Research

The Albert lab studies how genomic variation influences gene expression and complex traits.

Each individual in a species carries their own, unique genome. These genomes differ from each other at thousands to millions of sites. Many of these differences have no effect. Others can dramatically influence the way an individual looks, how it behaves, or which diseases it is susceptible to. How can we tell which DNA differences have consequences for the organism? How exactly do these polymorphisms exert their effects? And how did this genomic diversity evolve?

We are examining these questions by combining experimental functional genomics and computational statistical genetics. A particular focus is on emerging technologies for high-throughput reading, editing, and synthesizing of genomes, which now allow us to systematically answer questions at the core of genetics. We deploy these tools in yeast and other species to learn fundamental principles of how genetic variation shapes phenotypes across eukaryotic life.

Genetics of gene expression variation in yeast

Many genetic variants influence an organism by changing how much a certain gene is expressed (Albert & Kruglyak, Nature Reviews Genetics 2015). Such “regulatory variants” are  responsible for most of the genetic risk for many common human diseases. Many fundamental questions about regulatory variation remain unsolved. How complex is the genetics of gene expression? How many variants influence a typical gene? When a variant influences mRNA levels, does it also influence protein levels? And of course – what are the individual DNA mutations that cause expression change? We are tackling these questions in the yeast Saccharomyces cerevisae, an ideal organism for examining basic principles of how regulatory variation operates.

For example, we have devised a novel method to study how genetic differences influence protein – as opposed to mRNA – levels (Albert et al., Nature 2014). Because we can study millions of individual yeast cells in a single experiment, this approach has much higher statistical power than is possible in other species. We’ve shown that genetic influences on protein expression are highly complex. Dozens of regions in the genome can influence the expression of a single gene. Studying these interleaved regulatory relationships will be a major focus of the lab.

Genetic effects on mRNA levels are often quite different from those on the protein levels of the same genes. We have used ribosome profiling to show that genetic differences on translation rates are typically too small to explain this discrepancy (Albert et al., PLoS Genetics 2014). How genetic variation can differentially influence mRNA vs. protein levels remains a fundamentally open question.

The lab offers many additional opportunities to work on regulatory variation. For example, together with our collaborators, we have generated datasets to dissect the full genetic complexity of the yeast transcriptome. We are also establishing high-throughput experimental systems to identify causal regulatory variants.

 

Yeast complex trait genetics

In addition to regulatory variation, yeast is an excellent model system for the genetic basis of variation in “higher order” traits that manifest at the level of the organism. Yeast strains are found in many locations around the globe. These strains are highly diverse both genetically (their genomes are five times more different from each other than those of two typical humans) and phenotypically (for example, different strains differ dramatically in their ability to grow on a wide range of substrates). We are contributing to ongoing efforts in the Kruglyak lab to understand how the genetic differences cause the rich phenotypic diversity. The ease with which yeast can be handled in the lab makes it possible to generate large experimental populations that provide statistical power well beyond what can be achieved in any other eukaryotic species, allowing us to directly address fundamental questions in complex trait genetics.

For example, we have shown that additive genetic effects are usually more important than genetic interactions (Bloom et al., 2015). We have also explored the contribution of rare vs. common genetic variants on cell signaling in a world-wide panel of strains (Treusch et al., 2015).

In our future work, we will connect this information on organismal traits with our expertise on regulatory variation to understand the biological mechanisms through which DNA variation affects complex traits.

 

Previous & completed work

Genetic influences on tameness and aggression

Domestication has dramatically altered several wild animal species, providing  vivid examples of rapid evolutionary change. Some of the most striking changes are behavioral. In the presence of humans, domesticated animals are calm, while their wild relatives are typically fearful or even aggressive.

In a long-running collaboration with Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and groups in Novosibirsk, Russia and Uppsala, Sweden, we have studied a unique experimental model of animal domestication. Beginning in 1972, our collaborators in Novosibirsk have selectively bred two populations of wild rats for tame and aggressive behavior towards humans. Today, these populations are dramatically different. The tame rats calmly tolerate and even seek out human contact. The aggressive rats flee or attack humans (read more about the rats here and here). While this difference is mostly due to genetics, the individual genes remain unknown.

We have localized genomic regions that contribute to these behavioral differences (Albert et al., 2009) and have shown that some of these regions influence the expression levels of certain genes in the brain (Heyne et al., 2014). We have also identified traces of the strong artificial selection in the genomic variation in the rat lines (Albert et al., 2011).

 

Evolution of gene expression in animal domestication

The evolution of mammal species over millions of years has led to an astounding diversity of forms, shapes and behaviors. On a much shorter timescale, the domestication of animals by humans has led to changes in these animals that are nearly as pronounced. The genetic basis of these evolutionary changes remains poorly understood. To better understand the molecular correlates of these evolutionary events, we have explored how the transcriptome has changed during the evolution evolution of mammals (Brawand et al., 2011) and during animal domestication in four species pairs: dogs and wolves, as well as domesticated and wild pigs, rabbits and guinea pigs (Albert et al., 2012).