Do Copy Number Variations Increase With Older Paternal Age, Is That Why Non-Familial Cancers, Autism, Schizophrenia, Autoimmune Diseases Increase

Canadian, British And American Scientists Launch Major New Genome Partnership To Catalogue All Common Copy Number Variations
Main Category: Genetics News


An international team will use state-of-the-art, high-density microarrays and new computer algorithms to improve the detection of variants in the human genome which are implicated in various diseases. The new systems are the foundation of Phase 2 of the Genome Structural Variation Consortium, which was set up in 2004 and seeks to identify structurally variable regions in the human genome.

In 2006, the Genome Structural Variation Consortium, along with other international collaborators, generated a first-generation map of copy number variants (CNVs) covering the human genome. The CNVs that they identified, which in many cases lead to deletion or duplication of genes along chromosomes, tended to encompass large stretches of DNA ranging from thousands to millions of chemical bases of DNA. These changes are part of the normal variability between apparently healthy people, but some may also predispose individuals to disease. The data also suggested that thousands more CNVs exist, but technological limitations associated with that earlier study precluded the discovery of more CNVs.

The new comprehensive map will be critical for studies attempting to identify genes involved in both rare and common diseases. "Our experiments will generate the highest-resolution CNV catalogue of worldwide populations. The initiative will also complement ours, and other efforts to sequence entire genomes", said Dr. Stephen Scherer, Senior Scientist and Director, The Centre for Applied Genomics (TCAG) at The Hospital for Sick Children (SickKids) in Toronto.

In its second phase, this international research collaboration will develop a comprehensive, higher resolution CNV map for the Human Genome - at a level 100-fold finer than the first map. Working with NimbleGen Systems, Inc. of Madison, Wisconsin, USA, the Consortium has designed a novel set of 2.1-million-feature microarrays that will enable genome-wide detection of CNVs with 42 million probes. The set of microarrays have been referred to as "whole-genome oligonucleotide tiling arrays" because they cover almost all DNA along chromosomes, spaced at intervals of only 50 bases, or letters of DNA code.

The international consortium is led by Scherer, Drs. Nigel Carter, Matthew Hurles, and Chris Tyler-Smith of the Wellcome Trust Sanger Institute, and Dr. Charles Lee from Brigham and Women's Hospital and Harvard Medical School.

To better understand CNVs and diseases, researchers and clinicians around the world are now accessing the new CNV maps from the "Database of Genomic Variants" (http://www.projects.tcag.ca/variation/) hosted by SickKids. TCAG is a genomics platform funded by Genome Canada through OGI.

"Copy Number Variation has emerged over the past few years as a novel and productive focus for understanding variation within the human genome as well as other species' genomes," noted Dr. Christian Burks, President and CEO of the Ontario Genomics Institute (OGI). "We are delighted, in conjunction with funding from Genome Canada and Ontario's Ministry of Research and Innovation, to be supporting this work, and to see Ontario and Canada at the forefront of this area of biomedical research."

"From our Phase 1 map, we suspected there remains much more CNV to be discovered," said Dr. Matthew Hurles, Investigator at the Wellcome Trust Sanger Institute. "Because of the higher resolution of the new systems, we will, for the first time, be able to uncover these smaller variants."

Dr. Nigel Carter, Senior Investigator at the Sanger Institute added, "The availability of flexible high-density oligonucleotide arrays has made a study of such scope possible. The first data from the 42 million probe set has confirmed the ability of this approach to identify copy number variants at least as small as 500 base pairs in size."

The new arrays will be used to scan DNA samples from dozens of individuals of diverse geographic background, in experiments designed to capture all CNVs with a frequency of five percent or greater in the world. As such, the project will generate more than 1.68 billion data points.

"We also anticipate being able to obtain fine-scale information on the anatomy of individual CNVs" said Dr Charles Lee, Director of Cytogenetics (Harvard Cancer Center), Brigham and Women's Hospital and Harvard Medical School. "Ultimately, the data generated from our Phase 2 studies will be important for disease association studies, cancer biomarker studies, and accurate interpretation of many genetic diagnostic tests."

