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 Maria Adams   |   Published 31 August 2007

A free, online database is now available that might help efforts to identify genes associated with an increased risk of bipolar disorder. This serious condition, also known as manic-depressive illness, causes unusual shifts in a person's mood, energy and ability to function.

The Bipolar Disorder Phenome Database has been created by combining retrospective clinical data collected over 20 years by researchers at the University of Chicago, Johns Hopkins and the National Institute of Mental Health [Potash JB et al. (2007)  Am J Psychiatry 164:1229-1237]. It offers detailed descriptions of the symptoms and course of disease in over 5 000 people with bipolar disorder. DNA samples are also available from many of the patients.

Although numerous family, twin and adoption studies indicate that there is a strong genetic component to the aetiology of bipolar disorder, as yet, none of the multiple susceptibility genes that are involved have been identified.

Using the database, which includes information from affected family members, the researchers have already shown that many symptoms of the disease are strongly familial. A statement from Dr James Potash, leader the Johns Hopkins group reads "This database describes the clinical picture of bipolar disorder in the fullest detail possible. It also lets us pick out meaningful clusters of symptoms that will ultimately help identify genes".

Comment: This database has the potential to distinguish clinical subtypes of bipolar disorder. This has been useful in determining the aetiology of other illnesses, such as Alzheimer’s disease and breast cancer, in which studying families with early onset illness has led to the identification of disease-associated genes.

News story   |   By Dr Philippa Brice   |   Published 29 August 2007

Chinese legislators are said to be discussing a draft amendment to the Law on Science and Technology Progress that would make failure of scientific projects more acceptable, whilst clamping down on fabrication of results and plagiarism. The draft amendment states: "Scientists and technicians, who have initiated research with a high risk of failure will still have their expenses covered if they can provide evidence that they have tried their best when they failed to achieve their goals" (see news report).

It is hoped that these changes would reduce levels of scientific fraud, whilst also encouraging innovative research. Currently, a general fear of failure is said to be common in science and medicine, with researchers who fail to achieve desirable results facing loss of reputation and funding; this is presumed to account for the relatively high levels of scientific fraud. The Chinese government has been making efforts to eliminate this practice in recent years, including blacklisting academicians for fraud.

News story   |   By Dr Caroline Wright   |   Published 24 August 2007

The US Food and Drug Agency (FDA) has announced the approval of an updated label for Coumarin, a branded version of the blood-thinning drug warfarin. The new label will explain that genetic variation in two specific genes influences how patients respond to the drug, including a statement that “lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes”. Larry Lesko, a director at the FDA’s Center for Drug Evaluation, has described the new label as bringing “personalized medicine to the mainstream”.

Warfarin is the most widely used anti-coagulant medication in the world, prescribed to over 2 million people a year to prevent blood clots, heart attacks and strokes. Patients can display markedly different responses to the drug, so doses vary enormously between individuals in order to reduce the risk of bleeding complications during treatment. Despite this awareness, it is estimated that complications from warfarin treatment send more than 43,000 emergencies to hospital each year in the US, which is more than any other drug except insulin.

Although a variety of behavioural factors influence a patient’s response to warfarin – including diet, alcohol intake and body mass – two genes have been identified that account for much of the variation. One gene, CYP2C9, produces a cytochrome P450 oxidase enzyme that helps the body metabolize warfarin and other medicines. Patients with various mutations in this gene process warfarin more slowly (see previous Journal Club article) and therefore need a smaller dose. A second gene, VKORC1, produces a vitamin K-dependent blood-clotting protein that is blocked by warfarin. Patients with mutations in this gene also need a smaller dose of warfarin as they produce less of the target protein. Indeed, some patients with a rare missense mutation in VKORC1 have complete warfarin resistance and therefore need a different anticoagulant altogether.

FDA economists estimate that by formally integrating genetic testing into routine warfarin therapy, the US alone would avoid 85,000 serious bleeding events and 17,000 strokes annually (see Associated Press article). Despite this fact, the FDA stopped short of recommending that physicians order genetic testing for all patients taking warfarin, saying that further studies are needed to establish its utility and cost-effectiveness. However, with a number of warfarin sensitivity tests already available, the new label is likely to persuade both patients and physicians to seek genetic reassurance before starting warfarin treatment.

News story   |   By Dr Alison Stewart   |   Published 23 August 2007

Recent months have seen publication of several research papers reporting striking success in the use of genome-wide association studies to find genetic variants (alleles) associated with common, complex diseases. These studies typically scan many thousands of single-nucleotide polymorphisms (SNPs) distributed across the genome, to look for differences between cases (i.e. individuals with the disease) and controls. The International HapMap project has facilitated some of this work by identifying ‘tagging’ SNPs that are representative of larger sets of SNPs (SNP haplotypes) in specific populations.

