Biology subjects

Sands, B.

Publications and source records attributed to Sands, B..

5 recordsLinked to original sources

bioRxiv2025

Diverse Patterns of Allele-Specific Expression in Healthy Human Tissues

Differences in gene sequence and gene expression underlie variation in traits. However, even monozygotic twins do not express their genes in the same way, develop divergence in traits, and succumb to distinct chronic diseases. During development, epigenetic silencing programs cause diversity in allele expression, resulting in differences in traits and chronic disease risk. To quantify human autosomal allele expression between individuals, we analyzed human allele-specific expression data from the GTEx project. For hundreds of genes, some individuals will express the gene biallelically, while many others may only express one allele or extreme bias towards one allele. We found gene-specific patterns of interindividual variation in allele bias. We found that some individuals have more genome-wide monoallelic/biased expression than others. Individuals also had distinct combinations of allele expression bias. These differences can underlie variation in traits, idiopathic or incompletely penetrant traits/diseases, and chronic diseases. Significance/ImpactAllele-specific expression can affect cancer, immune response, and genetic disease. This work reveals 1) gene-specific multimodal patterns of interindividual variation in allele bias, 2) that individuals can maintain bias across tissues, and 3) that different individuals have distinct combinations of silenced alleles. These different patterns and the weighted classifications demonstrate how allele bias manifests between individuals; there are individuals and tissues with more biased/non-Mendelian expression and some tissues have more age-related changes in which alleles are silenced.

genomics↗

bioRxiv2024

Maternal histone methyltransferases antagonistically regulate monoallelic expression in C. elegans

Undefined epigenetic programs act to probabilistically silence individual autosomal alleles, generating unique individuals, even from genetic clones. This sort of random monoallelic expression can explain variation in traits and diseases that differences in genes and environments cannot. Here, we developed the nematode Caenorhabditis elegans to study monoallelic expression in whole tissues, and defined a developmental genetic regulation pathway. We found maternal H3K9 histone methyltransferase (HMT) SET-25/SUV39/G9a works with HPL-2/HP1 and LIN-61/L3MBTL2 to randomly silence alleles in the intestinal progenitor E-cell of 8-cell embryos to cause monoallelic expression. SET-25 was antagonized by another maternal H3K9 HMT, MET-2/SETDB1, which works with LIN-65/ATF7ZIP and ARLE-14/ARL14EP to prevent monoallelic expression. The HMT-catalytic SET domains of both MET-2 and SET-25 were required for regulating monoallelic expression. Our data support a model wherein SET-25 and MET-2 regulate histones during development to generate patterns of somatic monoallelic expression that are persistent but not heritable.

systems biology↗

bioRxiv2019

Introns Control Intrinsic Noise

Introns are noncoding DNA elements found in between coding exons of most genes in most metazoans. Introns are known to both increase expression levels and provide means for making different protein products from the same gene via alternative splicing. It is thought that evolution has selected for these functions of introns. Here we present evidence for an additional reason why so many metazoan genes have introns, and why some do not. We found that introns control stochasticity in metazoan gene expression. They do this by controlling stochastic autosomal allele bias. We determined this by measuring the expression of differently colored reporter alleles with and without introns. We find that introns control stochastic autosomal allele biases using a 5-position dependent mechanism. Intron control of allele expression noise provides an additional mechanism to consider when pondering why so many metazoan genes have introns and why some have lost them.

systems biology↗

bioRxiv2018

In vivo measurements reveal a single 5’ intron is sufficient to increase protein expression level in C. elegans

Introns can increase gene expression levels using a variety of mechanisms collectively referred to as Intron Mediated Enhancement (IME). To date, the magnitude of IME has been quantified in human cell culture and plant models by comparing intronless reporter gene expression levels to those of intron-bearing reporter genes in vitro (mRNA, Western Blots, protein activity), using genome editing technologies that lacked full control of locus and copy number. Here, for the first time, we quantified IME in vivo, in terms of protein expression levels, using fluorescent reporter proteins expressed from a single, defined locus in Caenorhabditis elegans. To quantify the magnitude of IME, we developed a microfluidic chip-based workflow to mount and image individual animals, including software for operation and image processing. We used this workflow to systematically test the effects of position, number and sequence of introns on two different proteins, mCherry and mEGFP, driven by two different promoters, vit-2 and hsp-90. We found the three canonical synthetic introns commonly used in C. elegans transgenes increased mCherry protein concentration by approximately 50%. The naturally-occurring introns found in hsp-90 also increased mCherry expression level by about 50%. Furthermore, and consistent with prior results examining mRNA levels, protein activity or phenotypic rescue, we found that a single, natural or synthetic, 5 intron was sufficient for the full IME effect while a 3 intron was not. IME was also affected by protein coding sequence (50% for mCherry and 80% for mEGFP) but not strongly affected by promoter 46% for hsp-90 and 54% for the stronger vit-2. Our results show that IME of protein expression in C. elegans is affected by intron position and contextual coding sequence surrounding the introns, but not greatly by promoter strength. Our combined controlled transgenesis and microfluidic screening approach should facilitate screens for factors affecting IME and other intron-dependent processes.

genetics↗

bioRxiv2018

Differences in protein dosage underlie nongenetic differences in traits

Phenotypic expression of many traits varies among isogenic individuals in homogeneous environments. Intrinsic variation in the protein chaperone system affects a wide variety of traits in diverse biological systems. In C. elegans, expression of hsp-16.2 chaperone biomarkers predicts the penetrance of mutations and lifespan after heat shock. But the physiological mechanisms by which cells express different amounts of the biomarker were unknown. Here, we used an in vivo microscopy approach to dissect the mechanisms of cell-to-cell variation in hsp-16.2 biomarker expression, focusing on the intestines, which generate most signal. We found both intrinsic noise and signaling noise are low. The major axis of cell-to-cell variation in gene expression is composed of general differences in protein dosage. Thus, hsp-16.2 biomarkers reveal states of high or low effective dosages for many genes. It is possible that natural variation in protein dosage or chaperone activity may account for missing heritability of some traits.

systems biology↗