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 Alison Hall   |   Published 29 October 2009

One of the concerns expressed when the Human Tissue Act was enacted in the UK in 2004 was that the legislation would have a stultifying effect on research. The Human Tissue Authority has commissioned some research to test the veracity of this claim and assess the effect of the legislation on researchers working with human tissue. The research carried out by Opinion Leader consisted of a questionnaire survey of 295 members of the research community supplemented by ten in depth interviews with a range of stakeholders (together with a literature review and stakeholder meeting).

The results, published in September 2009 in a report - The Impact of legislation and Human Tissue Authority regulation on research suggested that respondents found it difficult to distinguish between the effects of the Human Tissue legislation and Human Tissue Regulation generally (including research ethics and research and development (R&D) governance). Moreover, the respondents were often sharply divided in their opinions. Those appointed as designated individuals pursuant to the Human Tissue Act licensing regime were less likely to be negative about the impact of the legislation, but pathologists and those working in the NHS were more likely to be negative. Indeed the majority of those questioned (59%) believed that the Human Tissue legislation and subsequent regulation by the Human Tissue Authority had a negative impact on research. 68% of respondents believed that the legislation resulted in samples being more difficult to get hold of, and 61%, that potentially valuable samples were being disposed of.

On a positive note, 70% of all respondents agreed that the legislation and HT regulation had helped to ensure that informed consent is given by donors, and more participants agreed than disagreed that the combined effect of the HT legislation and regulation had resulted in increased public confidence in what happens to donated tissue.

Comment: It is unsurprising that those with a positive attitude to governance generally were more likely to be positive about the HT Act particularly as pathology was one of the sectors most critical of the legislation as it passed through Parliament. The complexity of governance in this area is confirmed by the findings of a survey of pathologists and pathology carried out by onCoreUK, in collaboration with the Pathological Society, in response to the National Cancer Research Institute Task Force on the role of pathology in cancer research. This also highlighted the need for guidance to be consolidated into an accessible, authoritative and consistent multi-regulator resource. As a result of these findings, the Medical Research Council has announced that their excellent Data and Tissues Tool Kit is to be strengthened by providing links to guidance from relevant regulatory and governance bodies, and more widely disseminated via a range of stakeholders to provide an authoritative resource in this area.

News story   |   By Dr Philippa Brice   |   Published 26 October 2009
The National Cancer Research Institute’s Confederation of Cancer Biobanks (CCB) is a consortium of UK organisations involved biobank resources for cancer research. The Confederation seeks to ‘promote and disseminate a collective view on best practices for biobanks’ and promote knowledge transfer, with the vision of each facility working in a seamless manner, creating an effective single ‘virtual biobank’ for the collection and distribution of biosamples for cancer research.

In January this year, the CCB held an expert Workshop on Ethics and Governance in Cancer Biobanking, the report from which is now available. Sections in the report, based on presentations and discussions, include an introduction to the CCB’s principles for good biobank governance, information governance, regulation of human tissue banking, ethical review of research tissue banks, the work of the UK Biobank Ethics and Governance Council and the need for greater public engagement in biobanking. The CCB say that many aspects of the discussions are relevant to biobanks in general, as well as cancer biobanks.

News story   |   By Dr Caroline Wright   |   Published 26 October 2009

The UK government has withdrawn its controversial proposals for the national DNA database (see BBC news report), which included keeping the DNA profiles of people without convictions for between six and twelve years (see previous news).


The proposals were open for public consultation from May to August 2009, during which time they received widespread condemnation from civil liberties campaigners citing Article 8 of the European Convention on Human Rights (which relates to personal privacy). In addition, the Government received criticism from wider scientific organisations and numerous individuals for the use of flawed and inappropriate statistical data as evidence to support the proposed measures (for example, see Bad Science article).


Following the consultation and resultant withdrawal of the Government’s proposals, a Home Office spokesman said they hoped to bring forward "further provisions" on DNA retention in the next policing and crime bill (see Guardian news article). It remains to be seen how police will respond in practice to any future legislation (or lack thereof), as current advice from the Association of Chief Police Officers is still to continue adding the DNA profiles of innocent individuals to the database (see Times news article).


Comment: It has been suggested that simply expanding the national DNA database to include DNA profiles from everyone in the UK – rather than only those accused of a crime – would be a fairer system and improve the ability of police to solve crimes. However, in addition to compelling civil rights arguments against such a system, as well as concerns over its broader social implications, there are also excellent technical reasons why enlarging the current DNA database may be unwise.


Firstly, new research has shown that DNA evidence can be faked using standard molecular biology techniques [Frumkin D et al. Forensic Sci Int Genet (2009) doi: 10.1016/j.fsigen.2009.06.009]. DNA profiles used for forensic purposes only contain a tiny amount of genetic sequence data, as they report simply on the number of repeated sequences at a handful of genetic loci in an individual (a ‘DNA fingerprint’). Therefore, artificial DNA can be synthesised to match any DNA fingerprint, either taken from a physical sample or an entry in a database. This synthetic DNA can subsequently be applied to surfaces and objects, or even incorporated into genuine human tissue (such as saliva or blood) from which cells from the donor individual are removed. This raises serious questions about security and the potential for misuse of DNA databases.


