Biology subjects

Phung, T. N.

Publications and source records attributed to Phung, T. N..

6 recordsLinked to original sources

bioRxiv2025

Identification of cell types associated with 14 brain phenotypes from more than 10 million single cells

Genome-wide association studies (GWAS) have yielded unprecedented insight into the genetic variants associated with many human traits. However, translating this insight into knowledge about causal biological mechanisms remains challenging. One promising recent strategy is to link GWAS-associated genes to information on expression levels of those genes in specific cell types. This strategy allows for the generation of specific, testable hypotheses about which cell types are important for a trait which can then be investigated in functional lab experiments for actual relevance. The success of this strategy strongly depends on the quality and systematic analysis of available single-cell RNAseq datasets. Here we present a comprehensive database of 388 datasets derived from 36 studies spanning different regions of the brain across developmental timepoints. Using this database, we tested for the presence of cell type enrichment in genes associated with 14 traits. We confirmed previous findings such as the association between microglia and Alzheimers disease in the entorhinal cortex. In addition, we found novel evidence for the involvement of specific cell types in disease, such as astrocytes being implicated in alcohol-related phenotypes or neuronal cell types at the prenatal stage in ADHD. Our database has been incorporated to FUMA, a publicly available and widely used tool for post-GWAS functional annotation analyses. Our work provides an approach to facilitate the prioritization of cell types in specific brain regions and/or developmental stages, further informing the design of follow-up experiments.

genetics↗

bioRxiv2025

Best practices for improving alignment and variant calling on human sex chromosomes

Sex chromosome complement is the largest karyotypic variation observed in humans. X and Y chromosomes were once a pair of homologous autosomes. Although chromosome X and Y differentiated from one another, they still share high levels of sequence similarity in some regions, like the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The sex chromosomes violate some assumptions of autosomal pairs, but are not always processed separately in genomics analyses. Here, we undertook a simulation study to assess the effects of standard autosomal versus sex chromosome complement-informed alignment, variant calling, and variant filtering strategies on variants detected on the human sex chromosomes. We find that aligning samples to a reference genome informed by the sex chromosome complement of the sample increases the number of true positives called in the PARs, and, in XX-samples only, also the XTR. In contrast, in XY-samples, masking the XTR during alignment results in a ten-fold higher rate of false positives. We further find that haploid calling on the sex chromosomes in XY-samples reduces the number of false positives compared to diploid calling, but does not decrease the number of false negatives. Improving the accuracy of variant calling results in detection of variants that could be relevant to studies of health and disease, including variants we recovered in genes implicated in cardiomyopathy, immunodeficiency, and Alzheirmers disease, among others. We recommend future genomic analyses implement the following best practices for detecting variants: aligning samples to versions of the human reference genome informed by the sex chromosome complement of the sample and using accurate ploidy parameters when calling variants.

genomics↗

bioRxiv2022

Sex differences in early and term placenta are conserved in adult tissues

BackgroundPregnancy complications vary based on the fetuss genetic sex, which may, in part, be modulated by the placenta. Further, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different time points throughout pregnancy and comparisons to adult tissues remains poorly characterized. MethodsHere, we collect and characterize sex differences in gene expression in term placentas ( [≥] 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx. ResultsWe identify 268 and 53 sex differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex differentially expressed genes observed in the term placentas, 31 are also sex differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males. ConclusionsWe find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes. HighlightsO_LISex differences in gene expression in late first trimester placentas are positively correlated with sex differences in gene expression in full term placentas; sex differences develop early and are maintained. C_LIO_LISex differences in gene expression on the sex chromosomes in the placenta are correlated to sex differences in adult tissues. C_LIO_LISex-linked gametolog genes require additional methodological approaches for accurate quantification. C_LI

genomics↗

bioRxiv2019

Patchy, incomplete, and heterogeneous X-inactivation in the human placenta

One of the X chromosomes in genetic females is silenced by a process called X chromosome inactivation (XCI). Variation in XCI across the placenta may contribute to observed sex differences and variability in pregnancy outcomes. However, XCI has predominantly been studied in human adult tissues. Here we sequenced and analyzed DNA and RNA from two locations from 30 full-term pregnancies. Implementing an allele specific approach to examine XCI, we report evidence that XCI in the human placenta is patchy, with large patches of either silenced maternal or paternal X chromosomes. Further, using similar measurements, we show that this is in contrast to adult tissues, which generally exhibit mosaic X-inactivation, where bulk samples exhibit both maternal and paternal X chromosome expression. Further, by comparing skewed samples in placenta and adult tissues, we identify genes that are uniquely silenced or expressed in the placenta compared to adult tissues highlighting the need for tissue-specific maps of XCI.

genomics↗

bioRxiv2019

Identification and characterization of constrained non-exonic bases lacking predictive epigenomic and transcription factor binding annotations

Annotations of evolutionarily constraint provide important information for variant prioritization. Genome-wide maps of epigenomic marks and transcription factor binding provide complementary information for interpreting a subset of such prioritized variants. Here we developed the Constrained Non-Exonic Predictor (CNEP) to quantify the evidence of each base in the human genome being in a constrained non-exonic element from over 60,000 epigenomic and transcription factor binding features. We find that the CNEP score outperforms baseline and related existing scores at predicting constrained non-exonic bases from such data. However, a subset of such bases are still not well predicted by CNEP. We developed a complementary Conservation Signature Score by CNEP (CSS-CNEP) using conservation state and constrained element annotations that is predictive of those bases. Using human genetic variation, regulatory sequence motifs, mouse epigenomic data, and retrospectively considered additional human data we further characterize the nature of constrained non-exonic bases with low CNEP scores.

genomics↗

bioRxiv2018

Complex patterns of sex-biased demography in canines

INTRODUCTION INTRODUCTION RESULTS DISCUSSION METHODS Data availability REFERENCES Studies of genetic variation have shown that the demographic history of dogs has been extremely complex, involving multiple bottleneck and admixture events. However, existing studies have not explored the variance in the number of reproducing males and females, and whether it has changed across evolutionary time. While male-biased mating practices, such as male-biased migration and multiple paternity, have been observed in wolves, recent breeding practices could have led to female-biased mating patterns in breed dogs. In addition, breed dogs are thought to have experienced the popular sire effect, where a small number of males father many offspring with a large number of females. Here we use genetic variation data to test how widespr ...

evolutionary biology↗