Biology subjects

Yaniv Erlich

Publications and source records attributed to Yaniv Erlich.

14 recordsLinked to original sources

bioRxiv2016

Genome-wide profiling of heritable and de novo STR variations

Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, STRs have proven problematic to genotype from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping, haplotyping, and phasing STRs from whole genome sequencing data and report a genome-wide analysis and validation of de novo STR mutations.

Genomics↗

bioRxiv2016

DNA Compass: a secure, client-side site for navigating personal genetic information

MotivationMillions of individuals have access to raw genomic data using direct-to-consumer companies. The advent of large-scale sequencing projects, such as the Precision Medicine Initiative, will further increase the number of individuals with access to their own genomic information. However, querying genomic data requires a computer terminal - an impediment for the general public.\n\nResultsDNA Compass is a website designed to empower the public by enabling simple navigation of personal genomic data. Users can query the status of their genomic variants for over 400 conditions or tens of millions of documented SNPs. DNA Compass presents the relevant genotypes of the user side-by-side with explanatory scientific resources. The genotypes data never leaves the users computer, a feature that provides improved security and performance. Nearly 2500 unique users have used our tool, mainly from the general genetic genealogy community, demonstrating its utility.\n\nAvailabilityDNA Compass is freely available on https://compass.dna.land.\n\nContactyaniv@cs.columbia.edu

Genomics↗

bioRxiv2016

Capacity-approaching DNA storage

DNA is an attractive medium to store digital information. Here, we report a storage strategy, called DNA Fountain, that is highly robust and approaches the information capacity per nucleotide. Using our approach, we stored a full computer operating system, movie, and other files with a total of 2.14 x 106 bytes in DNA oligos and perfectly retrieved the information from a sequencing coverage equivalent of a single tile of Illumina sequencing. We also tested a process that can allow 2.18 x 1015 retrievals using the original DNA sample and were able to perfectly decode the data. Finally, we explored the limit of our architecture in terms of bytes per molecules and obtained a perfect retrieval from a density of 215Petabyte/gram of DNA, orders of magnitudes higher than previous techniques.

Synthetic Biology↗

bioRxiv2016

Democratizing DNA Fingerprinting

We report a rapid, inexpensive, and portable strategy to re-identify human DNA using the MinION, a miniature sequencing sensor by Oxford Nanopore Technologies. Our strategy requires only 10-30 minutes of MinION sequencing, works with low input DNA, and enables familial searches. We also show that it can re-identify individuals from Direct-to-Consumer genomic datasets that are publicly available. We discuss potential forensic applications as well as the legal and ethical implications of a democratized DNA fingerprinting strategy available to the public.

Genomics↗

bioRxiv2016

Case-control association mapping without cases

The case-control association study is a powerful method for identifying genetic variants that influence disease risk. However, the collection of cases can be time-consuming and expensive; if a disease occurs late in life or is rapidly lethal, it may be more practical to identify family members of cases. Here, we show that replacing cases with their first-degree relatives enables genome-wide association studies by proxy (GWAX). In randomly-ascertained cohorts, this approach enables previously infeasible studies of diseases that are absent (or nearly absent) in the cohort. As an illustration, we performed GWAX of 12 common diseases in 116,196 individuals from the UK Biobank. By combining these results with published GWAS summary statistics in a meta-analysis, we replicated established risk loci and identified 17 newly associated risk loci: four in Alzheimers disease, eight in coronary artery disease, and five in type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping using family history of disease as a phenotype to be mapped. We anticipate that this approach will prove useful in future genetic studies of complex traits in large population cohorts.

Genetics↗

bioRxiv2016

Population-Scale Sequencing Data Enables Precise Estimates of Y-STR Mutation Rates

Short Tandem Repeats (STRs) are mutation-prone loci that span nearly 1% of the human genome. Previous studies have estimated the mutation rates of highly polymorphic STRs using capillary electrophoresis and pedigree-based designs. While this work has provided insights into the mutational dynamics of highly mutable STRs, the mutation rates of most others remain unknown. Here, we harnessed whole-genome sequencing data to estimate the mutation rates of Y-chromosome STRs (Y-STRs) with 2-6 base pair repeat units that are accessible to Illumina sequencing. We genotyped 4,500 Y-STRs using data from the 1000 Genomes Project and the Simons Genome Diversity Project. Next, we developed MUTEA, an algorithm that infers STR mutation rates from population-scale data using a high-resolution SNP-based phylogeny. After extensive intrinsic and extrinsic validations, we harnessed MUTEA to derive mutation rate estimates for 702 polymorphic STRs by tracing each locus over 222,000 meioses, resulting in the largest collection of Y-STR mutation rates to date. Using our estimates, we identified determinants of STR mutation rates and built a model to predict rates for STRs across the genome. These predictions indicate that the load of de novo STR mutations is at least 75 mutations per generation, rivaling the load of all other known variant types. Finally, we identified Y-STRs with potential applications in forensics and genetic genealogy, assessed the ability to differentiate between the Y-chromosomes of father-son pairs, and imputed Y-STR genotypes.

