Gene communities in co-expression networks across different tissues.

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 that KRTAP3-1, KRTAP3-3, and KRTAP3-5 share regulatory elements in skin and pancreas. Furthermore, we find that CELA3A and CELA3B share 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.

A paleogenome from a Holocene individual supports genetic continuity in Southeast Alaska.

Many specifics of the population histories of the Indigenous peoples of North America remain contentious owing to a dearth of physical evidence. Only few ancient human genomes have been recovered from the Pacific Northwest Coast, a region increasingly supported as a coastal migration route for the initial peopling of the Americas. Here, we report paleogenomic data from the remains of a ∼3,000-year-old female individual from Southeast Alaska, named Tatóok yík yées sháawat (TYYS). Our results demonstrate at least 3,000 years of matrilineal genetic continuity in Southeast Alaska, and that TYYS is most closely related to ancient and present-day northern Pacific Northwest Coast Indigenous Americans. We find no evidence of Paleo-Inuit (represented by Saqqaq) ancestry in present-day or ancient Pacific Northwest peoples. Instead, our analyses suggest the Saqqaq genome harbors Northern Native American ancestry. This study sheds further light on the human population history of the northern Pacific Northwest Coast.

Balancing selection on genomic deletion polymorphisms in humans.

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains an imperative exercise. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS (genome-wide association studies) associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years.

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.