Genetic Abnormalities Discovered After Creation of Stem Cells

Discovery sheds new light on the process of stem cell generation, and will help promote safer stem-cell based studies and future clinical trials
Thursday, 10 March 2011

Dr. Andras Nagy's laboratory at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital and Dr. Timo Otonkoski's laboratory at Biomedicum Stem Cell Center, University of Helsinki, as well as collaborators in Europe and Canada have identified genetic abnormalities associated with reprogramming adult cells to induced pluripotent stem (iPS) cells. The findings give researchers new insights into the reprogramming process, and will help make future applications of stem cell creation and subsequent use safer.

The study was published in Nature.

The team showed that the reprogramming process for generating iPS cells (i.e., cells that can then be 'coaxed' to become a variety of cell types for use in regenerative medicine) is associated with inherent DNA damage.

This damage is detected in the form of genetic rearrangements and 'copy number variations,' which are alterations of DNA in which a region of the genome is either deleted or amplified on certain chromosomes. The variability may either be inherited, or caused by de novo mutation.

"Our analysis shows that these genetic changes are a result of the reprogramming process itself, which raises the concern that the resultant cell lines are mutant or defective," said Dr. Nagy, a Senior Investigator at the Lunenfeld.

"These mutations could alter the properties of the stem cells, affecting their applications in studying degenerative conditions and screening for drugs to treat diseases. In the longer term, this discovery has important implications in the use of these cells for replacement therapies in regenerative medicine."

"Our study also highlights the need for rigorous characterization of generated iPS lines, especially since several groups are currently trying to enhance reprogramming efficiency," said Dr. Samer Hussein, a McEwen post-doctoral scientist who initiated these studies with Dr. Otonkoski, before completing them with Dr. Nagy.

"For example, increasing the efficiency of reprogramming may actually reduce the quality of the cells in the long run, if genomic integrity is not accurately assessed."

The researchers used a molecular technique called single nucleotide polymorphism (SNP) analysis to study stem cell lines, and specifically to compare the number of copy number variations in both early and intermediate-stage human iPS cells with their respective parental, originating cells.

Drs. Nagy and Otonkoski and their teams found that iPS cells had more genetic abnormalities than their originating cells and embryonic stem cells. Interestingly, however, the simple process of growing the freshly generated iPS cells for a few weeks selected against the highly mutant cell lines, and thus most of the genetic abnormalities were eventually 'weeded out.'

"However, some of the mutations are beneficial for the cells and they may survive during continued growth," said Dr. Otonkoski, Director and Senior Scientist at the Biomedicum Stem Cell Center.

Stem cells have been widely touted as a source of great hope for use in regenerative medicine, as well as in the development of new drugs to prevent and treat illnesses including Parkinson's disease, spinal cord injury and macular degeneration. But techniques for generating these uniquely malleable cells have also opened a Pandora's Box of concerns and ethical quandaries. Health Canada, the U.S. Food and Drug Administration and the European Union consider stem cells to be drugs under federal legislation, and as such, subject to the same regulations.

"Our results suggest that whole genome analysis should be included as part of quality control of iPS cell lines to ensure that these cells are genetically normal after the reprogramming process, and then use them for disease studies and/or clinical applications," said Dr. Nagy.

"Rapid development of the technologies in genome-wide analyses will make this more feasible in the future," said Dr. Otonkoski.

"In addition, there is a need to further explore if other methods might mitigate the amount of DNA damage generated during the generation of stem cells," both investigators agreed.

About the Samuel Lunenfeld Research Institute of Mount Sinai Hospital
The Samuel Lunenfeld Research Institute of Mount Sinai Hospital, a University of Toronto affiliated research centre established in 1985, is one of the world's premier centres in biomedical research. Thirty-six principal investigators lead research in diabetes, cancer biology, epidemiology, stem cell research, women's and infants' health, neurobiology and systems biology.


About Biomedicum Helsinki
Biomedicum Helsinki, located on the Meilahti Campus of the University of Helsinki, is one of the leading medical research institutions in Scandinavian countries, hosting about 200 principal investigators of the University of Helsinki and Helsinki University Central Hospital. Research strengths of Biomedicum Helsinki encompass topics in basic and clinical science related to molecular and cellular biology, molecular genetics, cancer biology, neuroscience, endocrinology, stem cell biology, and metabolic diseases.


Source: Samuel Lunenfeld Research Institute
Contact: Karin Fleming (SLRI) and Päivi Lehtinen, University of Helsinki
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Genetic Abnormalities Identified in Pluripotent Stem Cell Lines

Genetic Abnormalities Identified in Pluripotent Stem Cell Lines
Thursday, 20 January 2011

A multinational team of researchers led by stem cell scientists at the University of California, San Diego School of Medicine and Scripps Research Institute has documented specific genetic abnormalities that occur in human embryonic (hESC) and induced pluripotent stem cell (iPSC) lines. Their study, "Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture" will be published in the January 7 issue of the journal Cell Stem Cell.

The published findings highlight the need for frequent genomic monitoring of pluripotent stem cells to assure their stability and clinical safety.

"We found that human pluripotent cells (hESCs and iPSCs) had higher frequencies of genomic aberrations than other cell types," said Louise Laurent, MD, PhD, assistant professor in the UCSD Department of Reproductive Medicine and first author on the study.

"Most strikingly, we observed a higher frequency of genomic duplications in hESCs and deletions in iPSCs, when compared to non-pluripotent samples."

The ability of human pluripotent stem cells to become every cell type in the body has made them potential sources of differentiated cells for cell replacement therapies.

"Since genetic aberrations are often associated with cancers, it is vital that cell lines destined for clinical use are free from cancer-associated genomic alterations," said senior author Jeanne F. Loring, PhD, professor and Director of the Center for Regenerative Medicine at the Scripps Research Institute.

The team identified regions in the genome that had a greater tendency to become abnormal in pluripotent cell lines. With hESCs, the observed abnormalities were most often duplications near pluripotency-associated genes; in iPSC lines, there were duplications involving cell proliferation genes and deletions associated with tumour suppressor genes.

These changes could not have been detected by traditional microscopic techniques such as karyotyping. The team instead used a high-resolution molecular technique called "single nucleotide polymorphism" (SNP) analysis, which allowed them to look for genetic changes at more than a million sites in the human genome.