Secondly, there are strong statistical arguments against the application of such a large database in forensics. Not only does the complexity of storing and searching such a large body of data increase substantially with the size of the database, but so too does the probability of errors, duplicates and false entries. Moreover, the chance of getting a false positive match is also much higher, simply due to the vast number of comparisons involved and the percentage of the population who have similar (or identical) DNA fingerprints.


Finally, the National DNA Database Annual Report 2007-09, released by the National Policing Improvement Agency only days after the Government’s policy U-turn, indicates that the number of detections using DNA evidence has fallen by nearly 25% (10,000 crimes) over the last 2 years, despite the DNA database growing at almost the same rate (from 4.6 to 5.6 million profiles) over the same time period. This calls into question the assertion that more crimes will necessarily be solved if more individual profiles are on the DNA database. If this assumption – which underlies much of the support for the DNA database – is actually false, then arguments in favour of expansion are seriously undermined .

News story   |   By Dr Philippa Brice   |   Published 22 October 2009

The UK Diagnostic Mutation Database (DMuDB) is an electronic data repository that facilitates information exchange about genetic variants associated with inherited diseases between UK diagnostic genetics laboratories. DMuDB is hosted by the National Genetics Reference Laboratory Manchester, and is used by National Health Service (NHS) scientists and clinicians who have identified novel genetic variants, to see whether or not these have been previously identified by others and what their significance may be. Not all such variants are published in the literature or other online databases; for example, DMuDB includes more than 850 unique variants in the BRCA1 and BRCA2 genes, half of which reportedly are not recorded in the Breast Cancer Information Core, a mutation database hosted by the US National Human Genome Research Institute (NHGRI). The DMuDB currently includes information about more than 12,000 individual variants in a total of 83 genes.

Now a new DMuDB service will allow clinical geneticists throughout the world to query data. Individuals 'with a legitimate interest' can query whether a given variant is recorded in DMuDB; if it is, they will be put in contact with the appropriate NHS laboratory (see press release). In the longer term, there are plans to link DMuDB data with other major variant database projects to further widen access.

News story   |   By Dr Philippa Brice   |   Published 21 October 2009

The Melanoma Genetics Consortium (GenoMEL), an international network coordinated by the University of Leeds' Cancer Research UK Centre, brings together researchers investigating the genetics of familial melanoma.

Melanoma is a form of malignant tumour arising from melanocyte cells, which are primarily found in the skin. The lifetime risk of developing malignant melanoma is around 1 in 91 for men and 1 in 77 for women in the UK (CancerHelp UK), although in Australia, where fair-skinned Caucasian populations are exposed to much higher levels of sunlight, it is much higher at 29.2 (Melanoma Patients Australia). Incidence is also rising in Europe and the US.

Although environmental factors play a key role in melanoma risk, genetic influences are also important. The GenoMEL consortium works to identify genetic susceptibility factors for melanoma, look at gene-environment interactions, determine what genetic variants mean in terms of individual risk of melanoma and develop materials for patients and health care professionals aimed at assessing and reducing risk.

Now the GenoMEL programme is set to expand to develop translational melanoma genetics research in Europe, with new partners in Eastern Europe, Australia, the US, and Israel (see GenomeWeb news article), and to widen gene-environment research to look at the effects of genetic factors and sun exposure in different latitudes. The link between family history and melanoma appears to differ significantly between countries (for example, ranging from 1% in a UK study to 11% in an Australian one, according to the GenoMEL website), which may be the result of gene-environment interactions. 

Meanwhile, preliminary results from a very small clinical trial have indicated that a new drug may offer promise as a treatment for some melanomas. The PLX4302 drug, which targets melanoma cells with mutations in the BRAF gene, reportedly reduced tumour size in more than half of the 22 patients (see Australian news article). Larger trials are expected to follow.

News story   |   By Dr Philippa Brice   |   Published 14 October 2009

Earlier this year, the US Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) released a draft report on gene patents and their impact on patient access to genetic tests for public consultation (see previous news). Following on from this, the final version of the draft report from the Task Force on Gene Patents and Licensing Practices was discussed at a SACGHS meeting last week. 

The group concluded that ‘Patents do not serve as powerful incentive to conduct genetics research, to disclose genetic discoveries, or to invest in the development of genetic tests’ and that their benefits in the area of genetic testing are therefore limited (see presentation). They also noted that patient access to genetic tests, whilst not in general affected adversely by patents, had in some cases been restricted (especially for poorer patients) when offered exclusively by a single or limited number of providers. This is typified by the exclusive US patent to the BRCA1 and BRCA2 genes held by Myriad Genetics, the subject of a legal challenge in May this year (see previous news). 

