In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

News story   |   By Dr Philippa Brice   |   Published 29 September 2010

The Human Proteome Project (HPP) is a recently established working group of the Canadian-based Human Proteome Organization (HUPO), aiming to co-ordinate international research efforts to fully characterise the 21,000 protein coding genes (the proteome) within the human genome, with a view to understanding ‘biological and molecular function’ and advancing diagnosis and treatment of diseases. This is a very demanding undertaking, since the potential for alternative expression and modification of proteins from each genes means that the actual complement of human proteins is much greater, in the millions.


The Australian arm of the project was launched in Sydney this week as part of the 10th HUPO World Congress (see The Australian), and various centres around the world are also involved, including the UK and US; the Swiss Federal Institute of Technology and the Institute for Systems Biology in Seattle have just announced completion of the first phase of their efforts to map the proteome using mass spectrometry.However, there is generally a significant dearth of funding for the HPP (see Life Scientist report), despite the arguably stronger prospects for prompt development of new diagnostics and therapeutics from the research than, by comparison, from the human genome sequence.

This has been countered by an announcement from the Beijing Proteome Research Center, that the newly named Chinese Human Proteome Project will expand from the current human liver proteomics research base to include analysis of proteins in the blood, brain, lungs, skin and other organs, The Chinese government will also fund  a national laboratory called the Pilot Hub of Encyclopedical proteomIX, or PHOENIX (see Nature news). 

News story   |   By Dr Philippa Brice   |   Published 27 September 2010

Plans to cut masses of UK quangos (quasi-autonomous non-governmental organizations) as part of ongoing public spending cuts by the coalition government have been mooted in the UK media. Following the announcement that various arms-length bodies including the Human Fertilisation and Embryology Authority (HFEA) and the Human Tissue Authority (HTA) were to be abolished (see previous news), a new list of nearly 180 groups has been reported by the BBC news and the Telegraph newspaper.

The BBC reports that of more than 600 quangos, 180 will be abolished, 124 merged and 56 reformed, with plans for a further hundred such groups still under consideration. Those reportedly (though not yet officially) to be abolished include the Human Genetics Commission (HGC), the Gene Therapy Advisory Committee (GTAC), the Genetics and Insurance Committee (GAIC) and various medical advisory committees in areas including transmissible spongiform encephalopathies (TESs), the safety of blood tissues and organs, dangerous pathogens and antimicrobial resistance.


Whilst a review of the large – many would say excessive – number of quangos at a time when urgent spending cuts are needed is a very good idea, some have expressed concern at the potential loss of expertise and accountability for the government set against minimal savings. Many of these are committees or bodies that do not cost a significant sum to operate, as opposed to whole organisations.

News story   |   By Dr Philippa Brice   |   Published 22 September 2010

The UK Economic and Social Research Council (ESRC) Genomics Forum has released findings from a small engagement exercise to explore public views on synthetic biology. 82 young adults (18-30) were questioned about their views, but they were not really a very representative public, being mostly students in science or related disciplines such as public health. Unsurprisingly therefore, most were broadly in favour of synthetic biology, subject to careful regulation and control.


The most popular applications were to create biofuels and pharmaceutical products; the least popular, creation of synthetic viruses for research into pandemic flu and modification of crop plants to enhance food production. 

The value of such a small-scale exercise is correspondingly very limited, especially compared with major consultations (see previous news), but interesting nevertheless. Even relatively-well informed participants clearly have concerns about the potential risks of synthetic biology, albeit set against a broadly supportive view of the area in general, lending weight to the need to ensure that these concerns are properly addressed. If scientifically literate people are worried, then the wider public probably are too, something policy-makers must continue to bear in mind.

Keywords : Public Involvement

News story   |   By Dr Philippa Brice   |   Published 14 September 2010

In the latest twist in the great saga of federally funded human embryonic stem (HES) cell research in the US (see previous news), the Court of Appeals for Washington, D.C has temporarily blocked the previous injunction banning such research (see New York Times) pending provision of further information by later this month.


In response, the NIH has rescinded its earlier suspension of relevant research projects (see previous news) pending the outcome of further legal actions (see announcement).

Meanwhile, moves by Congress are underway to permanently legalise federal funding of such research via the Stem Cell Research Enhancement Act, which would render the outcome of the current legal case irrelevant are underway (see AP news). Previously passed by Congress and twice vetoed by the then-President George Bush, this Act was reintroduced in 2009, but effectively side-stepped by President Barack Obama’s Executive Order to expand funding. Now this fast-tracking approach has been called into legal question, the longer process is being accelerated. 