"We were surprised to see profound genetic changes occurring in some cultures over very short periods of time, such as during the process of reprogramming somatic cells into iPSCs and during differentiation of the cells in culture," Laurent said.

"We don't know yet what effects, if any, these genetic abnormalities will have on the outcome of basic research studies or clinical applications, and we need to find out."

Loring concluded:

"The results of the study illustrate the need for frequent genomic monitoring of pluripotent stem cell cultures. SNP analysis has not been a part of routine monitoring of hESC and iPSC cultures, but our results suggest that perhaps it should be."

Source: University of California at San Diego
Contact: Debra Kain

Reference:
Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ESCs and iPSCs during Reprogramming and Time in Culture
Louise C. Laurent, Igor Ulitsky, Ileana Slavin, Ha Tran, Andrew Schork, Robert Morey, Candace Lynch, Julie V. Harness, Sunray Lee, Maria J. Barrero, Sherman Ku, Marina Martynova, Ruslan Semechkin, Vasiliy Galat, Joel Gottesfeld, Juan Carlos Izpisua Belmonte, Chuck Murry, Hans S. Keirstead, Hyun-Sook Park, Uli Schmidt, Andrew L. Laslett, Franz-Josef Muller, Caroline M. Nievergelt, Ron Shamir, Jeanne F. Loring
Cell Stem Cell, Volume 8, Issue 1, 106-118, 7 January 2011, 10.1016/j.stem.2010.12.003
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New Methods Detect Subtleties in Human Genomes Repetitive Landscapes

These techniques spot minute variations linked to evolution, diversity and brain development
Thursday, 28 October 2010

Scientists have invented methods to scout the human genome's repetitive landscapes, where DNA sequences are highly identical and heavily duplicated. These advances, as reported today in Science, can identify subtle but important differences among people in the number and content of repeated DNA segments.

These copy number variations partly account for the normal diversity among people. Copy number variations might also be why some people, and not others, have certain disorders or disease susceptibilities, and might also determine how severely they are affected.

Until about a year ago, locating and counting the number of duplicated copies of DNA sequences was almost impossible. The more copies of a duplicated gene that are present, the harder they are to assess accurately.

"These difficulties resulted in a lack of understanding of the true extent of human copy number variation, " said Dr. Evan E. Eichler, University of Washington (UW) professor of genome sciences and senior author of the Science paper.

"The most dynamic and variable genes are frequently excluded from genome-wide studies."

These hard-to-study genes are also among the most interesting because of their suspected contributions to human evolution, brain development, metabolism and disease immunity.

Researchers in Eichler's lab have developed several analytical and computational techniques to overcome obstacles in looking at multi-copy genes. The lead authors of the study are Peter H. Sudmant and Jacob O. Kitzman, both graduate students in the UW Department of Genome Sciences.

Working with colleagues in the 1000 Genomes Project and at Agilent Technologies, the UW group used the new techniques to deeply probe and compare the genomes of 159 individuals. In assessing the entire genomes of these individuals, the researchers were able to accurately assay previously intractable duplicated genes and gene families.

The researchers demonstrated that the methods could estimate correctly the absolute number of copies of segments as small as 1,900 DNA base pairs, and could count numbers of copies ranging from zero to 48. A human genome is made up of about 3 billion DNA base pair. Each pair consists of two bonded molecules called nucleotides, the basic structural unit of DNA.

"We identified 4.1 million singly unique nucleotide positions informative in distinguishing specific copies," the authors reported. The researchers took this information to genotype the number of copies and the content of genes that had been duplicated to or more different positions on the genome thereby became free to function on their own. These duplicated genes reveal changes that occurred during evolution.

The data allowed the researchers to identify duplicated genes specific to humans, in comparison to apes like gorilla, orang-utans, and chimps. The researchers observed that these duplications occurred in genes associated with brain development. These include genes implicated in the growth and branching of brain cell connections, in abnormally large or small head size, in a particular dopamine (reward signal in the brain) receptor, in visual-spatial and social deficits, in reducing the severity of spinal muscular atrophy, and in intellectual disability and epilepsy.

Copy number variations occur in only about 7 percent to 9 percent of human genes, the researchers found. Most of our genes come standard: two copies. Even among copy number variable genes, the researchers learned that 80 percent of them vary between zero and five copies.

"Extreme gene variation," the researchers noted, "is limited to only a few gene families." In this study, they identified 56 of the most variable gene families. These ranged in median copy number from five to approximately 368.

"These genes were dramatically enriched for segmental duplication," the researchers noted. Segmental duplications are regions that were originally identified in the Human Genome Project as long, repeated blocks of the genome.

The researchers report discovering about 44 "hidden" members of duplicated gene families never before identified in the reference model of the human genome.

"The missing members of these gene families," the researchers suggested, "should be targeted for sequence finishing in order to more accurately capture the architecture and diversity of the human genome."

While duplications of segments of the genome appear to have led to many of the qualities that distinguish human beings from other primate species, areas of the genome in which duplications promote recurrent rearrangements have also been associated with debilitating diseases like intellectual disability, schizophrenia and autism.

"Extreme variation resulting from duplications may contribute to genomic instability associated with disease," the researchers therefore hypothesize.

Overall, the results of the study shows scientists can now leverage newly developed techniques to explore some of the most complex genetic regions of the human genome. Still, a portion of the genome remains impenetrable. About 28 large regions of the human genome have such extraordinary complexity that as yet it is impossible to interpret the underlying pattern of genetic diversity, the authors said.

Despite this limitation, the approaches tested in the study hold promise for improving the understanding of how copy number variation contributes to human health and illness.

"Our approach makes many of the highly duplicated regions of the human genome – and the more than 1,000 previously inaccessible human genes that lie therein –accessible to genetic studies of disease association," the researchers concluded.

