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Nov 4, 2013

Mom or Dad? DNA Study May Boost Personalized Medicine

  • Ludwig Cancer Research scientists report the development of a new technique that can determine whether a particular genetic sequence comes from an individual's mother or father. Reporting their work (“Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing”) in Nature Biotechnology, they believe their method will accelerate studies of how genes contribute to disease, improve the process of matching donors with organs, and help scientists better understand human migration patterns.

    “The technique will enable clinicians to better assess a person’s individual risk for disease. It is potentially transformative for personalized medicine,” says Bing Ren, Ph.D., Ludwig scientist at the University of California, San Diego School of Medicine, who led the research on the new method, called “HaploSeq.”

    “HaploSeq [is] an approach for assembling chromosome-scale haplotypes that exploits the existence of ‘chromosome territories.’ We use proximity ligation and sequencing to show that alleles on homologous chromosomes occupy distinct territories, and therefore this experimental protocol preferentially recovers physically linked DNA variants on a homolog,” wrote the investigators. “To resolve haplotypes for a human genome, which has a low density of variants, we coupled HaploSeq with local conditional phasing to obtain haplotypes for ~81% of alleles with ~98% accuracy from just 17x sequencing.”

    “In the not too distant future, everyone's genome will be sequenced,” adds Dr. Ren. But, he explains, “There has been a problem with this scenario.”

    Except for the sex chromosomes, everyone has two copies of each chromosome. One copy comes from mom, and the other from dad. Current techniques cannot distinguish between the two copies of each gene and, therefore, are not very good at determining whether particular genetic differences, such as a single-letter change in the DNA, originate with an individual's mother or father, which muddies genetic analyses. [Note: Complete Genomics reports that its LFR technology had already previously performed this function; see comment section below.]

    Dr. Ren’s new technique, a mixture of molecular biology and computational biology approaches, bypasses this problem. The method enables researchers to quickly determine which genetic variants occur together on the same stretch of chromosome and, therefore, came from the same parent. “This advance has direct implications for the utility of genomics in clinical practice and will also have profound effects on genetic research and discovery,” says Ludwig scientist Siddarth Selvaraj, Ph.D., who contributed to the study.

    More immediately, the technique will enable clinicians to better assess a person’s individual risk for disease, a cornerstone of personalized medicine. For instance, people at risk for a disease such as cancer often have more than one DNA mutation. HaploSeq could enable clinicians to determine if the two mutations are on the same chromosome or on different chromosomes, which can help in risk assessment. For example risk may be reduced if two mutations are on the same chromosome, since the ‘good’ chromosome can often compensate.

    One advantage of the new technique is that it builds on common sequencing technologies and should be easily adapted for use by clinicians and researchers alike, according to Dr. Ren.

Readers' Comments

Posted 11/10/2013 by Isabella Sya

there was a problem parsing the message

Posted 11/07/2013 by Dr. Radoje Drmanac

Complete Genomics’ Long Fragment Read (LFR) technology allows us to provide the most accurate whole human genome sequencing results and also, through phasing, to determine which parental chromosome a mutation occurred on. We have been able to distinguish between maternal and paternal chromosomes for several years and the U.S. Patent and Trademark Office has already issued us two patents on our LFR technology. Some of our advances in this area are documented in this company press release ( and Nature paper from July 2012. Our LFR Nature paper is cited in the discussed paper. The positive impact of our LFR technology was also demonstrated in a Prader-Willi Syndrome (PWS) study which Complete published with researchers at Baylor College of Medicine and the University of Texas Health Science Center in Nature Biotechnology in September 2013. In this last example, a modified version of our LFR technology was used to confirm that the MAGEL2 mutation, responsible for the patient’s PWS symptoms, was on the paternal gene. – Dr. Radoje Drmanac, co-founder and chief scientific officer at Complete Genomics.

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