Biology subjects

O'Brien, E.

Publications and source records attributed to O'Brien, E..

4 recordsLinked to original sources

bioRxiv2018

Matrilineal Transmission of Familial Excess Longevity (mtFEL): Effects on Cause-specific Mortality in Utah, 1904-2002

The heritable component to a long and healthy life is likely to involve the actions and interactions of both nuclear and mitochondrial genetic variants. Using computerized genealogical records with accompanying cause of death information from the Utah population, we previously reported cause-specific mortality rate distributions associated with the nuclear genetic component of familial exceptional longevity. Here we identify Utah matrilineages (mitochondrial lineages) in which overall survival is better than expected, and compare cause-specific mortality rates in those matrilineages to cause-specific mortality rates in the general population. We also examine the effects on cause-specific mortality of interactions between the nuclear and mitochondrial components of familial excess longevity (nuclear FEL and mtFEL). Among individuals from the bottom quartile of nuclear FEL, those who were also in the top quartile for mtFEL had lower all-cause, heart disease, cancer, stroke, and diabetes mortality rates than those in the bottom quartile of mtFEL. In contrast, among individuals from the top quartile of nuclear FEL, the mortality rates from these diseases were similar for those also in the top quartile of mtFEL vs. those also in the bottom quartile of mtFEL, with the exception of diabetes mortality, which was dramatically suppressed in the high nuclear FEL + high mtFEL group as compared to the high nuclear FEL + low mtFEL group. Moreover, the highest mortality rates from diabetes were found in individuals aged 90 years or older who were members of both the high nuclear FEL and low mtFEL quartiles. These results support the hypothesis that some nuclear genetic variants contributing to long life carry an increased risk of dying from diabetes that is strongly ameliorated by some mitochondrial DNA variants.

epidemiology↗

bioRxiv2018

Mitochondrial genetics of exceptional longevity in multigeneration matrilineages

Some heritable mitochondrial DNA (mtDNA) sequence variants may slow the rate of aging. The European mitochondrial haplogroup K has previously been reported to be increased in frequency in centenarians and nonagenarians relative to its frequency in younger individuals, by standard case/control study designs. To select for mitochondrial genomes likely to carry beneficial genetic variants, we screened a large genealogical database (the Utah Population Database, UPDB) for mitochondrial lineages in which the frequency of survival past 90 years was significantly higher than in the general population, and also significantly higher than in close non-matrilineal relatives. We ranked 14,900 distinct matrilineages by the strength of their association with longevity. Full sequencing of the mtDNAs from a single individual from each of 53 matrilineages in the top longevity ranks and each of 374 control matrilineages from the general Utah population, followed by analyses of the mtDNA haplogroup frequencies, identified haplogroup K2 as the haplogroup most enriched in frequency by the longevity selection (Odds Ratio = 23.05). We then analyzed overall survival and cause-specific mortality in the several thousand individuals aged 40 years or older whose mtDNA genotypes could be imputed from the 374 fully sequenced control mtDNAs. In these control matrilineages Haplogroup K2 individuals (n=332) enjoyed a significantly lower all-cause mortality risk than the general population (HR=0.81), attributable in part to a significantly lower risk of dying from heart disease (HR=0.50), as well as lower (though not significantly lower) risks of dying from cancer (HR=0.72) and diabetes (HR=0.74). Furthermore, K2 was the only haplogroup in which mortality was reduced for all three of these common causes of death.

genetics↗

bioRxiv2018

Model-driven design and evolution of non-trivial synthetic syntrophic pairs

Synthetic microbial communities are attractive for applied biotechnology and healthcare applications through their ability to efficiently partition complex metabolic functions. By pairing auxotrophic mutants in co-culture, nascent E. coli communities can be established where strain pairs are metabolically coupled. Intuitive synthetic communities have been demonstrated, but the full space of cross-feeding metabolites has yet to be explored. A novel algorithm, OptAux, was constructed to design 66 multi-knockout E. coli auxotrophic strains that require significant metabolite cross-feeding when paired in co-culture. Three OptAux predicted auxotrophic strains were co-cultured with an L-histidine auxotroph and validated via adaptive laboratory evolution (ALE). Time-course sequencing revealed the genetic changes employed by each strain to achieve higher community fitness and provided insights on mechanisms for sharing and adapting to the syntrophic niche. A community model of metabolism and gene expression was utilized to predict the relative community composition and fundamental characteristics of the evolved communities. This work presents a novel computational method to elucidate metabolic changes that empower community formation and thus guide the optimization of co-cultures for a desired application.

systems biology↗

bioRxiv2016

Familial heterogeneity in breast cancer predisposition: a study of 22 Utah families

The problem of \"missing heritability\" in genome-wide analyses of complex diseases is thought to be attributable to some combination of: rare variants of moderate to large effect, common variants of very small effect, and epigenetic, epistatic, or shared environmental effects. Rare variants do not affect large numbers of people by definition, but identified genes and pathways frequently lead to important insights into pathogenesis, and become targets of chemoprevention or therapy. Family studies remain an efficient way to identify rare variants with sizable effects on disease risk. We present a genome-wide study of breast cancer in 22 large high-risk families including 154 women diagnosed with breast cancer. Appropriate marker spacing was achieved by simulation studies of founder haplotypes to reduce the chance that linkage disequilibrium produced spurious linkage peaks. For each family, we generated 100 simulations of null linkage genome-wide to estimate the probability that individual results were due to chance. We identified a total of 12 putative susceptibility regions with per-family genome-wide probability < 0.05. These regions were located on 10 chromosomes; 10 of the 22 families showed linkage at these locations; two or more families showed linkage to 6 regions on 5 chromosomes (4q, 5q, 6p, 14q, 18p, and 18q). These results indicate that there is considerable heterogeneity among families in genomic regions and thus variants predisposing to breast cancer. Moreover, they suggest that uncommon high- or medium-risk genetic variants remain to be found, and that family designs can be an efficient way to identify them.

cancer biology↗