АвторТема: Доклады на 59-й конференции Американского Общесства Генетики Человека (ASHG)  (Прочитано 2665 раз)

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  • קַח-נָא אֶת-בִּנְךָ אֶת-יְחִידְךָ אֲשֶׁר-אָהַבְתָּ, אֶת-יִצְחָק
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Discovering Distant Relatives within a Diverse Set of Populations Using DNA Segments Identical by Descent.
L. Hon, B. M. Henn, J. M. Macpherson, N. Eriksson, A. Wojcicki, L. Avey, S. Saxonov, J. L. Mountain 23andMe, Inc, Mountain View, CA.

Close familial relationships, such a parent-offspring relationships, are inferred readily from genotype and allele frequency data for a limited number of single nucleotide polymorphisms (SNPs) or short tandem repeat (STR) polymorphisms. However, researchers have not focused on accurately inferring the degree of relationship between individuals who share a common ancestor 3-10 generations ago; such inference requires high density genome-wide information not available until recently. In order to characterize relatively distant relationships for a sample, we analyzed the sharing of DNA identical by descent (IBD) in a large database of self-selected individuals of European ancestry, including a subset identified as Ashkenazim. Individuals from more endogamous ethnic populations, such as the Ashkenazim, share on average more DNA identically by descent than do individuals of Asian ancestry or of European ancestry broadly defined. Extensive population-level sharing of identical genomic segments complicates the prediction of relationship level for a pair of individuals since identical segments may reflect common ancestry older than the most recent ancestor for a pair of individuals in a pedigree. In order to understand the pattern of the observed population-level sharing, we simulated extended pedigrees using different populations to calculate the expected amounts of sharing for 1st through 10th cousins. Specifically we assessed the relationship between the length of the longest segment and the most recent common ancestor. From the simulations, we also determined bounds for predicted cousinships given a specific amount of segmental sharing. Using these bounds as a guide, we detected at least one distant relative, between 2nd-8th degree cousin, for 90% of individuals in our dataset of more than 5000 individuals with European ancestry. An even higher fraction of our Ashkenazi sample, 99%, had at least one distant relative between 2nd-7th degree cousinship in our dataset.


Fine-scale Population Structure in Worldwide Ethnic Populations as Revealed by Identical by Descent Segments.
B. M. Henn, L. Hon, J. M. Macpherson, N. Eriksson, A. Wojcicki, L. Avey, S. Saxonov, J. L. Mountain 23andMe, Inc, Mountain View, CA.

It is well established that human population genetic diversity reflects continental-level geographic divisions, and that within-continental geographic and linguistic differences contribute to population structure between regions. The continental and regional differences reflect ancient demographic events, such as early migrations Out of Africa into Eurasia. However, it is not clear how recent demographic processes occurring on the order of hundreds, rather than thousands, of years affect patterns of genomic diversity. We analyzed the sharing of DNA identical by descent (IBD) inferred from 580,000 SNPs using a large database of individuals with European ancestry, including a subset identifying as Ashkenazim. We also explored the pairwise distributions of identical by descent segments in populations from the Human Genome Diversity Panel (HGDP-CEPH), a diverse set of ethnic groups from across the world. We observed that the average number and sizes of shared genomic segments differ substantially across the ~55 populations. The different patterns are likely attributable to differences in population histories such as recent bottlenecks and sub-structure. In particular, populations that are highly structured will contain individuals that share elevated amounts of IBD, indicative of recent common ancestry through multiple ancestors. In order to understand the pattern of the observed population-level sharing, we simulated extended pedigrees using empirical data from several populations and calculated the expected amounts of sharing for 1st through 10th cousins. We assumed random mating within each population for the simulations. Interestingly, the average sharing in the simulated distant cousins was consistently less than the observed average sharing in each population sample. This finding indicates the presence of fine-scale population structure for many ethnic groups, such as the Ashkenazim, within the last 10 generations (200-300 years).


Direct-to-consumer personal genomic services: An exploratory case study of product claims, disclaimers, and performance.
R. Sterling1, S. Adams2, H. McLeod3, J. Evans4 1) Center for Genomics and Society, University of North Carolina, Chapel Hill, NC; 2) School of Medicine, University of North Carolina, Chapel Hill, NC; 3) School of Pharmacy, University of North Carolina, Chapel Hill, NC; 4) Department of Genetics, University of North Carolina, Chapel Hill, NC.

Advances in genomic research have enabled the commercialization of whole genome profiling or personal genomic services (PGS). Direct-to-consumer (DTC) marketing and sale of PGS has raised concerns among clinicians, researchers, and policy makers. In 2008, the Secretary’s Advisory Committee on Genetics, Health and Society reported 29 gaps in the oversight of genetic services and New York and California issued a provisional moratorium on the DTC sale of PGS, fueling debates about whether restrictions that limit consumer choice are warranted to avoid potential harm to consumers. As policy makers work to improve oversight of genetic services, the continued DTC sale of PGS warrants examination of advertising. Although federal regulations do not specifically address advertising for genetic services, various laws and recommendations set forth basic requirements and a normative standard. In this study, we purchased two PGS kits from two companies (23andMe and deCODE) and examined: 1) whether websites provided information recommended by experts, 2) website claims and disclaimers, and adherence to Federal Trade Commission (FTC) requirements for product advertising, and 3) whether claims were supported by product performance. In our content analysis of websites, we found both PGS companies presented information on topics repeatedly recommended by experts, such as lab certifications, test limitations, and privacy. However, they did not meet FTC requirements that disclaimers be presented in close proximity to claims. FTC also requires that disclaimers qualify and not contradict claims; however, we found several examples of disclaimers that contradicted claims, particularly in regard to medical relevance. Finally, our independent genotyping of submitted specimens confirmed the accuracy of genetic profiles reported by both companies, but reported risk profiles showed significant variability. Of the 14 conditions profiled by both companies, risks for five conditions were reported in opposite directions for the same specimen. The current lack of a “gold standard” to guide the interpretation of genotypic profiles is a substantial limitation to the utility of PGS and poses a major challenge to advertisers charged with both increasing PGS sales and avoiding deceptive advertising. We encourage PGS companies in the US and abroad to adhere to FTC requirements regarding product claims and disclaimers to enable informed decision-making by consumers.