Source: University of Washington
Contact: Leila Gray

Reference:
Diversity of Human Copy Number Variation and Multicopy Genes
Peter H. Sudmant, Jacob O. Kitzman, Francesca Antonacci, Can Alkan, Maika Malig, Anya Tsalenko, Nick Sampas, Laurakay Bruhn, Jay Shendure, 1000 Genomes Project, Evan E. Eichler
Science 29 October 2010, Vol 330, 641-646.
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Technique to Determine Ethnic Origin of Stem Cell Lines

Cells more representative of the US and world populations could lead to more accurate research and safer, more effective therapies, Scripps research team says Monday, 04 January 2010 An international team of scientists led by researchers at The Scripps Research Institute has developed a straightforward technique to determine the ethnic origin of stem cells. The Scripps Research scientists initiated the study — published in the January 2010 edition of the journal Nature Methods — because the availability of genetically diverse cell lines for cell replacement therapy and drug development could have important medical consequences. Research has shown that discordance between the ethnic origin of organ donors and recipients can influence medical outcomes for tissue transplantation, and that the safety and effectiveness of specific drugs can vary widely depending on ethnic background. The team's analysis of a variety of human embryonic stem cell lines currently in use in research laboratories around the world found that these cells originated largely from Caucasian and East Asian populations, with little representation from populations originating in Africa. In response to these results, the scientists used skin cells from an individual of West African Yoruba heritage to create a new stem cell line, the first to carry the genetic profile of this ethnic group. "Ethnic origin is a critical piece of information that should come with every cell line," said Scripps Research Professor Jeanne Loring, Ph.D., who is senior author of the paper. "Everyone who works with stem cells should be doing this kind of analysis." "Knowing that a big push in the future is using these lines in the clinic and in drug development, there's a need to have an ethnically diverse population of cells," added Louise Laurent, M.D., Ph.D., assistant professor at the University of California, San Diego (UCSD). She is also a research associate at Scripps Research, who is first author of the paper with Caroline Nievergelt, Ph.D., also an assistant professor at UCSD. Greater diversity in cell samples would set the stage for more broadly relevant research by labs in academia and industry, more robust results on the safety and efficacy of potential therapies, and more successful tissue transplants. The Promise of Stem Cells Normally, cells develop from stem cells into a myriad of increasingly more specialized cell types during early development and throughout a lifetime. In humans and other mammals, these developmental events are usually irreversible. This means that when tissues are damaged or cells are lost, the body has limited means by which to replenish them. Having a source of stem cells would be useful in many medical situations because these cells are "pluripotent," having the ability to become any of the body's cell types. Pluripotent stem cells would potentially provide physicians with the ability to replace or repair damaged tissues throughout the body. For example, pluripotent stem cells could be differentiated into the damaged cell type and transplanted. Much research on pluripotent stem cells to date has been conducted on human embryonic stem cells, which are harvested from discarded embryos (those created but not used for the purposes of in vitro fertilization, a technique to help couples conceive). However, recently another source of pluripotent stem cells has come onto the scene. These cells — called induced pluripotent stem cells — are created by taking a sample of skin cells or another type of differentiated cell and using chemicals and molecular biology techniques to coax them back into a pluripotent state. The current analysis included 47 human embryonic stem cell lines collected from labs located around the world — including Korea, Australia, and Finland. The analysis also included five induced pluripotent stem cell lines. Ancestors Forgotten and Remembered To determine the ethnic origins of the stem cell lines and to link them to genetic "signatures" that might affect medical outcomes, the scientists drew on previous research from the International HapMap Project, published in the journal Nature in 2003. This research linked single-letter alterations in the genetic code — known as single nucleotide polymorphisms, or SNPs — with people of known ethnic origins. This data provided a way to identify the ethnic heritage of a donor of any cell. Laurent noted that simply asking cell donors about their ethnic heritage does not provide accurate data. "There's often an ancestor from a different area who a person doesn't know about," she said. The technology used for the new study, known as SNP genotyping, uses microarrays, which are easily available, inexpensive, and relatively straight forward for scientists to use. When the Scripps Research scientists applied the technique to the embryonic stem cell lines, they found that Caucasians were especially well represented among the samples, followed by East Asians. Cells of some mixed heritage were also common. Notably lacking from the samples were cell lines representing African heritage. In addition, the authors found that the country in which a cell line was generated did not necessarily predict the ethnicity of the donor. In creating a new pluripotent stem cell line from an individual with a West African Yoruba background, the scientists generated a line that contains distinct genetic markers for disease risk and drug metabolism. "There's not a lot of value in making a new pluripotent stem cell line now unless it has something new to offer," said Loring. "I think that increasing ethnicity and genetic diversity is an important reason for generating new lines." The data generated by the study — which Loring describes as the foundation of a new database of human pluripotent stem cell genetic information — will be available for other researchers to access for studies on specific genes, stem cell transplantation, and other topics. ......... ZenMaster

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Research Teams Map Genetic, Genomic Patterns in Han Chinese Population

