In the news

The UK Border Agency has reportedly launched a new Human Provenance pilot project intended to use genetic testing as an additional element to other forensic techniques used to determine the true nationalities of asylum seekers (see Observer news article). The project is initially testing samples provided on a voluntary basis by asylum seekers from Africa who have failed linguistic tests and are suspected of claiming false nationality – for example, Kenyans who claim to be Somalis fleeing persecution – but could be extended to other nationalities if deemed successful. 

The pilot will use mitochondrial DNA and Y chromosome testing, as well as single-nucleotide polymorphisms (SNP) analysis in an attempt to help determine the true nationality of applicants. However, the plans have attracted serious criticism about the scientific basis for this application of genetic testing. The Border Agency has reportedly released a written response saying: “This project is working with a number of leading scientists in this field who have studied differences in the genetic backgrounds of various population groups” (see ScienceInsider article), although these scientists are not identified. 

Other leading scientists say that using genetic data to attempt to determine nationality in this manner is flawed; Professor Sir Alec Jeffreys of the University of Leicester (who invented the forensic DNA fingerprinting technique) told Science that it was “wildly premature, even ignoring the moral and ethical aspects”, also pointing out that even were sufficient research evidence on the ability of DNA testing to identify ethnic origin from that region available, genetic indications of ethnicity would still not establish nationality.

Although many companies now offer genealogical or ancestry DNA testing services, their utility is highly questionable; they typically use 'methods that were developed for the study of human populations rather than individuals' (see Information on genetic ancestry testing). The concern is that asylum seekers will feel compelled to provide DNA samples for analysis and that the results may be inappropriately interpreted when officials attempt to use them in deciding on nationality.

New guidance released by the UK General Medical Council (GMC) says that doctors may in some circumstances share confidential genetic information about patients with their relatives against the wishes of the patient. The guidance recognises that the obligation of confidentiality is not always absolute, and that information about an individual may be disclosed without their consent if (and only if) it is necessary to prevent serious harm to another person.

For any inherited form of disease, doctors will explain to a patient if family members may also be at risk of the same condition; it is suggested that doctors should ask patients what information they would like to share, with whom, and under what circumstances. For serious genetic diseases - for example, hereditary forms of cancer, where regular screening and prompt treatment can make it much more likely that affected people will survive - if patients cannot be persuaded to tell relatives who are at risk, clinicians may, having weighed up the risks and benefits for both patient and relatives, decide to inform them. Similarly, if children have been adopted, doctors could decide to take steps to let them know they are at risk. The guidance emphasises measures that should be taken to protect the identity of the original patient if possible. Consultant Dr Frances Flinter said that doctors could trace relatives via the NHS and get in touch indirectly via their own doctors (see Times news article).

Dr Henrietta Campbell, who chaired the GMC’s working group on confidentiality, said: “This guidance makes clear that, in the first instance, doctors should explain to a patient if their family might be at risk of inheriting a condition. In those circumstances, most will readily share information about their health. However, if a person refuses, it is the responsibility of the doctor to protect those who may be at risk” (see press release).

The new guidance, Confidentiality, addresses broad issues of medical confidentiality, setting out the principles that doctors must follow in respecting the privacy of patients, and looking at the ethical and legal factors that influence decision-making. The general guidance is supported by supplementary guidance on various specific situations such as reporting serious communicable diseases, or concerns about fitness to drive. The revised guidance was produced following a public consultation, to which the PHG Foundation responded last year, and will come into effect on 12 October 2009.

The Canadian Stem Cell Foundation, an independent non-profit organisation dedicated to promoting the role of stem cell science in health, has launched a Stem Cell Charter. The purpose of the Charter (slogan: a stem cell can renew the world) is to attract signatories to affirm their support of research into stem cell medicine. It is hoped that one day stem cell therapeutics could offer cures for serious diseases such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, and for spinal cord injuries that cause forms of paralysis.

The Charter was created in collaboration with a working group of scientists, patients, ethicists and public representatives. It sets out five principles for the advancement of stem cell science: responsible science, protection of citizens, intellectual freedom, transparency, and integrity.

