Haplotype Map

‘More than one million SNPs have been identified. Looking at the genetic differences between people – one variation every 500 to 1000 bases (letters) – will usher in a new era of personalised medicine. Currently more than 1.4 million of these variations, known as SNPs (single nucleotide polymorphisms) have been found. Overall, humans are 99.8 per cent genetically similar.’ Wellcome Trust

‘Joining forces: Towards a haplotype map of the human genome - On 29 October 2002, a group of scientists gathered in Washington DC to launch the International HapMap Project; a major new initiative to create a map of human genetic variation. The map will be based on common haplotype patterns, of DNA sequence variants that are usually found together. The haplotype map will considerably simplify the search for medically important DNA sequence variations and provide new insights into human population structure and history…How the map will be made – the International HapMap Project will be carried out by a consortium of public and private institutions in five countries; Canada, China, Japan, the USA and the UK… It is expected to take three years to complete. The map will be based on DNA samples obtained from hundreds of people in geographically distinct populations: Nigerian Yorubas, Han Chinese, Japanese, and US residents of European origin. These populations have been selected for their diverse population histories, which may result in differences in haplotype structure and frequencies, and are not meant to be representative of different ethnic or racial groups. DNA samples will be distributed to the participating organizations who will use high-throughput genotyping technologies to work out the organization of common haplotype patterns in the genome.  We are only just beginning to get a handle on the nature of variation within the human genome, patterns of variation across the globe, and how variation has changed during human history. The International HapMap project is sure to provide deep insight into the characteristics and distribution of SNP alleles and haplotype blocks; some of the most important aspects of our genetic inheritance. ‘ Wellcome Trust, 2003

‘Establishing a catalogue of all common variants in the human population, including single-nucleotide polymorphisms (SNPs), small deletions and insertions, and other structural differences, began in earnest several years ago. Many SNPs have been identified, and most are  HYPERLINK "http://www.ncbi.nlm.nih.gov/SNP" publicly available. A public collaboration,  HYPERLINK "http://www.genome.gov/10001688" The International HapMap Project, was formed in 2002 to characterize the patterns of linkage disequilibrium and haplotypes across the human genome and to identify subsets of SNPs that capture most of the information about these patterns of genetic variation to enable large-scale genetic association studies. To reach fruition, such studies need more robust experimental and computational methods that use this new knowledge of human haplotype structure.  A comprehensive understanding of genetic variation, both in humans and in model organisms, would facilitate studies to establish relationships between genotype and biological function. The study of particular variants and how they affect the functioning of specific proteins and protein pathways will yield important new insights about physiological processes in normal and disease states.  An enhanced ability to incorporate information about genetic variation into human genetic studies would usher in a new era for investigating the genetic bases of human disease and drug response.’ A Vision for the Future of Genomics Research, US National Human Genome Research Institute, 2003

‘Scientists have completed a map of the most common differences in the human genome, which could lead to personalised treatments for diseases. An international team mapped the entire genome of 269 people, and identified tiny differences in key areas of DNA. The "HapMap" study will make it easier to look for genetic variations linked to common diseases such as diabetes. But some experts said HapMap, detailed in Nature, told "half the story" as it could not be used for rare diseases. Humans are genetically 99.9% identical, but the remaining 0.1% accounts for important differences between people. Much of the genetic variation between individuals is caused by single letter differences in DNA called single-nucleotide polymorphisms (SNPs). They are grouped into inherited families called "haplotypes", which are combinations of minute variations in DNA that have travelled together over evolutionary time. There are thought to be around 10 million SNPs. The multi-million pound HapMap study involved more than 200 scientists from the United States, Canada, the UK, China, Japan and Nigeria. It looked at people from Africa, the Far East and western Europe. It identified 300,000 SNPs which can provide around 90% of the information obtained by looking at all 10 million. This is because they act as "tags", indicating variations at a number of sites. The researchers say this will mean a 20-fold cut in the cost of carrying out research into the genetic causes of disease. HapMap data is already being used by scientists. A UK team this year identified a genetic defect that substantially increases the risk of age-related macular degeneration, the leading cause of impaired vision in the elderly. Other teams are using the data to look at conditions including diabetes, Alzheimer's disease, cancer, schizophrenia, asthma, high blood pressure and heart disease. In the HapMap research, the vast majority of both rare and common genetic differences were found in all the populations studied. However, there was evidence some variations are linked to local geography and environment, including the Duffy blood group, which offers resistance to malaria and is almost exclusively seen in black Africans. Professor Peter Donnelly, of Oxford University, one of the lead authors of the research, told the BBC News website: "HapMap heralds a new era in medical research. This report describes a remarkable step in our journey to understand human biology and disease. The human genome sequence provided us with the list of many of the parts to make a human. The HapMap provides us with indicators - like Post-It notes - which we can focus on in looking for genes involved in common disease." Dr Panos Deloukas, from the Sanger Institute in Cambridge, said: "It has been both fascinating and rewarding to be part of this collaborative enterprise that has already mapped one million SNPs and will shortly add another two million to the map." But Dr Jim Wilson, of the Medical Research Council's Human Genetic Unit in Edinburgh, said there were some drawbacks to HapMap. "How well does this relate to rare variations - which might be very important. And how well do these three populations who were studied match what happens in other populations. If you were looking at a population of stroke patients in the UK, how well would they mirror what was found in HapMap. It will save a huge amount of time for researchers, but it is not a panacea." The HapMap emerged from the Human Genome Project that produced the first human genetic blueprint in 2003.’ BBC, 2005