First 'genetic map' of Han Chinese may aid search for disease susceptibility genes Wednesday, 25 November 2009 A pair of papers in the American Journal of Human Genetics today is highlighting the genetic and genomic variation present within the Han Chinese population. It is the largest ethnic population in the world. In the first of these papers, a Genome Institute of Singapore-led team developed a genetic map of the Han Chinese population by genotyping thousands of individuals from across China. This first historical genetic variation map is providing insights into Han Chinese population structure and evolutionary history — for instance, revealing North-South population structure in China. And down the road, researchers say, the results should pave the way for genome-wide association and other studies in the population. Based on genome-wide DNA variation information in over 6,000 Han Chinese samples from 10 provinces in China, this new map provides information about the population structure and evolutionary history of this group of people that can help scientists to identify subtle differences in the genetic diversity of Asian populations. Understanding these differences may aid in the design and interpretation of studies to identify genes that confer susceptibility to such common diseases as diabetes in ethnic Chinese individuals. Understanding these differences also is crucial in exploring how genes and environment interact to cause diseases. With the genetic map, the GIS scientists were able to show that the northern inhabitants of China were genetically distinguishable from those in the south, a finding that seems very consistent with the Han Chinese's historical migration pattern. The genetic map also revealed that the genetic divergence was closely correlated with the geographic map of China. This finding suggests the persistence of local co-ancestry in the country. "The genome-wide genetic variation study is a powerful tool which may be used to infer a person's ancestral origin and to study population relationships," said Liu Jianjun, Ph.D., GIS Human Genetics Group Leader. "For example, an ethnic Chinese born and bred in Singapore can still be traced back to his or her ancestral roots in China," Dr. Liu said. "By investigating the genome-wide DNA variation, we can determine whether an anonymous person is a Chinese, what the ancestral origin of this person in China may be, and sometimes which dialect group of the Han Chinese this person may belong to.” "More importantly, our study provides information for a better design of genetic studies in the search for genes that confer susceptibility to various diseases," he added. Of particular interest to people in Singapore are the findings that while the majority of Singaporean Chinese hail from Southern China as expected, some have a more northern ancestral origin. GIS Executive Director Edison Liu, M.D., said: "Genome association studies have provided significant insights into the genes involved in common disorders such as diabetes, high cholesterol, allergies, and neurological disorders, but most of this work has been done on Caucasian populations.” "More recently, Dr. Liu Jianjun from our institute has been working with his Chinese colleagues to define the genetic causes of some of these diseases in Asian populations," the GIS Executive Director added. "This work refined those tools so that the results will not be obscured by subtle differences in the genetic diversity of Asian populations. In the process, Dr. Liu has reconstructed a genetic historical map of the Chinese people as they migrated from south to north over evolutionary time." "There are definite differences in genetic architecture between populations," noted Chia Kee Seng, M.D., Head, Department of Epidemiology & Public Health, National University of Singapore (NUS), and Director, NUS-GIS Centre for Molecular Epidemiology. "We have seen this in the Singapore Genome Variation Project, a Joint NUH-GIS effort. Understanding these differences is crucial in exploring how genes and environment interact to cause diseases," he added. The research results published in American Journal of Human Genetics is part of a larger ongoing project on the genome-wide association study of diseases among the Chinese population. The project is a collaboration between GIS and several institutions and universities in China. In Jan. 2009, Nature Genetics published the findings of researchers at the GIS and Anhui Medical University, China, on psoriasis, a common chronic skin disease. In that study, led by Dr. Liu Jianjun at the GIS and Dr. Zhang Xuejun at the Anhui Medical University, the scientists discovered a genetic variant that provides protection against the development of psoriasis. The collaboration's recent discovery of over a dozen genetic risk variants for systematic lupus erythematosus (SLE) in the Chinese population was published in Nature Genetics in Oct. 2009. In a second AJHG paper, a Chinese research team genotyped more than 1,700 Han Chinese individuals from dozens of sites in China as part of another study aimed at understanding the genetic and genomic patterns within the Han Chinese population. The researchers genotyped 1,721 Han Chinese samples at about 160,000 SNPs for this paper. They collected more than 1,500 of the samples, while 44 were collected through the Human Genome Diversity Panel project and 171 were collected in Beijing and Denver as part of the HapMap project. That team detected north-south stratification similar to that reported by the Singapore-led team, though they designated three main Han Chinese clusters from northern, southern, and central parts of China. Again, individuals from the cities — in this case Beijing, Shanghai, and Guangzhou — did not represent populations that were as homogenous as those in other locations were. The researchers also found some SNPs that were strongly differentiated in different parts of the country. For instance, they reported, the frequency of SNPs in the genes FADS2 and HCP5 varied from north to south. Based on several simulated GWAS, each involving 300 cases and 300 controls, the team suggested that even the relatively subtle genetic variation within China could lead to excess false-positive associations. "Although differences in allele frequencies among Han Chinese clusters are small, our study has demonstrated the importance of accounting for population stratification in order to reduce false-positive associations," the researchers wrote. Reference: Genetic Structure of the Han Chinese Population Revealed by Genome-wide SNP Variation Jieming Chen, Houfeng Zheng, Jin-Xin Bei, Liangdan Sun, Wei-hua Jia, Tao Li, Furen Zhang, Mark Seielstad, Yi-Xin Zeng, Xuejun Zhang, Jianjun Liu The American Journal of Human Genetics, 25 November 2009, doi:10.1016/j.ajhg.2009.10.016 Genomic Dissection of Population Substructure of Han Chinese and Its Implication in Association Studies Shuhua Xu, Xianyong Yin, Shilin Li, Wenfei Jin, Haiyi Lou, Ling Yang, Xiaohong Gong, Hongyan Wang, Yiping Shen, Xuedong Pan, Yungang He, Yajun Yang, Yi Wang, Wenqing Fu, Yu An, Jiucun Wang, Jingze Tan, Ji Qian, Xiaoli Chen, Xin Zhang, Yangfei Sun, Xuejun Zhang, Bailin Wu and Li Jin The American Journal of Human Genetics, 25 November 2009, doi:10.1016/j.ajhg.2009.10.015 ......... ZenMaster

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Jumping Genes, Gene Loss and Genome Dark Matter

New map of copy number variation in the human genome is a resource for human genetics Monday, 12 October 2009 In research published last week by Nature, an international team describes the finest map of changes to the structure of human genomes and a resource they have developed for researchers worldwide to look at the role of these changes in human disease. They also identify 75 'jumping genes' - regions of our genome that can be found in more than one location in some individuals. However, the team cautions that they have not found large numbers of candidates that might alter susceptibility to complex diseases such as diabetes or heart disease among the common structural variants. They suggest strategies for finding this 'dark matter' of genetic variation. Human genomes differ because of single-letter variations in the genetic code and also because whole segments of the code might be deleted or multiplied in different human genomes. These larger, structural differences are called copy number variants (CNVs). The new research to map and characterize CNVs is of a scale and a power unmatched to date, involving hundreds of human genomes, billions of data points and many thousands of CNVs. "This study is more than ten times as powerful as our first map, published three years ago," explains Dr Matt Hurles from the Wellcome Trust Sanger Institute and a leader on the project, "and much more detailed than any other. Importantly, we have also assigned the CNVs to a specific genetic background so that they can be readily examined in disease studies carried out by others, such as the Wellcome Trust Case Control Consortium.” "Nevertheless, we have not found large numbers of common CNVs that we can tie strongly to disease. There remains much to be discovered and much to understand and our freely available genotyped collection will drive that discovery." The results show that any two genomes differ by more than 1000 CNVs, or around 0.8% of a person's genome sequence. Most of these CNVs are deletions, with a minority being duplications.

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Chromosomes are shown colour-coded in the outermost circle. Inside are lines connecting the origin and the new location (where known) of 58 out of 75 putative inter-chromosomal duplications, coloured according to their chromosome of origin. Credit: Jan Aerts, Wellcome Trust Sanger Institute.

