Human Genomics

 

Human genomics: from hypothetical genes to biodigital materialisations

Edited by Kate O'Riordan

Contents

Introduction

Sections

Section: 1 - Biodigital life: mobilising individual genomes in genomic research

In this article the direct-to-consumer genetics company, 23andMe, publish their results from self-reporting or crowd sourced samples. These participant driven studies potentially open up consumer derived genetic databases and self reported phenotypical information to biomedical research.

• Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, et al. 2010 Web-Based, Participant-Driven Studies Yield Novel Genetic Associations for Common Traits. PLoS Genet 6(6): e1000993.

Author Summary

Twin studies have shown that many human physical characteristics, such as hair curl, earlobe shape, and pigmentation are at least partly heritable. In order to identify the genes involved in such traits, we administered Web-based surveys to the customer base of 23andMe, a personal genetics company. Upon completion of surveys, participants were able to see how their answers compared to those of other customers. Our examination of 22 different common traits in nearly 10,000 participants revealed associations among several single-nucleotide polymorphisms (SNPs, a type of common DNA sequence variation) and freckling, hair curl, asparagus anosmia (the inability to detect certain urinary metabolites produced after eating asparagus), and photic sneeze reflex (the tendency to sneeze when entering bright light). Additionally our analysis verified the association of a large number of previously identified genes with variation in hair color, eye color, and freckling. Our analysis not only identified new genetic associations, but also showed that our novel way of doing research—collecting self-reported data over the Web from involved participants who also receive interpretations of their genetic data—is a viable alternative to traditional methods.

Section: 2 - Personal genomes: attempting clinical relevance.

So far personal genomics has not had much application in clinical contexts. The overwhelming amount of highly specialised data generated by whole genome sequencing, and the light touch probabilities of genome scanning present either too much, or too little information. This paper outlines an attempt to put personal genomics in a clinical context.

• Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, Dudley JT, Ormond KE, Pavlovic A, Morgan AA, Pushkarev D,Neff NF ,Hudgins L, Gong L, Hodges LM, Berlin DS, Thorn CF, Sangkuhl K, Hebert JM, Woon M, Sagreiya H, Whaley R, Knowles JW, Chou MF, Thakuria JV, Rosenbaum AM, Zaranek AW, Church GM, Greely HT, Quake SR, Altman RB (2010) Clinical assessment incorporating a personal genome. Lancet 375: 1525-35. PMID: 20435227

Section: 3 - Bioinformatic approaches  

Bioinformatics has become the dominant paradigm for working with genomics in many areas. This does raise the question of who can make sense of genomics – biologists or computer scientists. The exome paper can been seen as one of the ways in which a debate about who is qualified to make sense of genomics is playing out. Reardon’s paper from Personalised Medicine (available via Medscape) examines these tensions in the field explicitly and gives a clear picture of some of the stakes.

• Genetic Variation in an Individual Human Exome

Abstract: Characterizing the functional variation in an individual is an important step towards the era of personalized medicine. Protein-coding exons are thought to be especially enriched in functional variation. In 2007, we published the genome sequence of J. Craig Venter. Here we analyze the genetic variation of J. Craig Venter's exome, focusing on variation in the coding portion of genes, which is thought to contribute significantly to a person's physical make-up. We survey ~12,500 nonsilent coding variants and, by applying multiple bioinformatic approaches, we reduce the number of potential phenotypic variants by ~8-fold. Our analysis provides a snapshot of the current state of personalized genomics. We find that <1% of variants are linked to any known phenotypes; this demonstrates the dearth of scientific knowledge for phenotype-genotype associations. However, ~80% of an individual's nonsynonymous variants are commonly found in the human population and, because phenotypic associations to common variants will be elucidated via genome-wide association studies over the next few years, the capability to interpret personalized genomes will expand and evolve. As sequencing of individual genomes becomes more prevalent, the bioinformatic approaches we present in this study can be used as a paradigm to pursue the study of protein-coding variants for the genomes of many individuals.

• [http://www.medscape.com/viewarticle/735061 Reardon, Jenny. 2011. The 'Persons' and

'Genomics' of Personal Genomics. Personalized Medicine. 2011;8(1):95-107. © 2011 Future Medicine Ltd.]

Abstract: At stake in the debate about personal genomics is what kind of person can be trusted to interpret genomes. Deciding this hinges not just on determining if consumers can interpret genomic information, but on deciding which biological and medical experts (if any) can perform these interpretive acts. Understanding why personal genomics has generated such tension and attention requires bringing these struggles, over who can interpret 'the code of life', into focus. While debates about personal genomics focus largely on relatively narrow issues of fraud and deception, this emerging new scientific and political terrain poses more fundamental questions about how the study of biological life, as well as the organization of democratic life, should proceed in genomic times.

Section: 4 - Genome Wide Association Studies (GWAS): from universal human genome to population variation.

Haplotype mapping raises a whole set of debates and questions about race and human difference. This article sets out some of the later findings of the HapMap and demonstrates the kinds of typing that is going on in this area. For detailed accounts of the practices and challenges of this kind of human genomics see both Jenny Reardon’s Race to the Finish and Amade M’Charek’s The.

• [http://hapmap.org/downloads/presentations/nature_hapmap3.pd International HapMap

Consortium. (2007) ][http://hapmap.org/downloads/presentations/nature_hapmap3.pd A second generation human haplotype map of over 3.1 million SNPs.] Nature[http://hapmap.org/downloads/presentations/nature_hapmap3.pd 449(7164):851-861.]

==== Section: 5 - Publishing the reference genome from the Human Genome Project ====

The Human Genome Project ran from the late 1980s to 2003 and produced the human reference genome. These two articles signal the completion of the so-called first draft, which was announced to the world by the leaders of the USA and UK governments in 2000. 