The Task Force therefore made two recommendations for longer-term statutory changes:

  • The creation of an exemption from liability for infringement of patent claims on genes for anyone making, using, ordering, offering for sale, or selling a test developed under the patent for patient care purposes.
  • The creation of an exemption from patent infringement liability for those who use patent-protected genes in the pursuit of research. Related health care and research entities also should be covered by this exemption.
  • Meanwhile, the Task Force on Gene Patents and Licensing Practices proposed that the Secretary of Health and Human Services (HHS) should discourage simple association patent claims – that is, those claiming a basic gene sequence, as opposed to applications relating to that sequence – because they ‘represent basic laws of nature that cannot be invented around’. Other suggestions included that the HHS should establish an advisory board to assess the public health impact of gene patenting and licensing practices, and that stakeholders should work together to develop consensus policies in this area, including steps to ensure patient access. The final report is expected by the end of the year.

    The SACGHS meeting also considered the Genetic Information Nondiscrimination Act (see previous news), ethical issues associated with genomic data sharing, genetics education and training, and ditrect-to-consumer genetic testing. Presentations are available from the meeting website.

    Comment: The proposed measures, if enacted, would effectively mean that individuals or organisations could perform research or offer tests relating to patented genes without licensing agreements from the patent holders. This could mean a substantial loss of revenue for the patent-holders, who might otherwise enjoy exclusive rights to such applications and charge fees to others who wanted to use them. In practice, many gene patent holders do not attempt to enforce their legal entitlements. Of note, the proposed exemption for those engaged in research already exists in the UK, where it is widely considered to be a beneficial measure, but this is quite different from provision of tests. 

    The patenting of basic gene sequences is highly contentious – and possibly increasingly redundant in the light of the increasing ease and low cost of whole genome sequencing; efforts to ensure reasonable patient access to genetic tests are also desirable, However, care may nevertheless be needed to ensure that the commercial sector retains sufficient financial incentives to continue research and development of genetic tests and related applications.

    News story   |   By Dr Philippa Brice   |   Published 12 October 2009

    Speaking at the recent World Stem Cell Summit, president of the International Society for Stem Cell Research (ISSCR) Irving Weissman reportedly announced that the creation of a new committee to regulate companies offering unproven stem cell therapies (see Nature news blog). The panel of lawyers, ethicists, stem cell scientists and representatives from the US Food and Drug Administration (FDA) have been discussing a web-based registry of companies that fail to comply with proposed measures to demonstrate credibility.

    These measures, also set out in a recent publication in the journal Cell Stem Cell [Weissman I (2009) Cell Stem Cell. 5(2):151-3], would be citation of peer-reviewed literature supporting the therapy in question is theoretically possible; demonstration of institutional review board oversight of the treatment; and approval from the FDA or other equivalent national regulatory body.

    The committee expects to produce a preliminary report by the end of the year, and formal guidelines early in 2010.

    News story   |   By Dr Philippa Brice   |   Published 8 October 2009

    Arab nations have some of the highest rates of genetic disorders in the world, according to the Centre for Arab Genomic Studies (CAGS). More than 900 different genetic diseases have been identified, around 200 of them prevalent only within the Gulf Cooperation Council states (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates). The figures appear to include diabetes and breast cancer; it is worth noting that the majority of cases of these conditions arise from a combination of environmental and genetic factors and are not technically ‘genetic diseases’, although genetic susceptibility to such conditions can be significant. There are additionally sub-groups of these diseases that are effectively inherited as single-gene (monogenic) disorders.

    The high prevalence of genetic disorders is due in part to the relatively high levels the result of consanguineous marriages (i.e. marriage between close relatives such as first cousins) in this region; in parts of the United Arab Emirates more than 50% of marriages are between relatives, for example. Other factors also have an effect; for example, social trends to continue childbearing up until the menopause can increase rates of chromosomal disorders [see Nat Genet. 2006 38(8):851].

    Information about the rates of genetic disease is from an ongoing CAGS project, the Catalogue for Transmission Genetics in Arabs (see previous news), a database for recording and identifying genetic disorders within the Arab world. The purpose of the CTGA database, which is continuously expanding with the recognition of new conditions, is to help plan regional health policies for treatment and prevention. According to CAGS assistant director Dr Ghazi Tadmouri, the aim is to give a “bird’s- eye view of each country on genetic diseases” (see The National news article). He noted that most of these conditions were single-gene disorders, for which screening (to aid early diagnosis, treatment and prevention) is relatively easy, but added that there was still generally poor monitoring of genetic diseases in most Arab countries, along with inadequate facilities for screening and prenatal diagnosis.

    News story   |   By Dr Caroline Wright   |   Published 7 October 2009

    Venkatraman Ramakrishnan (Laboratory for Molecular Biology, UK), Thomas Steitz (Howard Hughes Medical Institute, US) and Ada Yonath (Weizmann Institute of Science, Israel) jointly share the Nobel Prize in Chemistry 2009 “for studies of the structure and function of the ribosome” (see


    Their work focused on one of the most ubiquitous biological molecules in all of nature – the ribosome – which lies at the very heart of the ‘central dogma’ of molecular biology. Following the transcription of DNA from coding regions of the genome into short-lived RNA molecules, the ribosome translates this messenger RNA into a chain of amino acids, which then form functional proteins. The ribosome itself comprises two subunits, both made from RNA, which fit together to form a complex three-dimensional structure that both reads the RNA sequence and catalyses the formation of amino acid chains. Ultimately, most of the activity of genes is realised through this mechanism; from approximately 20,000 genes, perhaps a hundred thousand proteins are produced, which collectively control biochemical processes, build cells, and integrate biological systems at a molecular level.