One problem with genome-wide association studies is that increasing the chances of finding associations by increasing the number of SNPs also increases the chances of false-positive results. This is sometimes known as the ‘multiple testing’ problem. A theoretical analysis published in the advance on-line publication section of the journal Human Molecular Genetics reports that, unless sample sizes (that is, the numbers of cases and controls) are sufficiently large, any advantage from increasing SNP coverage is wiped out by the increased risk of spurious associations [Nannya Y et al Hum Mol Genet. 2007 Jul 31; (Epub ahead of print)]. According to their analysis, conducted by simulating large numbers of case-control panels based on empirical data from the HapMap project, studies using around 1000 cases and 1000 controls are adequate for detecting variants with relative risks of at least 1.7. However, many gene-disease associations in common disease are expected to have relative risks considerably lower than this; studies to detect these weaker alleles while avoiding false positives should, according to Nannya et al, concentrate on achieving large sample sizes rather than denser SNP coverage.

News story   |   By Dr Alison Stewart   |   Published 18 August 2007

Earlier in the summer, the US Food and Drug Administration (FDA) issued new guidance for pharmacogenetic and genetic tests for heritable markers. The guidance is intended for use by the pharmaceutical and biotech industries in preparing pre-market approval applications and pre-market notification submissions, and by FDA staff involved in assessing these applications. The guidance, which applies to both single and multiple genetic markers (for example, array-based tests), has been developed primarily with DNA and RNA tests in mind, but may also be applied to other types of test where the purpose is to provide genetic information (for example, some protein-based tests).

In preparing a submission to the FDA for a genetic or pharmacogenetic test, applicants are advised to supply information on the test’s intended use or uses. If it is to be used in population screening programme, particular care is recommended in defining the target population, the prevalence of the genotype of interest in that population, and the positive and negative predictive values of the test.

Criteria for assessing the test’s analytical and clinical validity are described. Where clinical studies are required to assess the test’s clinical validity, the guidance’s list of points to be addressed includes validation of genotype/phenotype correlations, clinical cut-off points (where applicable), and a description of the statistical methods used and confidence intervals. Data are also required on quality control, reporting and interpretation of results, and precautions for the test’s use.

The FDA’s guidance is not legally binding. Rather, it is described as a set of recommendations that represent the Agency’s current thinking on this topic. Further refinement of the guidance is expected as the field of genetic testing develops.

News story   |   By PHG Foundation   |   Published 16 August 2007

The US National Institutes of Health (NIH) has announced plans to fund a Translational Research Network between eight US medical schools to advance research into diseases that disproportionately affect minority populations (see press release).

The three year $9.5 million grant from the National Center for Research Resources at the NIH will be used to target cancer, diabetes, renal disease, infant mortality, HIV/AIDS, and cardiovascular diseases. In addition the enhanced research capacity and infrastructure will be used to provide greater opportunities for minority populations to participate in clinical trials. It is hoped that by providing computer-based tools for analyzing and managing clinical research data, clinical trial recruitment and information sharing with patients, the network will facilitate more effective collaboration between researchers and with their communities.

Keywords : cancer_genCHDFundingUS

News story   |   By Dr Alison Stewart   |   Published 15 August 2007

Nature magazine reports that a single US Senator, Republican Tom Coburn, has blocked the Genetic Information Nondscrimination Act that is currently before the US Congress [Wadman M (2007) Nature 448(7154):631]. The Act proposes that there should be a ban on use of genetic information in connection with employment or insurance underwriting decisions. President George Bush has indicated that he will approve the Act, which was passed by the House of Representatives in April, once it has cleared the Senate (see previous newsletter article). Senator Coburn has placed a ‘hold’ on the Act, reportedly because of discrepances in the definition of genetic tests in different sections of the text, and because in his view the Act would make it too easy in some cases for individuals to sue employers who were alleged to have breached its provisions.

Many geneticists and public policy advocates in the US firmly support the Act and are outraged by this further delay to its becoming law. However, given the difficulty of defining ‘genetic information’ and ‘genetic tests’ in any fair and consistent way, some critics argue that caution is justified. In the UK, current proposals by the Discrimination Law Review for a single Equality Bill do not support a legislative approach on this issue (see newsletter article).

News story   |   By PHG Foundation   |   Published 15 August 2007

Research Councils UK (RCUK), has announced its first strategy for supporting international research collaboration. With a combined research budget of over £2.8 billion a year, the seven councils which make up RCUK are the UK’s biggest public funders of scientific research and a major influence on UK research priorities. One of the aims of the new strategy is to extend this influence to the global research agenda and ensure that UK and international priorities are aligned. The strategy will also promote the movement of researchers between countries and encourage collaboration between UK researchers and their international counterparts. Moreover RCUK hopes to give UK researchers access to data, facilities and resources and promote the UK as a world centre for research and innovation.