Canadian Stem Cell Foundation President and CEO James Price commented that everyone had a vested interest in developing stem cell medicine, saying of the Charter: “It's something that everyone, whether they are doctors, scientists, policy makers or the general public, can get behind. It unifies us in support of this vital area of research" (see Medical News Today article).

This effort to boost public support for this area of research may be considered a necessary counter to concerns about the ethics of those areas of stem cell research that use or stem cell lines derived originally from embryos, although there are prospects for producing therapeutic stem cells without the use of embryonic material (see previous news). At the same time, public expectations of stem cell medicine are often very high, with frustration that the marvellous cures promised by scientists have yet to materialise in the clinic, and an expanding market for unproven treatments (see previous news).

Comment: The website introduction features a video of scientists saying that “right now there’s a way to cure disease…generate organs…prevent heart attacks…let bodies heal themselves…it’s called a stem cell, and it can do all that…not in a hundred years, or in fifty…but in ten”. Will these assertions be borne out? Hopefully there will indeed be some effective therapeutics in this projected timescale, but it is unlikely that the science can deliver on all these ambitious promises in so short a time. Researchers must walk a tightrope between convincing potential funders and those who influence them of the potential importance of this area of research for medicine, and over-hyping the short-term benefits.

A new policy statement from the Toronto International Data Release Workshop calling for pre-publication data release such as that pioneered by the publicly funded Human Genome Project, has been published in Nature. The Toronto statement [2009 Nature 461, 168-170; doi:10.1038/461168a] was produced by a group of scientists, ethicists, lawyers, and scientific journal editors who attended the workshop hosted by Genome Canada and other bodies in May 2009.

The attendees noted that the pre-publication, public release of large-scale biomedical data sets “can be profoundly valuable to the scientific enterprise and lead to public benefits” and should extend beyond genomic and proteomic data to other types of information, including metabolomic and RNA interference data and annotated clinical resources such as cohorts, tissue banks and case-control studies. The group also proposed that pre-publication data-release policies should include whole genome or mRNA sequences of reference organisms, microbial communities (microbiomes) or tissues, genome-wide association and whole-genome expression profiling data.

An editorial accompanying the statement further notes the power of ‘legacy’ data sets to generate new discoveries, including via applications and analyses of the data that the original producers could not have envisioned [2009 Nature 461, 145; doi:10.1038/461145a].

The Toronto participants noted that researchers using data made available in this manner should protect the original research subjects and avoid any ethically dubious applications. They should also respect scientific etiquette such that the originators of the data should publish the first global analysis, and be kept properly informed of (and cited by) subsequent research, calling for transparent and explicit co-operation between data producers, analysts, reviewers and journal editors. 

The group also recommended that funding bodies adopt a policy of pre-publication data release for research involving genotypic analysis, and help researchers to meet this requirement including the development of suitable protocols to ensure the consent and privacy requirements of research subjects are met. They note that “proactive engagement of funders is beneficial throughout a project” as evinced by initiatives such as ENCODE, the 1000 Genomes Project, the International Cancer Genome Consortium and the Human Microbiome Project.

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US company Complete Genomics Inc. announced today that it has sequenced and analysed fourteen complete human genome sequences this year. The company says that customers including academic and commercial research organisations are using these genome sequences for small-scale disease studies to investigate conditions as diverse as cancer (breast, lung, colorectal and melanoma), HIV and schizophrenia.

CEO Dr. Clifford Reid said: “Sequencing one human genome is a scientific curiosity. We need to sequence thousands of them to be able to make meaningful discoveries about the genetic basis of disease. To that end, Complete Genomics plans to sequence 10,000 human genomes in 2010" (see press release). The company is targeting high-volume customers, for whom prices will be as low as $5,000 per genome, although they will also offer smaller-scale services, with prices from $20,000 per genome for a minimum of eight genomes.

This is a very different business proposition from companies that are currently focused on the sale of personal genome sequences to individual customers. As the cost of human genome sequencing continues to fall (see previous news), commercial outsourcing of sequencing for research purposes may become increasingly popular.  At the same time, efforts such as the 1000 Genomes Project continue to provide publicly accessible human genome sequence data for research purposes (see previous news).

Of note, different applications of human genome sequence data (whether for various forms of research, or for potential future clinical applications) may have different requirements in terms of accuracy and coverage, and so cost, whilst important, is not the only factor that will influence how the field develops and different sequencing providers move forward.

