Ilya Shlyakhter

Integrating common and rare genetic variation in diverse human populations.

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called ‘HapMap 3’, includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of ≤5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

Alcoa: the alloy constraint analyzer

Alcoa is a tool for analyzing object models. It has a range of uses. At one end, it can act as a support tool for object model diagrams, checking for consistency of multiplicities and generating sample snapshots. At the other end, it embodies a lightweight formal method in which subtle properties of behaviour can be investigated. Alcoas input language, Alloy, is a new notation based on Z. Its development was motivated by the need for a notation that is more closely tailored to object models (in the style of UML), and more amenable to automatic analysis. Like Z, Alloy supports the description of systems whose state involves complex relational structure. State and behavioural properties are described declaratively, by conjoining constraints. This makes it possible to develop and analyze a model incrementally, with Alcoa investigating the consequences of whatever constraints are given. Alcoa works by translating constraints to boolean formulas, and then applying state-of-the-art SAT solvers. It can analyze billions of states in seconds.

Identifying Recent Adaptations in Large-Scale Genomic Data

Although several hundred regions of the human genome harbor signals of positive natural selection, few of the relevant adaptive traits and variants have been elucidated. Using full-genome sequence variation from the 1000 Genomes (1000G) Project and the composite of multiple signals (CMS) test, we investigated 412 candidate signals and leveraged functional annotation, protein structure modeling, epigenetics, and association studies to identify and extensively annotate candidate causal variants. The resulting catalog provides a tractable list for experimental follow-up; it includes 35 high-scoring nonsynonymous variants, 59 variants associated with expression levels of a nearby coding gene or lincRNA, and numerous variants associated with susceptibility to infectious disease and other phenotypes. We experimentally characterized one candidate nonsynonymous variant in Toll-like receptor 5 (TLR5) and show that it leads to altered NF-κB signaling in response to bacterial flagellin. PAPERFLICK:

Reconstructing 3D tree models from instrumented photographs

Our computer modeling technique reproduces a trees 3D volume and skeleton from instrumented photographs. The technique involves first constructing the skeleton (trunk and the major branches) of the tree, and then applying an L-system starting from this skeleton. L-systems are one of the better known procedural models in the graphics community, especially after their popularization by P. Prusinkiewicz and A. Lindenmayer (1990).

A micromodularity mechanism

A simple mechanism for structuring specifications is described. By modelling structures as atoms, it remains entirely first-order and thus amenable to automatic analysis. And by interpreting fields of structures as relations, it allows the same relational operators used in the formula language to be used for dereferencing. An extension feature allows structures to be developed incrementally, but requires no textual inclusion nor any notion of subtyping. The paper demonstrates the flexibility of the mechanism by application in a variety of common idioms.

ALLPATHS 2: small genomes assembled accurately and with high continuity from short paired reads.

We demonstrate that genome sequences approaching finished quality can be generated from short paired reads. Using 36 base (fragment) and 26 base (jumping) reads from five microbial genomes of varied GC composition and sizes up to 40 Mb, ALLPATHS2 generated assemblies with long, accurate contigs and scaffolds. Velvet and EULER-SR were less accurate. For example, for Escherichia coli, the fraction of 10-kb stretches that were perfect was 99.8% (ALLPATHS2), 68.7% (Velvet), and 42.1% (EULER-SR).

F-SOFT: software verification platform

In this paper, we describe our verification tool F-Soft, which is developed for the analysis of C programs. Its novelty lies in the combination of several recent advances in formal verification research including SAT-based verification, static analyses and predicate abstraction. As shown in the tool overview in Figure 1, we translate a program into a Boolean model to be analyzed by our verification engine DiVer [4], which includes BDD-based and SAT-based model checking techniques. We include various static analyses, such as computing the control flow graph of the program, program slicing with respect to the property, and performing range analysis as described in Section 2.2. We model the software using a Boolean representation, and use customized heuristics for the SAT-based analysis as described in Section [2.1]. We can also perform a localized predicate abstraction with register sharing as described in Section [2.3], if the user so chooses. The actual analysis of the resulting Boolean model is performed using DiVer. If a counter-example is discovered, we use a testbench generator that automatically generates an executable program for the user to examine the bug in his/her favorite debugger. The F-Soft tool has been applied on numerous case studies and publicly available benchmarks for sequential C programs. We are currently working on extending it to handle concurrent programs.

Model checking C programs using F-Soft

With the success of formal verification techniques like equivalence checking and model checking for hardware designs, there has been growing interest in applying such techniques for formal analysis and automatic verification of software programs. This paper provides a brief tutorial on model checking of C programs. The essential approach is to model the semantics of C programs in the form of finite state systems by using suitable abstractions. The use of abstractions is key, both for modeling programs as finite state systems and for reducing the model sizes in order to manage verification complexity. We provide illustrative details of a verification platform called F-Soft, which provides a range of abstractions for modeling software, and uses customized SAT-based and BDD-based model checking techniques targeted for software.

Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.

The Plasmodium falciparum parasites ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.

Static analysis in disjunctive numerical domains

The convexity of numerical domains such as polyhedra, octagons, intervals and linear equalities enables tractable analysis of software for buffer overflows, null pointer dereferences and floating point errors. However, convexity also causes the analysis to fail in many common cases. Powerset extensions can remedy this shortcoming by considering disjunctions of predicates. Unfortunately, analysis using powerset domains can be exponentially more expensive as compared to analysis on the base domain. In this paper, we prove structural properties of fixed points computed in commonly used powerset extensions. We show that a fixed point computed on a powerset extension is also a fixed point in the base domain computed on an “elaboration” of the programs CFG structure. Using this insight, we build analysis algorithms that approach path sensitive static analysis algorithms by performing the fixed point computation on the base domain while discovering an “elaboration” on the fly. Using restrictions on the nature of the elaborations, we design algorithms that scale polynomially in terms of the number of disjuncts. We have implemented a light-weight static analyzer for C programs with encouraging initial results.