Genomics↗

bioRxiv2015

Biological screens from linear codes: theory and tools

Molecular biology increasingly relies on large screens where enormous numbers of specimens are systematically assayed in the search for a particular, rare outcome. These screens include the systematic testing of small molecules for potential drugs and testing the association between genetic variation and a phenotype of interest. While these screens are \"hypothesis-free,\" they can be wasteful; pooling the specimens and then testing the pools is more efficient. We articulate in precise mathematical ways the type of structures useful in combinatorial pooling designs so as to eliminate waste, to provide light weight, flexible, and modular designs. We show that Reed-Solomon codes, and more generally linear codes, satisfy all of these mathematical properties. We further demonstrate the power of this technique with Reed-Solomonbased biological experiments. We provide general purpose tools for experimentalists to construct and carry out practical pooling designs with rigorous guarantees for large screens.

Bioinformatics↗

bioRxiv2015

Integration of mobile sequencers in an academic classroom

The rapid development of DNA sequencing technologies creates new educational opportunities for hands-on training. We report our experience in integrating handheld DNA sequencers (Oxford Nanopore Technologies MinION) as part of an academic class. This manuscript describes lessons learned to facilitate successful integration and provides educational resources for the benefit of the community.

Genomics↗

bioRxiv2015

A vision for ubiquitous sequencing

Genomics has recently celebrated reaching the $1000 genome milestone, making affordable DNA sequencing a reality. With this goal successfully completed, the next goal of the sequencing revolution can be sequencing sensors miniaturized sequencing devices that are manufactured for real time applications and deployed in large quantities at low costs. The first part of this manuscript envisions applications that will benefit from moving the sequencers to the samples in a range of domains. In the second part, the manuscript outlines the critical barriers that need to be addressed in order to reach the goal of ubiquitous sequencing sensors.

Genomics↗

bioRxiv2015

Abundant contribution of short tandem repeats to gene expression variation in humans

Expression quantitative trait loci (eQTLs) are a key tool to dissect cellular processes mediating complex diseases. However, little is known about the role of repetitive elements as eQTLs. We report a genome-wide survey of the contribution of Short Tandem Repeats (STRs), one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from linked SNPs and indels and found that eSTRs contribute 10%-15% of the cis-heritability mediated by all common variants. Functional genomic analyses showed that eSTRs are enriched in conserved regions, co-localize with regulatory elements, and are predicted to modulate histone modifications. Our results show that eSTRs provide a novel set of regulatory variants and highlight the contribution of repeats to the genetic architecture of quantitative human traits.

Genomics↗

bioRxiv2014

Redefining Genomic Privacy: Trust and Empowerment

Fulfilling the promise of the genetic revolution requires the analysis of large datasets containing information from thousands to millions of participants. However, sharing human genomic data requires protecting subjects from potential harm. Current models rely on de-identification techniques that treat privacy versus data utility as a zero-sum game. Instead we propose using trust-enabling techniques to create a solution where researchers and participants both win. To do so we introduce three principles that facilitate trust in genetic research and outline one possible framework built upon those principles. Our hope is that such trust-centric frameworks provide a sustainable solution that reconciles genetic privacy with data sharing and facilitates genetic research.

Genomics↗

bioRxiv2014

The Landscape of Human STR Variation

Short Tandem Repeats are among the most polymorphic loci in the human genome. These loci play a role in the etiology of a range of genetic diseases and have been frequently utilized in forensics, population genetics, and genetic genealogy. Despite this plethora of applications, little is known about the variation of most STRs in the human population. Here, we report the largest-scale analysis of human STR variation to date. We collected information for nearly 700,000 STR loci across over 1,000 individuals in phase 1 of the 1000 Genomes Project. This process nearly saturated common STR variations. After employing a series of quality controls, we utilize this call set to analyze determinants of STR variation, assess the human reference genomes representation of STR alleles, find STR loci with common loss-of-function alleles, and obtain initial estimates of the linkage disequilibrium between STRs and common SNPs. Overall, these analyses further elucidate the scale of genetic variation beyond classical point mutations. The resource is publicly available at http://strcat.teamerlich.org/ both in raw format and via a graphical interface.