A consortium of European and Chinese bodies concerned with the ethical governance of biomedical research, BIONET, has called for more effective regulation of stem cell research and therapeutics across the world. Medical ‘stem cell tourists’ with incurable conditions are increasingly travelling to countries with clinics that offer novel stem cell novel therapies; however, most such treatments have not undergone clinical trials. 

A BIONET expert group of scientists, clinicians, ethicists, lawyers and policy makers have looking at stem cell therapeutics have identified concerns in different countries that research was moving too rapidly into clinical practice, and called for proper clinical trials to investigate the safety and efficiency of new treatments before they are offered to patients. It was also found that treatments were often over-hyped to potential patients desperate for a cure. Professor Nicholas Rose of the London School of Economics, who co-chaired the group, said: "The key is informed consent. Doctors should be able to tell the patient about the short-term and long-term prognosis and the things we don't know about the risks" (see BBC news report). 

The group also called for transparency over the source of germ cells, embryos and embryonic tissues used for treatments; for ethical safeguards to prevent coercion of potential donors or patients; and for quality standards for stem cells used in clinical practice to be established. Their recommendations follow on from guidance on issues surrounding the clinical translation of stem cells issued by the International Society for Stem Cell Research in 2008 (see previous news). 

China introduced new regulations earlier this year that require clinical trials before new stem cell treatments can be offered to patients. BIONET Expert Group co-chair Professor Qiu Renzong of the Chinese Academy of Social Sciences commented: “Stem cell research is tremendously exciting and may lead to potential treatments. However its development must be governed in an ethical and responsible way if it is to fulfil its potential and not experience a backlash from public opinion. Many countries, including China and those in the EU, are now starting to regulate these therapies. However, if patients are to be properly protected, regulation needs to be enforceable and effective” (see press release). 

The BIONET expert group has produced a series of additional recommendations for the ethical and structural development of European-Chinese collaborative research in the biological sciences, including stem cell and genomic research, launched at a conference last week. These include calls for improved regulation of clinical trials, international consensus on ethical issues related to biobanking, and the establishment of a permanent China-Europe partnership on research ethics.

The UK Human Genetics Commission (HGC) has launched a public consultation on its draft document A Common Framework of Principles for direct-to-consumer genetic testing services. This follows on from their earlier reports on genetic tests supplied to the public, Genes Direct published in 2003 and More Genes Direct published in 2007.

The Common Framework of Principles is intended to “promote high standards and consistency in the provision of direct-to-consumer genetic tests amongst commercial providers at an international level, in order to protect the interests of people seeking genetic tests and their families”. Companies and governments may use these principles as a guide to good practice or for developing Codes of Conduct or other regulatory responses. This approach stands in a stark contrast to the paternalistic German legislation regulating to genetic testing, in which DTC genetic tests are essentially banned (see previous news).

The Principles were developed by an expert working group, including Dr Ron Zimmern from the PHG Foundation as well as clinicians, laboratory scientists, genetic counsellors and representatives from both patient groups and commercial genetic testing providers. The Principles are intended to cover all types of genetic tests sold or marketed to the public, including diagnostic, pre-symptomatic, carrier, pharmacogenetic, susceptibility, lifestyle / behavioural, nutrigenetic, phenotypic, relatedness (e.g. paternity), ancestry and genetic matching. Recommendations are made relating to the marketing, advertising and regulation of genetic tests, information provision, consent and data protection, sample handling and laboratory processes, interpretation of the results, availability of continuing support, and complaints procedures.

The draft is accompanied by a set of consultation questions. Of particular note are questions addressing the need for pre- and post-test genetic counselling, the usefulness of drawing a distinction between presymptomatic and susceptibility tests, and whether children (or those lacking the capacity to give informed consent) should be able to purchase tests.

The consultation period closes on 6 December 2009, and the PHG Foundation will be submitting a formal response in due course.

Prostate cancer is the most common cancer in men, with an average absolute lifetime risk of around 12% across the population. However, there is continuing controversy over whether to implement screening programmes for this disease. Despite numerous studies, it remains unclear whether screening for prostate specific antigen (PSA) does more harm than good (see previous news). Great hope has therefore been placed in finding common genetic variants that might be used to stratify the population into risk categories, so that screening could be targeted at those considered to be at highest risk (see previous news).

