Category Archives: Human Genetics

Jan. 13, 2014 Geneticists from Ohio, California and Japan joined forces in a quest to correct a faulty chromosome through cellular reprogramming. Their study, published online today in Nature, used stem cells to correct a defective "ring chromosome" with a normal chromosome. Such therapy has the promise to correct chromosome abnormalities that give rise to birth defects, mental disabilities and growth limitations.

"In the future, it may be possible to use this approach to take cells from a patient that has a defective chromosome with multiple missing or duplicated genes and rescue those cells by removing the defective chromosome and replacing it with a normal chromosome," said senior author Anthony Wynshaw-Boris, MD, PhD, James H. Jewell MD '34 Professor of Genetics and chair of Case Western Reserve School of Medicine Department of Genetics and Genome Sciences and University Hospitals Case Medical Center.

Wynshaw-Boris led this research while a professor in pediatrics, the Institute for Human Genetics and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UC, San Francisco (UCSF) before joining the faculty at Case Western Reserve in June 2013.

Individuals with ring chromosomes may display a variety of birth defects, but nearly all persons with ring chromosomes at least display short stature due to problems with cell division. A normal chromosome is linear, with its ends protected, but with ring chromosomes, the two ends of the chromosome fuse together, forming a circle. This fusion can be associated with large terminal deletions, a process where portions of the chromosome or DNA sequences are missing. These deletions can result in disabling genetic disorders if the genes in the deletion are necessary for normal cellular functions.

The prospect for effective counter measures has evaded scientists -- until now. The international research team discovered the potential for substituting the malfunctioning ring chromosome with an appropriately functioning one during reprogramming of patient cells into induced pluripotent stem cells (iPSCs). iPSC reprogramming is a technique that was developed by Shinya Yamanaka, MD, PhD, a co-corresponding author on the Nature paper. Yamanaka is a senior investigator at the UCSF-affiliated Gladstone Institutes, a professor of anatomy at UCSF, and the director of the Center for iPS Cell Research and Application (CiRA) at the Institute for Integrated Cell-Material Sciences (iCeMS) in Kyoto University. He won the Nobel Prize in Medicine in 2012 for developing the reprogramming technique.

Marina Bershteyn, PhD, a postdoctoral fellow in the Wynshaw-Boris lab at UCSF, along with Yohei Hayashi, PhD, a postdoctoral fellow in the Yamanaka lab at the Gladstone Institutes, reprogrammed skin cells from three patients with abnormal brain development due to a rare disorder called Miller Dieker Syndrome, which results from large terminal deletions in one arm of chromosome 17. One patient had a ring chromosome 17 with the deletion and the other two patients had large terminal deletions in one of their chromosome 17, but not a ring. Additionally, each of these patients had one normal chromosome 17.

The researchers observed that, after reprogramming, the ring chromosome 17 that had the deletion vanished entirely and was replaced by a duplicated copy of the normal chromosome 17. However, the terminal deletions in the other two patients remained after reprogramming. To make sure this phenomenon was not unique to ring chromosome 17, they reprogrammed cells from two different patients that each had ring chromosomes 13. These reprogrammed cells also lost the ring chromosome, and contained a duplicated copy of the normal chromosome 13.

"It appears that ring chromosomes are lost during rapid and continuous cell divisions during reprogramming," said Yamanaka. "The duplication of the normal chromosome then corrects for that lost chromosome."

"Ring loss and duplication of whole chromosomes occur with a certain frequency in stem cells," explained Bershteyn. "When chromosome duplication compensates for the loss of the corresponding ring chromosome with a deletion, this provides a possible avenue to correct large-scale problems in a chromosome that have no chance of being corrected by any other means."

"It is likely that our findings apply to other ring chromosomes, since the loss of the ring chromosome occurred in cells reprogrammed from three different patients," said Hayashi.

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Study discovers chromosome therapy to correct severe chromosome defect

January 10, 2014

Brett Smith for redOrbit.com Your Universe Online

Finally, some good news for men, as a new study in PLOS Genetics has found that the human race may not be losing the Y chromosome after all. Some popular theories have posited that the male sex chromosome is destined to diminish and disappear.

The Y chromosome has lost 90 percent of the genes it once shared with the X chromosome, and some scientists have speculated that the Y chromosome will disappear in less than 5 million years, said study author Melissa A. Wilson Sayres, a post-doctoral evolutionary biologist at the University of California, Berkeley.

Some mammal species have lost their Y chromosome, yet still have the ability to sexually reproduce viable offspring fueling suspicions that the chromosome may not be essential in humans.

