being identified. Whilst the risk conferred by each is typically small, in combination there may be potential to use these markers to improve risk prediction.


A new study evaluates risk associated with 14 breast cancer risk variants (SNPs), alone or in combination, for half a dozen cancer subtypes [Reeves et al. (2010) JAMA 304(4):426-434], to look at how individual variants and polygenetic risk models correspond to breast cancer risk and subtype. This large prospective study used more than ten thousand women with breast cancer and about as many healthy controls without breast cancer. The scientists used meta-analysis of results from the study as well as of other studies. The analyses of the results suggested that SNPs in the FGFR1 and TNRC9 genes, as well as a third SNP on chromosome 2, were most closely tied to overall breast cancer risk, and that risk prediction was most reliable for oestrogen receptor (ER) positive cancers and lower grade tumours.

The researchers also developed polygenic risk models using combined data on four, seven, or 10 of the SNPs that were most strongly associated with breast cancer. They concluded that women under 70 years of age with the highest polygenic risk scores have an estimated breast cancer risk of 8.8% compared with a risk of 4.4% in women with the lowest polygenic scores. They also found that the polygenic risk score was substantially more predictive for ER-positive cancers (ranging from a high of 7.4% to a low of 3.4%) than ER-negative breast cancers (a range of just 1.4% to 1.0%).

This is an important study which evaluates the predictive value of selected genetic markers identified by different studies and finds that it varies for different tumour subtypes. However, the authors caution that whilst their findings are potentially useful for understanding disease mechanisms, they would not be useful for individual breast cancer risk prediction or population stratification as known risk factors for breast cancer such as family history are more predictive. Nevertheless, this is an interesting line of enquiry and it may be that ultimately the combination of established and novel environmental and genetic risk factors could refine risk prediction for targeted population screening.

Ancient iceman's gene map underway

Otzi, the 5,000-year-old frozen mummy, undergoes modern genetic mapping this year, an international team announced Tuesday.

Members of the team that recently completed gene maps of Egyptian pharaoh King Tutankhamun's family will join with gene sequencing expert Andreas Keller to create a biomedical gene map of the famous iceman, discovered by Alpine hikers in 1991, linking his lineage to diseases and cell biology.

"We are dealing here with old DNA which in addition is heavily fragmented", says Albert Zink of the EURAC Institute for Mummies, in a statement. "It was only by using the very latest technology with its low failure rate that we scientists were able to decode Ötzi's DNA in its entirety within this short space of time."

A look at Otzi's maternal DNA in a 2008 Current Biology report found no links between the iceman, killed by flint arrowhead fired into his back, and modern Europeans. The team hopes to find more about possible living relatives from the enhanced genetic map and look for signs of changes in human genes since Otzi's death.

Colonoscopy Humor

A physician claimed that the following are actual comments made by his patients (predominately male) while he was performing their colonoscopies:

1. Take it easy, Doc . You're boldly going where no man has gone before!

2. Find Amelia Earhart yet?

3. Can you hear me NOW?

4. Are we there yet? Are we there yet? Are we there yet?

5. You know, in Arkansas , we're now legally married.

6. Any sign of the trapped miners, Chief?'

7. You put your left hand in; you take your left hand out...

8. Hey! Now I know how a Muppet feels!

9. If your hand doesn't fit, you must quit!

10. Hey Doc, let me know if you find my dignity.

11. You used to work for the Inland Revenue Service bad payers division, didn't you?

12. God, now I know why I am not gay.

And the best one of all...

13. Could you write a note for my wife saying that my head is not up there?

Prox1 gene linked to memory

Scientists have found that a gene named Prox1 is a key player in normal development of a brain structure crucial for learning and memory and remains active throughout life, nurturing the cells vital for making new memories. The study by St. Jude Children's Research Hospital focused on a small region of the hippocampus known as the dentate gyrus, a brain structure needed for memory and learning that is home to the subgranular zone where the neural stem cells destined to become granule cells are housed.

The dentate gyrus is one of two regions of the adult brain where neural stem cells continue to produce the precursor cells that ultimately differentiate into neurons.

Although investigators knew Prox1 was expressed during development of the dentate gyrus, this is the first report detailing the gene's function in this region of the brain. Prox1 is a transcription factor that functions like an on-off switch for genes.

Researchers showed that by removing Prox1 at different stages of mouse development, the dentate gyrus fails to develop properly. Investigators also demonstrated that Prox1 remains important throughout mammalian life to ensure production of new granule cells, which are needed to form new memories.

The findings raise the possibility that subtle mutations in Prox1 might be linked to memory and learning problems, said the paper's senior author Guillermo Oliver, member of the St. Jude Department of Genetics.

"The more we understand about how signaling pathways work in the brain, the more we will eventually be able to manipulate the system to promote or block the differentiation process," he said.

More evidence ties smoking, decreased fertility

If you're looking to make a baby, you might want to put out your cigarette before getting down to business: There's now more evidence linking smoking with decreased fertility in men and women — and their offspring.
A new study shows smoking by women during early pregnancy reduces the number of germ cells in the embryo. Germ cells later develop into eggs or sperm, so this reduction has the potential to reduce the baby's future fertility.
And men who smoke develop an imbalance in their levels of a protein, called protamine, that is vital to sperm fertility, another new study suggests.
The findings fall in line with past studies on the effects of smoking and secondhand smoke on fertility, researchers say. Research from the University of Buffalo in 2005 showed male smokers' sperm had a more difficult time binding to an egg than non-smokers' sperm. And research from the University of Rochester in 2008 showed that women who had been exposed to secondhand smoke as children or young adults were more likely to have trouble getting pregnant.
Germ cell study researcher Claus Yding Andersen of the University Hospital of Copenhagen said more research is needed to demonstrate whether the reductions in germ cells are permanent or are compensated for later in the pregnancy. Either way, he told MyHealthNewsDaily, "If women plan to get pregnant, this should be an incentive to quit smoking."
For male embryos, the number of germ cells was reduced by more than half when their mothers smoked during the first trimester of pregnancy, compared with mothers who didn't smoke at all, said Andersen. For all embryos, the reduction in germ cells averaged 41 percent.
And the more a mother smoked, the greater the reduction in the germ cells of her embryo, he said.

NHS buys porn for sperm donors

The hard-up NHS is blowing taxpayers' cash on porn for sperm donors, a report reveals today.
A health think-tank discovered one in three hospitals with fertility services lays on dirty mags. Some also offer blue movies.

Last night the smut was slammed as an affront to the three-quarters of NHS staff who are women - many of whom fear for their jobs. Seventeen hospitals admitted buying in porn when contacted by the think-tank 2020health.org, which campaigns against NHS waste.

Most top-shelf mags were purchased from newsagents.

But two hospitals confessed they bought porn direct from publishers.

Others said stashes were donated by staff, patients and visitors. One was given material by a top consultant.

The think-tank's director Julia Manning said: "We know of no government authorisation that sanctioned this.

"The reality of porn today is that it increasingly uses younger girls and is more violent and extreme. Seventy-seven per cent of the NHS workforce is female and they should never have to work in an environment that endorses pornography."

She pointed out that only 33 out of 92 hospitals in the investigation used porn as a helping hand for donors.

The Sun revealed earlier this year how Liverpool Women's NHS Foundation Trust splashed out £7,500 on computers, flat-screen TVs, a DVD unit and blue movies for hospital sperm donors.