 

Four new studies have been published online in the journal Nature Genetics, identifying over a dozen new prostate cancer susceptibility loci. Taken together, these studies involve over 100,000 individuals enrolled as either cases or controls in studies across the globe. Two studies focus on a region of chromosome 8 (8q24.21), which has previously been associated with numerous cancers including prostate, showing that multiple SNPs in this region are independently associated prostate cancer risk [Yeager M et al. (2009) Nat Genet doi:10.1038/ng.444; Al Olama AA et al. (2009) Nat Genet doi:10/1038/ng.452]. Although this region contains no known protein-coding genes, the oncogene MYC is nearby and appears to be the most attractive candidate for the underlying causal association. This gene encodes the transcription factor c-myc, which is linked with the regulation of numerous genes involved in cell proliferation.

 

The other two papers report large genome-wide association studies (GWAS), between them finding or verifying SNPs associated with prostate cancer on chromosomes 2, 3, 4, 8, 11, 19 and 22 [Eeles RA et al. (2009) Nat Genet doi:10.1038/ng.450; Gudmundsson J et al. (2009) Nat Genet doi:10.1038/ng.448]. Although most of the risks associated with each variant are modest, with per allele odds ratios of around 1.1-1.3, there are now over 20 prostate cancer susceptibility variants. When combined, these variants confer a risk of approximately double for the top 10% of the population, and triple for the top 1%, relative to the population average. Moreover, taken together, these loci may explain around 20% of the familial risk of prostate cancer.

 

Comment: Various commentators have suggested that these studies are likely to herald a new era of targeted prostate cancer screening (for example, see The Times). Whilst such claims are likely to be somewhat premature – due the requirement for robust and systematic evidence of the benefits, harms and costs of rolling out a national screening programme – there is no doubt that relative risks of 2-3 are large enough to be potentially clinically useful, as they are comparable with the twofold relative risk conferred by first-degree relatives. Further research is needed to understand whether those at a high genetic risk of developing prostate cancer are also at highest risk of developing the aggressive form of the disease, for which early treatment is undoubtedly beneficial, or the more common benign form, for which treatment is unnecessary and potentially harmful.

Meiosis is the process of cell division that halves the number of chromosomes per cell and in animals this process results in the production of gametes – sex cells. During the initial phase of meiosis homologous chromosome pairs align and one of each pair is subsequently separated into a different cell, resulting in a haploid cell. Failure of chromosomes to separate properly during the final stages of meiosis in the formation of human oocytes (egg cells) – a phenomenon that becomes increasingly common with advancing maternal age – causes aneuploidy (abnormal number of chromosomes) in the oocyte and any subsequent fetus. Many forms of aneuploidy are lethal, but the milder forms are a relatively common genetic cause of birth defects such as Down, Edwards and Patau syndromes.

Researchers at Florida State University studying chromosomal structural organisation in yeast have made a discovery that may explain why chromosomes fail to segregate properly (see press release). The pairing of homologous chromosomes is mediated by the synaptonemal complex (SC), which also plays an important role in meiotic recombination and genomic integrity. The importance of this complex is demonstrated by its conservation across species. Jin et al have shown that the absence of a protein Pds5 results in a failure of homologous chromosomes to pair and lead to formation of SC like complex between sister chromatids [Jin H et al. (2009) J Cell Biol. 186(5):713-25].

Previous studies have shown that Pds5 is required in maintaining cohesion between sister chromatids, an important step required prior to the assembly of the SC complex. To discover more about the role of Pds5 in this process, the researchers created yeast mutant cells in which the Pds5 protein was completely depleted specifically during meiosis. Surprisingly these mutant cells had only minor defects in sister chromatid cohesion, but homologous chromosomes failed to pair and an SC like structure formed between sister chromatids, resulting in them pairing instead. By investigating one of the factors that interacts with Pds5 they were also able to demonstrate a possible mechanism that lead to a disruption. The researchers suggest that Pds5 modulates the function of another protein, Rec8 in order facilitate the morphological changes in chromosomes which are required for normal segregation during meiosis, as well as other functions.