News story   |   By Dr Philippa Brice   |   Published 14 September 2010

A major new initiative to investigate epigenetics has been launched in the UK. Epitwin is a collaborative venture between the TwinsUK research group based at King’s College London (see previous news) and the Bejing Genomics Institure (BGI) in Shenzhen, China (see previous news).


The £20 million project will examine and compare the epigenetic signatures of 5,000 twins; these are heritable patterns of DNA modification other than changes to the DNA coding sequence, in this instance ‘CpG islands’ of methylation, chemical modifications to the DNA molecule backbone. These may arise in response to environmental (external) factors, but can then be passed on to subsequent generations, and are thought to potentially influence health outcomes.


The researchers will be examining differences in epigenetic patterning between twin pairs – who share identical DNA sequences – and relate this information to data on different medical traits, in an attempt to identify epigenetic factors that may account for the difference between twins in terms of diseases they develop. The project will focus initially on obesity, diabetes, allergies, heart disease, osteoporosis and longevity; it is the largest epigenetic study of this kind to date.


Director of TwinsUK Professor Tim Spector commented: ‘‘Finding the crucial differences between twins will lead us to the key genes that are being turned on and off, and so to the cause of disease, with great potential to find key targets for drug treatments”, whilst BGI Executive Director Professor Jun Wang added: “We hope to unlock many secrets about human genetics that we don’t currently understand, and to accelerate research and applications in human healthcare” (see press release).


Research articles

Research article   |   By Dr Caroline Wright and Dr Gurdeep Sagoo   |   Published 30 September 2010

Attention-Deficit Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder influenced, like all common complex conditions, by both multiple genetic and environmental factors. It is believed to be the most common behavioural disorder in the UK, estimated to affect 3-9% of school-aged children and young people (see NHS Choices website).

A new study published online in The Lancet has investigated whether rare large copy number variants (CNVs) across the genome are present more often in individuals with ADHD compared with controls, and whether these regions overlap with other neurodevelopmental disorders such as autism and schizophrenia [Williams NM, et al. Lancet (2010) doi:10.1016/S0140-6736(10)61109-9]. The UK-based study involved a genome-wide analysis of large, rare CNVs – those greater than 500kb in size and present in less than 1% of the population – in 410 children with ADHD and a further 1156 controls.

Full data were available for 366 cases and 1047 controls, with 57 CNVs (15.6%) identified in 50 cases (14%) and 78 CNVs (7.5%) in 75 controls (7%), indicating an enrichment of large CNVs in children with ADHD. Twelve of these cases also had DNA from both parents available for analysis. Of the 15 CNVs identified in these twelve cases, six were inherited from the mother, five from the father, and four were novel. The CNVs identified showed considerable overlap with regions implicated in both autism and schizophrenia. Duplications on chromosome 16 were also identified more often that expected in the cases, and this finding was replicated in an independent Icelandic set of 825 patients with ADHD and 35,243 population controls.

Comment: Despite being highly heritable, the underlying causes of ADHD are still poorly understood. Whilst some strongly believe that environmental factors such as diet, poor parenting, and fetal exposure to maternal smoking or maternal stress are largely to blame, this study uncovers clues to the genetic basis of ADHD. As with other common complex diseases, there is no simple cause. Genetic factors, environmental factors, as well as an interaction between the two, all contribute to disease occurrence to varying degrees.

As our understanding is aided by advances in technology (see previous news), more rare CNVs are being identified associated with behavioural disorders, such as ADHD and autism (see previous news). In some individuals, these findings may explain a large part of the disease (see previous news), whilst in others, genetic factors may play a much smaller role.

Research article   |   By Dr Gurdeep Sagoo   |   Published 24 September 2010

In 2005, according to the World Health Organisation, around 1.6 billion adults and a further 20 million children under the age of five were overweight across the world. By 2015, there are expected to be more than 700 million obese adults (increasing from 400 million in 2005). Although this epidemic has largely been driven by changes in lifestyle, such as the increase in availability of calorie-rich foods coupled with an increasingly sedentary lifestyle, recent genome-wide association studies (GWAS) have shown that genetic factors also play an important role. A study published in PLoS Medicine assesses how a physically active lifestyle impacts on an individual’s genetic predisposition to obesity [Li et al. (2010) PLoS Med 7(8):e1000332. doi:10.1371/journal.pmed.1000332].

Using a large population-based study design, Li et al. genotyped 12 SNPs in obesity susceptibility loci in 20,000 individuals of white European descent. These SNPs were then used to calculate a genetic predisposition score based on adding the number of BMI-increasing alleles across the 12 SNPs. Physical activity was assessed by means of a validated self-administered questionnaire, with data available for 20,000 individuals at baseline and 12,000 at a second health check 3-4 years later. Interactions between the genetic predisposition scores and levels of physical activity were then assessed based on obesity risk and changes in BMI over time.

