Biology subjects

Coffey, L.

Publications and source records attributed to Coffey, L..

4 recordsLinked to original sources

bioRxiv2020

Single amino acid mutations effect Zika virus replication in vitro and virulence in vivo

The 2014-2016 Zika virus (ZIKV) epidemic in the Americas resulted in large deposits of next-generation sequencing data from clinical samples. This resource was mined to identify emerging mutations and trends in mutations as the outbreak progressed over time. Information on transmission dynamics, prevalence and persistence of intra-host mutants, and the position of a mutation on a protein were then used to prioritize 544 reported mutations based on their ability to impact ZIKV phenotype. Using this criteria, six mutants (representing naturally occurring mutations) were generated as synthetic infectious clones using a 2015 Puerto Rican epidemic strain PRVABC59 as the parental backbone. The phenotypes of these naturally occurring variants were examined using both cell culture and murine model systems. Mutants had distinct phenotypes, including changes in replication rate, embryo death, and decreased head size. In particular, a NS2B mutant previously detected during in vivo studies in rhesus macaques was found to cause lethal infections in adult mice, abortions in pregnant females, and increased viral genome copies in both brain tissue and blood of female mice. Additionally, mutants with changes in the region of NS3 that interfaces with NS5 during replication displayed reduced replication in the blood of adult mice. This analytical pathway, integrating both bioinformatic and wet lab experiments, provides a foundation for understanding how naturally occurring single mutations affect disease outcome and can be used to predict the of severity of future ZIKV outbreaks. Author summaryTo determine if naturally occurring individual mutations in the Zika virus epidemic genotype effect viral virulence or replication rate in vitro or in vivo, we generated an infectious clone representing the epidemic genotype of stain Puerto Rico, 2015. Using this clone, six mutants were created by changing nucleotides in the genome to cause one to two amino acid substitutions in the encoded proteins. The six mutants we generated represent mutations that differentiated the early epidemic genotype from genotypes that were either ancestral or that occurred later in the epidemic. We assayed each mutant for changes in growth rate, and for virulence in adult mice and pregnant mice. Three of the mutants caused catastrophic embryo effects including increased embryonic death or significant decrease in head diameter. Three other mutants that had mutations in a genome region associated with replication resulted in changes in in vitro and in vivo replication rates. These results illustrate the potential impact of individual mutations in viral phenotype.

microbiology↗

bioRxiv2019

Characterizing allele-by-environment interactions using maize introgression lines

Relatively small genomic introgressions containing quantitative trait loci can have significant impacts on the phenotype of an individual plant. However, the magnitude of phenotypic effects for the same introgression can vary quite substantially in different environments due to allele-by-environment interactions. To study potential patterns of allele-by-environment interactions, fifteen near-isogenic lines (NILs) with >90% B73 genetic background and multiple Mo17 introgressions were grown in 16 different environments. These environments included five geographical locations with multiple planting dates and multiple planting densities. The phenotypic impact of the introgressions was evaluated for up to 26 traits that span different growth stages in each environment to assess allele-by-environment interactions. Results from this study showed that small portions of the genome can drive significant genotype-by-environment interaction across a wide range of vegetative and reproductive traits, and the magnitude of the allele-by-environment interaction varies across traits. Some introgressed segments were more prone to genotype-by-environment interaction than others when evaluating the interaction on a whole plant basis throughout developmental time, indicating variation in phenotypic plasticity throughout the genome. Understanding the profile of allele-by-environment interaction is useful in considerations of how small introgressions of QTL or transgene containing regions might be expected to impact traits in diverse environments.\n\nKey MessageSignificant allele-by-environment interactions are observed for traits throughout development from small introgressed segments of the genome.

plant biology↗

bioRxiv2019

Maternal antibodies provide partial protection from postnatal Zika viremia in nonhuman primates

Zika virus (ZIKV) will remain a public health threat until effective vaccines and therapeutics are made available in the hardest hit areas of the world. Recent data in a nonhuman primate model showed that infants postnatally infected with ZIKV were acutely susceptible to high viremia and neurological damage, suggesting the window of vulnerability extends beyond gestation. We addressed the susceptibility of two infant rhesus macaques born healthy to dams infected with Zika virus during pregnancy. Passively acquired neutralizing antibody titers dropped below detection limits between 2 and 3 months of age, while binding, possibly non-neutralizing antibodies remained detectable until viral infection at 5 months of age. Post-infection acute serum viremia was substantially reduced relative to adults infected with the same dose of the same stock of a Brazilian isolate of ZIKV (n=11 pregnant females) and another stock of the same isolate (n=4 males and 4 non-pregnant females). Virus was never detected in cerebrospinal fluid nor in neural tissues at necropsy two weeks after infection, suggesting reduced viral burden relative to adults and published data from infants. However, viral RNA was detected in lymph nodes, confirming some tissue dissemination. Though protection was not absolute, our data suggest infants born healthy to infected mothers may harbor a modest but important level of protection from postnatally acquired ZIKV for several months after birth, an encouraging result given the potentially severe infection outcomes of this population.

microbiology↗

bioRxiv2017

Genotype-by-Environment Interactions Affecting Heterosis in Maize

The environment can influence heterosis, the phenomena in which the offspring of two inbred parents exhibits phenotypic performance beyond the inbred parents for specific traits. In this study we measured 25 traits in a set of 47 maize hybrids and their inbred parents grown in 16 different environments, and each had varying levels of average productivity. By quantifying 25 vegetative and reproductive traits across the life cycle we were able to analyze interactions between the environment and multiple distinct instances of heterosis. The magnitude and rank among hybrids of better-parent heterosis (BPH) varied for the different traits and environments. Across the traits, a higher within plot variance was observed for inbred lines compared to hybrids. However, for most traits, variance across environments was not significantly different for inbred lines compared to hybrids. Further, for many traits the correlations of BPH to hybrid performance and BPH to better parent performance were of comparable magnitude. These results indicate that inbreds and hybrids are showing similar trends in environmental response and are both contribute to genotype-by-environment interactions for heterosis. This study highlights that degree of heterosis is not an inherent trait of a specific hybrid, but varies depending on the trait measured and the environment where that trait is measured. Studies that attempt to correlate molecular processes with heterosis are hindered by the fact that heterosis is not a consistent attribute of a specific hybrid.

genetics↗