A number of other factors also interact with Pds5 and these are currently being investigated. The researchers hope “to achieve a comprehensive understanding of the molecular mechanisms behind chromosomal birth defects and see our research contribute to the creation of targeted interventions during meiosis" (see press release).

Comment: Whilst understanding the molecular mechanisms underlying human birth defects is important, any form of ‘targeted intervention’ during meiosis would not be practical or affordable for the vast majority of cases. Almost 95% of birth defects (the majority of which have genetic causes) occur in the developing world where high-tech prenatal genetic manipulation would certainly not be feasible. The PHG Foundation is currently embarking on a new project to reduce the suffering associated with birth defects in poorer countries by simple, practical measures to improve care and prevention.

A group of drugs have already been shown to be able to specifically target cancer cells containing BRCA mutations via a mechanism known as synthetic lethality, and early clinical trials have shown encouraging results (see previous news). New research published in EMBO Molecular Medicine has demonstrated that these PARP inhibitors can also function as selective inhibitors of tumours in cells with PTEN mutations. 

The phosphatase and tensin homolog (PTEN) gene is a tumour suppressor gene; loss of PTEN gene expression is significantly associated not only with BRCA1-associated familial breast cancers [Saal LH et al. (2008) Nat Genet. 40(1):102-7], but also with various sporadic (non-familial) cancers. It is one of the most commonly mutated genes in human tumours, including breast, prostate, melanoma (skin), endometrial and colon cancers.

Researchers from the Institute of Cancer Research (ICR) in London showed that human cellswith PTEN mutations, like those with BRCA1/2 mutations, are defective in the normal process by which double-stranded breaks in cellular DNA are repaired [Mendes-Pereira AM et al. (2009) EMBO Mol. Med. DOI 10.1002/emmm.200900041]. PARP inhibitors increase the rate of formation of double-stranded breaks in the DNA and thereby selectively target cells with these mutations over normal healthy cells. Selective drug action of this type is not only good news for efficacy, but also reduces the level of toxic side-effects for patients.

The researchers found that human tumour cells with defective PTEN genes were up to 25 times more sensitive to PARP inhibitor drugs than normal cells. They also transplanted human cells with PTEN mutations into mice; growth of the transplanted tumours was significantly suppressed in mice treated with the PARP inhibitor olaparib, but this effect was not seen in mice with tumours arising from human cells without PTEN mutations. The authors therefore propose that PAP inhibitors such as olaparib may be effective against human tumours containing PTEN mutations.

Researcher Professor Alan Ashworth, Director of the ICR Breakthrough Breast Cancer Research Centre commented: “Clinical trials have already shown the potential of PARP inhibitors for patients with tumours caused by faulty BRCA genes. We now need to test whether the promising results from this study can be matched in the much larger group of patients with PTEN-related tumours” (see press release).

Comment: The potential opportunities for new forms of personalised cancer therapeutics continue to expand; of note, treatments that rely on genetic features of the tumour will require tumour testing to assess these features. There may be challenges in communicating to the general public that any new ‘wonder-drugs’ will only be suitable for use in patients whose tumours have the relevant genetic feature/s.

US researchers have reported in Nature that they have effectively cured red-green colour blindness in adult monkeys using gene therapy [Mancuso K. et al. (2009) Nature Sep 16 ePub ahead of print]. The widely-reported research offers the possibility of such treatments being used to treat colour blindness and other visual problems in people.

Red-green colour blindness is the most common single gene disorder in humans, affecting approximately 1 in 12 men. It is not usually considered to be a serious or debilitating condition, but those affected can be barred entry into certain occupations that depend upon the ability to reliably discriminate between different hues.

The study used male squirrel monkeys, all of whom are born red-green colour blind: Full colour vision requires two versions of the opsin gene located on the X chromosome; since male monkeys have only one X chromosome they only have one version of the gene, and so are unable to distinguish between red and green. A similar mechanism accounts for the same form of colour blindness in men.

The researchers injected human opsin genes contained within a viral vector into the subretinal tissue of the monkeys’ eyes. The genes were accompanied by regulatory elements selected to induce the expression of the gene only in colour-sensitive cone cells. The monkeys were repeatedly tested before and after treatment by being required to touch coloured patches on a screen in order to receive a treat. 20 weeks following treatment there was a ‘dramatic’ improvement in the monkeys’ ability to distinguish colours, and this enhanced vision has remained stable for the past two years without adverse side effects.