Notably, RCUK point to the fact that Collaborators and competitors are no longer confined to the obvious, developed nations….In particular, research spending in China and India has grown rapidly’. The research growth in these countries is also recognized in RCUK’s decision to open offices in China in 2007 and India in early 2008.

Ian Pearson, Minister for Science and Innovation commented: "By providing a coordinated approach to international research, RCUK will be able to make the UK more visible and attractive as a research partner for organizations, research teams and individuals from all over the world" (see press release).

Keywords : Fundingrinternational

News story   |   By Dr Maria Adams   |   Published 13 August 2007

The European Commission has launched a Green paper on bio-preparedness. Prompted by recent terrorist attacks in cities such as London, Madrid and New York, the intention is to stimulate Europe-wide consultation on ways to reduce biological risks, and enhance response capabilities in the event of a biological incident. Although the risk of bio-terrorist attack is low, such a debate is also needed in order to limit disruption following either natural outbreaks of disease, or the inadvertent release of disease agents in a laboratory accident.

The green paper highlights the following areas: awareness about the existing legislative framework; minimal security standards; deficits in European analytical capacity for reducing biological risks; potential misuse of research; lack of detection capabilities; and the need for multi-agency and multi-sectoral cooperation.

The document provides an opportunity for all stakeholders in Member States to identify the mechanisms and frameworks that are already in place and how they are implemented, as well as existing deficits and areas for improvement. In this context, stakeholders include national authorities responsible for risk prevention and response, public health, customs, civil protection, law enforcement authorities, the military, bio-industry, epidemiological and health communities, academic institutions and bioresearch institutes.

Health Commissioner, Markos Kyprianou said: "Protecting the health and wellbeing of EU citizens is a top priority for the European Commission. For that reason, we invite stakeholders to provide us with input on how existing instruments can be enhanced to deal with biological threats that may arise to public safety" (see press release).



News story   |   By PHG Foundation   |   Published 13 August 2007

As feared (see previous news story), Harriet Harman, the Leader of the UK House of Commons, has announced that the Science and Technology Select Committee (STC) will be dissolved. In its place, there will be a science focused permanent sub-committee of the new Committee for the Department for Innovation, Universities and Skills, with effect from November 2007.

The STC works on a cross-departmental basis, and Ian Pearson, Minister for Science and Innovation, reportedly told the Times Higher that the new science and technology committee would retain this power. However, some are concerned that science policy will not be subject to proper Parliamentary scrutiny. In an open letter published in the national news last month, a group of prominent UK scientists called for the UK government to “enhance its reputation further by ensuring the continuation of this, either through a stand-alone science and technology committee or through an adequately resourced and autonomous subcommittee of the DIUS select committee” (see Guardian news article).Current STC chairman Phil Willis has also expressed concern; in a letter to chief whip Geoff Hoon prior to the decision Willis wrote: "I am sure that you will agree that given the government's focus on evidence-based policy-making and the wide consensus on the value of science in our society, this would be the wrong time to downgrade or reduce the scrutiny of cross-cutting science issues within parliament" (see Guardian news article).

News story   |   By Dr Caroline Wright   |   Published 13 August 2007

The first in a new class of antiretroviral drugs for use in adults with HIV was recently approved by both the US Food and Drug Agency (FDA)and the European Medicines Agency (EMEA) (see FDA and EMEA press releases). Maraviroc, which will be sold by Pfizer under the trade name Selzentry® in the US and Celsentri® in Europe, is an entry inhibitor. In order to enter an uninfected cell, the HIV virus must first attach itself to proteins on the surface of the immune cell, specifically the CD4 receptor and a co-receptor. Maraviroc blocks one of the co-receptors called the chemokine (C-C) motif receptor 5 (CCR5) preventing the virus from successfully binding and infecting cells.


However, some viruses use a different co-receptor called CXCR4, so potential maraviroc patients will have to undergo pharmacogenetic testing to prove that their particular strain of HIV enters their cells via the CCR5 molecule. Patients will be screened using Trofile™, a molecular assay from Monogram Biosciences, which determines whether a particular viral strain gains entry into cells via the CCR5 co-receptor, the CXCR4 co-receptor, or a combination of the two. Following amplification of the viral genome extracted from a patient’s blood, HIV particles specific to that patient are generated and used to infect two different cell lines each expressing one of the different co-receptors. If the virus is able to gain access to the cell, subsequent expression of a reporter gene produces a visible signal.