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Two consequences are particularly striking in this study of apparently healthy people. First, 75 regions have jumped around in the genomes of these samples; second, more than 250 genes can lose one of the two copies in our genome without obvious consequences and a further 56 genes can fuse together potentially to form new composite genes. "This paper detailing common CNVs in different world populations, and providing the first glimpse into evolutionary biology of such class of human variation, is unquestionably one of the most important advances in human genome research since the completion of a reference human genome," says Professor James R. Lupski, Vice Chair of the department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. "It complements the cataloguing of single nucleotide variation delineated in the HapMap Project and will both enable some new approaches to, and further augment other studies of, basic human biology relevant to health and disease." "The genetic 'blueprint' of humans is the human genome," says Sir Mark Walport, Director of the Wellcome Trust. "But we are each unique as individuals, shaped by variation in both genome and environment. Understanding the variation amongst human genomes is key to understanding the inherited differences between each of us in health and disease. A whole new dimension has been added to our understanding of variation in the human genome by the identification of copy number variants." The results also give, for the first time, a minimum measure of the rate of CNV mutation: at least one in 17 children will have a new CNV. In many cases, that CNV will have no obvious clinical consequences. However, for some the effects are severe. In those cases the data are captured in the DECIPHER database, a repository of clinical information about CNVs designed to aid the diagnosis of rare disorders in young children. However, CNVs are not only about here and about now; they are also ancient legacies of how our ancestors adapted to their environments. Among the most impressive variations between populations are CNVs that modify the activity of the immune system, known to be evolving rapidly in human populations, and genes implicated in muscle function. The researchers propose that the consequences of these CNVs can be dissected in population studies. The team scanned 42 million locations on the genomes of 40 people, half of European ancestry and half of West-African ancestry. The scale of the method meant they could detect CNVs as small as 450 bases occurring in one in 20 individuals. However, the researchers concede that their map of common variants will not account for much of the 'dark matter' of the genome - the missing heritability where, despite diligent searches, genetic variants have not been found for common disease. "CNV studies have made huge advances in the past few years, but we are still looking only at the most common CNVs," explains Dr Steve Scherer of the Hospital for Sick Children, Toronto. "We suspect that there are many CNVs that have real clinical consequences that occur in perhaps one in 50 or one in 100 people - below the level we have detected.” "Success in the hunt for the missing genetic causes of common disease has become possible in the last few years and we expect to find more as higher resolution searches become possible." The research group have maximized the value of their research by not only mapping the CNVs, but by also genotyping them - assigning them to a specific genetic background that makes them readily useful in wider genetic studies, such as the Wellcome Trust Case Control Consortium. "We were determined to develop not only the map, but also to provide the resources that help other researchers and clinical cytogeneticists most rapidly use our CNV results," comments Dr Charles Lee, one of the project leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, USA. "Already, the data that we have generated is benefiting other large-scale studies such as the 1000 Genomes Projects as well as making an enormous difference in the accurate interpretation of clinical genetic diagnoses.” "Nonetheless, the human CNV story is far from over." ......... ZenMaster

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Are We Selling Personalized Medicine Before Its Time?

Limitations of genetic screening reported in Public Library of Science study Friday, 06 February 2009 We may be a long way off from using genetics to reliably gauge our risks for specific diseases, say researchers at the University of Pittsburgh Schools of the Health Sciences in a study published on Feb. 5 in the online journal PLoS Genetics. Yet, many companies currently offer personalized genetic testing for diseases like cancer, heart disease and diabetes, and tout the ability of DNA testing to predict future health risks. "The rapid discovery of new genetic risk factors is giving us vitally important insights into human health, but a strong association between these factors and disease risk may not reliably predict which health issues a specific individual will face in the future," said Daniel E. Weeks, Ph.D., senior author and professor of human genetics and biostatistics at the University of Pittsburgh Graduate School of Public Health. "Our study indicates that even though we can paint a picture of our genetic makeup with current tests, this may not be enough to help us understand our individual risk for disease." The study focused on single nucleotide polymorphisms, or SNPs – variations in short DNA sequences that have been linked to the presence of particular diseases, and that exist in the millions in the human genome. A number of companies currently offer individualized estimates for disease risks based on genome-wide SNP genotyping. These tests typically scan 500,000 to 1 million SNPs, searching for only a handful associated with a specific disease. Dr. Weeks and colleagues focused their study on diseases for which there are strongly associated genetic variants: age-related macular degeneration, type 2 diabetes, prostate cancer, cardiovascular disease and Crohn's disease. They found that a strong genetic association did not guarantee they could accurately discriminate between actual disease cases and controls in both mathematical models and real-world examples. Part of the problem may be a statistical one. To provide meaningful insights, a test for disease risk needs to accurately identify positive cases and, at the same time, provide a low false positive rate. One of the challenges with current approaches to genetic testing is that they are based on a very small number of common variants, "making it likely that you will identify people at high risk who may not be at risk at all," said Dr. Weeks. "With such a small pool of variants, it's difficult to develop a very meaningful test for predicting disease risk." In addition, he said, few health care providers have adequate genetics training to make sense of the risk calculations now commercially offered and to advise their patients accordingly. Dr. Weeks suggests the need for longitudinal studies to define true risk and to understand how genetic susceptibility may interact with known environmental and lifestyle risk factors. "With more study, our hope is that genetic testing will benefit people and encourage positive lifestyle changes and guide clinical decisions. In the meantime, we need to take a step back and proceed with caution and allow the insights gained from these new association findings to be used to explore the basic biological causes of disease," he said. ......... ZenMaster

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The Nonsense in Our Genes

Is 1 in 200 human genes superfluous? Thursday, 05 February 2009 A study of the genetic code of more than 1,000 people, published in the American Journal of Human Genetics, has found that at least one in 200 human genes can be inactivated in apparently healthy people. The findings suggest that, though these genetic mutations can be harmful, they generally have little effect on the individual and could occasionally even be beneficial in evolutionary terms. The study also found that individuals carry on average 46 of these inactivating mutations. 1 in 200 of our human genes can be inactivated with no detectable effect on our health. A study by Wellcome Trust Sanger Institute scientists raises new questions about the effects of gene loss on our wellbeing and evolution. The study, published today in The American Journal of Human Genetics, explores single letter changes in our genetic code that affect the ability of genes to produce proteins. The researchers' findings suggest that such mutations, while sometimes harmful, generally have little consequence for the individual and may occasionally even be beneficial in evolutionary terms. The team studied variations in the genetic code of more than 1000 people from around the world. They focused their work on single-letter changes (called SNPs) that disrupt proteins, leading to versions that are either shorter or completely absent. One might intuitively expect that such a change - called a nonsense-SNP - would be harmful to the person. "We knew that these mutations existed and that many have been associated with genetic diseases, but we were amazed to find that they were so common in the general population," said Bryndis Yngvadottir, lead author on the study.