The Centre for Applied Genomics (TCAG) is located in the Research Institute of The Hospital for Sick Children (SickKids), Toronto, and is a Science and Technology Platform of Genome Canada, funded by Genome Canada through the Ontario Genomics Institute. TCAG provides genomics infrastructure to facilitate a wide variety of research, including human genomics and disease, model organisms, and agricultural and food sciences. The Centre's services are available to all clients in the academic, government or private sectors. TCAG supports a number of large-scale Genome Canada projects, other national and international genomics efforts, as well as hundreds of additional researchers in Ontario, Canada, and worldwide.

http://www.tcag.ca

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.

http://www.sanger.ac.uk/humgen/cnv/

Brigham and Women's Hospital (BWH) is a 747-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 800 physician-investigators and renowned biomedical scientists and faculty supported by more than $400M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative.

http://www.brighamandwomens.org
http://www.chromosome.bwh.harvard.edu

The Ontario Genomics Institute (OGI) is a private, not-for-profit corporation focused on providing leadership for Ontario in helping build a globally-competitive life sciences sector by creating leverageable genomics resources with top-notch research. Through its relationship with Genome Canada, the Ontario Ministry of Research and Innovation (MRI), and other private and public sector partners, OGI helps Ontario-based scientists secure funding for research in genomics and proteomics as well as for commercialization activities. OGI also focuses on the potential ethical and social issues that can arise with and from such research.

http://www.OntarioGenomics.ca

How Much Would It Cost To Tell Men That There Is A Male Biological Clock? How Much Money Would Be Lost By Preventing Austim, etc.?

The $2,000,000 for Mark Rothmeyer doesn't surprise me at all. Neither do the other expenses and salaries. If anyone is interested in the causes of autism and the history of its creation as a mysterious disorder go to the autism prevention blogspot. Autism, until 1994 used to be a diagnosis given for a very specific set of symptoms and it was sometimes considered the severest example of early childhood schizophrenia. The paper by Kanner on classical autism can be linked to on the site.


Autism Speaks never does anything to help anyone with autism, or prevent even one case of autism. The causes of autism are known, the way to prevent more autism is known in a percentage of cases. How to take a tragic disorder and turn it into a lucretive business venture is demonstrated again by Autism Speaks and the Institutions it funds.

.....................................................................................


GINGER of ADVENTURES IN AUTISM

Thursday, June 07, 2007
I Take Back Every Nice Thing I Have Ever Said About Autism Speaks

"I read this today and it just made me sick. I don't even have the words to comment on it."~Ginger
....................................................................................
I am a professional that has reviewed many non profit organization's IRS Form 990s. Autism Speaks Form 990 raises serious red flags. Serious. This is all from the official filing for 2006.





1. Three members of the Board of Directors received $2.5 million for their own organizations.

2. The President Mark Rothmeyer, just received a 5 year contract for about $2,000,000 including bonuses with no prior background with autism.

3. The grants are primarily going to those representing institutions that are reviewing the grants. There is no indication that these conflicts are independently reviewed

4. The location of this small and new foundation is in very expensive downtown New York facilities rented for $200,000 by the institution that is run by the Chairman of Autism Speaks.

5. A expense of a Private Jet plane for $57,000 was noted. This is very unusual for a new non profit groups.

6. The head of the scientific review received the majority of the funds for 2005 for his institution for a data base - almost $3 million

Since the funding is now from the public - and the advertising and promotion tugs at the publics heart strings with images of families in need - the funds collected MUST be about those it raises the money for.

The following are all taken from the Form 990 filing

Web Site $830,000
Software for the computer $514,000
Lawyers $440,000
Computers $337,000
Public relations $285,000
Office annual rent $200,000
HR consultant $110,000
Editorial Consultant $76,000
Private Jet Plane for someone that entertained $57,000


Mark Rothmeyer* $360,000
Peter Bell [$240,000?]
Alison Singer $168,000
Mr Ringall $150,000
Andy Shik $110,000

Remember all the above also gets significant fring benefits that
probably add.