Within the brotherhood, such similarity

that difference tells of significant stories;

migration and roots, colour of sun,

earth beneath the feet; milk, blood,

seed in the belly, what rivers ran where,

which seas became entrapped in veins -

then what convoluted journeys did they run -

what sickness meet, beat, subdue, incorporate.

All printed still in the Genome’s secret press -

opening history-bound covers for comparison

of books so nearly all identical,

the HapMap will find a comma,

plural - grammatical shift of the same words,

in all the volumes of Shakespeare; The Bible.

‘A particularly promising example of the gene-based approach to therapeutics is the application of 'chemical genomics'. This strategy uses libraries of small molecules (natural compounds, aptamers or the products of combinatorial chemistry) and high-throughput screening to advance understanding of biological pathways and to identify compounds that act as positive or negative regulators of individual gene products, pathways or cellular phenotypes. Although the pharmaceutical industry applies this approach widely as the first step in drug development, few academic investigators have access to this methodology or are familiar with its use.Providing such access more broadly, through one or more centralized facilities, could lead to the discovery of a host of useful probes for biological pathways that would serve as new reagents for basic research and/or starting points for the development of new therapeutic agents (the 'hits' from such library screens will generally require medicinal chemistry modifications to yield therapeutically usable compounds).’ A Vision for the Future of Genomics Research, US National Human Genome Research Institute, 2003

‘The International HapMap Consortium has published a comprehensive catalogue of human genetic variation, a landmark achievement that is already accelerating the search for genes involved in common diseases, such as asthma, diabetes, cancer and heart disease. In the report, published in the journal Nature on 27 October 2005, more than 200 researchers from Canada, China, Japan, Nigeria, the UK and the USA describe the initial results from their three-year public-private effort to chart the patterns of genetic variation that are common in the world's population. Their findings show that the search for clinically relevant genes can be simplified by using the map of variation developed by the  HYPERLINK "http://www.hapmap.org/" HapMap Project. Much of our genetic variation is caused by single-nucleotide differences in our DNA code: these are called single nucleotide polymorphisms, or SNPs. As a result, each of us has a unique genetic code that typically differs in about three million nucleotides from every other person. The HapMap project has shown patterns of association between SNPs studied in different populations from around the world. These can be used to simplify studies to understand how genetic variation contributes to health and disease. "Humans are genetically 99.9 per cent identical: it is the tiny percentage that is different that holds the key to why some of us are more susceptible to common diseases such as diabetes and hypertension or respond differently to treatment with certain drugs," said Dr Panos Deloukas at the Wellcome Trust Sanger Institute...Medical genetics will benefit enormously from the increased power that the HapMap provides. By using HapMap data to compare the SNP patterns of people affected by a disease with those of unaffected people, researchers can survey the whole genome and identify genetic contributions to common diseases more efficiently than has been possible without this genome-wide map of variation: the HapMap Project has simplified the search for gene variants as much as 20-fold. The publicly available SNP datasets were used by medical researchers even before the first draft of the map was completed. For example, in March 2005, studies published in the journal Science used HapMap data to uncover a genetic variation that substantially increases the risk of age-related macular degeneration, the leading cause of severe vision loss in the elderly.’ Wellcome Trust, 2005

Plotting populations

Refining the human map - plotting populations -

variations, distributions as once sky and cosmos

were mapped - and before that the world - from

sensibly flat to bewilderingly round, unexplored.

Once I stood on a Scottish mountain skull, moved

a smallish boulder, and put my foot where nobody

else had ever trod - now shivering - as when I fitted

my own shoe into a foot-printed rock where it’s said

Columba once looked over the sea, saying:

‘There must be a church here’, and there is.

And that place on the map where a hole in air

is bounded by stone, and wishes are to be had

if you know the ritual; just as magic mushrooms

truly grow in fairy rings, or something is marked

in a stone circle’s ground – by a molecular map

of standing rock, symbiotic gaze of ancient Sun;

saying nothing now that is truly comprehensible

to modern deafness, silent air printed with music.