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Frequency of nonsense SNPs in the study sample.

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"We found that 167 genes could be inactivated by nonsense mutations, and that individuals carry on average at least 46 such variations. For 99 of the genes, both copies could be lost in adults living a normal existence." Human DNA contains approximately 20,000 genes: the total of 99 genes with nonsense-SNPs means that at least 1 in 200 genes is dispensable. Some harmful nonsense-SNPs were also present among the 167 genes studied: 8 are listed in the Human Gene Mutation Database which catalogues disease-causing mutations. While the researchers found that inactivating genes was, on the whole, slightly harmful, there were exceptions. In East Asia, but not in other places, it seems to have been advantageous to lose the MAGEE2 gene. "There is a theory that 'less is more' where genes are concerned" explained the study's coordinator, Chris Tyler-Smith, "and we already knew of a couple of examples of advantageous gene loss. But this is the first large-scale investigation of its significance for recent human evolution.” "The MAGEE2 gene is an interesting new example, although we have absolutely no idea what this gene does, or why some people are better off without it. However, our study suggests that overall, gene loss has not been a major evolutionary force: our genome does not seem to be in a hurry to get rid of these 'superfluous' genes." "Certain types of genes tend to be lost preferentially. We found the biggest decrease in the genes that contribute to our sense of smell. Perhaps early humans didn't like smelly partners, and so when humans started to live together in big groups it helped their chances of finding true love if they couldn't smell their partner too strongly," speculated Bryndis Yngvadottir. Genetic variation in nonsense-SNP numbers was significant: participants in the survey had between 29 and 65 of these mutations each and varied on average by 24 genes as a consequence. 18 of the 169 nonsense-SNPs investigated are also present in the Craig Venter genome published last year. About: The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992 as the focus for UK sequencing efforts. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms such as mouse and zebrafish, and more than 90 pathogen genomes. In October 2005, new funding was awarded by the Wellcome Trust to enable the Institute to build on its world-class scientific achievements and exploit the wealth of genome data now available to answer important questions about health and disease. These programmes are built around a Faculty of more than 30 senior researchers. The Wellcome Trust Sanger Institute is based in Hinxton, Cambridge, UK. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. Reference: A Genome-wide Survey of the Prevalence and Evolutionary Forces Acting on Human Nonsense SNPs Bryndis Yngvadottir , Yali Xue , Steve Searle , Sarah Hunt , Marcos Delgado , Jonathan Morrison , Pamela Whittaker , Panos Deloukas and Chris Tyler-Smith The American Journal of Human Genetics, 05 February 2009, 10.1016/j.ajhg.2009.01.008 ......... ZenMaster

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Scientists Begin Untangling Genetics behind Dog Breeds

Discovery offers potential benefits for dogs and their owners Monday, 23 June 2008 What makes a pointer point, a sheep dog herd, and a retriever retrieve? Why do Yorkshire terriers live longer than Great Danes? And how can a tiny Chihuahua possibly be related to a Great Dane? Dogs vary in size, shape, colour, coat length and behaviour more than any other animal and until now, this variance has largely been unexplained. Now, scientists have developed a method to identify the genetic basis for this diversity that may have far-reaching benefits for dogs and their owners. In the cover story of today’s edition of the science journal Genetics, research reveals locations in a dog's DNA that contain genes that scientists believe contribute to differences in body and skull shape, weight, fur colour and length – and possibly even behaviour, trainability and longevity. "This exciting breakthrough, made possible by working with leaders in canine genetics, is helping us piece together the canine genome puzzle which will ultimately translate into potential benefit for dogs and their owners," said study co-author Paul G. Jones, PhD, a Mars Veterinary™ genetics researcher at the Waltham® Centre for Pet Nutrition – part of Mars® Incorporated, a world leader in pet care that has been studying canine genetic science for the past eight years. "By applying this research approach, we may be able to decipher how genes contribute to physical or behavioural traits that affect many breeds." Dogs originally derived from the wolf more than 15,000 years ago – a blink of the eye in evolutionary terms. Selective breeding produced dogs with physical and behavioural traits that were well suited to the needs or desires of their human owners, such as herding or hunting ability, coat colour and body and skull shape and size. This resulted in the massive variance seen among the more than 350 distinct breeds that make up today's dog population. Until now, the genetic drivers of this diversity have intrigued scientists who have been trying to explain how and why the difference in physical and behavioural traits in dogs changed so rapidly from its wolf origins. An international team of researchers, which included scientists at the National Human Genome Research Institute, the University of Utah, Sundowners Kennels in Gilroy, California and Mars' Waltham Center for Pet Nutrition in the United Kingdom, studied simple genetic markers known as Single Nucleotide Polymorphisms, or SNPs, to find places in the dog genome that correlate with breed traits. Because many traits are "stereotyped" – or fixed within breeds – researchers can zero in on these "hot spots" to see what specific genes are in the area that might contribute to differences in traits. The research used 13,000 dog DNA samples provided by Mars Veterinary, which holds one of the most comprehensive canine DNA banks in the world. This collection has been built up with the help of pet owners who have consented to their pets providing cheek swabs and blood samples for the database. Mars' DNA bank allowed the study to cover most of the American Kennel Club recognized breeds that span a wide variety of physical and behavioural traits and differences in longevity. "With further refinement and additional data, this method could be used to tailor products that may benefit the health of pets," Jones said. "Pet owners and veterinarians may be able to develop better care regimes based on this knowledge. In addition, genetic information about behavioural traits, such as trainability and temperament, could also help veterinarians identify the most lifestyle-appropriate pet for an owner." This research may also have implications for human health, as dogs suffer from many of the same diseases that we do. Reference: Single-Nucleotide-Polymorphism-Based Association Mapping of Dog Stereotypes Paul Jones, Kevin Chase, Alan Martin, Pluis Davern, Elaine A. Ostrander and Karl G. Lark Genetics, Vol. 179, 1033-1044, June 2008, doi:10.1534/genetics.108.087866 ......... ZenMaster