    Studying the structure and function of the ribosome is not only important for developing our scientific understanding of life itself, but also has direct practical implications for health. For example, because bacterial ribosomes differ substantially from those found in humans, various diseases can be cured by using antibiotics which block the function of the ribosome and hence selectively kill bacterial cells.


    The Nobel committee said that “this year's three Laureates have all generated 3D models that show how different antibiotics bind to the ribosome. These models are now used by scientists in order to develop new antibiotics, directly assisting the saving of lives and decreasing humanity's suffering.”

    Keywords : Molecular Genetics

    News story   |   By Dr Philippa Brice   |   Published 6 October 2009

    The US National Heart, Lung, and Blood Institute (NHLBI) has announced $64 million funding for a large-scale DNA sequencing and molecular profiling project that will use samples from several major population studies for research into the basis of heart, lung, and blood diseases (see GenomeWeb news article).

    The project, which will run for two years, will analyse genomic data from existing cohorts with well-documented phenotypic and clinical data, in the search for genetic factors that contribute to disease, including gene-environment interactions. The conditions that will be investigated include heart attack, stroke, diabetes, obesity, asthma, chronic pulmonary disease, hypertension, and pre-cancerous blood disorders.

    The funding includes $25 million each to two genome sequencing centres at the University of Washington and the Broad Institute of MIT and Harvard, which have developed their own methods of exome sequencing, as part of the Exome Project – an initiative to develop cost-effective, high-throughput sequencing for all of the protein coding regions (exons) in the human genome, funded and run jointly by the NHLBI and the National Human Genome Research Institute (NHGRI).  

    This news follows the recent allocation of more than $1 billion for applied genomics research by the US Government (see press release), including $175 million for The Cancer Genome Atlas (TCGA) project, which seeks to map and understand the genetic basis of cancer (see previous news). This sum will be boosted by an additional $100 million from the NHGRI and National Cancer Institute (NCI), and will be used over two years for the collection and analysis of in excess of 20,000 tissue samples from more than 20 cancers. The project aims to produce comprehensive maps of the genomic changes in ten of these cancers, with sequencing and characterisation of at least 100 tumours of up to fifteen additional cancer types.

    News story   |   By Dr Caroline Wright   |   Published 5 October 2009

    Americans Elizabeth Blackburn (University of California San Francisco), Carol Greider (Johns Hopkins School of Medicine) and Jack Szostak (Howard Hughes Medical Centre, Harvard) jointly share the Nobel Prize in Physiology or Medicine 2009 “for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase” (see


    Their work focused on how the ends of chromosomes are protected from degradation during replication. Blackburn and Szostak discovered a repeated sequence (TTAGGG) at the end of chromosomes, known as the telomere, in which a single strand of DNA loops back on itself to form a 4-stranded stacked arrangement called a G-quadruplex. This knot-like structure effectively caps the end of the chromosome, preventing degradation of the functional genetic material. In normal cells, as the cell ages, the telomeres shorten and eventually disappear, resulting in uncapped chromosome ends which triggers cell death (apoptosis). This process has been widely linked to systemic aging, and some anti-aging strategies have focused on trying to lengthen the telomeres. Putative G-quadruplex sequences have also been found throughout the genome, and may play an important role in regulating gene expression.


    Blackburn and Greider went on to discover the enzyme telomerase, which maintains telomeres and hence keeps cells young and able to divide indefinitely. The enzyme contains an RNA template of the telomeric repeat, which it uses to extend the DNA repeat at the ends of chromosomes. Although most cells do not divide frequently, and hence do not express telomerase, it is active in stem cells and in around 90% of human tumours. As a result, numerous anti-cancer agents - many of which are currently in clinical trials - have been directed at inhibiting the action of this enzyme.


    The Nobel committee said that “the discoveries by Blackburn, Greider and Szostak have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies.”

    Keywords : cancer_genStem Cells

    Research articles

    Research article   |   By Simon Leese   |   Published 30 October 2009

    Following on from our recent report on the success of gene therapy to treat colour blindness in monkeys, a gene therapy trial has brought significant improvements to the sight of human patients [Maguire A.M. et al. (2009) Lancet 24 Oct epub ahead of print]. 

    The phase 1 trial was conducted on a group of 12 children and adults with Leber’s congenital amaurosis (LCA) - a group of heritable eye diseases caused by mutations in any one of 13 genes - in which severe visual impairment in childhood generally progresses to total blindness by the time the patient is in their 30’s. There is no current treatment for the disorder. A phase 1 trial is the initial testing stage of a new treatment; its primary aim is to establish safety and to give some guidance on dosage, which is then further refined in subsequent larger-scale trials.

    The patients aged 8-44 years all had RPE65-associated LCA and were first assessed to determine their baseline retinal and visual function. They were then each given one sub-retinal injection in their worst eye – at either low, medium or high dose - of adeno-associated virus (AAV) containing healthy copies of the RPE65 gene which encodes the protein required for normal activity of the retinal pigment epithelium. Follow-up assessment of the patients was carried out for up to two years.