Mark Rothmayer also can get $50,000 more with a bonus a year benefits

THE IDEA THAT GERM LINE CNVs OCCUR IN THE SPERM OF OLDER MEN IS CERTAINLY A POSSIBILITY AND A VERY IMPORTANT RESEARCH LINE TO FOLLOW IN SZ AND AUTISM

"The idea that germ line CNVs occur in the sperm of older men (or women for that matter) is certainly possible and a very important research line to follow in schizophrenia and autism. However, the best experiment would be to identify de novo CNVs in patients with SZ by doing CGH and comparing the results with parental CGH (as recently reported by Sebat et al in autism). The possibility of a finding might increase if sporadic, non-familial cases are used. One cannot examine the sperm directly because the frequency of such a defect would be very low and the spermatozoan with a new CNV would be diluted by a large population of cells that do not have it. The sensitivity of current methods used to assess CNV are too low to detect such changes."

CNVs and SNPs Methods paper

CARAT: A novel method for allelic detection of DNA copy number changes using high density oligonucleotide arrays
Jing Huang1 , Wen Wei1 , Joyce Chen1 , Jane Zhang1 , Guoying Liu1 , Xiaojun Di1 , Rui Mei1 , Shumpei Ishikawa2 , Hiroyuki Aburatani2 , Keith W Jones1 and Michael H Shapero1
1Affymetrix, Inc. 3420 Central Expressway, Santa Clara CA 95051, USA
2University of Tokyo, Genome Science Division Research Center for Advanced Science and Technology, 4-6-1 Komaba, Meguro, 153-8904, Tokyo

BMC Bioinformatics 2006, 7:83 doi:10.1186/1471-2105-7-83

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2105/7/83

Received 2 July 2005
Accepted 21 February 2006
Published 21 February 2006

© 2006 Huang et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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DNA copy number alterations are one of the main characteristics of the cancer cell karyotype and can contribute to the complex phenotype of these cells. These alterations can lead to gains in cellular oncogenes as well as losses in tumor suppressor genes and can span small intervals as well as involve entire chromosomes. The ability to accurately detect these changes is central to understanding how they impact the biology of the cell.

Results

We describe a novel algorithm called CARAT (Copy Number Analysis with Regression And Tree) that uses probe intensity information to infer copy number in an allele-specific manner from high density DNA oligonuceotide arrays designed to genotype over 100, 000 SNPs. Total and allele-specific copy number estimations using CARAT are independently evaluated for a subset of SNPs using quantitative PCR and allelic TaqMan reactions with several human breast cancer cell lines. The sensitivity and specificity of the algorithm are characterized using DNA samples containing differing numbers of X chromosomes as well as a test set of normal individuals. Results from the algorithm show a high degree of agreement with results from independent verification methods.

Conclusion

Overall, CARAT automatically detects regions with copy number variations and assigns a significance score to each alteration as well as generating allele-specific output. When coupled with SNP genotype calls from the same array, CARAT provides additional detail into the structure of genome wide alterations that can contribute to allelic imbalance

BACK TO THE SUBJECT OF COPY NUMBER VARIATIONS IN SPORADIC AUTISM IN 10% OF THE OFFSPRING IN SEBAT AND WIGLER'S STUDY? IS IT DAD'S SPERM?

Genomics & Proteomics
Advantage Business Media





We tested the hypothesis that de novo copy number variation (CNV) is associated with autism
spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the
genomic DNA of patients and unaffected subjects to detect copy number variants not present in
their respective parents. Candidate genomic regions were validated by higher-resolution CGH,
paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping.
Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were
identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients
with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs
were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous
and included mutations of single genes. These findings establish de novo germline mutation as a
more significant risk factor for ASD than previously recognized.

'THERE IS NO EVIDENCE THAT THE RISK OF A DE NOVO CNV IS RELATED TO THE AGE OF EITHER PARENT"

~ARTHUR L. BEAUDET

THIS IS INTRIGUING, IS THERE EVIDENCE THAT DE NOVO CNVs ARE NOT RELATED TO AGE?
Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

"De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent."




There are several CNVs are associated with 17 conditions of the nervous system including Parkinsons and Alzheimer's disease. Sebat and Wigler et al. have found them in sporadic autism. Also there are CNVs involved in the genes that are involved with the immune system and in human evolution.

