Breast cancer gene clue discovery

Five genetic clues to why some women have a family history of breast cancer have been identified by UK researchers.

It brings to 18 the number of common genetic variations linked to a small increased risk of breast cancer.

The Cambridge University-led research, published in Nature Genetics, could see targeted screening and treatment of women more likely to get breast cancer.

It is thought about one in 20 of all breast cancers are down to inherited faults in known genes.

Breast cancer is the most common cancer in the UK with more than 45,500 new cases diagnosed each year.

The precise reasons why a woman develops the disease are still unknown.

However, inherited, environmental and lifestyle factors are all thought to play a role.

In the largest project of its kind, the researchers scanned the entire genetic code of around 4,000 British patients with a family history of breast cancer.

They then studied the DNA of another 24,000 women, with and without breast cancer.

The researchers found five "spots" on the human genome linked to a family history of breast cancer. Another 13 have already been located.

Scientists also know about two high risk genes which are more likely to be defective in someone with breast cancer, known as BRCA1 and BRCA2.

Genetic profiling

Dr Douglas Easton of the University of Cambridge, is lead author of the study.

He told the BBC: "We know for sure that these gene variations are associated with risk.

Breast cancer risk factors Breast cancer risk factors are related to lifestyle, life choices and the environment, or inherited Established risk factors include age, alcohol, genetics, HRT, pregnancy, the contraceptive pill and weight Possible risk factors include diet and stress Source: Breakthrough breast cancer

"It is not the whole picture but it will contribute ultimately to genetic profiling of risk.

"It also contributes to our understanding of why the disease develops and will lead to a better understanding of the biology of the disease."

Women with a strong family history of breast cancer are already given early screening for signs of tumours.

They are also entitled to genetic tests if they have a close relative with breast cancer.

The 18 genetic changes linked to breast cancer are not currently tested for. They are thought to account for around 8% of inherited cases of breast cancer.

Dr Caroline Hacker, policy manager at Breakthrough Breast Cancer, said: "This could lead to new genetic tests which may help identify women who have an increased risk of breast cancer due to inherited faults in genes.

"Hereditary breast cancer is rare and only around one in 20 of all breast cancers are due to inherited faults in breast cancer genes.

"Although there isn't anything we can do about the genes we inherit, we do know that you can reduce your risk of breast cancer by maintaining a healthy weight, limiting alcohol consumption and exercising regularly."

Dr Helen George, head of science information at Cancer Research UK, said: "This research takes us a step closer to developing a powerful genetic test for the disease.

"Such a test could help doctors identify women who have an increased breast cancer risk so that they can make informed decisions about how to take steps to reduce their chance of developing the disease."

When it rains, buffalo have more sons

Findings may be evidence of so-called sex-ratio genes in large mammals

Something strange happens when it rains in Kruger National Park in South Africa: Buffalo mothers give birth to more sons. Now, scientists think they know why — it's in their genes.

The results from a new study suggest that certain genes in male buffalos distort the genetic material in their sperm so that they father only sons. And these genes are "turned on" when there's plenty of grass to chow down on, as happens during the rainy season.

However, there appears to be a few systems in play so that overall, the proportion of males to females tends to even out. For one thing, the males with these sex-distorting genes are usually less fertile than other males. Another possibility is that a different set of genes, triggered by the dry season, influence the resulting brood so that there's slightly more females. 

If true, the findings would be the first evidence of so-called sex-ratio genes in large mammals. These genes have so far only been observed in insects, such as files, and in rodents.

The findings suggest that sex-ratio genes might be present in more animals than scientists have suspected, and perhaps even in humans, according to study researcher Pim van Hooft of Wageningen University in The Netherlands.

"I think it's not unique for the buffalo," van Hooft said.

Sex genes
Sex-ratio genes are located on the chromosomes that determine an animal's gender. Chromosomes are packets of DNA inside a cell's nucleus. In buffalo and people, one pair of chromosomes, called the X and Y chromosomes, are considered sex chromosomes. 

Each parent provides one sex chromosome to the offspring, with males giving either an X or Y and females giving only X chromosomes. Offspring with XX become female and those with XY become males.

Sex-ratio genes are malicious, however. They work by either killing or disabling the opposite sex chromosome. So if they are lurking on the Y chromosome, they kill off the X, meaning the father's sperm will contain only Y chromosomes, so he'll only produce male offspring. And if they're on the X chromosome, the opposite happens. Sex-ratio genes are thought to carry out their attack during spermatogenesis, or the formation of male sperm.

"Because the males have a distorted sex-ratio [gene] in their sperm, you get a distorted sex ratio at birth," van Hooft said.

Too much diversity
Van Hooft examined blood samples collected from buffalo during 1998. Because the samples included the age of the animal, he was able to go back in time, looking at the genetics of buffalo that varied in ages from 0 to 15 years.

What he found was quite strange. The amount of genetic variation on the Y chromosome was surprisingly different between buffalo of different ages, even if they were only a year apart. It was as if there were two different types of Y chromosomes, and the ratio of these Y-chromosome types fluctuated from season to season, and also from year to year.  