    Improved function was detectable as early as 7 days after injection. All of the 12 patients reported improved vision from two weeks after treatment, and all showed sustained improvement in both subjective and objective measures of vision. The most significant improvements were found in the children in the group, all of whom gained ambulatory vision (defined as being able to see objects and move around a room without stumbling or bumping into obstacles), probably because they had suffered less age-related cellular degeneration of their retinal tissues; one 8-year old was reported to have attained virtually normal levels of light sensitivity. Six individuals attained enough improvement to alter their designation as legally blind. The study found no clearcut dose effect; the improvement in those receiving the lowest dose was as substantial and stable as those receiving the highest dose, and none of the patients experienced any serious adverse events.

    Comment: For a preliminary trial of a new treatment, these results are remarkable and show enormous promise. The extent of the improvements of the patients’ vision, along with their apparent stability and safety support the further development and use of such gene therapy for treatment of inherited retinal diseases, with the greatest benefits to be expected from early intervention.

    Theoretically this same treatment should prove just as effective for any one of the other forms of LCA by substituting normal copies of the appropriate missing gene, and paves the way for developing cures for other forms of heritable blindness in which a missing or faulty gene prevents otherwise healthy tissue functioning.

    News reports of the study have tended to focus on the story of one of the patients, 9 year-old Corey Haas, whose family have given press interviews. A CBS interview with Corey and his family, including video of his attempts to negotiate an obstacle course before and after his treatment can be seen here:

    Keywords : syndromesGene Therapy

    Research article   |   By Dr Philippa Brice   |   Published 28 October 2009

    Mitochondrial disorders are a group of diseases, many very serious, caused by mutations in mitochondrial genes (see previous news). Together they have an estimated prevalence of around 1 in 5,000, and can affect multiple organs. Their clinical presentation is highly variable, and the underlying mutations may lie in one of hundreds of mitchondrial genes, most of which lie within the main genome in the cell nucleus, but a small number of which (thirteen) form the small separate mitochondrial genome.

    Diagnosis of a mitchondrial disorders is therefore very difficult, but prompt and accurate diagnosis is important to allow effective treatment to minimise the potentially life-threatening disease progression. At the same time, some mutations associated with mitochondrial diseases also appear to be common in the general population; the penetrance of such mutations is also very variable, further complicating the clinical picture.

    Now US researchers have used a combination of next-generation sequencing (see previous news) and microarray technology to create a new screening technique to identify mitchondrial mutations. Publishing in the open access journal Genome Medicine, they report the use of this technique to screen for variations in all the mitochondrial genes and a total of 362 nuclear genes previously associated with mitochondrial function or disease [Vasta V et al. (2009) Genome Med. 1(10):100].

    The screen was tested on three DNA samples, two from previously characterised patients with known mitochondrial disorders and one control sample from the HapMap resource (see previous news). Both known mutations were correctly identified by the screen. In addition, the researchers reported detection of up to 336 further variants for each DNA sample, of which 90-94% were recorded in existing SNP databases and 6-10% were novel. One of these new variants was thought to be potentially harmful.

    The authors propose that their molecular diagnostic tool “will increase the capacity for early and rapid identification of mitochondrial disorders” and potentially also help in the ongoing investigation of mutations associated with the conditions. They note that as more information is recorded about genetic variants associated with mitchondrial disease, there will be decreasing requirements for investigation of potentially harmful new mutations identified by screening.

    Comment: The authors themselves acknowledge that the new screening technique requires considerable further development – three patient samples being on the small side even for a proof-of-concept study – but are right to assert that further analysis of mitochondrial mutations (which could be facilitated by methods such as their own) is likely to help expand understanding of this group of serious genetic disorders.

    Research article   |   By Dr Sowmiya Moorthie   |   Published 27 October 2009
    DNA sequence databases are often used by researchers to cross-reference unknown sequences with that of known sequences. Consequently, information on the completeness and accuracy of the sequence is important. Principal investigators participating in the Human Genome Project established world standards for genome sequence fidelity in 1997. Referred to as the Bermuda standards, they categorized sequences into either ’Finished‘ or Draft‘ sequences. Finished sequences were those that were contiguous (with no gaps) and had fewer than one error per 10,000 bases; almost all other sequences were classified as Draft. However, developments in sequencing technologies have led to a proliferation of sequence data deposited in publicly accessible databases. Much of this data has been classified as ’Draft‘ sequence, although the quality of these sequences can be very variable. Factors affecting sequence quality include the sequence technology used, which can lead to inherent errors in the sequencing process itself, and the ability of software programs to assemble these sequences.

    A recent paper published in Science has now proposed more detailed standards and classification of sequence data for researchers who generate and/or use this data [Chain et al. (2009) Science 326: 236-7]. The new standards have been compiled by an international team of researchers and classify genomes into six categories ranging from Standard to Finished. The Standard draft is the minimum standard for submission to the public databases and comprises unfiltered or minimally filtered data. Although these sequences are of poor quality and may be incomplete they still possess useful information. Finished refers to the current gold standard as described above and can act as high quality reference genomes for comparative purposes. Intermediate categories include high-quality draft, improved high-quality draft, annotation-directed improvement and non-contiguous finished.