Genomics↗

bioRxiv2013

OTX2 Dosage Sensitivity is Implicated in Hemifacial Microsomia

Hemifacial microsomia (HFM) is the second most common facial anomaly after cleft lip and palate. The phenotype is highly variable and most cases are sporadic. Here, we investigated the disorder in a large pedigree with five affected individuals spanning eight meioses. We performed whole-exome sequencing and a genome-wide survey of segmental variations. Analysis of the exome sequencing results indicated the absence of a pathogenic coding point mutation. Inspection of segmental variations identified a 1.3Mb duplication of chromosome 14q22.3 in all affected individuals that was absent in more than 1000 chromosomes of ethnically matched controls. The duplication was absent in seven additional sporadic HFM cases, which is concordant with the known heterogeneity of the disorder. To find the critical gene in the duplicated region, we analyzed signatures of human craniofacial disease networks, mouse expression data, and predictions of dosage sensitivity. All of these approaches implicated OTX2 as the most likely causal gene. Moreover, OTX2 is a known oncogenic driver in medulloblastoma, a condition that was diagnosed in the proband during the course of our study. Our findings highlight dosage sensitivity of OTX2 in human craniofacial development and suggest a possible shared etiology between a subtype of hemifacial microsomia and medulloblastoma.

Genetics↗

bioRxiv2013

Routes for breaching and protecting genetic privacy

We are entering the era of ubiquitous genetic information for research, clinical care, and personal curiosity. Sharing these datasets is vital for rapid progress in understanding the genetic basis of human diseases. However, one growing concern is the ability to protect the genetic privacy of the data originators. Here, we technically map threats to genetic privacy and discuss potential mitigation strategies for privacy-preserving dissemination of genetic data.\n\nAbout the AuthorsYaniv Erlich is a Fellow at the Whitehead Institute for Biomedical Research. Erlich received his Ph.D. from Cold Spring Harbor Laboratory in 2010 and B.Sc. from Tel-Aviv University in 2006. Prior to that, Erlich worked in computer security and was responsible for conducting penetration tests on financial institutes and commercial companies. Dr. Erlichs research involves developing new algorithms for computational human genetics.\n\nArvind Narayanan is an Assistant Professor in the Department of Computer Science and the Center for Information Technology and Policy at Princeton. He studies information privacy and security. His research has shown that data anonymization is broken in fundamental ways, for which he jointly received the 2008 Privacy Enhancing Technologies Award. His current research interests include building a platform for privacy-preserving data sharing.\n\nSummaryO_LIBroad data dissemination is essential for advancements in genetics, but also brings to light concerns regarding privacy.\nC_LIO_LIPrivacy breaching techniques work by cross-referencing two or more pieces of information to gain new, potentially undesirable knowledge on individuals or their families.\nC_LIO_LIBroadly speaking, the main routes to breach privacy are identity tracing, attribute disclosure, and completion of sensitive DNA information.\nC_LIO_LIIdentity tracing exploits quasi-identifiers in the DNA data or metadata to uncover the identity of an unknown genetic dataset.\nC_LIO_LIAttribute disclosure techniques work on known DNA datasets. They use the DNA information to link the identity of a person with a sensitive phenotype.\nC_LIO_LICompletion techniques also work on known DNA data. They try to uncover sensitive genomic areas that were masked to protect the participant.\nC_LIO_LIIn the last few years, we have witnessed a rapid growth in the range of techniques and tools to conduct these privacy-breaching attacks. Currently, most of the techniques are beyond the reach of the general public, but can be executed by trained persons with varying degrees of effort.\nC_LIO_LIThere is considerable debate regarding risk management. One camp supports a pragmatic, ad-hoc approach of privacy by obscurity and the other supports a systematic, mathematically-backed approach of privacy by design.\nC_LIO_LIPrivacy by design algorithms include access control, differential privacy, and cryptographic techniques. So far, data custodians of genetic databases mainly adopted access control as a mitigation strategy.\nC_LIO_LINew developments in cryptographic techniques may usher in an additional arsenal of security by design techniques.\nC_LI

Genomics↗