Public Release: 

Genome Research publishes special issue: Personal Genomes and Variation

Cold Spring Harbor Laboratory

September 1, 2009 - The September 2009 issue of Genome Research (www.genome.org), entitled "Personal Genomes and Variation," is a special issue dedicated to the burgeoning field of personal genomics.

The issue features novel biological insights gained from primary research comparing individual genomes, targeted resequencing efforts to find rare variants that contribute to disease phenotypes, cancer genomes, ancestral reconstructions, cutting-edge methods to characterize variation within and across populations and new large-scale genome sequencing projects and resources in genomic medicine that lead the way forward into the era of Personal Genomes. The following sections highlight several of the papers published in the issue.

1. Genome sequences of African and Korean individuals

In the first demonstration of a human genome sequenced on the Applied Biosystems SOLiD System platform, McKernan et al. sequenced and analyzed the genome of an African individual. Nearly four million single nucleotide polymorphisms (SNPs) were accurately identified, 19% of which are novel. Furthermore, structural variation was mapped in detail, providing a comprehensive survey of the landscape of genetic variants in this individual. As structural variation is increasingly recognized as significantly contributing to genomic variation, this study will serve as a guide for future genome sequencing efforts aimed at understanding ancestry and disease.

Reference: McKernan KJ et al. Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding. Genome Res. doi:10.1101/gr.091868.109

Also in this issue, scientists from South Korea have sequenced the genome of a Korean individual, known as "SJK." Ahn et al. characterized more than 420,000 novel SNPs in the SJK genome, as well as a significant number of structural variants. Considerable differences between SJK and the genome of a Chinese individual were identified, indicating that there is significant genomic variation even between closely related ethnic groups. This work demonstrates that the construction of reference genomes for minor socio-ethnic groups will be essential for future studies of variation between closely related populations.

Reference: Ahn S et al. The first Korean genome sequence and analysis: Full genome sequencing for a socio-ethnic group. Genome Res. doi:10.1101/gr.092197.109

2. Mobile elements and structural variation in an individual genome

Approximately half of the human genome is composed of repetitive mobile elements, and these sequences are believed to play a major role in creating structural variation and shaping the genome. The advent of personal genomics is now allowing researchers to assess the role of mobile elements in structural variation at the level of the individual.

In this issue, a research team led by Jinchuang Xing and Lynn Jorde at the University of Utah performed the first comprehensive analysis of mobile element-related structural variants in the genome sequence of an individual, comparing the recently published HuRef genome sequence to the human genome reference sequence. The authors analyzed more than 8,000 structural variants that differed between the HuRef and Human Genome Project reference genomes and found that a significant number of these were mediated by mobile elements, indicating that they play a substantial role in the creation of inter-individual variation.

Reference: Xing J et al. Mobile elements create structural variation: Analysis of a complete human genome. Genome Res. doi:10.1101/gr.091827.109

3. A suite of tools for personal genomics research

Also published in this special issue of Genome Research are several tools developed to provide efficient sequencing read mapping, infer ancestry of individuals from stratified populations based on genotypes, and visualize comparative genomic data.

In order to handle the vast quantities of data generated by next-generation sequencing platforms, researchers are faced with the challenge of designing bioinformatics tools that not only accurately map sequencing reads back to a reference genome, but also do so in a time-efficient manner. In a significant advancement beyond current read mapping algorithms, Weese et al. have developed RazerS. The authors demonstrate that RazerS outperforms currently available algorithms, and is also flexible, allowing users to control sensitivity and speed depending upon the project at hand.

Reference: Weese et al. RazerS--fast read mapping with sensitivity control. Genome Res. doi:10.1101/gr.088823.108

Genetic variation within human populations due to differences in ancestry, known as population stratification, is a serious problem for genetic association studies. Bioinformatic tools have been developed to estimate and correct for ancestry differences in populations, however current methods suffer from slow run-times and other statistical limitations. In order to overcome these challenges, Alexander et al. have developed ADMIXTURE. A model-based algorithm, ADMIXTURE reduces computation time from hours to minutes, opening up possibilities for using significantly larger sets of markers to estimate ancestry and correct for stratification in genetic association studies.