    The authors have tried to develop standards that apply to all types of whole genome sequencing projects independent of technology used. They have also avoided rigid numerical thresholds in order to take into account products achieved by combination of technology and/or finishing processes.


    Research article   |   By Dr Gurdeep Sagoo   |   Published 23 October 2009
    Blood measurements are commonly used clinical parameters, with abnormal results potentially indicative of many different diseases including anaemia, cancer, cardiovascular, metabolic, infectious and immune conditions. Blood measurements such as the number and volume of cells are highly heritable, and vary widely between individuals. The HaemGen consortium was established to search for genetic loci that contribute to variation in blood parameters, and to assess potential correlations with disease outcomes. Soranzo et al. recently reported the findings of the first systematic genome-wide meta-analysis of eight clinically relevant haematological traits [Soranzo et al. Nat Genet (2009) doi:10.1038/ng.467]. The consortium measured six parameters directly (concentration of haemoglobin, the numbers of red blood cells, white blood cells and platelets, and the volumes of red blood cells and platelets) and derived the two red cell measures of mean corpuscular haemoglobin content and concentration.

    The first stage of their study made use of more than 4,500 healthy individuals of British and European ancestry with genotyping data for over 2 million SNPs. Using a meta-analysis to combine the results, the most promising 89 SNPs were then analysed in a further 9,000 individuals of European ancestry. In all, 23 of these SNPs were found to reach genome-wide significance in the combined sample of almost 14,000 individuals. Of the 22 loci represented by these 23 SNPs – of which 15 were novel discoveries – six loci were strongly associated with red blood cell parameters, 15 with platelet parameters and only one with total white blood cell count. No loci linked to haemoglobin concentration or mean corpuscular haemoglobin concentration were identified at genome-wide significance level.

    The 23 SNPs were then examined for associations with coronary disease, because of known associations between several blood traits and coronary artery disease or myocardial infarction. An initial stage tested association with 4,000 cases and almost 6,000 controls of European ancestry, identifying two SNPs (both from the 12q24 region) of nominal significance (p<0.05) that were further tested in an additional 5,500 cases and 4,500 controls. Both SNPs, which are in high linkage disequilibrium, also showed association in this second stage. Further investigations identified these genetic variants as unique to individuals of European ancestry. The authors suggest that they may have conferred a selective advantage thousands of years ago for their increased protection against infection, but may now contribute to an increased risk of heart disease, coeliac disease and type 1 diabetes.

    Comment: Blood measurements are an important clinical tool. This study has discovered novel genetic determinants of blood cell parameters ’providing important insights into novel biological mechanisms underlying the formation of blood cells by the blood stem cells and their role in disease’. A greater understanding of the genetics underlying blood parameter variation may lead to more refined disease risk stratification and disease prognosis for conditions such as blood cell cancer.

    Keywords : journalCHD

    Research article   |   By Dr Caroline Wright   |   Published 19 October 2009

    Since almost every cell in the body contains the same genetic sequence, additional mechanisms are required to achieve tissue-specific gene expression and cell differentiation. Thus, heritable biological factors that influence gene expression can be divided into two categories: the DNA sequence itself (the genome) and other factors (the epigenome).


    One of the major molecular mechanisms by which information about gene activity is maintained and inherited is through the methylation of cytosine bases in DNA. Usually, high levels of DNA methylation indicate that a gene is silenced, whilst active genes generally have lower levels of methylation. Unlike other epigenetic mechanisms – such as modification of the histone proteins around which the DNA is coiled – DNA methylation is relatively stable and easily measurable. However, unlike genetic information which is (largely) immutable, epigenetic information can change dynamically over time and differs enormously between cells. Therefore decoding the human epigenome is proving to be a much more ambitious task than sequencing the genome (see previous news).


    A team of American researchers has now provided the first map of the methylation state of every cytosine residue of the genome in two types of human cells, embryonic stem cells and lung fibroblasts (connective tissue cells) [Lister, R. et al. Nature (2009) doi: 10.1038/nature08514]. As expected, there were substantial differences in the location of DNA methylation in the two cell types. The surprise discovery was a significant difference in the type of cytosine residues that were methylated between the two cell lines. Like most adult cells, the fibroblast cells were predominantly methylated at so-called ‘CG sites’, where the cytosine is followed by a guanine base; in the stem cells, on the other hand, almost a quarter of the methylated cytosines were followed by a different base. Moreover, although standard CG-methylation is generally symmetrical (with both DNA strands being methylated), methylation in a non-CG context was almost always only present on only one strand. The authors hypothesize that this may be a general feature of human embryonic stem cells, which is necessary for maintaining pluripotency and is lost upon differentiation.


    Akin to the reference genome sequence, which has proved to be enormously important in genomics, the authors conclude that “these reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development”.