Maraviroc is intended for patients for whom other antiretroviral HIV drugs no longer work, and due to the growing problem of drug-resistant HIV, Maraviroc received priority review. Amongst patients who have previously received HIV medications, only around 50% to 60% have viruses which bind CCR5 (so-called CCR5-tropic HIV-1). Therefore nearly half of all AIDS patients will be ineligible for maraviroc.


This approval is the first case in which a patient’s virus must undergo a genetic test before its host is eligible for the drug. With the inevitable development of more CCR5 antagonists, along with CXCR4 antagonists to treat the remaining 40%-50% of patients, pharmacogenetic testing of AIDS patients may soon become commonplace. Fortunately, in this case, many of the social, ethical and legal issues surrounding pharmacogenetic testing can be side-stepped, as the test reveals nothing about the patient’s own genome.

News story   |   By Dr Maria Adams   |   Published 7 August 2007

The European Group on Ethics (EGE) has delivered its most recent opinion on the ethics of EC Seventh Framework Programme (FP7) research projects using human embryonic stem cells (hESCs). The EGE is a group of 15 independent experts that have been appointed by the European Commission to examine ethical questions arising from science and new technologies. The groups’ aim is to promote responsible research that is transparent, in the public interest, respects Member States' autonomy, preserves public trust, promotes international cooperation and requires the embedding of ethics within research practice.

The Group’s recommendations say that actions to stimulate public debate on this research area are needed at EU level, and propose that the following considerations must apply to all EU-funded research involving hESCs:

  • FP7 hESC lines must result from non-implanted IVF embryos
  • hESC lines banked in the European Registry should be used where possible
  • If alternatives to hESCs with the same scientific potential as embryo-derived stem cells are found in the future, their use should be maximised
  • Donors' rights (in terms of health, informed consent, data protection and free donation) have to be protected and safeguarded

This report was issued following debate with scientific experts and parties representing other interests, including NGOs (non-governmental organizations), patient and consumer organisations, and industrial stakeholders. However, the EGE acknowledge the divergent views within stakeholder groups, as well as between members of the EGE, regarding the moral status of the human embryo and its use in research.

News story   |   By Alison Hall   |   Published 3 August 2007

The UK Parliamentary Joint Select Committee published its report on the Human Tissue and Embryos (Draft) Bill on 1 August 2007. The Committee has gathered an impressive array of evidence, engaged in novel methods of public engagement (see previous news), and has produced a thoughtful and balanced report. It seems appropriate that the opening chapters of the report deal with the central place of public opinion, and value of ethical deliberation. The report notes that whilst a variety of witnesses claimed that their views reflected public opinion ‘responses to public consultations often come from those with strong views which may not be representative of those held by the general public’ and the views expressed are by their nature self-selecting. As a consequence, independent public policy research commissioned by Government is needed, as is a more active approach by the Government and the regulator to improve and inform public understanding.

Given the plurality of the deeply held views expressed to the Committee, establishing an ethical framework is not straightforward. This role, the Committee argues, falls to Parliament, and they call for the establishment of a joint bioethics committee of both Houses of Parliament to provide ethical input to legislation, such as the Human Tissue and Embryos (Draft) Bill which raises significant issues in bioethics.

Regulatory architecture

Turning specifically to the draft Bill, they challenge the prescriptive regulatory architecture within the Bill which provides for a limited set of regulatory options. Instead they advocate a clear framework based on the principle of devolved regulation, establishing criteria for permitted regulation. Significantly, they dismiss plans to merge the HFEA and HTA on the basis that ‘evidence against establishing RATE [was] overwhelming and convincing’ and judge that oversight provided by the two existing regulatory authorities is better given the distinctive remit of both authorities: the HTA being concerned with the policing of consent and the HFEA with the complex moral and ethical issues surrounding the use of embryos.

Reforming the Human Tissue legislation

Despite representations that it was premature to consider reforming the recently enacted human tissue legislation, the Committee were persuaded that amendments to the Human Tissue Act (2004) may be necessary, particularly to amend the status of post-mortem tissue samples so that they are held as part of the medical record (as provided by the Human Tissue (Scotland) Act 2006). They were also persuaded that it is sometimes appropriate for samples collected after sudden infant death, to be retained rather than to be destroyed. They also acknowledge that the draft Bill may be an opportunity to review operational problems that have arisen in respect of surgically retained tissue from the living, and storage licences for research.