• [http://www.nature.com/nature/journal/v409/n6822/pdf/409860a0.pdf International Human Genome

Sequencing Consortium (2001).  ][http://www.nature.com/nature/journal/v409/n6822/pdf/409860a0.pdf "Initial sequencing and analysis of the human genome."] Nature[1]409[http://www.nature.com/nature/journal/v409/n6822/pdf/409860a0.pdf (6822): 860–921. ]doi:10.1038/35057062. PMID 11237011.

• Venter, JC, et al. (2001).  [http://www.sciencemag.org/cgi/reprint/291/5507/1304.pdf "The

sequence of the human genome." ]Science[2]291[http://www.sciencemag.org/cgi/reprint/291/5507/1304.pdf (5507): 1304–1351. ]doi:10.1126/science.1058040. PMID 11181995.

Section: 6 - Biochemistry, patents and genomics

In the early 1980s the technique called PCR – Polymerase Chain Reaction was developed (see Rabinow for an anthropological account). Kary Mullis won the Nobel Prize for his work in this area but his key article ‘An unusual origin of PCR’ is not freely available and only accessible via subscription.  However, a far more detailed and accessible article in the Journal of Biomedical Discovery and Collaboration (Fore, Weichers and Cook-Deegan 2006) is more useful at this point and is included here. 

 This article examines the effect that the patent on PCR had on its use in the sciences.  This is a useful piece because it provides a review of PCR in the genome sciences but also because it considers two key issues in genomics with particular relevance for the humanities. These are the related issues of commercial science and patenting.

The two issues are linked but not inseparable. Commercial companies and publicly funded research institutions both take out patents on inventions or discoveries.  PCR is a technique for reproducing large amounts of DNA and this facilitates sequencing. Kary Mullis’s work on this area was developed in a commercial setting.  Patenting and other commercial imperatives in the life sciences are part of the everyday reality of working in this area. Genomics is a 20^th century science and has been developed within a highly commercialised system.

The most controversial dimensions of commercial practice in this area is not the patent on PCR per se, but is around the question of the patenting of genes and of genetic tests.  This area is discussed further in relation to DNA in general in The Ethics of Patenting DNA: A Discussion Paper (2002, Nuffield Council on Bioethics).

 Fore,[3][http://www.ncbi.nlm.nih.gov/pubmed/16817955 Joe, Wiechers, lse ]R. and Cook-Deegan, Robert. 2006. The effects of business practices, licensing, and intellectual property on development and dissemination of the polymerase chain reaction: case study Journal of Biomedical Discovery and Collaboration[http://www.ncbi.nlm.nih.gov/pubmed/16817955 2006, 1:7doi:10.1186/1747-5333-1-7][4]

Section: 7 - Constructing maps

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686077/?tool=pubmed Botstein D, White RL, Skolnick M, Davis RW ](1980) Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet. 32: 314-31

Abstract: We describe a new basis for the construction of a genetic linkage map of the human genome.

• Subcommittee of the
Health and Environmental Research Advisory Committee (HERAC). 1987. Report, Office of Health and Environmental Research, Prepared for Dr. Alvin W. Trivelpiece, 
Director, Office of Energy Research U.S. Congress, Office of Technology Assessment. 1988. Mapping Our Genes-The Genome Fast? OTA-BA-373 (Washington, DC: U.S. Government Printing Office, April 1988).

Section: 8 - Making catalogues

In 1966 a medical field coalesces through a catalogue and Dr Victor McKusick publishes the first print edition of Mendelian Inheritance in Man (MIM). This was an attempt to catalogue what was known about Mendelian phenotypes – or the physical expression of genetic material - as medically relevant characteristics. It later became Online Mendelian Inheritance in Man (OMIM).

• Amberger, Joanna. Bocchini, Carol A. Scott, Alan F. and Hamosh, Ada. McKusick's Online Mendelian Inheritance in Man (OMIM®) Nucleic Acids Res. 2009 January; 37(Database issue): D793–D796.

Abstract: McKusick's Online Mendelian Inheritance in Man (OMIM®; http://www.ncbi.nlm.nih.gov/omim), a knowledgebase of human genes and phenotypes, was originally published as a book, Mendelian Inheritance in Man, in 1966. The content of OMIM is derived exclusively from the published biomedical literature and is updated daily. It currently contains 18 961 full-text entries describing phenotypes and genes. To date, 2239 genes have mutations causing disease, and 3770 diseases have a molecular basis. Approximately 70 new entries are added and 700 entries are updated per month. OMIM® is expanding content and organization in response to shifting biological paradigms and advancing biotechnology.

Section: 9 - The new genetics

The genetics of the 1950s helped to signal a break from the associations that had been made between human genetics and forms of social eugenics in the late 19th century and first half of the 20th century. This period of ‘discovery’ science also lead the way in providing narratives of scientific heroes as ordinary guys (McNeil). A version of scientific discovery that still resonates today as genetic heroics were reproduced by Craig Venter and John Sulston during the Human Genome Project, in biographies, autobiographies, popular science writing, news media and documentary.

In July 25, 1953 Rosalind Franklin and Gosling detail the distinctions between the A and B structures of the double helix in DNA and Watson and Crick publish their article on the structure of DNA.

• Franklin R. and Gosling R.G. 1953. Evidence for 2-Chain Helix in Crystalline Structure of Sodium Deoxyribonucleate Nature 172, 156-157 (1953)
• Watson J.D. and Crick F.H.C. 1953. A Structure for Deoxyribose Nucleic Acid Nature 171, 737-738 (1953)