Li et al. found adding each BMI-increasing allele to an individual’s genetic predisposition score resulted in an increase in BMI equivalent to 445 grams body weight in an adult 1.70 metres tall. Increasing physical activity resulted in a decrease in BMI equivalent to 904g in body weight. Individuals with a physically active lifestyle have a smaller increase in body weight per increase in genetic predisposition (379g) whereas those with a physically inactive lifestyle exhibit a more pronounced increase in body weight (592g). Obesity risk per increase in genetic risk was also reduced in the physically active compared to the physically inactive.


Comment: Overweight and obesity are associated with serious health consequences. Increasing physically activity reduces obesity risk, and this advice was thought to be equally applicable to everyone. However, this large study shows that those individuals with a greater genetic predisposition to obesity may find this advice even more beneficial, prompting the question whether increased genetic risk can be effectively used in order to target interventions to a group that would have a greater gain.


A limitation of the study which the authors themselves acknowledge is that the participants self-reported their levels of activity. It would be both more difficult and more expensive to use a more objective measure of physical activity.

Research article   |   By Dr Philippa Brice   |   Published 23 September 2010

Beta-thalassaemia is a serious genetic disease and particularly common among populations of Mediterranean, Middle Eastern and Asian descent. There is therefore a considerable driving force behind efforts to develop effective gene therapy, and various approaches have been taken (see previous news).

Now, a new paper in Nature reports on a patient with severe beta-thalassaemia in whom a gene therapy procedure has removed the need for monthly blood transfusions, the only available treatment other than tissue-matched bone marrow transplantation, if a suitable donor can be found.


The gene therapy took place almost three years earlier, and involved removal and treatment of blood precursor cells (haematopoietic stem cells or HSCs) from two adult subjects [Cavazzana-Calvo M et al. (2010) Nature 467(7313):318-22]. The treatment delivered a virus-like gene therapy vector containing a modified form of the human beta-globin gene encoding a protein designed to restore normal function, whilst still being distinguishable from normal adult beta-globin proteins by specialised analysis.


The beta-thalassaemia patients each had chemotherapy to suppress the remaining, diseased HSCs left in their body, followed by transfusion of their treated HSCs. The transfused cells did not engraft and grow properly in the first patient, reportedly because they ‘had been compromised by the technical handling of the cells’, so that transfusion of other cells was necessary.


However, the second patient showed a good response to the therapy. The genetically modified HSCs grew and gave rise to increasing levels of new HSCs producing functional beta-globin protein. The patient was later able to cease receiving standard blood transfusions, and has been without a transfusion for almost two years.


The authors note that one genetically modified HSC line (comprising about half of all the cells) in which the gene therapy vector inserted into the HMGA2 gene showed increased production of the corresponding HMGA2 protein in some cells. This is normally involved in the control of gene expression, and the concern would be that it could lead to abnormal gene expression and potentially drive transformation to a cancer cell. Cancer caused by inappropriate insertion of gene therapy vectors into target cells is a significant risk for gene therapy to date (see previous news), and the patient will require life-long monitoring for this, as well as to ensure that his beta-globin levels remain high.


Comment: This is a cheering proof-of-principle showing that gene therapy can be effective as a treatment for beta-thalassaemia in humans. Obviously, the long-term outcome for the patient in question is not yet known, and the general efficacy and safety will need to be assessed for larger numbers of patients in further carefully controlled clinical trials. Gene therapy is, however, moving forward.

Research article   |   By Dr Caroline Wright   |   Published 22 September 2010

Standard genome-wide association studies tend to use a case-control design to compare identify genetic variant that increase risk of disease. However, such studies are less likely uncover variants that effect the rate of progression of disease, for which disease cohorts are needed. By looking for associations between with quantitative traits - such as blood lipids (see previous news) - in individuals with disease, and following those cohorts longitudinally over time, the effect of genetic variants upon the disease itself can be assessed.

A new study published in PLoS Genetics uses biomarkers in the cerebrospinal fluid (CSF) to investigate the role of common genetic variants in the progression of Alzheimer’s disease (AD) [Cruchaga C et al. PloS Genet (2010) 6(9):e1001101]. The study focused on 384 single nucleotide polymorphisms (SNPs), chosen in 34 genes involved in modification or metabolism of the protein tau, which is found in aggregated tangles in the brains of those with AD, where it causes neuronal death. A strong association was found in 353 AD patients between the level of a modified form of tau (phosphorylated-tau) in the CSF, which has previously been shown to be a biomarker for dementia, and a SNP (rs1868402) located in the PPP3R1 gene encoding a phosphatase. This finding was replicated in an independent cohort of 493 further AD cases.