A map showing sites of disease,

markers of health and probable

reactions to vaccination, drugs;

searching those paper chains

of men under melded fibres -

molecular mash. Unspinning,

comparing on a fabulous scale;

where the lottery of geography

has put black iron in the heart,

or snow upon a strong limb -

gain, loss and compensation;

gift and curse, reconciliation

of warring genes, factions -

dancing politely on through

gritted chemistry; weakness,

susceptibility, some immunity,

written in the humblest verses

that wrote the human species

from evolving earth,

moulded him thus -

from many creatures,

many places; nothing is lost.

We will find ourselves here

in our own map - document

of mankind - our home,

ancient hunting ground;

water-body, sea-blood -

in our fingers of earth -

our coming from stars;

absolute need for light.

‘A good way to think about haplotypes and haplotype blocks is to imagine the SNP alleles as children sharing school minibuses.  If there are lots of children and they arrive at the bus stop individually, then the combination of children on any one minibus is going to be random. However, if all the children living in the same street walk to the bus stop together, they are likely to catch the same bus and they will tend to travel to school every day as the same group. So, if Jane, John, Fred and Annabel live in the same street, they will tend to share the same school bus., if Jane is on a particular bus, it follows that John, Fred and Annabel are on it too. In this example, Jane, John, Fred and Annabel are SNPs making up the haplotype, and Jane is the haplotype tag SNP.’ Wellcome Trust, 2003

‘What happens if there’s one kid who is crap at getting up and keeps missing the bus, or prefers to walk, or stops to look at the hawthorn growing unexpectedly among the hedge leaves, or a little pride of dandelion heads or clocks begging to be blown, or goes into the shop for a Jelly Crocodile…Or am I not getting this metaphor properly? Or taking it too literally…’ Gillian Ferguson, The Human Genome: Poems on the Book of Life

‘Clone-by-clone sequencing - how is the initial map made? One of the earliest maps of the human genome came from studying how characteristics are passed on in families. If two (or more) characteristics tend to crop up together, we might suppose that they were coded for on the same chromosome. However, even if two characteristics are coded for on the same chromosome, occasionally they will occur separately because chromosome pairs can exchange regions of DNA when sperm or egg cells are formed (meiotic crossing over). If two characteristics on the same chromosome are frequently separated, then we can conclude that they are far away from each other on the chromosome. If they are only rarely separated, then the two characteristics must be very close together on the chromosome. By looking at how characteristics are inherited in patterns, we can draw up a draft map of where the genes are on the chromosomes. This sort of map is called a linkage map. Genes that are on the same chromosome are said to be 'linked', and the distance between genes on the same chromosome is called a linkage distance. Producing a map was one of the early objectives of the Human Genome Project. Accuracy of conventional genetic maps depends on the number of individuals who are analysed. Humans, however, take a long time to grow up and have children, so it is only usually possible to look at three or four generations of a single family at a time. Also, there are often not enough children in each family to work out the linkage distances accurately.’ YourGenome.org

It is harder to map one human being

It is harder to map one human being

than all stars and planets in the sky -

so old the celestial bodies, but out there,

visible, spotted, sighed and dreamt upon

for so much longer than this inner geography;

slowly mapping theads from parent to child -

until the parent is worm, earth, sea, light;

and child Einstein, Mozart, Shakespeare.

‘The ENCODE Project: encyclopedia of DNA Elements - In April 2003, the sequence of the human genome will be essentially complete. Although this is a significant achievement, much remains to be done. Before the best use of the information contained in the sequence can be made, the identity and precise location of all of the protein-encoding and non-protein-encoding genes will have to be determined. The identity of other functional elements encoded in the DNA sequence, such as promoters and other transcriptional regulatory sequences, along with determinants of chromosome structure and function, such as origins of replication, also remain largely unknown. A comprehensive encyclopedia of all of these features is needed to fully utilize the sequence to better understand human biology, to predict potential disease risks, and to stimulate the development of new therapies to prevent and treat these diseases. To encourage discussion and comparison of existing computational and experimental approaches, and to stimulate the development of new ones, the NHGRI proposed to create a highly interactive public research consortium to carry out a pilot project for testing and comparing existing and new methods to identify functional sequences in DNA. Working together in a highly cooperative effort to rigorously analyze a defined portion of the human genome sequence, investigators with diverse backgrounds and expertise will be able to evaluate the relative merits of each of a diverse set of techniques, technologies and strategies in identifying all the functional elements in human genomic sequence, to identify gaps in our ability to annotate genomic sequence, and to consider the abilities of such methods to be scaled up for an effort to analyze the entire human genome. …The ultimate goal of this project is to improve access to information, resources, ideas, expertise, and technology beyond the scope of any single group, and to affect the entire community of researchers interested in mining genomic sequence. The hoped-for outcome will be a clear path to determining all of the functional elements in the entire human genome sequence and integrating the information in a manner that will guide future basic and clinical research…’ National Human Genome Research Institute

