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With the recent availability of tissue-specific gene expression data, e.g., provided by the GTEx Consortium, there is interest in comparing gene co-expression patterns across tissues. One promising approach to this problem is to use a multilayer network analysis framework and perform multilayer community detection. Communities in gene co-expression networks reveal groups of genes similarly expressed across individuals, potentially involved in related biological processes responding to specific environmental stimuli or sharing common regulatory variations. We construct a multilayer network in which each of the four layers is an exocrine gland tissue-specific gene co-expression network. We develop methods for multilayer community detection with correlation matrix input and an appropriate null model. Our correlation matrix input method identifies five groups of genes that are similarly co-expressed in multiple tissues (a community that spans multiple layers, which we call a generalist community) and two groups of genes that are co-expressed in just one tissue (a community that lies primarily within just one layer, which we call a specialist community). We further found gene co-expression communities where the genes physically cluster across the genome significantly more than expected by chance (on chromosomes 1 and 11). This clustering hints at underlying regulatory elements determining similar expression patterns across individuals and cell types. We suggest thatKRTAP3-1,KRTAP3-3, andKRTAP3-5share regulatory elements in skin and pancreas. Furthermore, we find thatCELA3AandCELA3Bshare associated expression quantitative trait loci in the pancreas. The results indicate that our multilayer community detection method for correlation matrix input extracts biologically interesting communities of genes.

 

Necroptosis is a type of programmed cell death. It is characterized by membrane permeabilization and is associated with the release of intracellular components due to compromised membrane integrity which induces a strong inflammatory response. We recently showed that the accumulation of very long chain fatty acids (VLCFAs) contributes to membrane permeabilization during necroptosis. However, the mechanisms that result in the accumulation of these cytotoxic lipids remain unknown. Using comparative transcriptomics and digital PCR validations, we found that several target genes of sterol regulatory element-binding proteins (SREBPs) were upregulated during necroptosis, suggesting that they might be responsible for the accumulation of VLCFA in this process. We demonstrated that activation of SREBPs during necroptosis exacerbates the permeability of the plasma membrane and cell death. Consistent with these observations, targeting sterol regulatory element-binding protein cleavage-activating protein (SCAP), a protein involved in SREBP activation, reversed the accumulation of VLCFAs, and restored cell death and membrane permeabilization during necroptosis. Collectively, our results highlight a role for SREBP in regulating lipid changes during necroptosis and suggest SREBP-mediated lipid remodeling as a potential target for therapeutics to reduce membrane permeabilization during necroptosis. 

Unlike PIWI-interacting RNA (piRNA) in other species that mostly target transposable elements (TEs), >80% of piRNAs in adult mammalian testes lack obvious targets. However, mammalian piRNA sequences and piRNA-producing loci evolve more rapidly than the rest of the genome for unknown reasons. Here, through comparative studies of chickens, ducks, mice, and humans, as well as long-read nanopore sequencing on diverse chicken breeds, we find that piRNA loci across amniotes experience: (1) a high local mutation rate of structural variations (SVs, mutations ≥ 50 bp in size); (2) positive selection to suppress young and actively mobilizing TEs commencing at the pachytene stage of meiosis during germ cell development; and (3) negative selection to purge deleterious SV hotspots. Our results indicate that genetic instability at pachytene piRNA loci, while producing certain pathogenic SVs, also protects genome integrity against TE mobilization by driving the formation of rapid-evolving piRNA sequences.

 

The persistence of versions of genes that cause severe disease in human populations has long perplexed scientists. It is common for many versions of a gene to exist. But scientists expect that over time natural selection will eliminate versions of genes harmful to human health. Sometimes, there are good reasons that a disease-causing gene may persist. For example, having two copies of a particular gene variant causes a condition, called sickle cell disease. But having one sickle cell-causing copy of the gene and one non-disease-causing copy protects against malaria. As a result, the version of the gene that causes sickle cell is more common in people from areas where malaria is prevalent despite the risks to people who end up with two copies. Scientists call this phenomenon balancing selection because trade-offs in the gene’s benefits and risks cause it to persist in the population. Aqil et al. show that balancing selection has likely caused many ancient gene variants to persist in human populations. In the experiments, Aqil et al. scoured the genomes of hundreds of modern humans from around the world and four groups of ancient human ancestors, including Neanderthals and Denisovans. The experiments looked for structural changes in genes, like deletions, that date back to more than 700,000 years ago – before modern humans split from their ancestors. They found large numbers of such ancient genes in modern humans. Using computer modeling, Aqil et al. showed that these ancient genes likely persist because of balancing selection. Many of these ancient genes regulate the immune response and metabolism. These genes may protect against infectious diseases outbreaks and starvation, which have occurred periodically throughout human history. But these same genes may cause immune or metabolic diseases in modern humans not currently facing these threats. The experiments show how such biological trade-offs have shaped human evolution and reveal that modern human populations, regardless of race or region of origin, share the same genetic variation that already our ancestors carried within them. 

Chemosensation (olfaction, taste) is essential for detecting and assessing foods, such that dietary shifts elicit evolutionary changes in vertebrate chemosensory genes. The transition from hunting and gathering to agriculture dramatically altered how humans acquire food. Recent genetic and linguistic studies suggest agriculture may have precipitated olfactory degeneration. Here, we explore the effects of subsistence behaviors on olfactory (OR) and taste (TASR) receptor genes among rainforest foragers and neighboring agriculturalists in Africa and Southeast Asia. We analyze 378 functionalORand 26 functionalTASRgenes in 133 individuals across populations in Uganda (Twa, Sua, BaKiga) and the Philippines (Agta, Mamanwa, Manobo) with differing subsistence histories. We find no evidence of relaxed selection on chemosensory genes in agricultural populations. However, we identify subsistence-related signatures of local adaptation on chemosensory genes within each geographic region. Our results highlight the importance of culture, subsistence economy, and drift in human chemosensory perception.

 

An increasing body of archaeological and genomic evidence has hinted at a complex settlement process of the Americas by humans. This is especially true for South America, where unexpected ancestral signals have raised perplexing scenarios for the early migrations into different regions of the continent. Here, we present ancient human genomes from the archaeologically rich Northeast Brazil and compare them to ancient and present-day genomic data. We find a distinct relationship between ancient genomes from Northeast Brazil, Lagoa Santa, Uruguay and Panama, representing evidence for ancient migration routes along South America's Atlantic coast. To further add to the existing complexity, we also detect greater Denisovan than Neanderthal ancestry in ancient Uruguay and Panama individuals. Moreover, we find a strong Australasian signal in an ancient genome from Panama. This work sheds light on the deep demographic history of eastern South America and presents a starting point for future fine-scale investigations on the regional level. 

Mucin proteins provide mechanistic insights into how genes can evolve to gain novel functions. 

Abstract Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants. 

Sex-dependent programs in the liver establish a trade-off between infectious and dietary pressures in mice.