A subset of patients from both these cohorts (259 in total) was then followed over time to investigate the impact of rs1868402 on disease progression, measured by a Clinical Dementia Rating. Although the length of follow-up and number of observations varied between individuals, a strong correlation was observed: homozygous carriers of the minor allele of rs1868402 (associated with high levels of phophorylated-tau in the CSF) progressed six times faster than those carrying only the major allele, and twice as fast as the average change. The same allele also showed significantly lower mRNA expression levels for PPP3R1 in brain samples from AD cases compared with controls.


A number of genetic variants have previously been associated with an increased risk of developing Alzheimer’s disease (see previous news), the most notable of which is APOE which has a significant effect on age at onset and an individual’s susceptibility to the disease (with a relative risk of around 12 for homozygote carriers of the high risk e4 allele, see previous news). Interestingly, this study found that APOE status was not correlated with the rate of disease progression. Moreover, a separate analysis in over a thousand cases and controls indicated that rs1868402 does not affect the risk of developing AD, or the age at onset.


Comment: This study suggests that different molecular mechanisms are involved in the development and progression of AD. Whilst variants associated with onset and susceptibility might eventually be useful for risk prediction and prevention, variants associated with progression could more immediately be useful for predicting prognosis and stratifying patients in clinical trials. Although this approach is broadly applicable to investigating the genetic factors influencing the progression of any disease, it is particularly useful in neurological diseases where measuring the relevant biomarkers may be difficult. 

Research article   |   By Dr Philippa Brice   |   Published 21 September 2010

People with mutations in the BRCA1 or BRCA2 genes are at greatly increased risk of developing breast and ovarian cancers compared with the general population. Mutation carriers may receive increased levels of screening to detect tumours (more effective for breast than ovarian cancers), or they may opt for preventative surgery to remove the breasts (mastectomy) or ovaries (oophorectomy). Major surgery of this kind is not undertaken lightly, but a significant number of women make this choice.


A new prospective study reports on the effect of preventativemastectomy and oophorectomy procedures in women with BRCA mutations [Domchek SM et al. (2010) JAMA 304(9):967-75]. The research involved a total of nearly 2500 women from centres in Europe and the US, looking at cases of breast and ovarian cancer, rates of cancer-related deaths, and overall mortality rates. Women who had preventative surgery of any kind, or ovarian cancer prior to enrolment in the study were excluded.


There were no breast cancers diagnosed in the 247 women who had had mastectomies over a three-year period, compared with 98 cases among the 1372 women who did not (around 7%), suggesting a significant risk reduction for breast cancer from the surgery.


A more complex picture was examined for oophorectomies. Of women who had this procedure, 1.1% developed ovarian cancer and 11.4% developed breast cancer, compared with 5.8% and 19.2% of those who did not have the surgery, respectively. The risk of death from both ovarian and breast cancers was reduced following oophorectomy, as was the overall mortality rate at 3.1% (compared with 9.8% among women who did not have surgery).


A significant decrease in the risk of ovarian cancer was observed for mutation carriers with and without previous breast cancers, and in the risk of breast cancer for carriers who had not previously had breast cancer, but the risk of subsequent breast cancers in those who had already had a primary breast cancer was not apparently reduced by oophorectomy.

Comment: Although this study has many limitations and leaves various questions unanswered, it does show that there is a genuine protective benefit from mastectomy and oophorectomy surgery for high-risk BRCA mutation carriers. This useful information should be weighed against alternative options – increased screening and chemoprevention – including the health risks of surgery, and premature menopause associated with the loss or suppression of ovarian function. 

Research article   |   By Simon Leese   |   Published 20 September 2010

A study published in PLoS Genetics has employed next-generation sequencing to compare twenty human genomes in order to evaluate the potential of this technique to identify the genetic cause of disease [Pelak et al. PLoS Genet (2010) doi:/10.1371/journal.pgen.1001111].


The team of researchers sequenced ten genomes from individuals with haemophilia A and ten non-haemophiliac genomes as controls, and compared them for a range of genetic variants using a variety of software tools. Haemophilia A was chosen for this study because it is a highly penetrant Mendelian disorder caused by mutations in the F8 gene, which codes for the blood clotting factor VIII.


The authors found that the cause of haemophilia A was ‘easily recognisable’ from the comparative data; the F8 gene standing out as the one containing the greatest number of functional variants in the haemophiliacs, versus none in the controls, which they conclude is proof of concept that this technique is able to pinpoint the genetic variations responsible for a Mendelian disease. The researchers also found that all twenty of the genomes contained many genes that are not expressed, suggesting the future possibility of a human ‘knock-out’ database – whereby an individual’s non-expressed genes are correlated with their phenotype – which they say could become a critical tool in human functional genetics.

