Mining the Common Heritage of Our DNA: Lessons Learned From Grotius and Pardo

The Human Genome Project generated oceans of DNA sequence data and spurred a multinational race to grab the bounties of these oceans. In response to these DNA property grabs, UNESCO, drawing upon international law precedents addressing analogous grabs in the past, declared the Human Genome the heritage of humanity. The UNESCO Declaration provided, first, that the heritage shall not, in its natural state, give rise to financial gains and, second, that countries establish an international framework to make the benefits from genome research available to all. This iBrief will first examine Grotius’s Mare Liberum to determine whether international law precedent indeed bars the private appropriation of a common heritage. Second, the iBrief will revisit the framework developed by Pardo for the exploitation of the mineral resources of the ocean floor and analyze whether it could serve as a model for an international framework for sharing the benefits of current genome research

A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals

WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene

Telomere length (TL) regulation is an important factor in ageing, reproduction and cancer development. Genetic, hereditary and environmental factors regulating TL are currently widely investigated, however, their relative contribution to TL variability is still understudied. We have used whole genome sequencing data of 250 family trios from the Genome of the Netherlands project to perform computational measurement of TL and a series of regression and genome-wide association analyses to reveal TL inheritance patterns and associated genetic factors. Our results confirm that TL is a largely heritable trait, primarily with mother’s, and, to a lesser extent, with father’s TL having the strongest influence on the offspring. In this cohort, mother’s, but not father’s age at conception was positively linked to offspring TL. Age-related TL attrition of 40 bp/year had relatively small influence on TL variability. Finally, we have identified TL-associated variations in ribonuclease reductase catalytic subunit M1 (RRM1 gene), which is known to regulate telomere maintenance in yeast. We also highlight the importance of multivariate approach and the limitations of existing tools for the analysis of TL as a polygenic heritable quantitative trait

Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with ‘true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05–0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r2, increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r2 improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r2 increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results

A framework for the detection of de novo mutations in family-based sequencing data

Germline mutation detection from human DNA sequence data is challenging due to the rarity of such events relative to the intrinsic error rates of sequencing technologies and the uneven coverage across the genome. We developed PhaseByTransmission (PBT) to identify de novo single nucleotide variants and short insertions and deletions (indels) from sequence data collected in parent-offspring trios. We compute the joint probability of the data given the genotype likelihoods in the individual family members, the known familial relationships and a prior probability for the mutation rate. Candidate de novo mutations (DNMs) are reported along with their posterior probability, providing a systematic way to prioritize them for validation. Our tool is integrated in the Genome Analysis Toolkit and can be used together with the ReadBackedPhasing module to infer the parental origin of DNMs based on phase-informative reads. Using simulated data, we show that PBT outperforms existing tools, especially in low coverage data and on the X chromosome. We further show that PBT displays high validation rates on empirical parent-offspring sequencing data for whole-exome data from 104 trios and X-chromosome data from 249 parent-offspring families. Finally, we demonstrate an association between father's age at conception and the number of DNMs in female offspring's X chromosome, consistent with previous literature reports