Inter-species embryos

Inter-species embryos is cited as ‘one of the most contentious issues in our inquiry and one in which many witnesses had opposing, deeply-held views’. The Committee criticised the attempt to apply a catch all definition, described by some witnesses as unintelligible and unworkable, branding the Government’s approach as ‘misguided and rest[ing] on no sound point of principle’. Instead if endorsed by Parliament on a free vote, the Committee advocates that the HFEA should decide which entities should be created, kept and used for research under licence, on a case by case basis, They go on to dismiss definitions for an inter-species embryo based upon a quantification of animal genes within an embryo, and instead offer a revised working definition:

An inter-species embryo is an embryo which –

(a)    contains genetic material of human and animal origin, and:

(b)   in which the genetic material of human origin consists of at least a complete set of haploid set of human chromosomes in one or more cells.

Ethical issues around fertility

The Committee argues that the State’s role in assisted conception implies a moral duty not to be party to a deliberate deception about a person’s genetic history. They urge the Government to consider in more detail the argument that donor conception should be registered on a person’s birth certificate.

Genetic registers

Given that 40% of children are born to unmarried couples, the Committee proposes extending access to registers of genetic relatedness to all prospective cohabitees, subject to consent from any prospective partner.

Saviour siblings, sex selection and the need for a father

In some respects, the regulatory hurdles imposed by the Bill are judged by the Committee as being too harsh. An example is the provision allowing the treatment of life–threatening conditions using umbilical cord blood stem cells from a saviour sibling. Instead, the Committee argue that the treatment of serious conditions should be sufficient justification. In other ways, the report suggests, the ethical framework adopted by the Bill is too lax: examples include allowing sex selection for reasons connected with the health of the child, rather than prohibiting sex selection for non-medical reasons, (the existing position, advocated by the Committee). Another example is the proposal to remove the ‘need for a father’ provision. Instead the balance of opinion from the Committee is that the provision be retained in an amended form which allows for interpretation as a ‘need for a second parent’. Again the recommendation is that the issue should be put to a free vote in both Houses.

Sperm sorting kits, surrogacy and internet sperm sorting

Some regulatory proposals were viewed as being unenforceable such as the criminal offence for advertising or supplying sperm sorting kits; but the draft legislation should be amended to include the regulation of surrogacy and provide for licensing of internet sperm donation, the Committee argue.

The Government is expected to publish a response to these proposals after the end of the Parliamentary recess on 8 October.

News story   |   By Dr Alison Stewart   |   Published 2 August 2007

The Royal Society’s response to the Human Fertilisation and Embryology Authority’s (HFEA) consultation on the ethical and social implications of creating human-animal hybrids in research sets out strong support for a policy of allowing this research.

The Society believes that research involving the transfer of a human nucleus into an animal egg will lead to important new knowledge about cell nuclear replacement (CNR) technology and, if it were to prove possible to produce embryonic stem cells by this route, would increase understanding of how to programme these cells to develop into different tissue types. The response points out that allowing such research would not only overcome some of the problems of low availability of human eggs but also, if animal eggs were sourced from abattoir material, could contribute to a reduction in the number of animals used specifically for research.

Research on other types of hybrid embryos, such as transgenic and chimaeric embryos, might also yield benefits, according to the Royal Society. Examples of applications include studies on human gene function, and creating animal models of human disease. In answer to the question of whether hybrid embryos created by CNR might be likely to develop if placed into a woman, the Royal Society notes that it is impossible to answer this question without carrying out an illegal experiment, but that experience to date with other inter-specific hybrid embryos suggests that development beyond the very earliest stages of gestation would be unlikely.

While pointing out some potential problems that could limit the usefulness of hybrid embryos in research, the Royal Society favours a regulatory approach that would broadly allow all types of human-animal hybrid or chimaeric embryos to be created for research purposes under licence by the statutory regulatory body (currently the HFEA).

News story   |   By Dr Philippa Brice   |   Published 1 August 2007

The World Health Organization (WHO) has announced that its web-based registry of clinical trial information now includes trial data from China and India, countries that are widely regarded as rapidly emerging economies in terms of biomedical research.

The registry search portal allows users (such as those involved in health care decision making) to track research activities without charge, with a view to increasing the transparency, accountability and quality of medical trials in human subjects across the world. Clinical trials seek to establish the outcomes of a broad range of health-related interventions including drugs, biological therapeutics and stem cell treatments. The WHO also runs a network of clinical trial registers to encourage collaborative working and the development of best practice

WHO Director-General Dr Margaret Chan said: "The addition of these two clinical trial registers is a milestone in a growing international movement for more transparency and accountability in research involving people…This development will contribute to improving the ethical conduct of and public trust in clinical trials, which are vital for testing new life-saving treatments" (see press release).

News story   |   By Dr Philippa Brice   |   Published 1 August 2007

According to a report in the UK’s Daily Telegraph newspaper, the UK Stem Cell Foundation, established to fund translational research to speed the development of clinically available stem cell therapies, is experiencing serious financial problems. Following the recommendations in the Pattison report, the then Chancellor Gordon Brown announced that the Government would inject a substantial amount of additional funding into stem cell science and technology, including support for joint funding of translational research by the Medical Research Council and the UKSCF. An initial two-year pilot of the joint funding scheme was to be followed, if successful, by a commitment to match funding raised by the UKSCF up to a maximum of £10 million per annum.