Our study demonstrates that the genes that have been maintained, and those that migrated from the X to the Y, are important, and the human Y is going to stick around for a long while, Wilson Sayres said.

Based the Y chromosome analysis of 16 men, researchers found genetic evidence of natural selection maintaining the chromosomes content, which has been shown to mostly play a role in male fertility. The researchers said the Y chromosomes diminutive size is a sign that it is stripped down to its 27 essential genes.

Melissas results are quite stunning. They show that because there is so much natural selection working on the Y chromosome, there has to be a lot more function on the chromosome than people previously thought, said co-author Rasmus Nielsen, UC Berkeley professor of integrative biology.

He added that the study will help advance estimates of humans evolutionary history that are done based on an analysis of the Y chromosome.

Melissa has shown that this strong negative selection natural selection to remove deleterious genes tends to make us think the dates are older than they actually are, which gives quite different estimates of our ancestors history, Nielsen said.

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Study Shows Men Won’t Be Losing Their Y Chromosome Anytime Soon

Weekly News Digest January 2, 2014 In addition to this week's NewsBreak(s), the editors have compiled the Weekly News Digest, featuring stories from the week just past that you should know about. Watch for additional coverage to appear in the next print issue of Information Today.

CLICK HERE to view all of this week's Weekly News Digest items.

Nature Publishing Group Announces OA Journal

Human Genome Variation, the sixth journal collaboration between NPG and JSHG, is a sister title of JSHGs Journal of Human Genetics. Katsushi Tokunaga, a professor at the University of Tokyo, will serve as editor-in-chief. The journal will feature original research articles, summaries, reviews, and data reports. Its audience is human genetics researchers and clinical geneticists.

The journal will provide a forum for scientists working in human genetics, variation and mutation to publish their discoveries, results, analysis and insights, says Dugald McGlashan, publisher of NPGs Asia-Pacific academic journals.

Authors may choose which Creative Commons license to apply to their research articles, which will be OA on publication.

NPG and JSHG will also develop a searchable database sourced from the journals data reports that includes content on genomic variation and variability.

Source: Nature Publishing Group

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Nature Publishing Group Announces OA Journal

PUBLIC RELEASE DATE:

9-Jan-2014

Contact: Melissa A. Wilson Sayres mwilsonsayres@berkeley.edu Public Library of Science

Is the male Y chromosome at risk of being lost? Recent work by Dr Wilson Sayres and colleagues at UC Berkeley, published in PLOS Genetics, demonstrates that the genes on the Y chromosome are important: they have probably been maintained by selection. This implies that despite its dwindling size, the Y chromosome will be sticking around.

The human Y chromosome contains 27 unique genes, compared to thousands on other chromosomes. Some mammals have already lost their Y chromosome (despite still having males, females and normal reproduction); this has led some researchers to speculate that the Y chromosome is superfluous.

As the X and Y chromosomes evolved, male-specific genes became fixed on the Y chromosome. Some of these genes were detrimental to females, so the X and Y chromosomes stopped swapping genes. This meant the Y chromosome was no longer able to correct mistakes efficiently and has thus degraded over time.

There is low genetic diversity in the human Y chromosome, and Dr Wilson Sayres and colleagues were able to precisely measure this by comparing variation on a person's Y chromosome with variation on that person's other 22 chromosomes, the X chromosome and the mitochondrial DNA. The researchers then showed that this low genetic diversity cannot be explained solely by a reduction in the number of males passing on their Y chromosome (successfully fathering male offspring). Instead, the low diversity must also result from natural selection, in this case purifying selection (the selective removal of deleterious alleles).

The movements of human populations around the world are tracked by variations in the Y chromosome. The increased understanding provided by this research will improve estimates of humans' evolutionary history.

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The human Y chromosome is not likely to disappear

PUBLIC RELEASE DATE:

9-Jan-2014

Contact: Aileen Sheehy press.office@sanger.ac.uk 44-012-234-92368 Wellcome Trust Sanger Institute

Contrary to a common belief, researchers have shown that genetic regions associated with increased risk of type 2 diabetes were unlikely to have been beneficial to people at stages through human evolution.

Type 2 diabetes is responsible for more than three million deaths each year and this number is increasing steadily. The harmful genetic variants associated with this common disease have not yet been eliminated by natural selection.

To try to explain why this is, geneticists have previously hypothesised that during times of 'feast or famine' throughout human evolution, people who had advantageous or 'thrifty' genes processed food more efficiently. But in the modern developed world with too much food, these same people would be more susceptible to type 2 diabetes.