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Human Genetic Variation

U-M researchers release most detailed global study of genetic variation Wednesday, 20 February 2008 University of Michigan scientists and their colleagues at the National Institute on Aging have produced the largest and most detailed worldwide study of human genetic variation, a treasure trove offering new insights into early migrations out of Africa and across the globe. Like astronomers who build ever-larger telescopes to peer deeper into space, population geneticists like U-M's Noah Rosenberg are using the latest genetic tools to probe DNA molecules in unprecedented detail, uncovering new clues to humanity's origins. The latest study characterizes more than 500,000 DNA markers in the human genome and examines variations across 29 populations on five continents. "Our study is one of the first in a new wave of extremely high-resolution genome scans of population genetic variation," said Rosenberg, an assistant research professor at U-M's Life Sciences Institute and co-senior author of the study, to be published in the Feb. 21 edition of Nature. "Now that we have the technology to look at thousands, or even hundreds of thousands, of genetic markers, we can infer human population relationships and ancient migrations at a finer level of resolution than has previously been possible." The new study, led by Rosenberg and National Institute on Aging colleague Andrew Singleton, produced genetic data nearly 100 times more detailed than previous worldwide assessments of human populations. It shows that:

• A recently discovered type of human genetic variation, known as a copy-number variant or CNV, is a reliable addition to the toolkit of population geneticists and should speed the discovery of disease-related genes. Rosenberg and his colleagues discovered 507 previously unknown CNVs, which are large chunks of DNA — up to 1,000,000 consecutive "letters" of the genetic alphabet — that are either repeated or deleted entirely from a person's genome. Various diseases can be triggered by an abnormal gain or loss in the number of gene copies.
• It's sometimes possible to trace a person's ancestry to an individual population within a geographic region. While previous studies have found that broad-scale geographic ancestry could be successfully traced, the new results indicate "it's becoming increasingly possible to use genomics to refine the geographic position of an individual's ancestors with more and more precision," Rosenberg said.
• Human genetic diversity decreases as distance from Africa — the cradle of humanity — increases. People of African descent are more genetically diverse than Middle Easterners, who are more diverse than Asians and Europeans. Native Americans possess the least-diverse genomes. As a result, searching for disease-causing genes should require the fewest number of genetic markers among Native Americans and the greatest number of markers among Africans.

The results are being made available on publicly shared databases. "I hope the study will be an invaluable resource for understanding genomic variability and investigating genetic association with disease," said the NIA's Singleton.

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A schematic of worldwide human genetic variation, with colours representing different genetic types. The figure illustrates the great amount of genetic variation in Africa. Illustration by Martin Soave/University of Michigan.

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The researchers analyzed DNA from 485 people. They examined three types of genetic variation: single-nucleotide polymorphisms, or SNPs; haplotypes; and CNVs. If the human genome is viewed as a 3-billion-letter book of life, then SNPs represent single-letter spelling changes, haplotype variations equate to word changes, and CNVs are wholesale deletions or duplications of full pages. The patterns revealed by the new study support the idea that humans originated in Africa, then spread into the Middle East, followed by Europe and Asia, the Pacific Islands, and finally to the Americas. The results also bolster the notion of "serial founder effects," meaning that as people began migrating eastward from East Africa about 100,000 years ago, each successive wave of migrants carried a subset of the genetic variation held by previous groups. "Diversity has been eroded through the migration process," Rosenberg said. In addition to his position at the Life Sciences Institute, Rosenberg is an assistant professor of human genetics, biostatistics, and ecology and evolutionary biology, as well as an assistant research professor of bioinformatics. "This data set is so rich. It provides a much more comprehensive, cross-sectional snapshot of the human genome than previous studies," said Paul Scheet, a post-doctoral researcher in the U-M Department of Biostatistics and one of the lead authors. "The next step for these studies is to sequence whole genomes," said Mattias Jakobsson, a post-doctoral researcher at the U-M Center for Computational Medicine and Biology and another lead author. "You would take 500 individuals, and you would just completely sequence everything, and then you'd have almost every important variant that's out there." The work was supported in part by National Institutes of Health grants, the U-M Center for Genetics in Health and Medicine, the Alfred P. Sloan Foundation, the Burroughs Wellcome Fund, the National Center for Minority Health and Health Disparities, and the Intramural Program of the National Institute on Aging. Reference: Genotype, haplotype and copy-number variation in worldwide human populations Nature 451, 998-1003 (21 February 2008) doi:10.1038/nature06742 .........

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Human Genetic Recombination Studied II

Gene variants may help to distribute the work of evolution between men and women Thursday, 31 January 2008 Scientists from deCODE genetics today report the discovery of two common, single-letter variants in the sequence of the human genome (SNPs) that regulate one of the principle motors of evolution. Versions of the two SNPs, located on chromosome 4p16, have a genome-wide impact on the rate of recombination — the reshuffling of the genome that occurs in the formation of eggs and sperm. Recombination is largely responsible for generating human diversity, the novel configurations of the genome that enable the species to adapt and evolve in an ever-changing environment. Yet remarkably, the versions of the SNPs that increase recombination in men decrease it in women, and vice versa. This highly unusual characteristic may enable the variants to help to maintain a fundamental tension crucial for evolutionary success: promoting the generation of significant diversity within a portion of the population but keeping the pace of this change within certain bounds, maintaining it relatively constant overall and so supporting the stability of the genome and the cohesiveness of the species. “This is the latest in a series of landmark papers from deCODE in which we have utilized our unique capabilities in human genetics to elucidate some of the key mechanisms driving human evolution,” said Kari Stefansson, CEO of deCODE. “We are also excited that we can now immediately enable individuals to see if they carry such variants, by folding the findings announced today — and others we expect to publish in the near future — into our deCODEme™ personal genome analysis service.” The deCODE team identified the SNPs through a genome-wide analysis of more than 300,000 SNPs in approximately 20,000 participants in the company’s gene discovery programs. The SNPs, referred to as rs3796619 and rs1670533, are within the RNF212 gene, and are estimated to account for approximately 22% of paternal variability in recombination and 6.5% of maternal variability. Little is known about RNF212, though it is a mammalian homolog of a gene called ZHP-3 known to be crucial for the success of recombination in other organisms. The paper, entitled ‘Sequence Variants in the RNF212 Gene Associate with Genomewide Recombination Rate,’ is published today in the online edition of Science. deCODE has made a number of breakthrough discoveries in the understanding of recombination, fertility and human evolution. In 2002, deCODE published the most detailed recombination map to date of the genome, demonstrating that there are hotspots and coldspots for recombination in all chromosomes, and that these are very different in women and men. This map provided a template for completing the final assembly of the sequence of the human genome. deCODE scientists then showed that recombination rate varies between families and between women; that recombination rate increases with the age of the mother; and that higher recombination rate correlates with fertility, indicating that evolution appears to place a premium on the generation of human diversity. In 2005, deCODE identified a genetic variant that correlates with higher recombination rate, the first genetic variant ever demonstrated to be under positive evolutionary selection in human populations in real time. References for these and all deCODE’s major discoveries can be found at www.decode.com. About deCODE deCODE is a biopharmaceutical company applying its discoveries in human genetics to the development of drugs and diagnostics for common diseases. deCODE is a global leader in gene discovery — our population approach and resources have enabled us to isolate key genes contributing to major public health challenges from cardiovascular disease to cancer, genes that are providing us with drug targets rooted in the basic biology of disease. deCODE is also leveraging its expertise in human genetics and integrated drug discovery and development capabilities to offer innovative products and services in DNA-based diagnostics, bioinformatics, genotyping, structural biology, drug discovery and clinical development. deCODE is delivering on the promise of the new genetics. ......... ZenMaster