However, the 2006/07 and 2007/08 funding, at £1 million per year, has reportedly been far from adequate. The Telegraph’s report claims that the Foundation has run out of money only four months into the current financial year and is in discussions with the Medical Research Council (MRC) about whether, with the MRC’s help, it can keep going until April 2008, when the Government’s increased funding commitment is due to begin.  

Keywords : FundingStem Cells

Research articles

Research article   |   By Dr Caroline Wright   |   Published 30 August 2007

Writing in a recent issue of PNAS, researchers have proposed a single genetic model to explain both sporadic and inherited forms of autistic spectrum disorder [Zhao X et al. (2007) PNAS 104(31):12831-12836].


Autism spectrum disorder (ASD) is a collection of developmental disorders, including autism and Asperger syndrome, characterized by varying degrees of impairment in communication skills and social interactions as well as restricted or repetitive patterns of behaviour. The incidence of ASD is nearly 1 in 150 children, affecting four times as many boys as girls. Although environmental effects cannot be ruled out, twin studies indicate that ASD has a strong genetic component despite being a complex, multifactorial disease. Monozygotic twins have a 60-92% concordance rate for ASD (depending upon the exact diagnostic criteria) whilst dizygotic twins show only 10% concordance [Bailey A et al. (1995) Psychol Med 25(1):63-77].


Affected families are generally divided into those containing just one autistic child (‘simplex’), which is often a sporadic case, and those with multiple autistic siblings (‘multiplex’) where ASD appears to be inherited. By analysing data from the Autism Genetic Resource Exchange (AGRE) consortium and the Interactive Autism Network (IAN), lead researcher Michael Wigler and his co-workers have proposed an overarching genetic theory to explain both sporadic and inherited ASD. Specifically, that autism is caused by de novo germline mutations, which could strike at any number of critical genetic loci, in anyone, at any time. Consistent with the “extreme male brain” theory of autism, females are more resistant to these mutations than males resulting in a significantly higher penetrance in males. According to this unified theory, sporadic ASD in low-risk families is due to spontaneous mutations in the parental germ cells, with high penetrance in males and low penetrance in females. Inherited ASD results from resistant, largely unaffected individuals (predominantly female carriers) passing these mutations on to their offspring in a dominant fashion.


Comment: This theory neatly explains the twin data and the pattern of inheritance of ASD in males. The hypothesis also makes a number of strong predictions, most notably that there should be higher incidence of ASD with advancing parental age as the number of germline mutations increases. Intriguingly, the results from a number of studies looking for just such a correlation with both paternal and maternal age are wholly inconsistent. This work also has wide reaching implications, not only for ASD, but more broadly, for our understanding of genetics. Germline mutations may play a greater role in disease than previously recognized and, given the frequency and complexity of ASD, the rate of de novo mutations in humans per generation may turn out to be surprisingly high.

Research article   |   By Dr Philippa Brice   |   Published 21 August 2007

A paper published in the Journal of Clinical Oncology reports the findings of a US study looking at disclosure of BRCA mutation status (and hence information on familial risk) by parents to children under the age of 25. Carrier status for BRCA mutations in women carries a lifetime risk of up to 85% for breast cancer and 41% for ovarian cancer.

Interviews with 42 mutation carriers from the University of Chicago Cancer Risk Clinic showed that around half of them had discussed familial cancer risk and/or revealed their own mutation status to their children, with such disclosures more commonly occurring to adolescent or adult children than younger children  [Bradbury AR et al. (2007) J Clin Oncol. 25(24):3705-11]. The decision to inform children was largely taken without consultation with a clinician (14% of respondents) or genetic counsellor (21% of respondents). Around half of the parents who told children of their own mutation carrier status reported that they did not appear to understand the significance of the information shared, and a similar proportion reported negative reactions such as anxiety and distress. However, only a third of parents said that they thought it would be helpful for their offspring to see a genetic counsellor.The authors propose that further research is required to assess the comprehension and psychosocial impact of hereditary cancer disclosure in young individuals.

Comment: Although very small, this study raises the interesting question of motivation to disclose genetic test results to family members, since (as with other adult-onset disorders), the children were too young for useful clinical interventions to reduce their own risk of disease. Rather, some mutation carriers suggested that the genetic information was of value to their offspring in its own right. More worrying is the possibility that even teenage and adult children may have failed to understand the potential implications of hereditary cancer, suggesting that communicating risk to family members should be considered as part of the process of genetic counseling and testing.