"This thrifty gene theory is an attractive hypothesis to explain why natural selection hasn't protected us against these harmful variants," says Dr. Yali Xue, lead author of the study from the Wellcome Trust Sanger Institute. "But we find little or no evidence to corroborate this theory."

The team tested this theory by examining 65 genetic regions that were known to increase type 2 diabetes risk, the most detailed study of its kind.

If these harmful variants were beneficial in the past, the team would expect to see a genetic imprint of this in the DNA around the affected regions. Despite major developments in tests for positive selection and a four-fold increase in the number of genetic variants associated with diabetes to work with, they found no such imprint.

"We found evidence for positive selection in only few of the 65 variants and selection favoured the protective and risk alleles for type 2 diabetes in similar proportions," notes Dr. Qasim Ayub, first author from The Wellcome Trust Sanger Institute, "This is no more than what we would expect to find for a random set of genomic variants."

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Why is type 2 diabetes an increasing problem?

PUBLIC RELEASE DATE:

8-Jan-2014

Contact: Susan Gilbert gilberts@thehastingscenter.org 845-424-4040 x244 The Hastings Center

(Garrison, NY) The Center for Research on Ethical, Legal, and Social Implications of Psychiatric, Neurologic, and Behavioral Genetics at Columbia University Medical Center unveils its mission today with the launch of its website. Two Hastings Center research scholars are core faculty members of the new center, which was recently awarded a five-year grant from the National Human Genome Research Institute.

As understanding of the genetic contributions to psychiatric, neurologic, and behavioral (PNB) traits and disorders grows rapidly, this knowledge is quickly being translated into clinical practice. But the information presents particular ethical, legal, and social challenges because of what it could reveal about characteristics associated with individual identity and many of our most feared afflictions. Because of the potential for stigma linked to many PNB disorders and traits, this information may negatively affect how people view themselves and how others see them. Examination of the impact of PNB genetic information and consideration of the implications for normative judgments and public policy are therefore critically needed.

"Scientific findings regarding PNB traits must be discussed with special attention to the human and social context because such traits and disordersfrom Alzheimer's, schizophrenia, and depression to empathy, aggression, and intelligencecan touch our sense of who we are as persons," said Erik Parens, PhD, a senior research scholar at The Hastings Center. Parens and Josephine Johnston, LLB, MBHL, a Hastings Center research scholar and director of research, are core faculty members of the new center, based in the Department of Psychiatry. "The new center is uniquely situated to offer such attention."

The center is focusing on three areas: 1) the impact of PNB genetic information in clinical and research contexts on patients, family members, and clinicians, including effects on treatment choices, health and lifestyle decisions, identity, and self-image; 2) the impact of PNB genetic information in nonclinical contexts in which such information may affect perceptions of autonomy and responsibility for behavior, with a special focus on attributions of responsibility in the judicial process and in everyday life; and 3) data to suggest how PNB genetic information should be used in policy judgments related to clinical contexts (e.g., diagnostic and treatment decisions), research contexts (e.g., access to genetic data), and nonclinical contexts (e.g., legal rules and health policy).

Parens and Johnston will lead the new center's investigation into the meaning of PNB genetics information and how it should be used in policies and practices, as well as the translation of the center's work into formats that can inform policies and practices.

"Our center offers the opportunity to advance knowledge of the ethical, legal, and social implications of one of the most rapidly developing areas of genetics. Drawing on our empirical studies and input from key stakeholders, we will develop strategies to guide the use of PNB genetic data in clinical and research settings, as well as in courts, legislatures, and regulatory agencies," said Paul Appelbaum, MD, director of the center and of the Division of Law, Ethics and Psychiatry in the Department of Psychiatry at Columbia University College of Physicians and Surgeons. "By integrating empirical researchers with experts in ethics, economics, law, and public policy, we hope to point the way toward beneficial use of the latest scientific findings in this exciting new area of genetics."

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New project on psychiatric, neurologic, and behavioral genetics

Mysterious episodes of genetic duplication in our great ape ancestors may have paved the way for human evolution

By Emily Singer and Quanta Magazine

SRGAP2: Whereas chimps and orangutans have only one, humans have multiple copies of the gene SRGAP2 which is believed to be involved in the development of the brain. Image: Dennis/Cell/Quanta

From Quanta Magazine (find original story here).

About 8 million to 12 million years ago, the ancestor of great apes, including humans, underwent a dramatic genetic change. Small pieces of DNA replicated and spread across their resident chromosomes like dandelions across a lawn. But as these dandelion seeds dispersed, they carried some grass and daisy seeds additional segments of DNA along for the ride. This unusual pattern, repeated in different parts of the genome, is found only in great apes bonobos, chimpanzees, gorillas and humans.