Comment: This study is an early demonstration of the potential for next-generation sequencing technologies and attendant analytic software to improve our ability to identify the genetic basis of disease. However, it also highlights some of the current limitations of these techniques. The study was able to identify the causal variant for haemophilia in only six out the ten genomes of those with the disorder, due to the difficulty in detecting some types of functional variants such as indels. The study authors’ suggestion of the future development of a large human knock-out database is interesting, but would present a great many obstacles to overcome in practice, including difficulties in assigning phenotypes and establishing the criteria for control subjects, as well as the non-trivial considerations of ethics and protocol. 

Research article   |   By Dr Susmita Chowdhury   |   Published 16 September 2010

Prostate cancer is the most common cancer diagnosed in the UK, with three-quarters of the cases occurring in men over 65 (according to the CRUK), and there is increasing demand for screening in older men. The huge increase in cases of prostate cancer (despite a stable mortality rate) over the last 20 years is attributed to TURP, a surgical procedure, and PSA, a blood test for Prostate Specific Antigens.


Screening for prostate cancer in the general population remains hugely controversial (see previous news) because PSA tests used cannot differentiate between men with aggressive cancer and men who would never have symptoms or need treatment, leading  to over diagnosis and treatment, including  surgery, radiation or hormone therapy that can cause serious side-effects such as impotence and incontinence. These issues have so far dissuaded many European countries from nationwide screening.


Nevertheless, the initial findings of a recent multinational screening study [Mitra et al. BJUI (2010) doi:10.1111/j.1464-410X.2010.09648.x] revealed results in support of continued targeted prostate cancer screening for men who are carriers of BRCA1 and BRCA2 gene mutations or  have family histories of breast and ovarian cancers. It is known that BRCA1 mutations double the risk of prostate cancer in men less than 65 yrs, and BRCA2 mutations by up to seven fold. The IMPACT study aims to recruit 1,700 men to find out whether screening those with genetic predispositions could lead to earlier but accurate diagnosis of prostate cancer.


The published study involved 300 men aged 40-69, 205 with confirmed BRCA1 or BRCA2 mutations and 95 who had tested negative; all were offered annual PSA blood testing. 24 men with raised PSA levels were given a follow-up biopsy, which revealed that 9 BRCA1/2 carriers had prostate cancer compared with just 2 in the control group without the mutations.


The positive predictive value (PPV) of screening in this selected sub-group of high risk men - that is, the proportion of patients with positive test results who are correctly diagnosed - was found to be high at 48%, and the authors suggest that the study provides evidence that screening men with genetic predisposition detects clinically significant prostate cancer.  


Comment: Although the authors claim a high PPV in their study, an important measure for diagnostic accuracy, this value may have been influenced by the higher proportion of men recruited with pre-existing prostate cancer. Also, the nature and prognosis of the cancers was not be determined. When the larger sample size and longer term follow up is completed via this study, more accurate measurements of PPV, test sensitivity and over diagnosis will be revealed. However, it must be recognised that the preliminary results of this study provide enough evidence to continue the screening of men who are at higher risk of the cancer, though population-wide screening remains controversial.


Research article   |   By Dr Caroline Wright   |   Published 15 September 2010

Cancerous tumours release naked, cell-free DNA fragments into the bloodstream as they develop and grow, which may be used as a marker for cancer if an appropriate genomic rearrangement can be found that is characteristic of the tumour. The development of next generation DNA sequencing technologies has enabled these rearrangements to be mapped in solid tumours (see previous news), allowing tests specific to a patient’s cancer genome to be designed (see previous news). A second proof-of-principle study has now been published, indicating that this technique can be used to quantify the disease burden and monitor progression in individual patients [McBride DL, et al. Genes, Chromosomes & Cancer (2010), doi: 10.1002/gcc.20815].


First, primary tumour tissue was biopsied from three patients, two with breast cancer and one with osteosarcoma – all of whom suffered severe relapses and multiple bone metastases. This material was studied using deep sequencing to indentify tumour specific genomic rearrangements not otherwise present in the patient’s germline DNA. Second, a panel of PCR assays were designed for several rearrangements in each patient, that were both specific and highly sensitive to tumour DN in the patient's plasma. One patient was subsequently monitored over time using this assay, indicating residual disease was present throughout both first and second-line therapy. The assay also detected a substantial increase in tumour DNA, which correlated with relapse and widespread metastases, despite the patient apparently showing clinical improvement during this time. The authors state that “this illustrates the potential for such an assay to identify failing therapies early, allowing quicker transfer to alternative therapeutic regimes”.