Research article   |   By Dr Caroline Wright   |   Published 16 August 2007

A new study published online in the journal Science has identified two key mutations in a single gene which account for nearly all cases of exfoliation glaucoma [Thorleifsson G et al. (2007) Science (Epub ahead of print)].


Glaucoma is a group of disorders that are characterized by damage to the optic nerve, resulting in progressive loss of vision and blindness. According to the World Health Organization (WHO), glaucoma is the second most common cause of visual impairment and blindness with around 60 million sufferers worldwide. A subtype known as exfoliation glaucoma is caused by exfoliation syndrome, which is characterized by the accumulation of abnormal fibrous deposits in the eye and has reported prevalence rates of 10-20% amongst the general population over age 60. Early diagnosis and treatment is severely hampered by the lack of symptoms in the early stages of the disease, so genetic testing could help identify individuals at risk.


The research to identify genetic variants that confer a risk of glaucoma was carried out by Icelandic gene-hunting company deCODE Genetics in collaboration with the National University Hospital in Reykjavik, Iceland and Uppsala University, Sweden. Nearly 16,000 patients and controls in Iceland and Sweden were involved in the study and over 300,000 SNPs were tested for association with glaucoma.


Two single nucleotide polymorphisms (SNPs) were identified within a single gene located on chromosome 15 coding for the lysyl oxidase protein 1 (LOXL1), an extracellular enzyme involved in elastic fiber homeostasis. Both SNPs identified are non-synonymous mutations located in the first exon of LOXL1, which encodes a pro-peptide that is cleaved off for catalytic activation of the enzyme following attachment to its substrate. The risk of exfoliation glaucoma is significantly increased by the presence of either of the high risk SNPs, whose effect appears to be to lower the expression of LOXL1. Together, the two variants account for over 99% of all exfoliation glaucoma cases.


This finding is in line with other recent research [Forsman E et al. (2007) Acta Opthalmol Scand.] suggesting that exfoliation syndrome is consistent with an autosomal dominant trait with incomplete penetrance. The discovery of a sub-group of a common disease where defects in a single gene are present in virtually all cases is highly unusual.

Research article   |   By PHG Foundation   |   Published 14 August 2007

Discredited stem cell scientist Professor Hwang Woo-suk (see previous news story) may have inadvertently made a remarkable breakthrough in stem cell research. The rise and fall of the Korean scientist has been well documented, and this latest twist is the result of research by experts at Harvard and Cambridge Universities.

A team of researchers led by George Daley of the Harvard Stem Cell Institute analyzed embryonic stem (ES) cells created by Hwang’s team and found that some of the cells actually derived from human eggs stimulated to undergo parthenogenesis, not somatic cell nuclear transfer as Hwang had claimed. Parthenogenesis occurs when eggs are stimulated to develop into early-stage embryos without being fertilised by sperm. This can happen spontaneously in humans but the defective embryos rapidly die.

Producing stem cells by parthenogenesis has been the goal of many scientists as it would be the first step in the creation of human tissues genetically identical to the egg donor. This would allow the cells to be used in the replacement of organ tissues to treat serious diseases without the problems of tissue rejection by the recipient’s immune system. In addition, the creation of stem cells from eggs rather than fertilised embryos is often regarded as less ethically problematic.

Writing in the journal Cell Stem Cell, the authors of this study note that: If careful genetic and functional analyses of tissues derived from human pES cells show them to be safe and effective, then pES cells might represent a favorable source for tissue replacement therapies” [Kim et al., Cell Stem Cell (2007), doi:10.1016/j.stem.2007.07.001].

New reviews and commentaries

Selected new reviews and commentaries, 3 August 2007

Reviews & commentaries : by Dr Philippa Brice

HER2 status in breast cancer—an example of pharmacogenetic testing. Kroese M, Zimmern RL, Pinder SE (2007) J R Soc Med. 100(7):326-9. Review of breast tumour HER2 testing for trastuzumab (Herceptin) treatment, including discussion of future options for the national provision of HER2 testing in the UK (PubMed).

Non-replication of association studies: "pseudo-failures" to replicate? Gorroochurn P, Hodge SE, Heiman GA, Durner M, Greenberg DA (2007) Genet Med. 9(6):325-31. Commentary arguing that the scientific community usually has unreasonably high expectations of replication success for genetic association studies (PubMed).

Update on psychiatric genetics. Zuchner S, Roberts ST, Speer MC, Beckham JC (2007) Genet Med. 9(6):332-340. Review of current understanding of the role of genetic factors in various psychiatric disorders, predicting future lines of research (PubMed).