I think its a missing piece of human evolution, said Evan Eichler, a geneticist at the University of Washington, in Seattle. My feeling is that these duplication blocks have been the substrate for the birth of new genes.

Over the past few years, scientists have begun to uncover the function of a handful of genes that reside in these regions; they seem to play an important role in the brain, linked to the growth of new cells, as well as brain size and development. In September, Eichlers team published a new technique for analyzing how these genes vary from person to person, which could shed more light on their function.

Much about the duplication process and its implications remains a mystery. Eichler and others dont know what spurred the initial rounds of duplications or how these regions, dubbed core duplicons, reproduced and moved around the genome.

Despite the duplication-linked genes potential importance in human evolution, most have not been extensively analyzed. The repetitive structure of the duplicated regions makes them particularly difficult to study using standard genetic approaches the most efficient methods for sequencing DNA start by chopping up the genome, reading the sequence of the small chunks and then assembling those sections like one would a puzzle. Trying to assemble repetitive sections is like trying to put together a puzzle made of pieces with almost the same pattern.

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A Missing Genetic Link in Human Evolution

Following the Supreme Courts rejection of gene patents, the U.S. proposes steep cuts to reimbursements for breast cancer-gene tests.

That natural human genes cannot be patented was one of the biggest biotechnology stories of 2013 and the effects of that Supreme Court decision are already threatening defendant Myriad Genetics.

The Salt Lake City-based molecular diagnostic company lost the ability to patent DNA sequences of genes known as BRCA1 and BRCA2, which are associated with the risk of developing breast and ovarian cancers (see U.S. Supreme Court Says Natural Human Genes May Not Be Patented). Hours after that decision was announced, other molecular-diagnostics companies announced that they would offer similar tests at a lower cost than Myriads test.

And now, the federal governments Centers for Medicare and Medicaid Services, or CMS, is proposing to lower the amount of money it pays for the tests. The new rate is approximately half of what the agency has previously reimbursed, according to GenomeWeb. The announcement was followed by analyst downgrades on Myriad stock.

CMS directly points to the Supreme Court decision in its announcement and notes that labs charge anywhere from $900 to $2,900 for the test. The new proposed reimbursement amount is $1,438. The proposal will likely lead to lower costs for BRCA testing even when private insurance companies are paying for it, as these companies usually base their rates on those of Medicare, according to the Wall Street Journal.

Myriad is likely to be hardest hit by such price drops because 85 percent of the companys revenue comes from BRCA testing, says the WSJ.

Is this a good deal for patients? With cheaper options available, its reasonable to think that more patients will have access to this testing. But as Robert Nussbaum wrote for MIT Technology Review, Myriad still has an unparalleled record of the natural variation in these important genes. Myriads competitors may offer more affordable tests, but they dont have access Myriads private database linking DNA variations to disease outcomes, a wealth of information the company built up over the years it monopolized BRCA testing. Thats why Nussbaum and colleagues are asking doctors to contribute such vital data for a free, public database that would help doctors interpret the potential effects of a patients BRCA sequences on their cancer risks.

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Cheaper Genetic Tests for Breast Cancer Risks in 2014?

The Rt Hon Robert Haldane Smith, Baron Smith of Kelvin. Chancellor of the Order

KNIGHTS BACHELOR

The Rt Hon Kevin Barron, MP. Member of Parliament for Rother Valley. For political and public service. (Rotherham, South Yorkshire)

Professor Adrian Peter Bird, CBE, FRS, FRSE. Buchanan Professor of Genetics, University of Edinburgh. For services to Science. (Edinburgh)

Professor Richard William Blundell, CBE, FBA. Professor of Economics, UCL and director, ESRC Centre for the Micro-Economic Analysis of Public Policy IFS. For services to Economics and Social Science. (London)

Ian Michael Cheshire. Chief executive, Kingfisher plc. For services to Business, Sustainability and the Environment. (London)

Michael Victor Codron, CBE. For services to the Theatre. (London)

Paul Collier, CBE. For services to promoting research and policy change in Africa. (Oxford, Oxfordshire)

David Nigel Dalton. Chief executive, Salford Royal NHS Foundation Trust. For services to Healthcare. (Willaston, Cheshire)

Roger Michael De Haan, CBE, DL. Philanthropist. For services to Education and to charity in Kent and Overseas. (Ashford, Kent)

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New Year Honours 2014: list in full

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