Normally, you would expect buffalo that were so close together in age to have very similar Y chromosomes, van Hooft said. After all, it's the same parent generation producing the kids for quite a few years, and shifts in the population genetics just don't happen that fast.

He also saw that the number of males and females born during each season was slightly skewed. During the rainy season, the ratio of males to females was about 53-to-48, so if there were 100 buffalo babies born, 53 would be male and 48 female on average. The reverse was seen in the dry season, with relatively more females born.

Van Hooft reasoned that sex ratios were at play, and that they were triggered by environmental conditions, which in turn affected the sperm.

"Apparently, these sex-ratio genes are triggered by the body condition, or the semen quality," van Hooft told LiveScience.

Here's what could be happening:Some sex-ratio genes are turned on by the wet season, causing some male buffalo in the population to produce only sons. This increases the proportion of males in the population, and the Y chromosomes from those males would be overrepresented.

During the dry season, a different set of sex-ratio genes could be turned on, ones that had the opposite effect. The final result is an increase in females, along with a fluctuation in Y chromosome types.

 

Putting names to the lost soldiers of Fromelles

The first of the remains of 250 World War I soldiers found in France are being reburied with military honours after painstaking efforts to identify them. How do you put the right name on a headstone after so long?

When the first chipped and battle-scarred bones were excavated from a muddy field in northern France last May, the story of the forgotten battle of Fromelles began to emerge.

The remains of 250 British and Australian soldiers had lain undiscovered for 93 years since falling on the Western Front.

Boots, purses, toothbrushes and other personal artefacts lay amongst the twisted skeletons at Pheasant Wood, offering partial clues about the men's identities.

But it is the unique genetic codes within these remains that offer the best chance of putting names to each unknown soldier.

So far, more than 800 UK families who think they may have lost a relative at Fromelles have given DNA samples, but many will be disappointed.

The man whose job it is to help identify the soldiers says it is like finding a needle in a haystack, albeit with a very good metal detector.

"The problem with DNA that's been in the ground for 90 years is it degrades in quality and quantity," says molecular geneticist Dr Peter Jones.

"If it's a very acidic site, there's no chance of DNA at all because acids attack DNA rapidly. If it's dry and arid like in a desert, you get good DNA. If it's wet, less good."

The remains extracted from Fromelle's muddy burial pits have produced small but workable amounts of DNA, says Dr Jones. The teeth, which preserve well because they are encased in enamel, give by far the best samples.

"The hardest part is finding the right families and getting them to come forward... you can have good DNA profiles, but no family to match it up to."

Tracing family DNA An individual's genetic code is carried by the DNA inside every cell of the body. A unique DNA profile and sequence can be made by extracting DNA from remains of the dead or mouth swabs of the living. DNA from Y chromosomes and mitochondrial DNA is then analysed. Families will share similar DNA traits. Family trees help establish paternal and maternal lines to trace who is alive today to provide DNA samples to match against those taken from the remains of the Fromelles soldiers. As long as a relative is on either the paternal or maternal line, then a match to a soldier should be possible. Clues to the soldier's identity would lie with his sons or grandsons, if he had any, as the male Y chromosome DNA is passed from father to son. If he did not have children, as in the example above, DNA from his brother's grandsons or great grandsons may do. On the soldier's maternal side, his sister's grandchildren or his sister's grandaughters' children will have inherited the same mitochondrial DNA he got from his mother. If there are no surviving members on one branch of the family, then going back generations to find another line is also valid. BACK 1 of 4 NEXT Although 250 bodies have been recovered from the graves, it's thought about 1,500 British and 5,500 Australian troops fell in the battle, making it all the harder to match. And when it comes to matching DNA samples across several generations, Dr Jones says the methods are far from perfect. Unlike the seven "markers" used for more exact matches on the National DNA Database, he only has two at his disposal - the Y (paternal) and mitrochondrial (maternal) profiles. IN PICTURES: THE ARTEFACTS Boots, bibles and tobacco pouches "If we had the children of the soldiers, we could use the same markers as the DNA database. But because we are three generations away, the markers get diluted out through each mother and father." Families searching for their ancestors have been asked to give maternal and paternal samples - preferably two each - using a simple cheek swab. The DNA results will be added to the anthropological, archaeological and historical information to try to get positive identifications. Families will be told sometime after March, once the remains of all 250 soldiers have been buried. Their final resting place will be a new war cemetery nearby, the first to be built in 50 years. The £3m project, funded by the British and Australian governments, is overseen by the Commonwealth War Graves Commission. Waiting for news will be Richard Parker, 47, who has spent 25 years trying to retrace the footsteps of his ancestor Leonard Twamley. His father's uncle was just 19 when he volunteered for the Royal Warwickshire Regiment. Six months later, the 20-year-old died at Fromelles. "He was an ordinary working class lad from Coventry working in a cycle factory, who gave his life because it was considered his patriotic duty to do so." Although interested in Len's story since his 20s, Mr Parker did not know he was killed at Fromelles until an amateur historian contacted him last year. Leonard Twamley's mother put this poignant notice in the Coventry Herald Since then he has made a pilgrimage to the French village with his father, who supplied DNA, along with Len's surviving nephews and nieces. "Even if his body isn't found, in some respects his memory is even more alive now. By researching what sort of person he was, we now know much more about him," Mr Parker says. "My grandmother died without knowing where Len was buried... this would bring proper closure to a family tragedy that goes back 95 years." Unknown soldiers The bodies that remain untraceable will be buried with a headstone marked simply "Known Unto God". Dr Jones fears many will suffer this fate. He estimates the final number identified to be up to 100, but more likely tens. THE BATTLE OF FROMELLES 19-20 July 1916, 19 days after Somme Campaign Intended as diversion to stop German soldiers going to Somme Troops of 5th Australian and 61st British divisions led attack at 6pm Within 11 hours, 5,533 Australians killed, wounded or taken prisoner and 1,547 similar British losses Soldiers from Gloucestershire, Bristol, Warwickshire and Worcestershire heavily involved Worst 24 hours in Australia's military history, considered a national tragedy Forces believed to have included the then 27-year-old Adolf Hitler Even if there is a DNA match, it may not necessarily be the right family because some DNA profiles are relatively common. Adoptions, women who married and changed names, and paternity issues can also throw a spanner in the works. Other families simply die out. But a match can be made through cousins, nephews or nieces on the family line. So if a family is missing a paternal link, they can trace the soldier's father, grandfather or brother, then locate their living relatives. Dr Jones says one family went back seven generations on the maternal side then came forward five to find a suitable relative. Forensic anthropologist Professor Margaret Cox says the team is so reliant on DNA matches as 90% of British enlistment records were destroyed in the Blitz. And the painstaking methods of extracting and cataloguing remains have been refined at the scenes of genocide and war crimes in Rwanda, the Balkans and Iraq. As at those sites, the bodies recovered gave clues to their fate - in this case, fractured bones showing damage from machine guns, rifles, mortar shells and shrapnel. But they were buried in deep graves with order and respect. "You try not to imagine what it was like, it makes it difficult to do our work," she says, adding that this is easier said than done at times. What brought the tragedy home were the artefacts - the inscribed bibles and lucky charms. For her, the two most poignant came from Australian soldiers. The first was a small lucky charm in the shape of a boomerang, to symbolise returning home. The other was the return half of a railway ticket from Freemantle to Perth, intended for the soldier's journey home to his family.