A Comparison of 23andMe and Navigenics Predictions for Five Individuals.
P. C. Ng1, S. S. Murray2, S. Levy1, J. C. Venter1 1) Genomic Medicine, J. Craig Venter Institute, San Diego, CA; 2) Scripps Genomic Medicine, Scripps Health and The Scripps Research Institute, San Diego, CA.

Direct-to-consumer (DTC) companies such as 23andMe, Navigenics, and deCODE provide disease risk predictions to customers who have their DNA genotyped. We compare the predictions between two DTC companies, 23andMe and Navigenics, for five individuals. We find that on average, approximately a third of the predictions do not match between the two companies. The primary reason for differences in disease prediction is determined by whether the companies used the same markers with moderate to high odds ratio (OR). This indicates that markers with high OR should only be included if there is strong evidence to suggest that they are real, and that these markers have been verified in replication studies. While consensus among which markers to include will cause prediction agreement between the DTC companies, the markers that are currently used may not have good predictability because their effect size is still small. This may be improved by sequencing in the future, when rare variants with large effects might be identified.


Genomic counseling in the setting of an institutional initiative for Direct-to-Consumer personal genomic testing.
E. Edelman1, R. R. Sharp1,2, C. Eng1 1) Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH; 2) Department of Bioethics, Cleveland Clinic, Cleveland, OH.

In January 2009, the Cleveland Clinic (CC) launched a genomic education initiative for physicians that included an opportunity for CC physicians to elect direct-to-consumer (DTC) SNP genotyping through 23andMe at no personal cost. Since the release of DTC SNP testing, medical and scientific experts have raised concerns that such testing is not yet ready for routine clinical application due to unknown clinical validity, utility of analyses, effect on behavior, and patient privacy. As genetics professionals we actively participated in this CC education campaign and created a system for providing accurate and accessible information regarding the risks, benefits, and limitations of DTC SNP profiling to interested staff physicians. This was a unique opportunity for physicians to explore the overlap of recreational and medical aspects of predictive SNP genotyping. Approximately 2800 staff and trainee physicians were given the opportunity to obtain 23andMe testing. The Genomic Medicine Institute (GMI) was charged with providing pre- and post-test education for individuals who chose to pursue DTC SNP genotyping. Speakers from GMI and the CC Bioethics Department (BD) presented a series of CME lectures to provide CC clinicians with education about genome-wide association studies, predictive SNP-based testing, ethical and legal implications of DTC/predictive genomic testing, the 23andMe product, and genetic counseling (GC) options. To ensure that CC’s offer of genetic testing to employees was compliant with the Genetic Information Nondiscrimination Act, GMI met with CC Legal Counsel (LC) to identify legal requirements and provide recommendations to CC Executive Administration (EA). Through collaborative efforts between GMI, BD, LC, and EA, we were successful in developing a mutually agreeable and responsible model for post-test genomic counseling. Due to the complex nature of results interpretation, it is essential for genetics professionals to be available for pre- and post-test education. We offered 2 post-test options: an opportunity to discuss 23andMe results with a genetic counselor but no personal risk assessment or a comprehensive genomic counseling appointment with discussion of both 23andMe results and family history assessment. We hope that our experiences can be used as an example of a viable model for both education and GC as other hospitals and institutions develop proactive genomic education programs that target their own institutional needs.


N. Eriksson1, J. M. Macpherson1, J. Tung1, L. Hon1, B. Naughton1, S. Saxonov1, L. Avey1, A. Wojcicki1, I. Pe'er2, J. Mountain1,3 1) 23andMe, Inc., Mountain View, CA; 2) Department of Computer Science, Columbia University, New York, NY; 3) Department of Anthropology, Stanford University, Stanford, CA.

We report on initial results from a participant-driven study of 22 common traits based on a novel research framework that facilitates the parallel study of a wide assortment of traits within a single cohort. The approach takes advantage of the interactivity of the web both to gather data and to present genetic information to research participants, while taking care to correct for the population structure inherent to this study design.
We present novel associations for hair curl, “asparagus anosmia” (the inability to smell the methanethiol produced after eating asparagus), and photic sneeze reflex. For hair curl, we identify two independent SNPs: rs17646946 (p-value less than 10-28, near TCHH) and rs7349332 (p-value less than 10-8.4, in WNT10A). For asparagus anosmia, we identify one SNP in a region of olfactory receptors, rs4481887, with a p-value less than 10-16. For photic sneeze reflex, we identify one SNP, rs1040173, with a p-value less than 10-9.7. In order to validate the web-based, self-reporting design, we have in addition replicated associations in the genes OCA2, HERC2, SLC45A2, SLC24A4, IRF4, MC1R, TYR, TYRP1 and ASIP for hair color, eye color, and freckling.
The other traits analyzed in this study include laterality preferences (handedness, footedness, ocular dominance, and hand-clasp), simple physical characteristics (whether participants have had cavities, have worn braces, have had wisdom teeth removed, have astigmatism, wear glasses, have attached earlobes, and suffer from motion sickness while riding in a car), and personality traits and preferences (optimism, a preference for sweet versus salty food, and preference for night-time versus morning-time activity).


© 2007 Молекулярная Генеалогия (МолГен)

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