Despite the monkeys having been colour blind since birth, adding the missing gene was enough to give them full colour vision, indicating that the formation of new neural connections was not required. This is in contrast to developmental conditions such as monocular deprivation, whereby if one eye is covered during early development sight cannot subsequently be restored in that eye – despite no tissue being damaged – because the neurons no longer respond to input from that eye.

Comment: The results of this study suggest the possibility that future gene therapies could enable function to be added or restored to the eye. Since colour blindness is not considered a serious condition, extensive further research will be required to categorically establish the safety of this technique before it is even considered for clinical trials. It is plausible however that this method could be employed to treat more debilitating visual problems with a genetic basis – trials are currently underway using gene therapy to treat Leber’s congenital amaurosis – perhaps ultimately leading to gene therapies that are able to restore sight in some blind people.

In September last year bodies such as the Wellcome Trust and the US National Institutes of Health (NIH) restricted access to databases containing genetic information following the publication of an article in PLoS Genetics (see previous news). The article described a statistical approach to the analysis of single nucleotide polymorphism (SNP) data sets to resolve individual genotypes [Homer N et al, (2008) PLoS Genet. 4(8), e1000167]. This technique was a major breakthrough for forensic science, but could also allegedly be applied to individual participants, in data obtained from genome-wide association (GWA) studies, although identification would require prior knowledge of the SNP profile of the individual concerned, or a close relative. GWA studies rely on combining data from multiple studies in order to in order to demonstrate genetic associations with appropriate statistical power, a process which is affected by restricted access to data. This problem of data access and anonymity may now have been overcome with the development of a mathematical formula and concurrent software program (reported by GenomeWeb).

It is possible to detect individual genotypes from a DNA pool if a sufficiently large number of common SNPs are known. However, accurate identification is also dependent on the allele frequencies of the SNPs, the number of individuals in the DNA pool, and the method used to detect an individual in the pool. Consequently, it may be possible to prevent the revelation of subject’s identity by limiting the SNP information in the dataset. A recent paper in Nature Genetics describes the development of an approach to elucidate which SNPs are ’safe‘ to reveal, thereby allowing configuration of datasets to increase anonymity.

Based on a study of statistical methods such as those developed by Homer et al., Sankararaman et al. have constructed a likelihood ratio test (LR test) to calculate the probability of identification of an individual genotype in a pooled data set Sankararaman et al. (2009) Nat Genet. doi:10.1038/ng.436]. The LR test is able to do this by taking into account the false-positive rate, the size of the pool and the number of exposed SNPs. As altering the number of exposed SNPs influences the LR value, the formula allows estimation of the chances of identifying an individual genotype within the pool in relation to exposed SNPs, thereby giving some guidance on how to alter the dataset to maintain anonymity.

Based on the mathematical formula the team went on to develop a software tool called SecureGenome, which allows users to identify a limited set of SNPs that can be safely revealed from a genotype dataset. The approach was validated using simulated data, as well as data from the Wellcome Trust Case Control Consortium and HapMap Project. The exposed SNPs in each data set were varied and the likelihood of identifying a specific test genotype was calculated, this allowed identification of SNPs that could safely be exposed.

However, the method has some limitations; it assumes that the SNPs are in linkage disequilibrium and does not factor in rare SNPs which make data much more identifiable. In addition, the set of SNPs which can be safely exposed may not necessarily be those in which researchers are interested.  

Alzheimer’s disease is the most common form of dementia, affecting around 417,000 people in the UK (according to the Alzheimer’s Society website). The common, late-onset form of the disease, which accounts for 90% of all cases, shows a relatively high degree of heritability, but genetic contributions to disease risk are undoubtedly complex. Despite large amounts of research conducted to date, the APOE gene is still the only one to be established unequivocally as a susceptibility gene. Harold et al. recently reported the findings of their two-stage genome-wide association (GWA) study started almost two years ago (see previous news). Association between Alzheimer’s disease risk and genetic variants in two genes (CLU and PICALM) was identified, and the well established APOE association replicated [Harold et al. (2009) Nat Genet 6 September doi:10.1038/ng.440].