Shar-pei wrinkles explained by dog geneticists

Just how did the Shar-pei get its famous wrinkled appearance?

Scientists who have analysed the genetics of 10 pedigree dog breeds believe they now have the answer.

Their research identifies 155 distinct locations in the animals' genetic code that could play a role in giving breeds their distinctive appearances.

In the Shar-pei, the team found differences in a gene known as HAS2 which makes an enzyme known to be important in the production of skin.

"There was probably a mutation that arose in that gene that led to a really wrinkly puppy and a breeder said, 'hey, that looks interesting, I'm going to try to selectively breed this trait and make more of these dogs'," explained Joshua Akey from the Department of Genome Sciences at the University of Washington, Seattle, US.

Small differences

The pedigree dog has become a fascination - and a remarkably useful research tool - for geneticists.

The domestication of the grey wolf more than 10,000 years ago, and the selective breeding that followed, has resulted in more than 400 breeds - each with a distinctive physique, coat colour and temperament.

The study compared the genetics of 10 pure-bred dog groups

These discrete populations give scientists the opportunity to compare and contrast the genetics of the different groups, making it easier to find the causes of specific traits.

"Man's best friend" is helping scientists locate the faulty genes that cause disease in both dogs and humans, as well giving a useful insight into how evolution works at a molecular level.

Dr Akey and colleagues studied 32 wrinkled and 18 smooth-coated Shar-peis and compared a specific stretch of their DNA with that of other breeds.

The team found four small, but significant, differences in the genetics of the two skin types of the Shar-pei versus the other breeds. These single nucleotide polymorphisms (SNPs), as they are called, were located in the HAS2 gene.

New targets

"HAS2 makes hyaluronic acid synthase 2, and it's an enzyme that makes hyaluronic acid, and that's one of the principal constituents of the skin," explained Dr Akey.

"There are rare human cases where there are mutations that lead to really severe wrinkling in humans, too.

"So, that suggested it was a good candidate to look at; and sure enough, when we sequenced it we saw that that gene explained wrinkling in Shar-peis," he told BBC News.

Science explained: What is a genome?

As well as giving insights into the Shar-pei, the research has also identified a raft of other locations in the dog genome that can now be investigated further to understand better why pedigree animals look the way they do.

"The thing that excites me most about our study is that in the last five years, five genes have been identified that contribute to this vast diversity in dog breeds," said Dr Akey.

"So our study found all five of those genes and then we found 150 new targets to explore. It's a powerful approach to look at the genetic legacy of selective breeding."

Dr Akey and colleagues report their findings in the Proceedings of the National Academy of Sciences (PNAS).