    Research article   |   By Dr Caroline Wright   |   Published 16 October 2009

    Whilst we often refer to the genome as if it were a simple linear sequence of DNA, in reality, it is folded up and squeezed into the nucleus of a cell. In humans, not only must all 46 chromosomes – six billion base-pairs, stretching over two meters in length – fit into a nucleus that may be only 0.01 millimetres across, but every gene that might be required by the cell must be accessible for transcription. That demands not only condensation, but also three-dimensional structural organisation within the nucleus.

    A new method known as Hi-C has provided a snapshot of the folded state of the genome inside a cell nucleus, by combining molecular biology techniques with next generation sequencing [Lieberman-Aiden, E. et al. Science (2009) 326:289-93]. By chemically cross-linking and labelling DNA inside the cell, and then purifying and sequencing the sheared fragments, it was possible to reconstruct a three-dimensional map of the nucleus to determine which parts of the genome sequence were close to each other. This revealed that clear ‘chromosome territories’ were evident, with sequence proximity generally being a good predictor of physical proximity. Interestingly, the small gene-dense chromosomes (16, 17, 19, 20, 21 and 22) were co-localised in the centre of the nucleus and were found to preferentially interact with each other. Within chromosomes, two regions were discernable – one gene-rich region with an open structure, and one densely packed area.

    This spatial compartmentalisation results in a self-organised DNA globule, which fills the nucleus without becoming entangled. The authors speculate that this knot-free structure ‘enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus”.

    Comment: Understanding the architecture of the nucleus could provide invaluable insights into gene activity in an active cell. The long range interactions between genetic sequences may allow specific loci to act as either enhancers or inhibitors for the expression of particular genes. Such three-dimensional organisation may therefore explain many of the somewhat counterintuitive results from genome-wide association studies (GWAS), where non-coding regions of the genome known as gene deserts have been associated with disease.

    Research article   |   By Dr Susmita Chowdhury   |   Published 16 October 2009

    Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterised by impairments in social interaction, in communication and by the occurrence of repetitive or stereotype behaviour. The prevalence of ASD among children is currently estimated to be around 1 in 100 in the UK (see National Autistic Society website ) and US (see Centers for Disease Control and Prevention website ).

    Autism spectrum disorders are known to be highly heritable (see previous news), although they are multi-factorial conditions that arise from complex interactions between multiple genetic and environmental factors. The genetic basis for ASD is not well understood, but recent research has implicated some specific genetic variants, including rare de novo germline mutations or copy number variations (see previous news ) and more common mutations. From an etiological point of view, autism is a genetically heterogeneous spectrum of disorders, meaning that patients with autism can have different underlying genetic causes.

    Earlier this year, a combined analysis of a series of genome-wide association studies (GWAs) found significant association with autism for a single SNP located between two known genes on chromosome 5p14 (see previous news ). Now the Harvard-based Autism Consortium has published a new GWA [Weiss LA et al. (2009) Nature. 261(7265):802-8] .

    The study was conducted using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (that is, families with multiple autistic children), and identified two novel regions of linkage, 6q27 and 20p13, although only the latter formally exceeded the threshold for genome-wide significance. Though initial analysis did not yield significant associations, subsequent genotyping in additional families revealed a SNP on chromosome 5p15 which was significantly associated with autism. The locus of the SNP was found to be between two known genes, the expression of one being reduced in the brains of autistic patients. However, the researchers observed no association at locus 5p14 as found in the earlier GWA study.

    Comment: The genetic basis of autism spectrum disorders remains unclear, including the relative contributions of rare mutations with major effects and multiple common mutations with individually minor effects. Recent GWA studies are providing further evidence of the involvement of several genes which may interact with each other and with environmental factors to cause autism. However, achieving a clear picture of the elusive and apparently highly complex genetic and environmental etiology of ASD is likely to remain a long way off.

    Research article   |   By Dr Caroline Wright   |   Published 8 October 2009

    The brave new world of consumer genomics has attracted enormous interest both in the popular press and amongst the scientific and medical establishment. Opinions vary widely about the validity and utility of these tests, and the extent to which such services should be regulated (see previous news). The internationally renowned journal Nature has now entered the foray with an editorial [Nature (2009) 461: 697-8] and an opinion piece [Ng PC et al. Nature (2009) 461:724-6] about direct-to-consumer (DTC) genetic testing companies.


    The editorial criticises the "Framework of Principles for direct-to-consumer genetic testing services” developed by the Human Genetics Commission (HGC), which is currently in draft form and open for public consultation (see previous news). It states that “the value of the tests remains debatable, which is why the industry needs a strong set of quality standards and codes of conduct to protect both its consumers and its own credibility”. Whilst this is unquestionably true, the level of regulation required to achieve appropriate standards which are in-line with other health-related tests available to the public remains contentious. Nature suggests that ultimately government regulators may need to be involved in order to adequately protect consumers.


