The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Abstract

Background: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers.

Methods: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant.

Results: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual.

Interpretation: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.

Figure 1:

Personal Genome Project Canada (PGPC) workflow. Potential participants in the project must meet eligibility criteria and undergo an entrance examination. Consent is sought and reaffirmed at stages throughout the process. Research ethics board protocols and consents, and genome data files are available at www.personalgenomes.ca. For adjunct analyses, we also assayed 55 samples using high-resolution microarrays (Affymetrix Cytoscan-HD) (Appendix 1), and we generated induced pluripotent stem cell lines for 3 individuals (Figure S4, Appendix 1).

Figure 2:

Analysis and interpretation of whole genome sequencing data. We analyzed data from WGS for variants in the nuclear and mitochondrial genome: single nucleotide variants (SNVs; alternate single bases), insertion/deletions (indels; small segments of DNA that are missing or replicated), structural variants (SVs; variations involving larger segments), including copy number variants (CNVs; deletions/losses or duplications/gains), as well as other rearrangements (inversions or translocations). We also analyzed the data for 391 variants in 14 pharmacogenes (Table S2, Appendix 3). *Two variants (in MUTYH and PCDH15) were both recessive pathogenic and dominant risk factors. Note: B = benign, CGD = Clinical Genomic Database, HGMD = Human Gene Mutation Database, P = pathogenic, LB = likely benign, LP = likely pathogenic, RF = risk factor, VUS = variant of uncertain significance, WGS = whole genome sequencing.

Figure 3:

Decline in the number of novel variants as additional samples were analyzed. The burden of new variants drops with each sample analyzed, in particular the number of variants classified as benign/likely benign and uncertain significance. For each of the 55 genetically unrelated participants (excluding the child in a mother–father–child trio) in the Personal Genome Project Canada, single nucleotide variants, insertion/deletions and copy number variants that overlapped genes from the Clinical Genomic Database were classified as benign/likely benign, variant of uncertain significance or pathogenic/likely pathogenic according to American College of Medical Genetics and Genomics interpretation guidelines. We then performed 1 million simulations; in each simulation, we randomly assigned the order of the samples, and the number of variants found in sample i that were not found in any of the samples 1, 2, …, i − 1 was calculated for each i, 1 ≤ i ≤ 55. The lines indicate the number of new variants for each value of i (averaged over the million simulations), whereas the shaded areas represent ±1 standard deviation from the mean, for each of the 3 variant categories: benign (green), variant of uncertain significance (blue) and pathogenic (red).