Reference: Alexander et al. Fast model-based estimation of ancestry in unrelated individuals. Genome Res. doi:10.1101/gr.094052.109

As new technologies speed the output of data from whole-genome studies, tools that assist comparative genomic analysis and make sense of this information are essential. Visualization of genomic relationships between individuals can be a powerful method for illustrating rearrangements, however traditionally this has been done in a linear fashion, where patterns often cannot be easily discerned when many rearrangement events are represented. Martin Krzywinski and colleagues have taken a different approach to this problem, developing Circos, a tool that can readily accommodate large datasets and complex structural relationships with flexible configurations that facilitate recognition of meaningful patterns in the data.

Reference: Krzywinski et al. Circos: An information aesthetic for comparative genomics. Genome Res. doi:10.1101/gr.092759.109

4. Personal genomics in the clinic

The era of personal genomics is expected to usher in dramatic new improvements in healthcare by using personal genomic information to deliver new diagnostics and treatments directly to patients in the clinic. Two papers published in this special issue of Genome Research are establishing the groundwork for the merger of genomics and clinical research.

The ClinSeq Project is a pilot program to apply large amounts of DNA sequencing data to clinical research, addressing issues such as the genetic basis of health, disease, and response to drugs. In this marker paper, Leslie Biesecker of the NHGRI and colleagues outline the design of the ClinSeq Project and describe the preliminary generation of data. The study has begun with the resequencing of a large set of genes believed to be involved in atherosclerosis, demonstrating that the approach taken by the ClinSeq Project will be an effective strategy for integrating sequencing information into medical care.

Reference: Biesecker et al. The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicine. Genome Res. doi:10.1101/gr.092841.109

Substantial efforts are underway to move patient medical records from paper to electronic form, which raises the possibility of harnessing routinely collected electronic records for large-scale population studies, such as genome-wide association studies. Murphy et al. have developed the Informatics for Integrating Biology and the Bedside (i2b2) resource, an informatics framework that mines electronic health records for potential cases and controls in an efficient and cost-effective manner.

Reference: Murphy et al. Instrumenting the health care enterprise for discovery research in the genomic era. Genome Res. doi:10.1101/gr.094615.109

Please direct requests for pre-print copies of the manuscripts to Peggy Calicchia, Editorial Secretary, Genome Research (calicchi@cshl.edu; +1-516-422-4012). In addition to the eight articles highlighted above, the following will also appear in the issue:

5. Harrill AH et al. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. doi:10.1101/gr.090241.108

6. Hoberman R et al. A probabilistic approach for SNP discovery in high-throughput human resequencing data. Genome Res. doi:10.1101/gr.092072.109

7. Chun S and Fay JC. Identification of deleterious mutations within three human genomes. Genome Res. doi:10.1101/gr.092619.109

8. Kumar S et al. Positional conservation and amino acids shape the correct diagnosis and population frequencies of benign and damaging personal amino acid mutations. Genome Res. doi:10.1101/gr.091991.109

9. Torkamani A and Schork NJ. Identification of rare cancer driver mutations by network reconstruction. Genome Res. doi:10.1101/gr.092833.109

10. Mefford HC et al. A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res. doi:10.1101/gr.094987.109

11. Yoon S et al. Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res. doi:10.1101/gr.092981.109

12. Hodges E et al. High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res. doi:10.1101/gr.095190.109

13. Li JB et al. Multiplex padlock targeted sequencing reveal human hypermutable CpG variations. Genome Res. doi:10.1101/gr.092213.109

14. Summerer D et al. Microarray-based multicycle-enrichment of genomic subsets for targeted next-generation sequencing. Genome Res. doi:10.1101/gr.091942.109

15. Skinner ME et al. JBrowse: A next-generation genome browser. Genome Res. doi:10.1101/gr.094607.109

16. Shaikh TH et al. High-resolution mapping and analysis of copy number variations in the human genome: A data resource for clinical and research applications. Genome Res. doi:10.1101/gr.083501.108.

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About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

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