Mental Retardation and Cancer CNVs Polymorphisms Germ-line Mutations/ Paternal Age?

Researchers Determine Genetic Causes of Mental Retardation
Marco Marra of the University of British Columbia and Lisa Lit of the University of California, Davis, discuss chromosome copy number in mental retardation.

VANCOUVER, Canada, December 11, 2006 — University of British Columbia scientists, led by Marco Marra and Jan Friedman, have identified chromosomal abnormalities—genetic duplications and deletions as small as 37.6 kb—that are responsible for the development of mental retardation in children. Using whole-genome sampling analysis (WGSA) with Affymetrix Mapping 100K Arrays, the researchers pinpointed the probable genetic causes of mental retardation in at least twice as many children as conventional cytogenetic analysis, and were able to detect smaller abnormalities than can be detected using BAC-tiling-path arrays.

The researchers examined 100 children and their unaffected parents; each of the children had been assessed by clinical geneticists who were unable to identify the cause of the child’s mental retardation. The team found that 11 children harbored genetic alterations, including eight deletions, two duplications and one with additional copies of chromosome nine in approximately 20 percent of cells. Some deletions were not unique—they appeared in more than one individual
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deletions and you’ll see associations of haplotypes of amplifications. In other words, we will begin to see how germ-line polymorphic alleles might be contributing to the cancer that develops. I think that’s one very exciting area which can really only be looked at using the SNP array platform.
Maris: Yes, I agree with that completely. The 500K especially is going to open up a whole new world in terms of doing classic genetic association studies as well as pretty novel cancer-specific genomics. So we’re excited about that as well.

For mainly technological reasons, we have had a very, uni-focal, looking-under-the-lamppost type of approach, and prognostic biomarkers have been assessed one at a time, a deletion here, or an amplification there by itself and correlated with corollary measures, clinical
factors. And it is very clear that it’s the pattern of DNA aberrations across the genome that really gives you a much more refined picture of the phenotype. There are cooperating loci and associations that if you can consider those together, may be more powerful than the uni-focal approach that we have now. So that’s one of the big areas of interest in our lab, what is the pattern of aberrations and can you learn more from the entire profile than you can from the region-by-region approach, considering things one at a time.

The only downside I see is as we’ve gotten higher and higher resolution, we’ve really run into this problem of how complex the human genome is in terms of copy number polymorphisms, and separating out the real signal from the noise is still a bit of a challenge.

Sellers: Some of that will be offset by the scale of
some of the germ-line studies that are planned by the medical population geneticists using the 500K. With researchers running 10,000 normal germ-line DNAs on the 500K, you’re going to have a pretty good map of polymorphisms pretty soon. It’ll never find the ones that are less than one in a thousand, but I think we can count on our medical population genetics colleagues to identify many of these, and that will help us just simply subtract these by database searches.

Maris: I agree. In the meantime, we are going to be scratching our heads until there is a big database of these copy number polymorphisms

LEE LAB HARVARD UNIVERSITY

CHARLES LEE Charles Lee of HMS and Brigham and Women's Hospital is one of the principal investigators in an international consortium that is creating a new map of human genetic diversity. (Staff photo Stephanie Mitchell/Harvard News Office)





During the two-year project, Lee and colleagues employed the
latest genome-scanning technologies to examine DNA samples
from 270 participants, who were a part of the International HapMap
Project, for these CNVs. Previous research only looked at single
base pair changes among this study group.
285 of the approximately 3,000 CNVs are already known to be
associated with disease, and copy number variations of some of
these genes have been or are now being speculated as risk
factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and
schizophrenia.One interesting observation that the researchers made during this study was that many of the CNVs have
population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in
certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an
increased risk of prostate cancer in African American men. As a result of this and other research, the consortium is
expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.

CNVs PROBABLY HAVE TO DO WITH IN THE SHUFFLING OF GENETIC MATERIAL THAT OCCURS IN THE PRODUCTION OF EGGS AND SPERM

The new understanding will change the way in which scientists search for genes involved in disease.

"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.


"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."
Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors. As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.