‘Complementing the computational detection of functional elements will be the generation of additional experimental data by high-throughput methodologies. One example is the production of full-length complementary DNA (cDNA) sequences, for example at the  HYPERLINK "http://mgc.nci.nih.gov/" Mammalian Gene Collection and  HYPERLINK "http://www.fruitfly.org/EST/EST.shtml" Expressed Sequence Tag Projects. Major challenges inherent in programmes to discover genes are the experimental identification and validation of alternate splice forms and messenger RNAs expressed in a highly restricted fashion. Even more challenging is the experimental validation of functional elements that do not encode protein (for example, regulatory regions and non-coding RNA sequences). High-throughput approaches to identify them will be needed to generate the experimental data that will be necessary to develop, confirm and enhance computational methods for detecting functional elements in genomes. Because current technologies cannot yet identify all functional elements, there is a need for a phased approach in which new methodologies are developed, tested on a pilot scale and finally applied to the entire human genome. Along these lines, the NHGRI recently launched the  HYPERLINK "http://www.genome.gov/10005107" Encyclopedia of DNA Elements (ENCODE) Project to identify all the functional elements in the human genome. In a pilot project, systematic strategies for identifying all functionally important genomic elements will be developed and tested using a selected 1% of the human genome. Parallel projects involving well-studied model organisms, for example, yeast, nematode and fruitfly, are ongoing. The lessons learned will serve as the basis for implementing a broader programme for the entire human genome.’ A Vision for the Future of Genomics Research, US National Human Genome Research Institute, 2003

‘A collaboration of 24 leading human geneticists, known as the Wellcome Trust Case Control Consortium, will search for the 'genetic signposts' for tuberculosis, coronary heart disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, Crohn's disease, bipolar disorder (manic depression) and hypertension (high blood pressure). Over 19 000 DNA samples will be analysed. For each disease, scientists will collect and analyse the genetic make-up of 2000 affected individuals. These will then be compared with 3000 control samples, to identify genetic differences between people who do and don't have each disease. It is hoped that by identifying these genetic signposts, researchers will be able to understand which people are most at risk and which genes are contributing to each disease. Eventually, this should lead to more effective treatments. The research will be conducted at a number of institutes and universities across the UK, including the Wellcome Trust Sanger Institute, Cambridge University and Oxford University. It will take around three years to complete. The project builds on the sequencing of the human genome – a third of which was completed at the Sanger Institute – and the HapMap Project, which produced a catalogue of common genetic variations within the genome. As a second project, the Wellcome Trust Case Control Consortium plans to analyse 15 000 samples to look for genetic variations relating to another four diseases: breast cancer, autoimmune thyroid disease, multiple sclerosis and ankylosing spondylitis (a chronic inflammatory disease of the spine and adjacent joints).’ Wellcome Trust, 2005

Maps within maps

Function, purpose, mechanisms; maps within

maps, within mapping of the Human Genome -

locations, Sites of Special Scientific interest,

towns and villages, rather than a motorway -

(unless an Angel of the North happens by,

a giant silver trumpet by miles of asphalt) -

linking significant bits; in this forest are trees

capable of curing the most complex diseases -

and firewood, all clustered looking the same -

at first, until the sub-sub-sub-micro-explorers,

with smashing machetes the size of atoms,

come slashing their virgin way accurately,

discarding these shapes that once were trees,

with rings, branches, leaves - but are dead -

just hulks, genome shadows, function chimeras

so indelibly printed in the genetic atmosphere

they can never be gone, banished - their ruined

chemistry may yet give up useful clues to why

their neighbour towers - grows medicine bountifully

as new green leaves, and turned, to boot, into a dog;

in another place, another country than the human

environment - our rugged territory where animals

still roam, primal vegetation; there are monsters

with no eyes – tails, and scaly wings when birds

were dinosaurs. So do come into the scary map,

festooned with moss, creepers, ferns - scuttling,

slithering things – look for the silver signposts -

see here, a polished note hanging on a dead tree

that one day became a violin; white feather

falling from a bird that turned into a pen -

ink liquifiying from primaeval darkness;

these golden instruments – bones, hearts,

that became art, medicine and science -

transforming themselves with chemistry.

See bundles, clusters of flashing genes,

stimulating, doing, functioning – being;

this genetic sparkle must be mapped -

mark shimmering sites, body factory;

plot silver threads as Orion is spun

in random sky - connections, roots;

here is the yellow root of sickness,

found in this ill-cast hook of genes,

this deterioration, burned stump,

that we might make green again.

*

Encyclopaedia of the human;

volumes revised from mass-

map - sentences identified;

meaning, definitions, shifts

in vocabulary over millennia