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. Acknowledgements: We especially thank all volunteers who participated in our study. This study made use of data generated by the ‘Genome of the Netherlands’ project, which is funded by the Netherlands Organization for Scientific Research (grant no. 184021007). The data were made available as a Rainbow Project of BBMRI-NL. Samples were contributed by LifeLines (http://lifelines.nl/lifelines-research/general), the Leiden Longevity Study (http://www.healthy-ageing.nl; http://www.langleven.net), the Netherlands Twin Registry (NTR: http://www.tweelingenregister.org), the Rotterdam studies (http://www.erasmus-epidemiology.nl/rotterdamstudy) and the Genetic Research in Isolated Populations programme (http://www.epib.nl/research/geneticepi/research.html#gip). The sequencing was carried out in collaboration with the Beijing Institute for Genomics (BGI). Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants HL080295, HL087652, HL105756 and HL103612 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629 from the National Institute on Aging (NIA). A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. The CROATIA cohorts would like to acknowledge the invaluable contributions of the recruitment teams in Vis, Korcula and Split (including those from the Institute of Anthropological Research in Zagreb and the Croatian Centre for Global Health at the University of Split), the administrative teams in Croatia and Edinburgh and the people of Vis, Korcula and Split. SNP genotyping was performed at the Wellcome Trust Clinical Research Facility in Edinburgh for CROATIA-Vis, by Helmholtz Zentrum München, GmbH, Neuherberg, Germany for CROATIA-Korcula and by AROS Applied Biotechnology, Aarhus, Denmark for CROATIA-Split. They would also like to thank Jared O’Connell for performing the pre-phasing for all cohorts before imputation. The ERF study as a part of EuroSPAN (European Special Populations Research Network) was supported by European Commission FP-6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme ‘Quality of Life and Management of the Living Resources’ of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by joint grant from the Netherlands Organisation for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). This research was financially supported by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). Statistical analyses for the ERF study were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam. We are grateful to all study participants and their relatives, general practitioners and neurologists for their contributions and to P. Veraart for her help in genealogy, J. Vergeer for the supervision of the laboratory work and P. Snijders for his help in data collection. The FamHS is funded by a NHLBI grant 5R01HL08770003, and NIDDK grants 5R01DK06833603 and 5R01DK07568102. The Framingham Heart Study SHARe Project for GWAS scan was supported by the NHLBI Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix Inc for genotyping services (Contract No. N02-HL-6-4278). DNA isolation and biochemistry were partly supported by NHLBI HL-54776. A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at the Boston University School of Medicine and Boston Medical Center. We are grateful to Han Chen for conducting the 1000G imputation. The Family Heart Study was supported by the by grants R01-HL-087700 and R01-HL-088215 from the National Heart, Lung, and Blood Institute (NHLBI). We would like to acknowledge the invaluable contributions of the families who took part in the Generation Scotland: Scottish Family Health Study, the general practitioners and Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes academic researchers, IT staff, laboratory technicians, statisticians and research managers. SNP genotyping was performed at the Wellcome Trust Clinical Research Facility in Edinburgh. GS:SFHS is funded by the Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. SNP genotyping was funded by the Medical Research Council, United Kingdom. We wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines and all the study participants. MESA Whites and the MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the NHLBI. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02.HL.6.4278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258 and R01HL071259. We thank the participants of the MESA study, the Coordinating Center, MESA investigators and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. Netherland Twin Register (NTR) and Netherlands Study of Depression and Anxiety (NESDA): Funding was obtained from the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants Middelgroot-911-09-032, Spinozapremie 56-464-14192, Geestkracht programme of the Netherlands Organization for Health Research and Development (Zon-MW, grant number 10-000-1002), Center for Medical Systems Biology (CSMB, NWO Genomics), NBIC/BioAssist/RK(2008.024), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL, 184.021.007), VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the European Science Foundation (ESF, EU/QLRT-2001-01254), the European Community’s Seventh Framework Program (FP7/2007-2013), ENGAGE (HEALTH-F4-2007-201413); the European Science Council (ERC Advanced, 230374); and the European Research Council (ERC-284167). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health, Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant 2R01LM010098), The Netherlands Organisation for Health Research and Development (NWO-Groot grant 175.010.2007.006, NWO VENI grant 916.761.70, ZonMw grant 90.700.441) and the Dutch Inter University Cardiology Institute Netherlands (ICIN). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W.J is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Genotyping was supported by the seventh framework programme of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database.Peer reviewedPublisher PD

Inalienably Yours? The new case for an inalienable property right in human biological material: Empowerment of sample donors or a recipe for a tragic Anti-Commons?

Modern biomedical research into the genetic component of common diseases calls for broad access to existing and novel collections of samples of human biological material, aka Biobanks. Groups of donors of these samples, however, increasingly claim a property right in their samples. They perceive the recognition of a personal property right in their biological material as the best means to serve two goals: to secure ongoing control over their samples after donation and to underpin their claim for a share in the proceeds that the research on their samples may yield. Given the objective of ensuring ongoing control, this property right is claimed to be inalienable. Recognition of a personal property right in ones biological material is problematic, especially where the requirement of inalienability seems at odds with the claim for a share of the profits. Yet, property rights in human biological material may be justified in a certain context, e.g. to enable subsets of patients to negotiate the terms and conditions of the research into their specific disorders. Biobanks, however, contain so many samples, which can be used for so many research purposes, that the unrestricted exercise of personal property rights by the sample donors will lead to a proliferation of rights. This proliferation is likely to deter or slow down both the creation of de novo Biobanks and the use of existing sample collections. Thus, recognising inalienable property rights in human biological material may lead to suboptimal use of these resources and create a classic anticommons property scenario. It would also undermine the current trend to simplify existing informed consent requirements which aims to facilitate broad and previously unanticipated research on de novo and existing Biobanks. In addition, the tradition of altruistic participation in research and the notion that large-scale collections of human biological material are global public goods are arguments against recognising inalienable personal property rights in human biological material, at least in the context of Biobanks. To avoid uncertainty over the issue of who owns collected human biological material, the principle that the property rights in such material vest in the entity lawfully collecting and storing the material should be implemented in legislation. This way most individuals and their offspring will benefit more than when they heed the call to stand up for their property rights in their samples