The journals of gerontology. Series A, Biological sciences and medical sciences, 2020
Tindale, Lauren C, Thiessen, Nina, Leach, Stephen, Brooks-Wilson, Angela R
The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in noncoding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression toward major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.
BMC geriatrics, 2019
Tindale, Lauren C, Salema, Diane, Brooks-Wilson, Angela R
Super-Seniors are healthy, long-lived individuals who were recruited at age 85 years or older with no history of cancer, cardiovascular disease, diabetes, dementia, or major pulmonary disease. In a 10-year follow-up, we aimed to determine whether surviving Super-Seniors showed compression of morbidity, and to test whether the allele frequencies of longevity-associated variants in APOE and FOXO3 were more extreme in such long-term survivors.
PloS one, 2018
Halaschek-Wiener, Julius, Tindale, Lauren C, Collins, Jennifer A, Leach, Stephen, McManus, Bruce, Madden, Kenneth, Meneilly, Graydon, Le, Nhu D, Connors, Joseph M, Brooks-Wilson, Angela R
To understand why some people live to advanced age in good health and others do not, it is important to study not only disease, but also long-term good health. The Super-Seniors Study aims to identify factors associated with healthy aging.
Bioinformatics (Oxford, England), 2020
Nieuwoudt, Christina, Brooks-Wilson, Angela, Graham, Jinko
We present the R package SimRVSequences to simulate sequence data for pedigrees. SimRVSequences allows for simulations of large numbers of single-nucleotide variants (SNVs) and scales well with increasing numbers of pedigrees. Users provide a sample of pedigrees and SNV data from a sample of unrelated individuals.
PloS one, 2019
Schuetz, Johanna M, Grundy, Anne, Lee, Derrick G, Lai, Agnes S, Kobayashi, Lindsay C, Richardson, Harriet, Long, Jirong, Zheng, Wei, Aronson, Kristan J, Spinelli, John J, Brooks-Wilson, Angela R
Inflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways.
Source code for biology and medicine, 2018
Nieuwoudt, Christina, Jones, Samantha J, Brooks-Wilson, Angela, Graham, Jinko
Studies that ascertain families containing multiple relatives affected by disease can be useful for identification of causal, rare variants from next-generation sequencing data.
Scientific reports, 2018
Zeng, Andy G X, Leung, Andy C Y, Brooks-Wilson, Angela R
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive hematological cancer for which mitochondrial metabolism may play an important role. Mitochondrial DNA (mtDNA) encodes crucial mitochondrial proteins, yet the relationship between mtDNA and DLBCL remains unclear. We analyzed the functional consequences and mutational spectra of mtDNA somatic mutations and private constitutional variants in 40 DLBCL tumour-normal pairs. While private constitutional variants occurred frequently in the D-Loop, somatic mutations were randomly distributed across the mitochondrial genome. Heteroplasmic constitutional variants showed a trend towards loss of heteroplasmy in the corresponding tumour regardless of whether the reference or variant allele was being lost, suggesting that these variants are selectively neutral. The mtDNA mutational spectrum showed minimal support for ROS damage and revealed strand asymmetry with increased C > T and A > G transitions on the heavy strand, consistent with a replication-associated mode of mutagenesis. These heavy strand transitions carried higher proportions of amino acid changes - which were also more pathogenic - than equivalent substitutions on the light strand. Taken together, endogenous replication-associated events underlie mtDNA mutagenesis in DLBCL and preferentially generate functionally consequential mutations. Yet mtDNA somatic mutations remain selectively neutral, suggesting that mtDNA-encoded mitochondrial functions may not play an important role in DLBCL.
Leukemia & lymphoma, 2017
Jones, Samantha J, Voong, Jackson, Thomas, Ruth, English, Amy, Schuetz, Johanna, Slack, Graham W, Graham, Jinko, Connors, Joseph M, Brooks-Wilson, Angela
We studied 140 families with two or more lymphoid cancers, including non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), for deviation from the population age of onset and lymphoid cancer co-occurrence patterns. Median familial NHL, HL, CLL and MM ages of onset are substantially earlier than comparable population data. NHL, HL and CLL (but not MM) also show earlier age of onset in later generations, known as anticipation. The co-occurrence of lymphoid cancers is significantly different from that expected based on population frequencies (p < .0001), and the pattern differs more in families with more affected members (p < .0001), suggesting specific lymphoid cancer combinations have a shared genetic basis. These families provide evidence for inherited factors that increase the risk of multiple lymphoid cancers. This study was approved by the BC Cancer Agency - University of British Columbia Clinical Research Ethics Board.
Tindale, Lauren C, Leach, Stephen, Spinelli, John J, Brooks-Wilson, Angela R
Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old 'Super-Seniors' (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer's Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.