Comment: There are strong parallels between this technique and the use of the cell-free fetal DNA circulating in the mother’s blood for non-invasive prenatal diagnosis, which could revolutionise antenatal testing (see PHG Foundation Report). Although this new methodology has so far only been applied to a few cancer patients, almost all cancers sequenced to date contain multiple unique genomic rearrangements, so the protocol should be widely and rapidly applicable.

It is important to note that, because solid tumours are extremely genetically heterogeneous, a unique testing  panel would need to be developed for each individual patient. However, although the first step of sequencing an individual’s cancer genome is currently still relatively new and expensive, the second step of using a PCR assay to test for specific fragments of DNA in plasma is both cheap and routine. These truly personalised diagnostic tests could potentially be used for years by an individual patient – to guide therapeutic strategies and monitor long-term prognosis – and could ultimately help transform cancer into a chronic, manageable disease. 

Research article   |   By Dr Caroline Wright   |   Published 10 September 2010

Malformations that occur during the development of the cerebral cortex, the outer most neural tissue of the brain, can lead to devastating structural brain disorders and severe mental retardation. Although the disorders are sometimes inherited in a Mendelian fashion, to date, the underlying genetic cause has been elusive.

New research published in Nature has now identified recessive mutations in the WDR62 gene on chromosome 19 as the cause of severe brain malformations in a small consanguineous family [Bilguvar K et al. Nature 467:207-211]. Using next generation sequencing technology to sequence the entire exome (i.e. all the coding regions of the genome) of two affected family members, a four base-pair deletion in WDR62 was found in both individuals, causing the resulting protein to be truncated. This mutation was confirmed to be homozygous in both affected subjects and heterozygous in both unaffected parents using standard Sanger sequencing, and absent in over 1,000 population controls.

This finding was confirmed by further Sanger sequencing of WDR62 in seven other (unaffected) family members, and by extending the investigation to include genome-wide genotyping of another 30 independent patients with mental retardation caused by similar brain malformations, revealing numerous other recessive mutations in the gene. Investigation of the expression profile of the gene indicated that the protein is localised to the nucleus of neuronal cells during development, and affects the expression of numerous other genes involved in RNA processing, the cell cycle and cellular differentiation.

Comment: This study marks the continuation of a growing trend of using whole exome or genome sequencing for gene discovery, to pinpoint hitherto unknown genetic causes of inherited diseases (see previous news). Within the context of traditional clinical genetics, this application of new DNA sequencing technologies should improve the proportion of patients who can be offered a precise molecular diagnosis and accompanying guidance on preventative and therapeutic options. 

Research article   |   By Dr Caroline Wright   |   Published 9 September 2010

The third instalment of the human HapMap, a catalogue of common human genetic variation, has been published in Nature  [The International HapMap Consortium (2010), Nature 467: 52-58]. 

The International HapMap consortium was launched in 2002, with the goal of “compare[ing] the genetic sequences of different individuals to identify chromosomal regions where genetic variants are shared”. The first phase was published in 2005 (see previous news), with around a million single nucleotide polymorphisms (SNPs) from 269 individuals from Africa, China, Japan and Western Europe, to which a further 2 million SNPs were added two years later (see previous news). HapMap3 casts the net even wider and includes 1.6 million SNPs from 1,184 individuals from 11 global populations. In addition, ten 100-kilobase ENCODE regions were fully sequenced in 692 of these individuals, allowing integration of both common and rare alleles, including both SNPs and copy number polymorphisms (CNPs).

Although common variants (present in >5% of the population) are shared across global populations and can be well assayed using standard genotyping chips, rarer variants are generally population specific and are currently inadequately sampled as they require deep sequencing. The authors state that this finding highlights “the importance of sampling widely to achieve a comprehensive understanding of human variation.” Providing a higher resolution catalogue with broader population coverage will no doubt improve the interpretation of genome-wide association studies, and inform the design of full sequencing projects such as the 1000 Genomes Project.


Research article   |   By Dr Anna Pokorska-Bocci   |   Published 8 September 2010

Potential new forms of personalised cancer therapeutics continue to emerge. Two recent discoveries may contribute to therapeutic advancement in management of breast cancer.

A study published in the Cell Stem Cell and reported in the New Scientist sheds new light on the origin of most common forms of breast malignant tumours. Till recently, it has been thought that most breast cancers originate from basal stem cells. A team of scientists at the Breakthrough Breast Cancer Centre in London, compared mice expressing mutant versions of the BRCA1 gene (a tumor suppressor gene), which is known to cause breast cancer, in a number of different breast cell types.


