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.
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.
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."
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ZenMaster
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The researchers grew the cells in an environment much like that found in natural tissues. They encapsulated the cells within a gel composed of the blood-clotting protein fibrin, which provided mechanical support to the cells, allowing them to form a three-dimensional structure. They also found that the cardiomyocytes flourished only in the presence of a class of "helper" cells known as cardiac fibroblasts, which comprise as much as 60 percent of all cells present in a human heart.
"If you tried to grow cardiomyocytes alone, they develop into an unorganized ball of cells," said Brian Liau, graduate student in biomedical engineering at Duke's Pratt School of Engineering. Liau, who works in the laboratory of assistant professor Nenad Bursac, presented the results of his latest experiments during the annual scientific sessions of the Biomedical Engineering Society in Pittsburgh.
"We found that adding cardiac fibroblasts to the growing cardiomyocytes created a nourishing environment that stimulated the cells to grow as if they were in a developing heart," Liau said.
"When we tested the patch, we found that because the cells aligned themselves in the same direction, they were able to contract like native cells. They were also able to carry the electrical signals that make cardiomyocytes function in a coordinated fashion."
"The addition of fibroblasts in our experiments provided signals that we believe are present in a developing embryo," Liau said. The need for helper cells is not uncommon in mammalian development. For example, he explained, nerve cells need "sheathe" cells known as glia in order to develop and function properly.
Bursac believes that the latest experiments represent a proof-of-principle advance, but said there are still many hurdles to overcome before such patches could be implanted into humans with heart disease.
"While we were able to grow heart muscle cells that were able to contract with strength and carry electric impulses quickly, there are many other factors that need to be considered," Bursac said.
"The use of fibrin as a structural material allowed us to grow thicker, three-dimensional patches, which would be essential for the delivery of therapeutic doses of cells. One of the major challenges then would be establishing a blood vessel supply to sustain the patch."
The researchers plan to test their model using non-embryonic stem cells. For use in humans, this is important for many reasons, both scientifically and ethically, Bursac said. Recent studies have demonstrated that some cells from human adults have the ability to be reprogrammed to become similar to embryonic stem cells.
"Human cardiomyocytes tend to grow a lot slower than those of mice," Bursac said.
"Since it takes nine months for the human heart to complete development, we need to find a way to get the cells to grow faster while maintaining the same essential properties of native cells."
If they could use a patient's own cells, the patch would also evade an immune system reaction, Bursac added.
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