The first stage of the study made use of almost 4,000 Alzheimer’s disease patients and 8,000 healthy controls of American, British and European ancestry, with genotyping data for 530,000 SNPs. Thirteen SNPs at the APOE locus were found to be statistically significant at a genome-wide threshold of P ≤ 9.4 x 10-8. Two other SNPs reached this significance level representing newly identified associations. The first SNP (rs11136000) is located within an intron of the CLU gene (which encodes a major brain apolipoprotein, clusterin) on chromosome 8. The second SNP (rs3851179) is located 88.5kb from the PICALM gene (which encodes the phosphatidylinositol-binding clathrin assembly protein) on chromosome 11. In the second stage of this study, these two SNPs were genotyped in an independent sample of 2,000 Alzheimer’s disease patients and 2,300 age-matched and cognitively screened controls of European ancestry, and shown to be independently associated in this sample. A meta-analysis combining data from both stages also showed significant association for both SNPs (rs11136000 P = 8.5 x 10-10, OR = 0.861, 95% CI 0.82-0.90; rs3851179 P = 1.3 x 10-9, OR = 0.859, 95% CI 0.82-0.90).

The investigators then moved their focus to trying to identify functional variants responsible for these associations. A synonymous SNP (rs7982) located in exon 5 of the CLU gene was identified as being in strong linkage disequilibrium with rs11136000 and also showed similar levels of evidence for association with the combined stage1 and stage 2 study data. This SNP is located in a region coding for the beta chain of the clusterin protein and may influence a predicted exon splicing enhancer. Several potentially functional SNPs were identified at the PICALM locus, and two of these show evidence of association with putative transcription factor binding and exon splicing functions; all these functions could influence gene expression.

Comment: Well-conducted and showing robust evidence for association, the study by Harold et al. identifies new genetic variants in two gene loci of interest, providing further avenues of investigation in uncovering the genetic architecture of Alzheimer’s disease. The study by Lambert et al. [Lambert et al. (2009) Nat Genet 6 September doi:10.1038/ng439], also published in the same issue of Nature Genetics, also provides replicated evidence for the CLU gene in 5,000 Alzheimer’s disease patients and 8,000 controls of European ancestry. These two studies provide interesting epidemiological evidence for Alzheimer’s disease genetics, although much more work is required before any possible clinical benefits could be realised.

Lung cancer is the most common cancer in the world, with 1.3 million new cases diagnosed every year, and is the second most common cancer diagnosed in the UK according to Cancer Research UK. Recently, it has been estimated that the lifetime risk of developing lung cancer is 1 in 14 for men and 1 in 21 for women in the UK, and it has one of the lowest survival outcomes of any cancer. Around 90% of lung cancers in men and 83% in women can be attributed to cigarette smoking, but there is recent evidence which indicates that inherited genetic factors may influence the development and progression of this disease.

 

In order to explore the impact of common genetic variation on the risk of lung cancer, a two phase genome-wide association (GWA) study followed by a meta-analysis was carried out by British and American scientists [Broderick P et al. (2009) Cancer Res 69(16):6633-41]. Nearly 5000 cases and 5000 controls were genotyped, and the strongest associations (p<10-7) were identified in single nucleotide polymorphisms (SNPs) mapping to a region of chromosome 15 (15q25.1), chromosome 5 (5p15.33) and chromosome 6 (6p21.33). The odds ratio associated with each of these variants was around 1.3, 0.9 and 1.2 respectively. These associations point towards four genes, all of which represent strong candidates for combined lung cancer susceptibility and predilection to smoking a priori: the acetylcholine receptor alpha-subunit (CHRNA; 15q), cisplatin resistance related protein (CLPTM1L; 5p), telomerase reverse transcriptase (TERT; 5p), and HLA-B-associated transcript 3 (BAT3; 6p). The relationship between these variants and both tumour histology and smoking behaviour was also examined; the variation at 5p15.33 was shown to influence lung cancer histology, while a strong relationship between all 15q25.1 variants and smoking was observed, which is consistent with earlier studies (see previous news).