They inserted a mutant version of the gene into either basal stem cells or luminal progenitor cells. Both sets of animals developed breast tumours but only tumours derived from the luminal cells mimicked the features of BRCA1- linked cancers in humans, and also so called sporadic basal-like breast cancers, showing aggressive growth and specific genetic markers [Molyneux G et al. (2010) Cell Stem Cell 7(3):403-417]. This accurate identification of the cellular origin of breast cancers constitutes an important step in development of new treatments.


Another important study linking DNA polymorphisms in the estrogen metabolism pathway to breast and endometrial cancer risks has been recently published in PLoS Genetics and discussed at the 2010 conference of the British Society of Human Genetics. This comprehensive genetic study involved more than 7,000 participants from Sweden and Finland and allowed the analysis of a large population of SNPs and the correlation of their potential effects on the production of estrogen and the development of breast and endometrial cancer [Low YL et al. (2010) PLoS Genet. 6:e1001012]


The genes analysed included the CYP19A1 gene encoding the enzyme aromatase, a known candidate target for cancer treatment in postmenopausal women. Although it has long been known that estrogen plays an important role in the breast cancer development, this recent study is the first to give exhaustive evidence of strong links between polymorphisms in genes involved in the estrogen metabolism pathway, and potential development of breast and endometrial cancer. These findings strengthen the scientific rationale for current chemoprophylaxis agents, and provide an opportunity for further advances in estrogen-related cancer treatment.


Prof Edison Liu, director of the Genome Institute of Singapore and lead author of the study, said, “This research raises the possibility of having a test using multiple genetic markers that, when added together, can give an estimate of risk for the most common forms of breast cancer. Previously such genetic risk determination was limited to rare forms of breast cancer. It was the combination of the markers rather than single markers, and our integration of the knowledge of the estrogen metabolism pathways that made the difference” (see press release).


Comment: These two recently reported studies give significant new prospects for novel therapeutic and prophylactic approaches in the battle with breast cancer.

Research article   |   By Dr Gurdeep Sagoo   |   Published 6 September 2010

There are potentially enormous clinical benefits of using an individual’s genetic sequence to predict how it affects the metabolism or function of a drug (pharmacogenetics), to allow improved dosage and minimise adverse reactions. The body of evidence is already growing with regard to warfarin treatment, the world’s most popular anti-coagulant (see previous news).


A recent study published online in the New England Journal of Medicine investigated whether the benefit of the drug clopidogrel when compared to placebo was decreased in carriers of alleles known to affect the function of a cytochrome P450 gene involved in drug metabolism [Paré et al. (2010) NEJM doi:10.1056/NEJMoa1008410]. When added to aspirin, clopidogrel reduces the rate of major vascular events in patients with acute coronary syndromes and atrial fibrillation, but recent reports have suggested that certain variants of the CYP2C19 gene may reduce its efficacy by causing a loss-of-function.


The study reports the outcomes of two large, randomised, double-blind, placebo-controlled trails comparing clopidogrel with placebo (both with combination with aspirin). The first trial (CURE) involves patients with acute coronary syndromes and the second trial (ACTIVE A) involves patients with atrial fibrillation with at least one additional risk factor for stroke whilst not being eligible for warfarin treatment. In the CURE trial, 5,000 participants of European or Latin American ancestry were genotyped for three alleles rs4244285, rs4986893 and rs12248560 (so-called *2, *3 and *17 alleles of CYP2C19, respectively), with 2,500 randomly assigned to each treatment group. In the ACTIVE A trial, 1,200 participants of European ancestry were genotyped for the same three alleles with 600 assigned randomly to each treatment group. The genotyped alleles were used to classify patients into metaboliser phenotype categories with carriers of two copies of loss-of-function alleles (*2 or *3) classified as ‘poor metabolisers’ and carriers of two copies of the gain-of-function allele (*17) classified as ‘ultra [fast] metabolisers’.


In the CURE trial, patients on treatment that carried loss-of-function alleles had similar outcomes to non-carriers, with both groups experiencing reduced cardiovascular events compared to their respective placebo groups. Patients on treatment that carried the gain-of-function alleles experienced a larger reduction in cardiovascular events versus the non-carriers when compared to their respective placebo groups. In the ACTIVE A trial, the effect of clopidogrel in reducing the rate of cardiovascular events was similar across carriers and non-carriers of all the functional alleles genotyped when compared to their placebo groups.


Comment: This well-conducted trial starts to clarify the confusion over whether loss-of-function alleles of the CYP2C19 gene alter the efficacy of clopidogrel. Previous studies were hampered by potential confounding factors, something these randomised trials can overcome. However, it is important to note that reductions in the clopidogrel treatment group were consistently observed regardless of metaboliser phenotype when compared to the placebo, suggesting that pharmacogenetic testing of this gene is unlikely to be either valid or useful for this drug.