    The opinion piece analyses the results for five individuals from two DTC genetics companies, both based in California: 23andMe and Navigenics. Although the concordance between the companies in terms of the genotype data (i.e. the analytical validity) was high, for the seven diseases analysed, less than 50% of the predictions from the two companies agreed across all five individuals. This is not a new discovery, nor is it particularly surprising given the different methods and genetic variants used by the two companies (see Genetic Future blog), but it nonetheless raises important issues about the clinical validity and any possible utility that could derive from the information as it stands. The authors highlight several important areas where further research by the genetics community is urgently needed, including monitoring behavioural outcomes following testing, prospective trials to determine the predictive value of multivariate genetic tests, and determining the underlying causal variants so that genetic sequencing (rather than SNP genotyping) can be used. In addition, the authors also make some useful recommendations specifically directed at DTC companies:

  • Report the genetic contribution for the markers tested, not just the role of genetics versus environment
  • Focus on high-risk predictions, to target lifestyle changes which could make a difference
  • Directly genotype risk markers, rather than choosing surrogate markers (which are in linkage disequilibrium with those in the published literature); although this practice is commonplace in population research, it may not be valid for individuals
  • Test pharmacogenomic markers, to reduce potential adverse drug reactions
  • Agree on strong marker effects, and hence use the same genetic variants in their predictions
  • Comment: These recommendations are useful, and would certainly improve the consistency and reliability of genomic risk profiling services. The first recommendation – to report on the genetic contribution made to the disease by the markers tested – would undoubtedly be a valuable addition to the information provided by the companies, and improve an individual’s ability to correctly interpret the significance of their results. However, the other four may be overly demanding compared with requirements for other sorts of commercial health tests and services. Whilst ensuring a high level of accuracy, reliability, validity and utility is vitally important within a state (or third party) funded health system, in order to achieve the equitable distribution of limited funds, the same is not necessarily true for the consumer market.


    Outside of the genetics field, companies can provide health-related information without being told what diseases they should focus on, as it is assumed that market forces will weed out the irrelevant tests; manufacturers are also at liberty to choose what biomarker to measure, so long as they can provide evidence that it is linked to their claims. Moreover, so long as the test device itself poses no direct physical harm to the consumer – which is certainly the case for most DTC genetic testing services – individual citizens are free to choose what to buy and how to react to their results. As the final paragraph of the editorial emphasises, regulators need to “proceed with care” and not apply more exacting standards to these tests simply because they are based on DNA.

    New reviews and commentaries

    Selected new reviews and commentaries, 1 October 2009

    Reviews & commentaries : by Dr Philippa Brice

    The expansion of newborn screening: is reproductive benefit an appropriate pursuit?
    Bombard Y, Miller FA, Hayeems RZ et al. Nat Rev Genet. 2009 Oct;10(10):666-7. 

    The ethics of egg manipulation.

    Nature. 2009 Aug 27;460(7259):1057.

    Genomics shifts focus to rare disease.
    Check Hayden E. Nature. 2009 Sep 24;461(7263):458.

    The ethical use of existing samples for genome research.
    Bathe OF, McGuire AL.Genet Med. 2009 Sep 10. [Epub ahead of print]

    Biobanks need pharma.

    Nature. 2009 Sep 24;461(7263):448.

    Genomic privacy and limits of individual detection in a pool.

    Sankararaman S, Obozinski G, Jordan MI, Halperin E. Nat Genet. 2009 Sep;41(9):965-7.

    Consent for biobank tissue in somatic-cell nuclear transfer.
    Jones DA, MacKellar C. Lancet. 2009 Sep 12;374(9693):861-3.

    Alzheimer's disease beyond APOE.

    van Es MA, van den Berg LH. Nat Genet. 2009 Oct;41(10):1047-8.


    Interferon-alfa, interferon-lambda and hepatitis C.

    O'Brien TR. Nat Genet. 2009 Oct;41(10):1048-50.


    Data's shameful neglect.

    Nature. 2009 Sep 10;461(7261):145.

    Huntington's disease: the case for genetic modifiers.
    Gusella JF, Macdonald ME. Genome Med. 2009 Aug 21;1(8):80.

    Cancer genomes - continuing progress.

    Downing JR. N Engl J Med. 2009 Sep 10;361(11):1111-2.

    Redefining cancer research.
    Alberts B. Science. 2009 Sep 11;325(5946):1319.

    Personalized medicine and inhibition of EGFR signaling in lung cancer.
    Gazdar AF. N Engl J Med. 2009 Sep 3;361(10):1018-20.


    Causes and consequences of microRNA dysregulation in cancer.

    Croce CM. Nat Rev Genet. 2009 Oct;10(10):704-14.

    A safer stem cell: on guard against cancer.
    Jandial R, Snyder EY. Nat Med. 2009 Sep;15(9):999-1001. 

    With new prenatal testing, will babies with Down syndrome slowly disappear?
    Skotko BG. Arch Dis Child. 2009 Jun 15.

    The evolutionary consequences of erroneous protein synthesis.

    Drummond DA, Wilke CO. Nat Rev Genet. 2009 Oct;10(10):715-24.

    Planning for translational research in genomics.
    Hawkins N, de Vries J, Boddington P, Kaye J, Heeney C. Genome Med. 2009 Sep 11;1(9):87.

    Can our understanding of epigenetics assist with primary prevention of congenital defects?
    Martínez-Frías ML. J Med Genet. 2009 Sep 15. [Epub ahead of print]

    Epistasis and its implications for personal genetics.
    Moore JH, Williams SM. Am J Hum Genet. 2009 Sep;85(3):309-20.

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