 

These findings were further strengthened through meta-analysis by pooling the UK-GWA Phase 1 and 2 with two other studies from France (IARC-GWA) and USA (Texas-GWA). This process conferred enough power to detect major common loci exerting risk at or above an odds ratio of around 1.2; however, a much larger class of low frequency or penetrance variants may be potentially identified in the future with the evolution of better technology combined with larger studies and meta-analyses.

The chance of a mutation occurring in an organism or a gene in each generation is referred to as the mutation rate and this varies between species and across different regions of the genome. Mutations are one of the main sources of genetic variation and thus our ability to accurately measure mutation rates can contribute greatly to our understanding evolutionary biology, by allowing better estimates of evolutionary timescales, and medical genetics, by providing a means of measuring factors that influence mutation rates. Traditional methods have estimated mutation rates by observations of phenotypic traits or comparisons of homologous sequences between closely related species. A recent paper in Current Biology describes the use of next generation high throughput sequencing technologies for direct measurement of mutation rate in humans of a gene on the Y-chromosome [Xue et al (2009) Curr. Biol. doi:10.1016/j.cub.2009.07.032].

In order to measure the base substitution mutation rate at the DFNY1 locus, the researchers cultured cells taken from two men who were distant relatives from the same Chinese family but separated by 13 generations. This particular family carries a mutation at the DFNY1 locus associated with Y-linked hearing impairment. The Y chromosome does not mix its DNA with other chromosomes through recombination during sexual reproduction, which makes it easier to estimate the mutation rate between generations. A 10.5 million base-pair region of the Y-chromosome containing this locus was sequenced and base substitutions catalogued. Alignment of these sequences against the reference Y chromosome sequence identified many more single nucleotide polymorphisms (SNPs) than expected; however, many of these were due to alignment and base-calling errors. In order to better identify candidate mutations, the SNPs were compared with those identified by the Y-Chromosome Consortium, resulting in a list of 23 candidate mutations. Twelve of these mutations were verified following traditional Sanger sequencing of DNA from cell lines; however, only four of these mutations were “true” as they were also present in blood DNA from the two men and their family members. The other mutations are thought to have subsequently occurred during cell culture.

Based on the number of mutations, the length of DNA examined and the number of generations separating the two men, the researchers were able to calculate the mutation rate as one mutation in every 15-30 million nucleotides. This corresponds to around 100-200 new mutations in the genome per generation (see Nature News).The study was conducted by an international team of researchers, including those at the Wellcome Trust Sanger Institute and is the first account of using next generation sequencing technologies to measure mutation rates (see press release).

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Genetics. More than just a copy.
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Genetics and neuropsychiatric disorders: treatment during adulthood.
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Insights from genomic profiling of transcription factors.
Farnham PJ. Nat Rev Genet. 2009 Sep;10(9):605-16.

Systems genetics analysis of cancer susceptibility: from mouse models to humans.
Quigley D, Balmain A. Nat Rev Genet. 2009 Sep;10(9):651-7.

Linking genes to diseases: it's all in the data.
Tiffin N, Andrade-Navarro MA, Perez-Iratxeta C. Genome Med. 2009 Aug 7;1(8):77.

Genetic susceptibility to psoriasis: an emerging picture.
Smith RL, Warren RB, Griffiths CE, Worthington J. Genome Med. 2009 Jul 22;1(7):72.

Genetic trickery - escape of leukemia from immune attack.
Barrett J, Blazar BR. N Engl J Med. 2009 Jul 30;361(5):524-5.

Inherited susceptibility to pediatric acute lymphoblastic leukemia.
Levine RL. Nat Genet. 2009 Sep;41(9):957-8.

Stem cell research. Recipe for induced pluripotent stem cells just got clearer.
Normile D. Science. 2009 Aug 14;325(5942):803.

An uphill battle toward pluripotency.
Graf T. Nat Genet. 2009 Sep;41(9):960-1.

Closing the gap between genotype and phenotype.
Gregersen PK. Nat Genet. 2009 Sep;41(9):958-9.

Tailoring antiplatelet therapy based on pharmacogenomics: how well do the data fit?
Bhatt DL. JAMA. 2009 Aug 26;302(8):896-7.

Cardiovascular disease gets personal.
Hayden EC. Nature. 2009 Aug 20;460(7258):940-1.

Common consent.
Nature. 2009 Aug 20;460(7258):933.

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