Keywords : CHDjournal

Research article   |   By Dr Susmita Chowdhury   |   Published 3 September 2010

Migraine is a common neurologic disorder characterised by recurrent attacks of severe and disabling headache. According to the NHS, migraines affect one in four women and one in 12 men in the UK. Although genetic factors are known to play a part in migraines, no genetic or molecular markers have been established for this disease so far.


Recently, researchers from the UK Wellcome Trust Sanger Institute have collaborated with scientists from across Europe to carry out a two stage genome –wide association study (GWAS) to identify variants associated with common forms of migraine [Anttila et al (2010) Nature Genetics doi:10.1038/ng.652]. In the ‘discovery stage’ of the study, 3,279 migraine cases and 10,747 healthy matched controls from specialized headache clinics in Europe were genotyped for over half a million single nucleotide polymorphisms (SNPs); in the ‘replication stage’, a further 3,202 cases and 40,062 controls were similarly genotyped. They identified a SNP (rs1835740) located on chromosome 8q22.1 which is significantly associated with migraine, (OR=1.18 with a p-value of 1.69×10−11 in meta-analysis) and is estimated to explain 1.5-2.5% of the genetic variance. The marker is located between two genes (MTDH and PGCP) which are strongly associated with the production of the neurotransmitter glutamate, which itself is known to be important in the pathophysiology of migraine. This provides indirect evidence of the role of rs1835740 SNP in the mechanism of migraine attacks due to excess accumulation of glutamate in the junction of nerve cells. An investigation of the impact of rs1835740 on gene expression levels also indicated a significant correlation with transcript levels of MTDH.


Comments: The authors state that this is “the first robust genetic association to migraine”. In order to examine the effect of this new variant on chromosome 8, especially in different migraine subgroups, further large scale studies in broader population–based migraine cohorts are essential. Once the underlying pathways are better understood, and more genetic variants responsible for migraine are discovered, it may be possible to design new treatments for this devastating condition. 

Keywords : journal

New reviews and commentaries

Selected new reviews and commentaries, 1 September 2010

Reviews & commentaries : by Dr Philippa Brice

Which way for genetic-test regulation? Assign regulation appropriate to the level of risk.

Javitt G. Nature. 2010 Aug 12;466(7308):817-8.

Which way for genetic-test regulation? Leave test interpretation to specialists.
Beaudet AL. Nature. 2010 Aug 12;466(7308):816-7.

New guidelines for genetic tests are welcome but insufficient
Lancet. 2010 Aug 14;376(9740):488.

The double-helix derailed: the story of the BRCA patent.
Matloff ET, Brierley KL. Lancet. 2010 Jul 31;376(9738):314-5

Individual genomes on the horizon.
Watkins D, Gallant C. N Engl J Med. 2010 Jul 8;363(2):195-6.

Infectious diseases not immune to genome-wide association.
de Bakker PI, Telenti A. Nat Genet. 2010 Sep;42(9):731-2.

Genetics: Pet project.
Cyranoski D. Nature. 2010 Aug 26;466(7310):1036-8.

Neurodegeneration: An expansion in ALS genetics.
Lagier-Tourenne C, Cleveland DW. Nature. 2010 Aug 26;466(7310):1052-3.

Genome editing with engineered zinc finger nucleases.
Urnov FD et al. Nat Rev Genet. 2010 Sep;11(9):636-46.

The ethics of using transgenic non-human primates to study what makes us human.
Coors ME, Glover JJ, Juengst ET, Sikela JM. Nat Rev Genet. 2010 Sep;11(9):658-62.

Replication error amplified.
Kaochar S, Paek AL, Weinert T. Science. 2010 Aug 20;329(5994):911-3.

Which parental gene gets the upper hand?
Wilkinson LS. Science. 2010 Aug 6;329(5992):636-7. No abstract available.

The emerging genetics of type 2 diabetes.
Bonnefond A, Froguel P, Vaxillaire M. Trends Mol Med. 2010 Aug 19.

Crohn's disease: Genes, viruses and microbes.
Simmons A. Nature. 2010 Aug 5;466(7307):699-700.

Genomics: Variations in blood lipids.
Shuldiner AR, Pollin TI. Nature. 2010 Aug 5;466(7307):703-4.

World view: Not by experts alone.
Sarewitz D. Nature. 2010 Aug 5;466(7307):688.

Biobanks: Importance, implications and opportunities for genetic counselors.
Hawkins AK.  J Genet Couns. 2010 Aug 3. [Epub ahead of print]

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