Preimplantation genetic screening in older mothers. Collins JA (2007) N Engl J Med. 357(1):61-3. Editorial accompanying research article on a trial of PGD, which reported that use of the technique reduced the rate of successful pregnancies and live births; the author concludes that PGD for aneuploidy should not be used solely for advanced maternal age, and calls for adequately powered randomized trials (PubMed).

Should families own genetic information? Yes. Lucassen A (2007) BMJ 335(7609):22. ‘Head to head’ debate article arguing that if anyone is to own genetic information, it should be all those who have inherited it (PubMed).

Should families own genetic information? No. Clarke A (2007) BMJ 335(7609):23. ‘Head to head’ debate article arguing that genetic information is private and personal, and that non-disclosure does not usually result in immediate grave damage to a family member; however, the author notes that specific disease-causing mutations, information could be said to belong to the laboratory or health service rather than the individual or family (PubMed).

NHS research ethics committees. Robinson L, Murdoch-Eaton D, Carter Y (2007)BMJ 335(7609):6. Editorial proposing that NHS research ethics committees need more commen sense and less bureaucracy (PubMed).


Genetic linkage and association analyses for trait mapping in Plasmodium falciparum. Su X, Hayton K, Wellems TE (2007) Nat Rev Genet. 8(7):497-506. Review of genomic information presently available for malaria parasites, and implications for the understanding of malaria pathogenesis, transmission and treatment (PubMed).


RNA regulons: coordination of post-transcriptional events. Keene JD (2007) Nat Rev Genet. 8(7): 533-43. Review of the function of RNA operons in different species, and their potential role in normal and pathological mechanisms (PubMed).

Communicating genetic information in the family: the familial relationship as the forgotten factor. Gilbar R (2007) J Med Ethics. 33(7):390-3. Discussion article advocating a relationalperception of autonomy with respect to genetic information, which would take into account the effect of disclosure or non-disclosure on family dynamics, and require a relaxation of medical confidentiality so that the family (rather than the patient) is perceivedas the unit of care (PubMed).

Stem cells: The magic brew. Rossant J (2007) Nature 448(7151):260-2. News and views piece on prospects for extending work creating embryonic stem-like cells from mouse skin cells into humans (PubMed).

Neurobiology: New order for thought disorders. Role LW, Talmage DA (2007) Nature 448(7151):263-5.News and views piece on insights into complex human psychiatric disorders gained from genetic studies in mice (PubMed).

The Role of Genetic Testing for Cancer Susceptibility in Gynecologic Practice. Karlan BY, Berchuck A, Mutch D (2007) Obstet Gynecol. 110(1):155-167. Discussion of the role of inherited cancer susceptibility, genetic testing for mutations and practical applications of results in gynaecological practice (PubMed).

Discriminating on genes. Nature 2007 448(7149):2. Editorial piece endorsing the recent US Genetic Information Nondiscrimination Act and calling for other countries to enact legislation to protect genetic information from insurers and employers (PubMed).

The search for genetic variants predisposing women to endometriosis. Di W, Guo SW (2007) Curr Opin Obstet Gynecol. 19(4):395-401. Review of current evidence on genetic factors that influence risk of endometriosis, concluding that further and more robust genetic epidemiological studies are required (PubMed).

Advancing stroke therapeutics through genetic understanding.Ross OA, Worrall BB, Meschia JF (2007) Curr Drug Targets. 8(7):850-9. Review looking at how validated associations between genetic variants and stroke may affect the development of novel and improved treatments (PubMed).

Rational design of cancer-drug combinations. Ramaswamy S (2007) N Engl J Med. 357(3):299-300. Clinical implications of basic research article on prospects and barriers for new, intelligent design of chemotherapeutics (PubMed).

Common pathways in inflammatory diseases revealed by genomics. Massey DC, Parkes M (2007) Gut Jul 16; [Epub ahead of print. Review of recent progress towards identifying genetic variants involved in predisposition to common diseases such as Crohn’s disease, from genome-wide association studies (PubMed).

Innate immunogenetics: a tool for exploring new frontiers of host defence. Bochud PY, Bochud M, Telenti A, Calandra T (2007) Lancet Infect Dis. 7(8):531-42. Article looking at prospects for improved understanding of genetic influences on innate immune responses, and potential applications in the development of anti-microbial interventions (PubMed).

Achondroplasia. Horton WA, Hall JG, Hecht JT (2007) Lancet. 370(9582):162-72. Seminar on this most common form of short-limb dwarfism, including epidemiology, genetics and pathophysiology (PubMed).

Genes, cancer risks, and clinical outcomes. Hartge P (2007) N Engl J Med. 357(2):175-6. Editorial accompanying report on the influence of BRCA1/2 mutation status on presentation, treatment and survival of breast and ovarian cancer patients (PubMed).

read more ...