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Human Genetic Recombination Studied I

Inherited individual variations influence patterns of gene shuffling Thursday, 31 January 2008 The first large-scale, high-resolution study of human genetic recombination has found remarkably high levels of individual variation in genetic exchange, the process by which parents pass on a mosaic-like mixture of their genes. In an article appearing February 1, 2008, in Science Express, the online version of Science, researchers from the University of Chicago locate nearly 25,000 recombination events that occurred in the transmission of the parental genomes to 364 offspring. The high-resolution of their maps allows them to provide the precise location of where these genetic exchanges occur, and to assess the differences in recombination rates between individuals. "Genetic recombination is a fundamental process, at the core of reproduction and evolution," said study author Graham Coop, PhD, post-doctoral fellow in the Department of Human Genetics at the University of Chicago, "yet we know very little about where it occurs or why there is so much variation among individuals in this important process." "Now," he said, "we know where it occurs. Understanding where it happens provides us with important clues as to how it happens, how it is regulated and what the mechanisms are that control this essential biological phenomenon." Recombination occurs during meiosis, a special kind of cell division that takes place only in the testicles and ovaries. In the process of making sperm or egg cells, the parent-to-be takes the chromosomes inherited from each of his or her parents and reshuffles them, swapping parts of one chromosome for the matching segments of the other version of that same chromosome. The result is a reproductive cell with a mosaic, or patchwork, of genes, about half from each parent, but shuffled together into entirely new combinations. This process leads to offspring having different combinations of genes than their parents and is thought to have many advantages. Errors in this recombination process during the production of sperm or egg cells underlie a variety of chromosomal abnormalities and can cause deletions of regions of the genome, miscarriage, or genetic disorders such as Down syndrome. The research team focused on the Hutterites, a genetically similar population of European immigrants who settled in the Dakotas in the 19th century and have maintained a communal agricultural lifestyle. One member of the research team, Carole Ober, PhD, professor of human genetics and of obstetrics and gynaecology at the University of Chicago, has been working closely with this group for many years on health and inheritance issues. The researchers collected DNA samples from 725 volunteers, representing 82 overlapping nuclear families, most of which included four or more children. These families are part of a larger 1650-person, 13-generation pedigree of the Hutterites in the US. They used 500,000 markers of genetic variation (SNPs) to determine, along each chromosome, whether the genetic material transmitted from the mother (or father) came from the child's maternal (or paternal) grandmother or grandfather. The large number of markers allowed the researchers to map out at high resolution the locations in the genome where ancestry shifts from one grandparent to another, which are known as recombination events. Chromosomes from the mother (not including the X chromosome) averaged around 40 recombination events per gamete. Those from the father had only 26. The authors confirm a previous finding that older mothers have more recombination events in the transmission of their genome to their offspring, while the father's age has no such effect. For both sexes, the majority of crossovers occur at genetic "hotspots," small regions where genetic exchanges are unusually common. Although the overall rate of hotspot use was similar between the two sexes, a subset of hotspots, "seems to be used mainly by one sex of the other," the authors note. Strikingly the pattern of hotspot used varied among individuals, but seemed to be passed on from generation to generation — a heritable difference potentially pointing to differences in the recombination machinery among individuals. The study uncovered "tremendous variation in recombination rates over all genomic scales considered and in particular heritable variation in hotspot use," the authors conclude. Their ongoing efforts to map this variation should offer insights into the "genetic basis of recombination-rate variation and the selective forces governing the evolution of recombination rates." The National Institutes of Health funded the research. Additional authors include Molly Przeworski, Jonathan Pritchard and Xiaoquan Wen of the Department of Human Genetics at the University of Chicago. ......... ZenMaster

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Genetic Testing: Customer DNA analyses

Genetic Testing: Customer DNA Analyses Sunday, 18 November 2007 Three companies have started or are planning services to test customers’ DNA at nearly one million locations (SNP’s) where the human genome is known to vary between individuals. All are offering services to help consumers interpret the information contained in their own genomes. Would you subscribe to such a service? 23andMe Mountain View, Calif. Available now for $999 Services: genotyping 580,000 SNPs using Illumina technology; Gene Journals reporting risk for 20 diseases and physical traits; tools for tracing ancestry and DNA similarity with family and friends; Genome Explorer to provide access to all data to allow customers to compare any published study with their own genotype; will provide referrals to genetic counsellors. Online: www.23andme.com deCODE Genetics Reykjavik, Iceland Available now for $985 Services: genotyping one million SNPs using Illumina technology; deCODEme will provide risk reports for about 20 diseases and physical traits; tools for tracing ancestry and DNA similarity with family and friends; genetic counsellors available for consultations. Online: www.decodeme.com Navigenics Redwood Shores, Calif. Available in 2008 for $2,500 Services: will genotype one million SNPs using Affymetrix technology; health Compass will provide risk reports for about a dozen diseases; results relayed by genetic counsellor. Online: www.navigenics.com/ Read more at: My Genome, Myself: Seeking Clues in DNA NY Times - November 17, 2007 ......... ZenMaster

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